The Clinical Diagnosis and Molecular Genetics of Kearns-Sayre Syndrome: a Complex Mitochondrial Encephalomyopathy

Jarosław Maceluch, PhD, Marek Niedziela, MD, PhD

Department of Pediatric Endocrinology and Diabetes, Poznan University of Medical Sciences, Poznan, Poland

Corresponding author: Dr. Marek Niedziela, Department of Pediatric Endocrinology and Diabetes, Poznan University of Medical Sciences, Szpitalna Street 27/33, 60-572 Poznan, Poland, Tel: +48 61 849 1481, Fax: +48 61 848 0291, Home Address: Palacza Street 122F/8, 60-278 Poznan, Poland, Tel: +48 61 662 13 24, e-mail: [email protected] REFERENCE N0 206 IS NOT MENTIONED IN THE TEXT PLEASE ADD

Introduction Abstract rom the first description by Kearns and Sayre in Kearns-Sayre syndrome (KSS; OMIM #530000) is a rare, sporadic 1958, this syndrome has been diagnosed in several disorder representing a heterogeneous group of metabolic F hundred patients. However, the labile character diseases known as mitochondrial encephalomyopathies. The of its clinical manifestations makes diagnosis difficult clinical picture of KSS consists of a classic triad of symptoms and delayed. Only recently, some thirty years from the namely: onset of the disease before 20 years of age; progressive first diagnosis, have we recognized mitochondrial DNA external ophthalmoplegia with ptosis; and pigmentary rearrangements as the molecular basis of the disease. degeneration of the retina. The disease is also manifested by This has lead to increasing interest in the contribution many secondary abnormalities including cardiac conduction which mtDNA deletions make to Kearns-Sayre Syndrome defects, muscle weakness, neurological abnormalities (neural (KSS) and other disorders. Although the true prevalence deafness, cerebellar ataxia, mental retardation, dementia, of this syndrome in the general population is unknown, a convulsions and neuropathy) and several endocrine disorders basic awareness of the KSS phenotype, as well as of the essential elements of patient evaluation is important for (diabetes mellitus, hypoparathyroidism, thyroiditis, appropriate patient management. Although methods of hypogonadism and short stature) (Table 1) (1-3). The true assessing patients for mtDNA rearrangements are well incidence is unknown, and no racial prevalence study has been developed, ambiguity in patient diagnosis often remains reported. KSS affects both sexes equally and is characterized even after detailed, multisystem testing. Advances in by progression of multisystemic clinical features leading to our understanding of the genetic background and the premature death in most cases. Mitochondrial DNA (mtDNA) tissue specific effects of mtDNA deletions, in addition to rearrangements lie at the molecular background of this resolving the inheritance pattern, will also increase our disease. The disease is usually dominated by the involvement ability to diagnose, manage and counsel patients with this of skeletal muscles and the nervous system because of disorder. mitochondrial dysfunction (hence the term “mitochondrial encephalomyopathy”). In most cases a variety of deletions Ref: Ped. Endocrinol. Rev. 2006;2:??-?? and/or duplications in mtDNA are found, affecting genes Key words: Kearns-Sayre Syndrome; KSS; Mitochondrial encoding respiratory chain proteins (4-7). These rearrangements DNA; Deletions; Duplications; Encephalomyopathy; impair oxidative phosphorylation and the energy metabolism of Inheritance mitochondria and lead to dysfunction of many tissues, especially those with high energy demand, such as muscles and brain. The characteristic histological manifestations of damaged mitochondria are the ragged red fibres seen in modified Gomori

22 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS trichrome stained muscle biopsies. On Electron Microscope (EM) Clinical manifestations of Kearns-Sayre images accumulations of abnormal mitochondria can be seen beneath the cell surface. Another characteristic laboratory syndrome finding in KSS is an elevated protein level (above 100 mg/ In 1958 Kearns and Sayre first described a specific dl) in the cerebrospinal fluid. The mutated mtDNA coexists multisystem disorder consisting of chronic progressive external with normal molecules (heteroplasmy) and the proportion ophthalmoplegia, retinitis pigmentosa and atrioventricular of mutated to normal mtDNA has an influence on both the heart block (9). Despite its rare occurrence, significant occurrence and severity of clinical symptoms. To date over progress has been made since then in delineating the natural 100 different deletions have been identified in human mtDNA history and complications of KSS, a prototype for mitochondrial [see MITOMAP database (8)], the most common is 4977 base genetic syndromes. Although the specific clinical phenotype pairs in length and spans between nucleotides 8469 and 13447. of KSS associated with mtDNA deletion is now well known, Deletion breakpoints are often flanked by direct repeats and, there are still problems in determining the correct diagnosis, in most cases, they occur spontaneously. There is no effective especially in non-classical cases, because of the significant treatment of KSS and the complicated character of its clinical overlap in clinical manifestations with other mitochondrial features makes the correct diagnosis of this disease extremely cytopathies (10). Diagnosis is now based on the clinical picture difficult. and the results of laboratory tests, inseparably including the genetic analysis of mitochondrial DNA. While genetic counseling is the primary focus of care, studies have shown the benefit of appropriate medical Ophthalmic Ptosis and surgical treatment. Ophthalmoplegia Children with Kearns-Sayre syndrome Pigmentary retinopathy usually appear normal at birth. Males and females are affected equally and although some patients have different, transient systemic Cardiac Cardiomyopathy abnormalities and metabolic disorders, the Dysrhythmia early development is normal. Ptosis is usually Conduction defects the first sign of the disease (Figure 1A); the child may be observed using their brow muscles Neurological Encephalomyopathy to elevate the eyelids. Ptosis is followed Sensorineural deafness within a few years by progressive external Cognitive impairment ophthalmoplegia (PEO) (11). PEO usually begins after the age of five. External ophthalmoplegia Cerebellar ataxia is a relatively common feature of patients with Seizures different mitochondrial encephalomyopathies Nystagmus (12). This weakness affects all the ocular muscles equally with respect to the pupils, Muscular Proximal myopathy which appear fully functional. Atypical retinitis Muscle weakness pigmentosa, with a “salt and pepper-like” Exercise intolerance appearance, is another ocular characteristic of KSS (Figure 1B) (13). Bone-spicule formation Endocrine Diabetes mellitus in the retina is uncommon, and as pigmentary Hypoparathyroidism epithelial change is not confined to the posterior pole, these changes differ from those Hypogonadism seen in standard retinitis pigmentosa (14,15). Short stature However, pigmentary changes indicate that Thyroid abnormalities the retinal pigment epithelium is affected and this can lead to blindness (14). Unusual Adrenal insufficiency ophthalmic presentations of KSS in early Delayed puberty childhood include congenital glaucoma and corneal dystrophy (16-18). Histopathologically Table 1. The clinical manifestations of Kearns-Sayre syndrome pigmentary epithelial atrophy, with overlying photoreceptor degeneration, occurs at first

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 23 Clinical and Molecular Review of KSS and reduced phagocytosis of photoreceptor debris can interval prolongation preceding 2nd or 3rd degree AV block. be noted. Macrophages containing the outer segments of Intracardiac electrophysiological studies of patients with KSS the photoreceptors may be observed within the affected have shown that primary abnormalities are concentrated in pigmentary epithelium, but peripheral photoreceptors are the AV node-His-Purkinje system with shortened atrial-His relatively spared (19,20). conduction, together with prolonged H-V intervals (27). At the cellular level, the mitochondria in patients with KSS have an abnormal structure and excessive augmentation. These, along with a loss of myofibrils in both skeletal and heart muscle cells, are the classical pathological features of the disease (28). There is poor correlation between ultrastructural abnormalities of the myocytes and clinical heart disease other than conduction abnormalities, which are observed as electrocardiographic changes (23). Recent advances in mitochondrial cytopathies have suggested that in the subgroup of mitochondrial encephalomyopathies, mtDNA deletions within the cardiomyocytes cause dilated cardiomyopathy, a known complication of KSS (29). The deletion of mtDNA at the “common deletion” site found in about one third of patients with KSS is thought to cause the cardiac conduction defect (5,30). Several studies have demonstrated that the same deletion of mtDNA is present in skeletal muscle and in myocardial tissues (31-33). The percentage of deleted mitochondrial genome in the heart muscle is reported to be between 15% and 40% (30,32). In addition to mtDNA deletions, the proportion of mtDNA duplications has been shown to be higher in patients with KSS, particularly in heart tissue (34). Further organ involvement, particularly that of the CNS, is common in Kearns-Sayre syndrome (35). Tissues with high energy demands such as skeletal muscle, the CNS and the retina, appear to be more severely affected and the clinical symptoms depend on Figures 1A and 1B: Ophthalmological symptoms of KSS. A – Both the extent of different organ affection (36). Since brain energetics eye ptosis in a 14-years-old girl with KSS. B – Atypical retinitis depends heavily on oxidative metabolism, the CNS is particularly pigmentosa, with a “salt and pepper-like” appearance, revealed in the fundus of the right eye of the same patient. susceptible to mitochondrial dysfunction (37,38). Furthermore, different brain regions seem to have different tolerance thresholds for metabolic dysfunction (39). The mtDNA rearrangements in KSS The cardiac manifestations dominate the later clinical which occur in mitochondrial Oxidative Phosphorylation (OXPHOS) picture of KSS (21). The heart is a highly ATP-dependant dysfunction cause many neurological disturbances. The most organ and mitochondria constitute about one-third of the common neurological symptom is cognitive impairment which ranges total cytoplasmic volume of cardiomyocytes. It has long from mildly delayed development to severe mental retardation (40). been speculated that inadequate energy production may be Muscle hypotonia, ataxia, dystonic movements, and myoclonias an important factor contributing to heart failure. Clinical are common. Sensorineural hearing loss is a clinically relevant and manifestations of cardiac disease occur in more than half treatable symptom (41,42). Nystagmus and dementia can develop, (57%) of the patients with KSS. These conditions include and spongiform degeneration may be seen in the cerebral cortex syncopal attacks, congestive heart failure and cardiac white matter, basal ganglia and brain stem (43). These lesions arrest (22). Those patients with KSS who have ventricular may affect the cranial nuclei, including the oculomotor nuclei. conduction defects are also shown to have an accelerated Brain stem lesions in the medulla may account for respiratory and unpredictable rate of progression to complete AV block, distress and the tendency for episodic coma in KSS patients (44,45). with an associated mortality rate of 20% in one study (23). The Moreover, intracranial calcifications are common (46). The CSF cardiac pathology in KSS typically involves the distal bundle protein content is usually elevated (over 100 mg/dl) and may of His, bundle branches and infranodal conductions (24-26). rise with time, with values exceeding 200 mg/dl having been Electrophysiological investigations have shown an increase reported (20). MRI scans of the brains of KSS patients reveal in the H-V interval at rest that lengthens further upon atrial widespread abnormalities, which are probably responsible for pacing (27). The ECG change typically found in KSS is PR the different neurological symptoms (40,47). Cerebral and

24 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS cerebellar atrophy are common findings. On T2-weighted spin- aspects of brain affection, comparatively little is known regarding echo images, the patients show high-signal lesions bilaterally neuropsychological capabilities in mitochondrial disease patients. in the subcortical white matter, thalamus, and brain stem Some reports showed equivocal results with respect to both general (Figure 2). The white matter lesions can extend into the deep intellectual capabilities and focal cognitive function (54-56). cerebral white matter and can also affect the cerebellum. A recent study of a well-defined group of patients with KSS or The combination of bilateral high-signal lesions in the globus CPEO (chronic progressive external ophthalmoplegia) examined pallidus with high-signal foci in subcortical cerebral white the range and extent of putative cognitive dysfunction using a matter is characteristic of KSS. Diffuse vacuolation of white comprehensive neuropsychological test battery and a group of matter has also been stressed as a characteristic feature in healthy controls (57). The neuropsychological testing in this study some histopathological studies (19). MRI abnormalities have did not reveal general intellectual deterioration, but provided been known to increase in parallel with neurologic progression evidence of specific focal deficits, suggesting particular impairment of KSS, although there is little correlation between specific of visuospatial perception associated with the parieto-occipital neurological deficits and any particular MRI finding (48). lobes and executive deficits associated with the prefrontal cortex. Progressive muscle weakness and exercise intolerance appear as common features, and cause many inconveniences to the patients. The muscular weakness affects the facial, pharyngeal, trunk and shoulder muscles in particular, leading to dysarthria and dysphagia in many patients (58), some of whom may even become malnourished as a result. The characteristic appearance of muscle fibres in biopsy specimens of KSS patients is also very informative. Once cellular energy production falls below a certain threshold in cells with perturbed oxidative phosphorylation, a compensatory proliferation of all mitochondria, including affected ones, occurs. Thus, a typical finding in muscle fibres is an increased number of atypical mitochondria which stain red with a modified Gomori trichrome stain, and hence are referred to as “ragged-red fibres” (RRF). A deficiency of cytochrome-c oxidase (COX) can often be shown by measurement of the enzyme activity in homogenates of affected muscles. Single COX-negative fibres, usually corresponding to ragged-red fibres, can be demonstrated histochemically on muscle biopsy specimens (Figure 3). Mitochondrial disorders like KSS are often believed to be rare conditions seen only in children with severe mental retardation and multi-system failure. These classical cases

Figure 2. Patient with Kearns–Sayre syndrome. Axial T2 weighted image demonstrates diffuse high signal intensity regions within the corona radiata and subcortical white matter. Reprinted from: Molecular Genetics and Metabolism; Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases; Copyright 2005;84:127-136 with permission from Elsevier.

Symptoms of CNS dysfunction, such as cognitive impairment Figure 3. Serial cross-sections of muscle from a patient with the Kearns–Sayre syndrome, showing increased mitochondrial activity in or dementia, have also been described in mitochondrial ragged-red fibers on staining with succinate dehydrogenase (asterisks encephalomyopathies. Considering the widespread physical in panel A; x120) and the absence of activity on staining with abnormalities the data on functional aspects of regional cytochrome c oxidase (asterisks in panel B; x120). Reprinted from: DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl cerebral energy dysfunction is limited and conflicting (49-52). J Med 2003;348:2656-2668. Copyright © 2003 Massachusetts Medical There is evidence for cerebral metabolic impairment, even Society. All rights reserved. in patients without obvious CNS symptoms (53). In contrast to extensive research into the morphological and metabolic

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 25 Clinical and Molecular Review of KSS are in reality only a part of the phenotype spectrum of and large scale rearrangements of mtDNA are found in most these disorders and primary involvement of a single system, thyroid diseases, including tumors and cancers (76). Large especially endocrine disease, in other way clinically normal scale deletions in mtDNA are quite prevalent in healthy and children is quite common. This is especially true early in diseased thyroid. However, the proportion of aberrant mtDNA the course of mitochondrial disease. Although endocrine molecules accounts for a very small part of total mtDNA and abnormalities are common in mitochondrial disorders, in the does not seem to correlate with the pathology of thyroid majority of patients they are masked by encephalomyopathy. tumors. Common deletion is most abundant in Hurtle cell Consequently, the correct etiological diagnosis is often missed tumors, yet it also occurs in other thyroid diseases as well as in when the disease first manifests as an endocrinopathy with normal tissue. The principal difference between the common normal neuromuscular function and no particular family deletion and other deleted mtDNA molecules is that the former history. Several cases of KSS in which various endocrinopathies does not depend on the relative mtDNA content in the tissue, were the presenting feature have been reported, including whereas in a subset of thyroid tumors, such as radiation- diabetes (59), adrenal insufficiency (59-61) and growth associated papillary carcinomas and follicular adenomas, there hormone deficiency (62,63). Tetany and other symptoms is a strong correlation between mtDNA levels and prevalence secondary to hypoparathyroidism induced hypocalcemia of large-scale deletions. Relative mtDNA levels by themselves can also be the first symptoms in cases with developing are elevated in most thyroid tumors in comparison to normal KSS (3,64). The most common endocrine organs affected thyroid tissue. Distinct differential distribution and prevalence in KSS are: the pituitary gland (leading to hypopituitarism, of mutational mtDNA burden in normal tissue and thyroid growth retardation, thyroid and gonadal dysfunction); the lesions suggest the implication of altered mtDNA in thyroid thyroid gland (65,66) (hypo- and hyperthyroidism, Hashimoto diseases, especially in cancer (76). thyroiditis); the parathyroid gland (64,67-69) (hypo- or Hypoparathyroidism is a frequent symptom in KSS patients hyperparathyroidism); pancreas (mitochondrial diabetes with multiple endocrine abnormalities. It can be demonstrated mellitus); the adrenal gland (60,61,70,71) (insufficiency with by low concentrations of PTH, hypocalcaemia, hypomagnesemia hypoaldosteronism, hyponatriaemia and Addison disease); or hyperphosphatemia and may be combined with coexisting or the gonads (72) (delayed puberty and hypogonadism). renal failure. Different types of mutations were described Symptoms of hypopituitarism or hypothyroidism may overlap in KSS patients presenting with hypoparathyroidism: single with symptoms of skeletal muscle manifestations such as deletions (64,77), multiple deletions (78), coexisting deletion fatigue, general weakness, slowing or hypotonia. Short and duplication (69,79), and a point mutation in tRNALeu stature is observed in about 38% of KSS cases, and diabetes gene (67). In the cases where the existence of duplications mellitus in 20% (3). Skin and renal involvement are rare in was confirmed biochemically, higher proportions of duplicated KSS (73-75). Delayed bone age and osteoporosis are also seen mtDNA in white blood cells were demonstrated (79-81). in KSS patients (72).Osteoporosis in those cases can result Regardless of the mtDNA defect, all patients reported had an from sex steroid deficiency, immobilization in later stages early onset of symptoms with a multisystemic involvement, of the disease, but also from growth hormone deficiency. In and in only three cases was hypoparathyroidism the initial some specific cases of KSS, where the first and predominant manifestation (69,78,82). The conclusion is that in these cases, symptoms of the disease were various endocrine disorders, the presence of a duplication/deletion of mtDNA may be more such as diabetes mellitus and adrenal insufficiency, a specific frequently associated with endocrinopathies, as suggested by 7.4 kb deletion in mtDNA was found (59). It has been proposed Poulton et al (83). The frequency of the duplications in these that this second most common deletion of mtDNA in KSS, cases could be higher than previously suspected because most should be considered as one of the candidate causes for of the KSS cases with multiple endocrine involvements reported phenotypically uncommon cases of endocrinopathies. earlier were not properly investigated for the presence of this The thyroid gland dysfunctions are quite common in the rearrangement. course of Kearns-Sayre Syndrome and other mitochondrial Abnormalities of the adrenal axis have been reported in encephalomyopathies (3). In most cases thyroid abnormalities several patients with KSS, but are not routinely investigated. present as hypo or hyperthyroidism, but there are also cases of Some patients with elevated plasma levels of renin and Hashimoto thyroiditis reported (65). In the latter, predisposed aldosterone (84-86) and some with salt craving of unknown by mitochondrial deletion, anti-thyroid antibodies may have pathogenesis (87,88) have been reported. Low basal morning interfered with mitochondrial cerebral function, causing cortisol levels with normal responses to corticotropin releasing Hashimoto encephalopathy and facilitating ophthalmoplegia – hormone was reported (63). One child was found to have it may be therefore important to study anti-thyroid antibodies partial growth hormone and ACTH deficiencies (89). Two cases in every case of KSS (65). But the spectrum of mtDNA deletions with KSS were reported to have low urinary 17-ketosteroid associated with thyroid dysfunction does not restrict only excretion, but clinical signs of Addison disease were not for mitochondrial encephalomyopathies. Point mutations mentioned (90). First report of non-autoimmune Addison

26 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS disease in KSS showed in 1998, and the authors stressed and feeding difficulties, being responsible for the resistance of that early recognition of adrenal insufficiency is crucial to mitochondrial cytopathy patients to GH treatment can also be prevent mortality from this cause (61). Primary adrenal considered. But these difficulties occur rarely in mitochondrial insufficiency as a presenting feature of mitochondrial disorder cytopathies, so their influence on commonly found growth were described only a few years ago (59,60). Formerly, only disturbances can only be marginal. The other important issue North and colleagues reported an 18-month-old girl with a is that the majority of KSS patients continue to experience respiratory chain defect and a usual phenotype characterized weight loss and weakness. Human GH has been reported to by neonatal onset of chronic lactic acidosis, lipid storage have an important role in regulating protein metabolism myopathy, bilateral cataracts, and, starting at 7 months of and lean body mass in GH-deficient adults (96). Therefore, age, primary adrenal insufficiency. The molecular genetic treatment with GH could promote protein synthesis and reduce defect in this case however, was not defined (71). Given the wasting in some patients, but care should be taken during GH fact that correct cause is not established in a number of cases therapy to avoid the possible adverse effects. The quality of with adrenal insufficiency, these reports may provide a clue life for some patients could be at least temporarily improved to the potential etiology in these patients as an impaired by GH treatment, but other patients can suffer from severe mitochondrial ATP production in adrenal gland resulting in a multi-system failures. KSS patients with growth disorders can defect in the secretory capacity of adrenocortical cells. undergo GH therapy, but they should be carefully monitored Although growth disturbance is a common feature in for effectiveness of GH stimulation, and when there is no mitochondrial encephalomyopathies (22,59,91), information significant improvement in growth velocity or new, or more regarding endocrine evaluation and the clinical effectiveness severe disease symptoms appear, the GH therapy should be of GH therapy is limited (62,92,93), mainly because terminated. deficiency of growth hormone only accounts for a part of Dysfunction of the pituitary-gonadal axis is also common these cases. Normal GH responses following insulin-induced (about 20% of cases) and affects both sexes equally. Females hypoglycemia and following arginine have been reported in present with late menarche, primary or secondary amenorrhoea most cases (3,63,94). In patients suffering from mitochondrial or delayed secondary sexual attributes development. Dynamic encephalomyopathies such as KSS, normal or nearly normal endocrine testing indicates that the pituitary is responsive to serum IGF-1 levels were reported, suggesting that their GnRH and the defect therefore resides at the hypothalamic hypothalamic-pituitary-somatomedin axis is mostly not level (3). In one case, a girl with KSS and diabetes also affected. GH treatment-induced increase in growth velocity presented with delayed puberty, primary amenorrhea, a in these patients is usually limited to the first years of the low FSH, and normal LH, suggesting a latent hypothalamic therapy, as generally found in short non-GH-deficient children hypogonadism. Boys presenting with similar symptoms were treated with GH. However, no catch-up growth is observed also reported (97). in mitochondrial encephalomyopathy patients. GH treatment There are several observations suggesting that mtDNA of patients suffering from mitochondrial disorders, such as deletions and dysfunction of the respiratory chain may be KSS/CPEO, may be ineffective or transient (95), indicating involved in the pathogenesis of diabetes mellitus (DM). First, that short stature in these cases may be caused by disease- diabetes mellitus is one of the clinical manifestations of related insufficient protein substrate support rather than by KSS (3,97-99). Complex mtDNA rearrangements (tandem GH deficiency. Growth stimulation induced by GH therapy duplications) have been described in patients with KSS, increases energy demand of the every cell in the patient’s suffering from diabetes (7,100), two other patients of body. Deficient oxidative phosphorylation productivity of mitochondrial disorders reported with duplications were also mutated mtDNA containing mitochondria cannot cope with the diabetic (74,101). In fact, between 0.5 and 1% of all diabetics needs of increased energy production and protein synthesis. harbour a causative mtDNA mutation (102). Second, direct As an effect, no significant or short lasting results of GH evidence for mtDNA involvement in diabetes has been found administration are observed. In some cases GH therapy may in pedigrees with maternally transmitted diabetes mellitus even lead to a worsening of other clinical symptoms and and deafness (103,104). The family described by Ballinger progression of the disease, due to elevated cellular energy et al. consisted of an affected mother, six affected children demands. Increased mitochondrial activity in the presence and an affected maternal grandmother. DM in this family of heteroplasmic mtDNA deletion may lead to the lowering was associated with a maternally inherited complex mtDNA of the threshold level when deficient mitochondria fail and, rearrangements (coexisting deletion duplication in mtDNA in consequence, to the occurrence of the disease symptoms involving identical breakpoint junctions). Third, it is more in new tissues and organs. Increased production of reactive common to inherit diabetes from an affected mother than oxygen molecules provoked by OXPHOS stress may also from an affected father, suggesting maternal inheritance of contribute to the failure of cellular energy production. The predisposing factors 105. Therefore mtDNA dysfunction may hypothesis of other factors, such as insufficient caloric intake play a role in the pathogeneicity of diabetes mellitus and

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 27 Clinical and Molecular Review of KSS large scale rearrangements of mtDNA in KSS patients may treat these associated disorders what will significantly improve be those predisposing factors. It has been demonstrated the patient’s quality of life in this complex syndrome. that mtDNA and intact respiratory function are necessary for glucose-stimulated insulin secretion in an insulin- Genetic Background of the Disease producing cell line studied in vitro (106). This suggests that mtDNA mutations and other causes of impaired respiratory One of the characteristic features that distinguish mitochondria chain function may lead to reduced insulin secretion and from other cellular organelles is the possession of their own subsequent development of diabetes. Diabetes mellitus in KSS DNA (mtDNA). The mitochondrial genome is a 16569 base pair, is usually non-insulin dependent in its origin, but the patients double-stranded, circular molecule (Figure 4A) (121). It encodes progressively become insulin-deficient and, finally, almost all 13 peptides of the respiratory chain, and also two rRNAs and 22 need insulin for their metabolic control (107). Non-insulin- tRNAs which are required for the expression of this genome. requiring diabetes in KSS may be demonstrable only on glucose All the other enzymes and factors which are necessary for tolerance testing, sometimes developing after glucocorticoid mitochondrial DNA transcription, translation and replication, therapy for neurological symptoms or, as reported in one are encoded by the nuclear genome, translated in the cytoplasm case, for nephrotic syndrome (108). Diabetic patients with and then imported into the mitochondrion (122). All 13 mtDNA mtDNA mutations are in general islet cell antibody - (ICA) encoded polypeptides are components of the respiratory chain/ and glutamic acid decarboxylase antibody - (GADA) negative oxidative phosphorylation (OXPHOS) system which is located in (109), although a few cases with low titres of ICA have been the inner mitochondrial membrane (Figure 4B). Somatic cells described (110,111). Insulin dependent diabetes mellitus usually contain many copies of the mitochondrial genome in (IDDM) may first appear with ketoacidosis (112) and no insulin each organelle and up to several hundred mitochondria per cell. resistance is described in KSS (113). Insulin therapy can even It is important to appreciate that all respiratory chain complexes be stopped for a considerable time and given again for a contain protein subunits encoded by the cell’s nucleus. Complex second episode of diabetic coma (113). In a 10 year follow-up I contains the largest number of mitochondrially encoded study of one patient with KSS and DM, a marked worsening of proteins, i.e. seven polypeptide chains, and only complex II is clinical symptoms was observed, but not those of the diabetes encoded entirely by the nuclear DNA. One important difference that was well controlled by once-a-day insulin therapy (114). between mitochondrial and nuclear DNA is that the genes Normal insulin receptors have been found in KSS patients encoded by mtDNA are contiguous with each other without without diabetes mellitus (115). Autopsies in some cases of introns and that translation of the mitochondrial mRNAs occurs KSS with DM have shown extensive fatty infiltration, or severe atrophy, of the pancreas (82,115). The mechanism of DM in on the mitochondrial ribosomes. Therefore, in order to be KSS is unknown. As mitochondrial oxidative phosphorylation able to evaluate the possible significance of mitochondrial and ATP production is impaired in KSS (117), what is also true DNA mutations, it is important to be aware of the differences for mitochondrial diabetes associated with deafness (118), between nuclear and mitochondrial genetics (58,123). In humans is the possibility that energy deficiency leads to pancreatic the inheritance of mitochondrial DNA is exclusively maternal. involvement, either in the form of a limited beta cell reserve Beginning from the zygote all the cells of an organism are or impaired insulin secretion (119). Abnormal function of the generated through mitotic cell division. Mitochondria within the rearranged mtDNA can have influence on both development cells replicate autonomously and are passed on from generation and function of pancreatic islet cells since glucose-stimulated to generation via the cytoplasm of the dividing cell. Thus insulin secretion is energy dependent. However, persistent segregation of mtDNA occurs at random and, in the case of an insulin secretion was observed many years after the onset of mtDNA mutation, may result in varying amounts of mutated the disease. On the other hand, increased oxidative stress may DNA in different cells of the body. The term for the state in also be present leading to premature ageing of pancreatic beta which more than one sequence variant of mtDNA, i.e. normal cells and concomitant decompensation of pancreatic function and deleted, co-exist in the same cell, or even in the same (120). Other immune, genetic and environmental factors may mitochondrium, is heteroplasmy. Heteroplasmy is a feature also contribute. of mtDNA diseases where homoplasmy for severe pathogenic In conclusion, it is highly probable that mtDNA rearrangements mutants may be lethal. One consequence of heteroplasmy is in mitochondrial disorders like KSS and their effect in reduced that the amount of mutated mtDNA determines the probability ATP production lead to impaired hormone production in of expression of mitochondrial disease and influences the endocrine organs, to no release of hormones at all, or to a clinical symptoms of affected individuals. In addition, tissue decrease in the number of endocrine cells themselves. It is specific threshold effects need to be taken into account as important to analyze every endocrine abnormality in detail in they may substantially influence the expression of the clinical each case and to study how the mtDNA dysfunction influences phenotype (124). The threshold for the disease is lower in the pathophysiology of the disorder. It is equally important to tissues that are highly dependent on oxidative metabolism,

28 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS

tissue. Moreover, mtDNA undergoes continuous replication, even in non-dividing cells (125). In patients with mitochondrial disease this may lead to a change in the level of heteroplasmy in non-dividing tissues, such as skeletal muscle and nerve, if the mutant and wild-type mtDNA replicate at different rates which may contribute to the late onset of symptoms found in some patients. Furthermore, the mutational rate of mtDNA is 10 to 20 times higher than that of nuclear DNA (126,127). Reasons for this greater rate are the lack of protective histones of mitochondrial DNA, inefficiency of the mitochondrial DNA repair system, the lack of intrones and the physical proximity of the mitochondrial genome to the respiratory chain where relatively high amounts of reactive oxygen species (ROS) are physiologically produced (128,129). The mitochondrial ageing theory claims that ROS, generated as by-products of the OXPHOS activity, react with and mutate mtDNA leading to impaired function of the respiratory chain which, in turn, is thought to further promote the generation of free radicals (130). Tissue specific gene expression and the specific energy demands of different tissues need to be taken into account when considering the possible pathogenicity of a mitochondrial mutation (131). Another complexity of mitochondrial disorders and their genetic basis is that a mitochondrial genotype changes throughout the life of an individual. The mitochondrial genome acquires somatic mutations during the normal life span. With age a wide spectrum of mtDNA rearrangements accumulate in postmitotic tissues such as the brain and skeletal muscle, which correlates with the marked age-related decrease in OXPHOS capacity (132-134). Figures 4A and 4B. Human mitochondrial DNA map (A), and schematic The rate of accumulation may be much faster in certain disease organization of the respiratory chain in the inner mitochondrial membrane (B). The mitochondrial genes encoding protein subunits of states [such as in the brain in Alzheimer’s disease (135,136) particular complexes are shaded in picture A in the same pattern as and in muscles in myocardial ischaemia (137) and inflammatory complexes in picture B. muscle disease (138,139)]. The mean level of these mutations A. The arrows indicate the direction of translation of particular genes. The tRNA genes are denoted with a single letter amino-acid in individual tissues is usually low (<1%) in comparison with code. The approximate position of the common, 4977-bp deletion pathogenic mtDNA mutations (132,133). Single cell studies is marked. Abbreviations: ND1-6: NADH dehydrogenase (complex have shown that the mutations may clonally accumulate to I); CYTb: cytochrome B (complex III); COI-III: cytochrome C oxidase (complex IV); ATP6, 8: ATP synthase (complex V); rRNA: ribosomal RNA high levels in ageing human tissues leading to mitochondrial genes. D-loop: displacement loop (regulatory region); OH, OL: origins dysfunction (140) but the importance of these mutations, and of replication of the heavy and light strands, respectively. their role in ageing and neurodegenerative diseases, remains to B. The respiratory chain is composed of five enzyme complexes (complexes I-V), coenzyme Q (CoQ) and cytochrome c (Cyt C). be determined. Electrons from oxidized NADH and succinate are transferred through Pathogenic mtDNA mutations of different types are found coenzyme Q, complex III, cytochrome c and complex IV to molecular + in about one in 8000 individuals (141,142). The common oxygen (O2), which is reduced to water (H2O). Protons (H ) are pumped out of the mitochondrial matrix by complexes I, III and IV. cause for Kearns-Sayre syndrome is mitochondrial DNA The proton gradient formed across the inner mitochondrial membrane rearrangements – either deletions or duplications (6,7,81). is used by ATP synthase (complex V) to synthesize ATP. These mtDNA rearrangements were the first pathogenic mtDNA mutations discovered (6). In one study the prevalence of such as brain, heart, skeletal muscle, retina, renal tubules, single, large scale deletions was calculated to be 1.6/100 000 and endocrine glands. These tissues will therefore be in the adult Finnish population (143). Large scale deletions especially vulnerable to the effects of pathogenic mutations in remove a part of the mtDNA molecule, approximately 9% mtDNA. Mitochondria are not partitioned equally to daughter to 50% of the mitochondrial genome, commonly removing cells during cell division which can result in the non-uniform mitochondrial genes encoding OXPHOS subunits and tRNA distribution of mutated mtDNA in these cells. This can result genes, but rarely removing rRNA genes (144). Deletions of in an individual having completely different amounts of normal mtDNA have at least two different consequences at different and mutant mtDNA in different tissues and indeed in the same levels of mitochondrial protein synthesis. Missing protein genes

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 29 Clinical and Molecular Review of KSS cause a defined enzyme deficiency, due to a defect at the recombination via direct repeats, are considered to be the level of transcription. The resulting impairment at this level most probable cause of human mtDNA deletions. of mitochondrial function depends on the influence of the It is not known for certain whether or not deletions of deleted protein on the total function of the mitochondrium. mtDNA at different levels of heteroplasmy correlate with Missing tRNA, however, causes dysfunction due to a defect at altered patterns of mitochondrial enzymes (161), nor how the level of translation. This translation defect necessarily these altered enzyme patterns influence the functional affects all mitochondrial encoded proteins and should have a properties of mitochondria (162,163). There are reports that higher impact on the impairment of mitochondrial function patients with larger deletions have an earlier onset of the than deletions of protein coding genes (145,146). The deleted disease (164,165). Another study reported that patients who mtDNA exists in a heteroplasmic manner within the cell and manifest non-neuromuscular multisystemic disorders at a the level of heteroplasmy affects the onset and severity of very young age usually harbour mutant mtDNA with novel the disease in different tissues. There is evidence in vitro or rare deletions (166). Generally it is assumed that only that reduced mitochondrial protein synthesis and biochemical severe enzyme defects are detectable as OXPHOS dysfunction, dysfunction result when this proportion is greater than 50-60% since the maximum activity of most single enzymes is higher of the total mtDNA (147-149). The level of heteroplasmy can than the maximum fluxes through the metabolic system of change during the life-span. There is some evidence that the mitochondria (162,167). This is the metabolic reason for proportion of deleted mtDNA in muscle increases with time, threshold in mitochondrial diseases. It was demonstrated that along with the amount of ragged-red fibres (150,151). It has in patients with single deletions at a heteroplasmy level of been suggested that any increase in the deleted fraction about 50%, the amount of mitochondria within the cells was results from a replicative advantage conferred by shorter nearly doubled (168). Therefore, even considerably reduced length, as most deletions preserve mtDNA replication origins levels of enzyme activity can be compensated by increased and rRNA genes, thus leaving the deleted molecule replication amounts of mitochondria. It may be speculated that increasing competent. On the other hand, some tissues may have a the amount of mitochondria in diseased skeletal muscles could different capability of selecting against mutant mtDNA, which be a strategy to minimize the functional consequences of may reflect the different replicative behavior of deleted deletions. In another investigation, an approximately ninefold and duplicated mtDNA in different tissues. In non-dividing amplification of mtDNA in muscle was detected (169). This tissues, i.e. muscle and brain, there is unlikely to be selection amplification was probably the reason for the normal levels of against deleted mtDNA as compared, for example, with rapidly respiratory chain enzyme activity and mild clinical course of dividing cells in bone marrow, spleen and testis (19). Deletions the disease found in the patients in this study, despite a high are prevalent in the postmitotic tissues of KSS patients but mutant load (92%). Other reports also indicate a synchronous are present only in trace amounts in blood (5,152). The increase in the levels of deleted and normal mtDNA in the most frequently identified deletion, the so-called “common course of KSS (170). deletion”, involves 4977 nucleotides in positions 8469 – 13447, Structurally more complex mtDNA duplications produce and is usually flanked by small, 13 bp direct repeats of the an mtDNA molecule that is larger than the normal mtDNA mtDNA sequence (152-155). The deleted mtDNA segment and contains two tandemly arranged mtDNA molecules – one contains all, or part of, the genes encoding for polypeptides for normal, with a full length 16.6 kb mtDNA molecule coupled complex I, one for complex IV, two for complex V and five tRNA to a deleted mtDNA molecule (81,100). Duplications of the genes. Approximately one-third to one-half of patients with mitochondrial genome can cause symptoms similar to those KSS and CPEO have been reported to harbour the “common with deletions, but not so severe (171,172). Deleted mtDNAs deletion” (5) and, interestingly, this deletion made up 63% are thought to be pathogenic, largely as a result of loss of of all the deletions in the tissues of a patient with multiple tRNAs, but this does not apply to duplicated molecules. It has mtDNA deletions (156). The presence of direct tandem repeat been suggested that translation products of the duplication- elements flanking the deletion breakpoints has been proposed deletion junction impair mitochondrial function (81). as a genetic criterion to classify mtDNA single deletions (157). Duplicated mtDNAs, although they may not be pathogenic in The mechanism by which single deletions are produced is and of themselves, could still have pathogenic consequences not well understood and several explanations have been if they are recombination intermediates that could give rise to proposed, namely intramolecular recombination via an unequal deleted mtDNAs, which are pathogenic (81,173). This concept crossing over mechanism (152,157), a “slip replication” model is supported by a decrease in the proportion of duplicated arising from the erroneous annealing of H and L strands of molecules throughout life concomitant with an increase in the mtDNA (154), an “illegitimate elongation” model (158), the proportion of deleted mtDNA (101). This is particularly relevant “pyrimidine content” hypothesis involving DNA polymerase to those disorders in which duplicated mtDNAs, but not the gamma (159), or a concept involving topoisomerase II (160). corresponding deleted mtDNAs, have been detected, such as However, mechanisms of slipped-replication or illegitimate maternally inherited diabetes and deafness (101,103,174).

30 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS

Unlike deletions, the mtDNA duplications in patients with KSS are but the persistence of the mutation in other tissues results usually present in moderate amounts in the blood (74,100,101). in the development of KSS. The blood content of deleted These duplications may represent a distinctive feature of mtDNA is critical in these cases and it appears that this tissue KSS that is absent from individuals with CPEO or PS (83,173). mutant load is susceptible to drastic changes during the life Alternatively, because patients with CPEO may have some, but span. There are conflicting reports of either an increase (151) not all, of the elements of KSS it has been suggested that CPEO or of a reduction in (184,185) mutated mtDNA levels in the and KSS describe different degrees of severity of the same hematopoietic system in PS, but in many reported cases the disease (175). Deletion dimers (two joined deleted molecules) percentage of deleted mtDNA in blood cells ranged from 80% to also occur and, theoretically, they should have the same effects 90% (183,186). A fully functional respiratory chain was observed on mitochondrial protein synthesis as standard deletions (81). in B lymphoblastoid cell lines from PS, despite the presence of Approximately 80% of KSS patients and 50% of CPEO patients 60% of deleted mtDNA (187). No more than 80% of mtDNA harbour mtDNA rearrangements (5,36). The mtDNA mutations was deleted in all the reported cases of KSS with deletions in usually arise spontaneously very early during embryonic blood cells. These lines of evidence suggest that 20% of normal development (176), although it is probable that duplications mtDNA may be sufficient for normal mitochondrial function in are maternally transmitted (74,101,177). An important factor blood cells, although the possibility of a higher demand during to consider in the analysis of KSS cases is the possibility that the critical neonatal period cannot be excluded. mtDNA point mutations in mitochondrial tRNA genes coexist in The majority of single large-scale deletions of mtDNA is the same fashion as large scale mtDNA rearrangements (178). sporadic and is therefore believed to be the result of the The existence of multiple mtDNA deletions, together with an clonal amplification of a single mutational event, occurring autosomal inheritance, is characteristic of an underlying nuclear in the maternal oocyte or early during the development of mutation, which is typical for CPEO (179,180). It is also possible the embryo (153,188). On the other hand, in many cases of that patients with KSS symptoms, but without identified mtDNA multiple rearrangements autosomal recessive or dominant trait deletions, may have unidentified mutations in either their of inheritance occurs. Since mitochondria depend on numerous nuclear or mitochondrial OXPHOS associated genes. nuclear encoded factors for its integrity and replication, Mitochondrial DNA deletions are also commonly found in two mutations in these factors affect mtDNA directly, either other clinical forms of encephalomyopathy, namely chronic quantitatively or qualitatively, and cause diseases that are progressive external ophthalmoplegia (CPEO), which primarily inherited as mendelian traits (189). These forms of mitochondrial affects the ocular muscles, and Pearson’s syndrome (PS). diseases are also called disorders of nuclear-mitochondrial PS is a fatal disorder which begins in early infancy and is intergenomic signaling (190). A quantitative alteration appears characterized by bone-marrow involvement with anemia, as abnormal reduction in the number of mtDNA molecules, leucopenia and thrombocytopenia, plus hepatic and exocrine down even to 35% of the normal mtDNA level – this abnormality pancreatic dysfunction. Pearson’s syndrome patients require is called mtDNA depletion syndrome (191,192). A qualitative frequent transfusions and most of them die before the age of alteration manifests itself by multiple deletions, in contrast to 3 years. Virtually all patients with KSS harbor single mtDNA the single mtDNA deletions occurring spontaneously in KSS and deletions that are detectable in muscle and other tissues by other mitochondrial disorders (180,193,194). Both quantitative Southern blot analysis (4,5). Approximately 50% of patients and qualitative defects may result from impairment of the with CPEO and ragged-red fibers have single deletions, integrity of the mitochondrial genome. Such impairment can detectable in muscles but not in other tissues (5,181). In PS, be direct (e.g., affecting proteins required for the replication a disorder mainly affecting the hematopoietic system, mtDNA and maintenance of mtDNA) or indirect (e.g. affecting deletions are abundant in white blood cells (182,183). In proteins required for proper maintenance of nucleotide polls fact, it is considered that PS, KSS and CPEO are all different in mitochondria). During the last few years several nuclear clinical manifestations of the same disorder caused by mtDNA genes were showed to influence mtDNA structure, replication rearrangements. Patients with Pearson’s syndrome who survive and stability. Autosomal dominant progressive external the first critical period may develop the features of Kearns- ophthalmoplegia (adPEO) is a mendelian disorder characterized Sayre syndrome in later childhood, suggesting that these two by the accumulation of multiple deletions of mtDNA in patients’ disorders represent different phenotypes of the same genetic tissues (179). This disease shares many clinical features with defect. The mode of initial presentation probably depends KSS (progressive muscle weakness, ophthalmoplegia, ptosis, on the amount of deleted mtDNA present and its distribution cardiomyopathy, hypogonadism and RRFs). Most of the adPEO between tissues (184). The mildest variant is CPEO, in which families carry heterozygous mutations in one of three genes: clinical symptoms develop during adulthood and are limited ANT1, encoding the muscle-heart-specific mitochondrial adenine mostly to the ocular system. A high prevalence of mtDNA nucleotide translocator, which is responsible for transporting deletions in blood cells will lead to PS in infancy. If the patient ATP across the inner mitochondrial membrane in exchange for survives, mtDNA rearrangements may disappear from the blood ADP (180); Twinkle, encoding a putative mtDNA helicase that

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 31 Clinical and Molecular Review of KSS may be involved in mitochondrial DNA replication (193); and Diagnosing KSS POLG1, encoding the catalytic subunit of the mtDNA-specific polymerase gamma (194). Mutations in Twinkle and ANT1 are As mitochondrial cytopathies are multisystemic disorders, not common; Twinkle mutations have been found in 15% of a comprehensive clinical investigation must be carried out in adPEO families and ANT1 mutations have been found in 11% of order to arrive at a correct diagnosis. In the case of Kearns- adPEO patients (193,195). The frequency of POLG1 mutations Sayre syndrome the discovery of classical symptoms, such as remains to be determined. All these three genes are strongly progressive external ophthalmoplegia, pigmentary retinopathy, involved in maintenance of mtDNA replication and integrity. cardiac conduction defects and muscle weakness, together Mutations in both POLG1 alleles were also found in autosomal with accompanying neurological abnormalities and a variety recessive PEO sibships with multiple affected members and in of endocrine disorders, provide the clinician with a definite apparently sporadic cases (196). The exact mechanism of how diagnosis. In non-classical cases more advanced and detailed mutations in POLG1 lead to the mtDNA deletions is unknown. It examinations have to be undertaken in order to obtain the was shown that a prevalent mutation in POLG1 gene, the Y955C final answer and here the biochemical and molecular genetic mutation, dramatically reduces the enzyme’s binding affinity tests help to confirm the clinical diagnosis. The family history for nucleoside triphosphates in vitro and also the accuracy for is also important to obtain the whole view of the disease and base pair substitutions (197), so it may provoke error prone its inheritance pattern (Figure 5). MtDNA disease is often only mtDNA replication in vivo and subsequent rearrangements considered after many other diagnoses have been excluded. of the whole mtDNA genome. Another disease in this series A simple baseline investigation for the diagnosis of KSS is is mitochondrial neuro-gastro-intestinal encephalomyopathy the determination of lactate and pyruvate levels in blood. As (MNGIE) clinically characterized by ophthalmoparesis, there is a demonstrable increase in blood lactate at rest and/ peripheral neuropathy, leucoencephalopathy, gastro-intestinal or during exercise testing in approximately 50% of patients syndromes (recurrent nausea, vomiting or diarrhea) with with KSS, it is wise to include a bicycle ergometer test in the intestinal dysmotility and histologically abnormal mitochondria investigation. Other clinical investigations such as an EMG in muscle including RRF (198). Mutations in the TP gene, (which may show a myogenic pattern), or tests for elevated encoding thymidine phosphorylase, causing the loss of CSF lactate and protein levels are also helpful. Proton magnetic enzyme function, are associated with MNGIE (199). TP is an resonance spectroscopy is a useful tool to demonstrate important factor involved in the control and maintenance of increased lactate levels in the damaged white brain matter the pyrimidine nucleoside pool of the cell. Defects of TP are of KSS patients and to support mitochondrial respiratory thought to produce an excess of thymidine, resulting in the chain insufficiency as the underlying cause. The discovery imbalance of dNTP pools that can ultimately affect both the of a doublet at 1.33 ppm is characteristic of the presence of rate and fidelity of mtDNA replication. This is reflected by a lactate (204). Other neuroradiological examinations, such as molecular phenotype of MNGIE, which is characterized by both multiple deletions and partial depletion of muscle mtDNA (200). The role of nucleotides is reinforced by the pathogenicity of the ANT1 mutations and by recent findings that mutations in mitochondrial thymidine kinase and deoxyguanosine kinase are associated with the myopathic and hepatocerebral forms of mtDNA depletion (201,202). Knowledge of these mutations makes prenatal diagnosis feasible for some families and may offer new approaches to therapeutic intervention [e.g., lowering blood thymidine concentrations in patients with MNGIE (203)].

Figure 5. Proposed pathway for patient evaluation in the diagnosis of KSS.

32 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS

MRI or CT, may visualize some characteristic brain changes. of other endocrine disturbances). Of great significance to the CT may reveal cortical and white matter atrophy, low density clinical management are the cardiovascular manifestations. in the cerebral and cerebellar white matter and variable low Patients with KSS should be routinely and regularly evaluated density or calcifications in the basal ganglia, thalamus and/or for AV conduction disturbances. Those with ophthalmoplegia cerebral hemispheres (46,205). The serum creatine kinase and retinitis, but without a confirmed diagnosis of KSS, may be raised, but is often normal even when the patient has should be followed carefully for heart block, because this a proximal myopathy (10). Urinary organic and amino acids typically develops after the ophthalmologic manifestations. may also be abnormal (178). Every patient with seizures or Because of the genetic basis of the disease, screening, which cognitive decline should have an electroencephalogram (EEG) should include a routine ECG, should be performed for family which may show evidence of seizure activity, or diffuse slow members of affected patients, although the yield may be waves suggestive of a subacute encephalomyopathy. low in otherwise asymptomatic individuals. It is important to Only three clinical features are significantly associated with realize that prophylactic pacemaker therapy is advisable in an mtDNA mutation: progressive external ophthalmoplegia, KSS patients because of the potential progression of the heart myopathy and pigmentary retinopathy. The only investigation conduction abnormalities and the high risk of sudden death. that provides specific evidence of an underlying mtDNA The fact that mitochondrial OXPHOS function in KSS changes mutation is histochemical staining of muscle biopsy before manifestations become clinically evident underscores specimens (296,207) and therefore a muscle biopsy is always the need for electrocardiographic surveillance to determine recommended for histological examination and to provide the optimal timing for pacemaker implantation (27). A recent material for molecular genetic testing. Atypical mitochondria study (208) illustrates the need to pace KSS patients with containing paracrystalline inclusions may sometimes be ECG changes indicative of conduction defects. This study, revealed by electron microscopy, even early in the course carried out between 1976 and 1999 on a substantial cohort of of the disease. In addition to the verification of ragged-red 67 patients, found that, over a 10 year period, patients had fibres, other histochemical and immunological investigations a 32% likelihood of sustaining cardiac conduction defects, a of the muscle tissue are helpful. These include staining for 12% likelihood of having a pacemaker implanted, and a 5% cytochrome-c oxidase (COX) and succinate dehydrogenase likelihood of sudden death. The authors therefore concluded (SDH) and immunohistochemical investigations, using antibodies that, without pacing, patients with KSS had a high risk of generated against the individual subunits of the respiratory sudden cardiac death. This study supports the practice of chain complexes. Muscle tissue provides the material for both pacemaker implantation in patients with KSS based on ECG biochemical investigation of the respiratory chain and for changes. The 2002 ACC/AHA (American College of Cardiology/ genetic testing. DNA isolated from blood is frequently used American Heart Association) guidelines also recommend that for genetic testing but, because of the continuous turnover pacing should be considered in patients with neuromuscular of mitochondria in this tissue, the mutation levels may be diseases with AV block, such as those with KSS, with or without low. It is therefore preferable, when looking for deletions and other symptoms, because there may be an unpredictable duplications, to use muscle tissue. It should be noted that, progression of AV conduction disease (209). owing to the different distribution of mutated DNA in different Further management includes the use of bicarbonate and tissues, a negative result does not exclude an mtDNA mutation. dialysis to correct episodes of severe lactic acidosis. Endocrine It is essential to assess cardiac function by ECG and function should be investigated and the necessary corrective echocardiography and to carry out an oral glucose tolerance measures initiated. Blood glucose levels should be checked test because of the high prevalence of both cardiac regularly. Caution should be exercised in the administration complications and diabetes in patients with mtDNA disease. If of anticonvulsants and anesthetics, as severe systemic the diagnosis of KSS is confirmed a regular cardiological follow- complications may occur (210,211). Surgical correction of up should be carried out so that any cardiac arrhythmias which ptosis is possible, but the benefits are usually transient. A may develop can be treated at an early stage. moderate degree of exercise has been shown to improve exercise tolerance and muscle metabolism, and this should Perspectives for the Patient be recommended to patients with mtDNA disease (212). A ketogenic diet may also bring some benefit in restoring proper No curative treatment is currently available for patients mitochondrial function, providing energy source through the with Kearns-Sayre syndrome (or indeed for those with other pathway omitting the deficient enzyme complexes in the mitochondrial cytopathies). Therapy must therefore consist energy production chain. Ketogenic treatment may even of the prevention and treatment of the typical symptoms lead to a reduction in the deleted mtDNA fraction, as has and complications associated with the disease (e.g., insulin been shown in vitro (213). Specific regeneration of mtDNA therapy in the cases with DM or hormone substitution in case mutation-affected muscle tissue from satellite muscle cells has

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 33 Clinical and Molecular Review of KSS also been tried, in an attempt to restore a wild-type muscle method of transfecting mammalian mitochondria exists. phenotype (214,215). One improvement in this area involving the import of In addition to the procedures mentioned above, various lacking tRNA into diseased mitochondria has recently been methods of medical treatment for KSS have been employed in described (235). One of the most promising approaches to gene an attempt to moderate the progression of the neurological therapy involves attempts to alter the level of heteroplasmy by disease process. These mainly consist of nutritional either selectively inhibiting the replication of, or destroying, supplements, such as coenzyme Q10 and ubiquinone the mutant DNA (236,237). In selected, isolated myopathy (216). Coenzyme Q10 is thought to function as an electron cases, reduction of heteroplasmic mutant load was obtained by carrier between flavoproteins and the application of this controlled muscle fibre damage and regeneration by mutation- supplementary therapy should compensate for reduced levels free satellite cells, using myotoxic drugs (238). Such strategies of Q10 in the mitochondria of KSS patients. This has been are based on the fact that a large amount of the mutant shown to accompany clinical improvement in both neurological mtDNA is required before the effect of the mutation becomes function and electrocardiographic abnormalities (217- phenotypically apparent. Effective reduction of the population 219). Other studies have shown a transient effect of such of mutant DNA, should lead to the propagation of wild-type supplements with a decrease in lactate levels within brain DNA, resulting in a normal phenotype. Additionally, recent in lesions (220). Some studies report an improvement of AV- vitro work has shown that sequence specific peptide nucleic block with this type of therapy, but others report no changes acids (PNA) used as antisense probes can selectively inhibit the in the electrocardiogram and echocardiogram, or in clinical replication of mutated mtDNA (239). function (221,222). Antioxidants, electron-transfer mediators, enzyme cofactors and calcium blocking agents have also been tried in patients with mitochondrial encephalomyopathies Inheritance of mtDNA Deletions (223). Other agents utilized in the treatment of patients with The majority of KSS cases are sporadic although, more respiratory chain defects include thiamine, riboflavin, biotin, rarely familial cases, which can be maternally inherited, do ascorbic acid, vitamin K and vitamin E, all of which have occur (177,240-242). Although mtDNA deletions themselves been used with some success in a small number of patients are not transmitted (181,243), mtDNA duplications may with complex II deficiency. The therapeutic effectiveness be transmitted from mother to offspring (74,101). The of all these dietary supplements still needs to be proven duplications themselves are not pathogenic (172) but they do (224), but at least in some cases they have been useful (225). predispose to deletion formation (81). It should be stressed Succinate, a respiratory chain substrate which is coupled to the respiratory chain via complex II, has been used in patients that mtDNA duplications are rare, but women harbouring with complex I deficiency and L-carnitine has been used in mtDNA duplication may have an affected child who could those patients with a secondary carnitine deficiency. Further also harbour a pathogenic mtDNA deletion (244). This therapeutic possibilities include the use of creatine (Cr), based mechanism might provide an explanation for the apparent on its potential neuroprotective and antioxidant effects (226). transmission of mtDNA deletions in some human pedigrees However, trials of Cr therapy in patients with mitochondrial but, in at least one instance the maternally transmitted cytopathies yielded controversial results regarding clinical and species appeared to be a deleted mtDNA molecule (242). ergogenic treatment effects (227-230). Overall, the usefulness It should also be realized that what may appear to be a of these treatment strategies in the clinical course of the maternal inheritance could simply reflect low levels of age- disease is not certain but, because they are relatively free related mtDNA deletions in the mother. Several children of of side effects, there is a rationale for their use in individual women with single mtDNA deletions were clinically normal cases. and had no detectable deletions (181,243,245). A recent As pharmacological therapy has proven to be of limited attempt to define and understand the recurrence risk for value, researchers have instead explored the possibility of mtDNA deletion disorders showed that the incidence of gene therapy. One such approach has involved the expression such a disease does not increase with maternal age and, of a wild-type copy of the mutated mitochondrial gene in also that unaffected mothers are unlikely to have more the nucleus and targeting of this cytoplasmically synthesized than one affected child (246). Conversely, affected women protein to mitochondria (231,232). Another attempt were previously thought to have a negligible risk of having included the selective destruction of mutant mtDNA through clinically affected offspring but the actual risk in this case importation of a restriction enzyme into mitochondria (233). study was found to be, on average, about one in 24 births. It The more obvious approach of direct transfection of affected is not clear why the inheritance pattern of mtDNA deletions mitochondria with wild-type mitochondrial genes has also and point mutations is so different, given that both types been attempted (234). However, the exogenous DNA was of mutation cause the same biochemical defect in OXPHOS neither replicated nor transcribed and currently no practical activity. It is possible that mtDNA deletions are embryonic

34 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS lethal and that all cases of apparent deletion transmission earlier onset of a more severe disease phenotype. By contrast, really occur because of intermolecular recombination of a tendency to decrease mutational load (negative selection) mitochondrial genomes with the formation of duplications as might simply lead to the loss of a deleterious mutation an intermediary stage (247). The recombination events may from the population without clinical effects (252). Both of occur only in the germ line and, as a result the duplications, these possibilities would have important implications for the may not be detected in the blood or muscle of the mother. counseling of women who harbour pathogenic mtDNA mutations Additionally, recent report of paternal transmission of mtDNA in their germ line. Thousands of families have now been given in skeletal muscle (but not in other tissues) in a patient with a diagnosis of mtDNA disease, and they regularly ask about the mitochondrial myopathy gives us an important warning that risk of transmitting an mtDNA defect to their offspring. maternal inheritance of mtDNA is not an absolute rule, and The complexities of mtDNA segregation cause difficulties in some specific cases other possibilities of the origin of the with prenatal diagnosis (251). A major component of the disease should be considered. Of course it does not negate variance in mtDNA heteroplasmy levels between individuals the primacy of maternal inheritance of mtDNA in particular seems to arise by the time oocytes are mature. If so, prenatal mitochondrial encephalomyopathies. diagnosis, by sampling the embryo prior to implantation, would Evidence supporting the idea that pathogenic deletions seem a logical strategy, although it would not be one that is associated with the ontogeny of sporadic KSS and CPEO can readily available in many places. On the other hand, the level be transmitted in the female germ line has come from the of mutated mtDNA in a chorionic villus sample (CVS) may be demonstration that the “common deletion”, which is present different from the level in the fetus. It is already known that in high amounts in many sporadic cases of KSS, can be detected the level of mutant mtDNA is not distributed evenly in most in human oocytes (188,248). Another study showed that both patients with mtDNA disease and this differential segregation oocytes and embryos harbour a KSS deletion in their mtDNAs, probably occurs at the later stages of development. Even but the percentage of this mutation is significantly reduced subtle variations in tissue mutation load may lead to a after fertilization (249). There was no correlation between the profound variation in the phenotype, and sampling of a single mtDNA deletion in human gametes and patient age, suggesting cell or chorionic villus may not reflect this load in clinically that this deletion is not a marker for reproductive senescence. relevant organs such as the brain. In isolated cases, the level It may be that deleted mtDNA cannot be transferred from the of mutant mtDNA has been uniformly distributed throughout oocyte to the implanted embryo, because of the postulated the fetus, which suggests that a chorionic villus sampling may presence of a “genetic bottleneck”, limiting the number give useful information (254,255). Furthermore, sampling of transmitted mtDNA (244,250). This theory argues that, oocytes (e.g. after diagnostic superovulation) for mutated during early germline development of oocytes, there is a mtDNA levels might be useful in any effort to advise individual transient reduction/amplification event with respect to the women about the likelihood of bearing an affected fetus (256). total number of mtDNA causing only a small proportion of the However, at present we know little about how the level of available mitochondrial genomes to propagate to the following mutant mtDNA might change during development and it will generations. This could lead to high proportions of mutated take some time before we know whether the mutation load in mtDNA in a very small number of oocytes and therefore to the CVS provides clinically useful information. the elimination of mutated mtDNA in the offspring of the next generation. According to this hypothesis, the expected frequency and percentage of mutated mtDNA in human Conclusions embryos should be low or possibly absent, when compared with oocytes. Although there have been recent advances in In this review we have outlined the complicated clinical our understanding of this phenomenon (251,252), it is unlikely and genetic picture of Kearns-Sayre syndrome, a classical that the simple mathematical models proposed will be of any disease of mitochondrial origin. Although we have gained much practical use in the clinic (253). The “bottleneck” hypothesis information about the clinical course and genetic background may describe the real events occurring in vivo, but the fine of KSS, since the first description of this syndrome almost 50 details need to be determined and reliable genetic counseling years ago, much still remains to be resolved. The variable, will only be possible when we have a much more complete multisystemic manifestation of KSS impedes the correct clinical understanding of the processes involved in the inheritance, diagnosis, which is critical for the early clinical treatment of segregation and expression of mtDNA defects. the disease. Many investigators have explored the widespread It is extremely important to determine whether positive spectrum of clinical manifestations of KSS, and it would appear or negative selection of heteroplasmy exists according to that we know almost everything about the physical side of transmission of mtDNA mutations in human pedigrees. If there them. However, as no curative therapy has been discovered is positive selection, and a tendency to increase mutational we still can do no more for our patients than attempt to treat load with subsequent generations, this would lead to the the symptoms and complications associated with the disease.

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 35 Clinical and Molecular Review of KSS

The molecular causes of the disease, lying in rearrangements 13. Isashiki Y, Nakagawa M, Ohba N, Kamimura K, Sakoda Y, Higuchi I, of mitochondrial DNA, are now well established. However Izumo S, Osame M. Retinal manifestations In mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand the complex and uncertain inheritance pattern of mtDNA 1998;76:6-13 rearrangements makes the genetic counseling of the growing 14. Beckerman BL, Henkind P. Progressive external ophthalmoplegia and number of women affected by KSS a demanding but vital task. benign retinal pigmentation. Am J Ophthalmol 1976;81:89-92 15. Herzberg NH, van Schooneveld MJ, Bleeker-Wagemakers EM. Kearns- We must therefore focus on preventing the spread of mtDNA Sayre syndrome with a phenocopy of choroideremia instead of deletions, and therefore precise presymptomatic diagnostic pigmentary retinopathy. Neurology 1993;43:218-221 methods must be found (257). Recent work has started to 16. Boonstra FN, Clearhout I, Hol FA, Smit GPA, van Collenburg JJM, Meire FM. Corneal decompensation in a boy with Kearns-Sayre syndrome. Ophthalmic unravel the complexities of mtDNA tissue segregation and Genet 2002;23:247-251 this should, hopefully, allow us to refine the counseling we 17. Nakagawa E, Hirano S, Yamanouchi H, Goto Y, Nonaka I, Takashima S. can give our patients in the future. There is also the pressing Progressive brainstem and white matter lesions in Kearns-Sayre syndrome: a case report. Brain Dev 1994;16:416-418 need to discover the role of mtDNA mutations in human 18. Ohkoshi K, Ishida N, Yamaguchi T, Kanki K. Corneal endothelium in a ageing and neurodegenerative disorders such as Alzheimer’s or case of mitochondrial encephalomyopathy (Kearns-Sayre syndrome). Parkinson’s disease (258-261). So the coming years should see Cornea 1989;8:210-214 19. Brockington M, Alsanjari N, Sweeney MG, Morgan-Hughes JA, Scaravilli F, even greater interest in the wide spectrum of molecular and Harding AE. Kearns-Sayre syndrome associated with mitochondrial DNA clinical mechanisms of mitochondrial DNA rearrangements. deletion or duplication: a molecular genetic and pathological study. J Neurol Sci 1995;131:78-87 20. Tanji K, Vu TH, Schon EA, DiMauro S, Bonilla E. Kearns-Sayre syndrome: Acknowledgements unusual pattern of expression of subunits of respiratory chain in the cerebellar system. Ann Neurol 1999;45:377-383 We would like to thank Prof. Geoffrey Shaw for his critical 21. Young TJ, Shah AK, Lee MH, Hayes DL. Kearns-Sayre syndrome: A case report and review of cardiovascular complications. PACE 2005;28:454-457 reading of the manuscript and helpful suggestions. This 22. Berenberg RA, Pellock JM, Di Mauro S, Schotland DL, Bonilla E, Eastwood A, work was financially supported by Research Grant nr 502-01- Hays A, Vicale CT, Behrens M, Chutorian A, Rowland LP. Lumping or splitting? 11004118-06037 from Poznan University of Medical Sciences “Ophthalmoplegia plus” or Kearns-Sayre syndrome? Ann Neurol 1977;1:37-54 23. Charles R, Holt S, Kay JM, Epstein EJ, Rees JR. Myocardial to M. Niedziela and Grant nr 2 P05A 070 30 from Ministry of ultrastructure and the development of atrioventricular block in Education and Science to J. Maceluch. Kearns-Sayre syndrome. Circulation 1981;63:214-219 24. Roberts NK, Perloff JK, Kark RAP. Cardiac conduction in the Kearns- Sayre syndrome (a neuromuscular disorder associated with progressive References external ophthalmoplegia and pigmentary retinopathy): Report of 2 cases and review of 17 published cases. Am J Cardiol 1979;44:1396-1400 1. DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial 25. Clark DS, Myerburg RG, Morales A, Befeler B, Hernandez FA, Galband H. Heart myopathies. Ann Neurol 1985;17:521-538 block in Kearns-Sayre syndrome: Electrophysiologic-pathologic correlation. 2. Berenbaum F, Cote D, Ishikawa Y, Minami R. Kearns Sayre syndrome. Chest 1975;68:727-730 Neurology 1990;40:193-194 26. Gallastegui J, Hariman RJ, Handler B, Lev M, Bharati S. Cardiac 3. Harvey JN, Barnett D. Endocrine dysfunction in Kearns-Sayre involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987;60:385-388 syndrome. Clin Endocrinol 1992;37:97-103 27. Polak PE, Zijlstra F, Roelandt RTC. Indications for pacemaker implantation 4. Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, in the Kearns-Sayre syndrome. Eur Heart J 1989;10:281-282 Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. 28. Anan R, Nakagawa M, Miyata M, Higuchi I, Nakao S, Suehara M, Neurology 1988;38:1339-1346 Osame M, Tanaka H. Cardiac involvement in mitochondrial diseases: 5. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, A study on 17 patients with documented mitochondrial DNA defects. Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, Nonaka I, Koga Y, Circulation 1995;91:955-961 Spiro AJ, Keith A, Brownell KW, Schmidt B, Schotland DL, Zupanc M, 29. Marin-Garcia J, Goldenthal MJ, Filiano JJ. Cardiomyopathy associated Fr-Vivo DC, Schon EA, Rowland LP. Mitochondrial DNA deletions in with neurologic disorders and mitochondrial phenotype. J Child Neurol progressive external ophthalmoplegia and Kearns-Sayre syndrome. N 2002;17:759-765 Engl J Med 1989;320:1293-1299 30. Muller-Hocker J, Jacob U, Seibel P. The common 4977 base pair 6. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of mitochondrial DNA deletion of mitochondrial DNA preferentially accumulates in the in patients with mitochondrial myopathies. Nature 1988;331:717-719 cardiac conduction system of patients with Kearns-Sayre syndrome. 7. Poulton J, Deadman ME, Gardiner RM. Duplications of mitochondrial Mod Pathol 1998;11:295-301 DNA in mitochondrial myopathy. Lancet 1989;1:236-240 31. Anan R, Nakagawa M, Higuchi I, Nakao S, Nomoto K, Tanaka H. Deletion 8. Brandon MC, Lott MT, Nguyen KC, Spolim S, Navathe SB, Baldi P, Wallace DC. of mitochondrial DNA in the endomyocardial biopsy sample from a MITOMAP: a human mitochondrial genome database – 2004 update. Nucleic patient with Kearns-Sayre syndrome. Eur Heart J 1992;13:1718-1719 Acids Res 2005;33:D611-D613, URL: http://www.mitomap.org 32. Shanske S, Mores CT, Lombes A, Miranda AF, Bonilla E, Lewis P, 9. Kearns TP, Sayre GP. Retinitis pigmentosa, external ophthalmoplegia Whelan MA, Ellsworth CA, DiMauro S. Widespread tissue distribution and complete heart block. Arch Ophthalmol 1958;60:280-289 of mitochondrial DNA deletions in Kearns-Sayre syndrome. Neurology 10. Jackson MJ, Schaefer JA, Johnson MA, Morris AA, Turnbull DM, Bindoff LA. 1990;40:24-28 Presentation and clinical investigation of mitochondrial respiratory chain 33. Remes AM, Hassinen IE, Majamaa K, Peuhkurinen KJ. Mitochondrial disease. A study of 51 patients. Brain 1995;118:339-357 DNA deletion diagnosed by analysis of an endomyocardial biopsy 11. Gross-Jendroska M, Schatz H, McDonald HR, Johnson RN. Kearns-Sayre specimen from a patient with Kearns-Sayre syndrome and complete syndrome: A case report and review. Eur J Ophthalmol 1992;2:15-20 heart block. Br Heart J 1992;68:408-411 12. Chinnery PF, Turnbull DM. The clinical features, investigation and 34. Fromenty B, Carrozzo R, Shanske S, Schon EA. High proportions of management of patients with mitochondrial DNA defects. J Neurol mtDNA duplications in patients with Kearns-Sayre syndrome occur in Neurosurg Psychiatry 1997;63:559-563 the heart. Am J Med Genet 1997;71:443-452

36 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS

35. Howell N. Human mitochondrial diseases: answering questions and 57. Bosbach S, Kornblum C, Schroder R, Wagner M. Executive and questioning answers. Int Rev Cytol 1999;186:49-116 visuospatial deficits in patients with chronic progressive external 36. Holt IJ, Harding AE, Cooper JM, Schapira AH, Toscano A, Clark JB, ophthalmoplegia and Kearns-Sayre syndrome. Brain 2003;126:1231-1240 Morgan-Hughes JA. Mitochondrial myopathies: clinical and biochemical 58. Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial features of 30 patients with major deletions of muscle mitochondrial cytopathies. J Neurol 2003;250:267-277 DNA. Ann Neurol 1989;26:699-708 59. Nicolino M, Ferlin T, Forest M, Godinot C, Carrier H, David M, 37. DiMauro S, Moraes CT. Mitochondrial encephalomyopathies. Arch Chatelain P, Mousson B. Identification of a large-scale mitochondrial Neurol 1993;50:1197-1208 deoxyribonucleic acid deletion in endocrinopathies and deafness: 38. Madsen PL, Linde R, Hasselbalch SG, Paulson OB, Lassen NA. report of two unrelated cases with diabetes mellitus and adrenal Activation-induced resetting of cerebral oxygen and glucose uptake in insufficiency, respectively. J Clin Endocrinol Metab 1997;82:3063-3067 the rat. J Cereb Blood Flow Metab 1998;18:742-748 60. Bruno C, Minetti C, Tang Y, Magalhaes PJ, Santorelli FM, Shanske S, 39. Sparaco M, Bonilla E, DiMauro S, Powers JM. Neuropathology of Bado M, Cordone G, Gatti R, DiMauro S. Primary adrenal insufficiency mitochondrial encephalomyopathies due to mitochondrial DNA defects. in a child with a mitochondrial DNA deletion. J Inher Metab Dis J Neuropathol Exp Neurol 1993;52:1-10 1998;21:155-161 40. Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. 61. Boles RG, Roe T, Senadheera D, Mahnovski V, Wong L JC. Mitochondrial DNA deletion with Kearns-Sayre syndrome in a child with Addison’s Neuroradiologic findings in children with mitochondrial disorders. Am disease. Eur J Pediatr 1998;157:643-647 J Neuroradiol 1998;19:369-377 62. Burns EC, Preece MA, Cameron N, Tanner JM. Growth hormone deficiency 41. Zwirner P, Wilichowski E. Progressive sensorineural hearing loss in in mitochondrial cytopathy. Acta Paediatr Scand 1982;7:693-697 children with mitochondrial encephalomyopathies. Laryngoscope 63. Quade A, Zierz S, Klingmuller D. Endocrine abnormalities in 2001;111:515-521 mitochondrial myopathy with external ophthalmoplegia. Clin Invest 42. Kornblum C, Broicher R, Walther E, Herberhold S, Klockgether T, 1992;70:396-402 Herberhold C, Schroder R. Sensorineural hearing loss in patients 64. Tulinius MH, Oldfors A, Holme E, Larsson NG, Houshmand M, Fahleson P, with chronic progressive ophthalmolegia or Kearns-Sayre syndrome. J Sigstrom L, Kristiansson B. Atypical presentation of multisystem disorders Neurol 2005;252:1101-1107 in two girls with mitochondrial DNA deletions. Eur J Pediatr 1995;154:35-42 43. Oldfors A, Fyhr IM, Holme E, Larsson NG, Tulinius M. Neuropathology in 65. Berio A, Piazzi A. A case of Kearns-Sayre syndrome with autoimmune Kearns-Sayre syndrome. Acta Neuropathol 1990;80:541-546 thyroiditis and possible Hashimoto encephalopathy. Panminerva Med 44. Ota Y, Miyake Y, Awaya S, Kumagai T. Early retinal involvement in 2002;44:265-269 mitochondrial myopathy with mitochondrial DNA deletion. Retina 66. Doriguzzi C, Palmucci L, Mongini T, Bresolin N, Bet L, Comi G, Lala R. Endocrine 1994;14:270-276 involvement in mitochondrial encephalomyopathy with partial cytochrome c 45. Chabrol B, Paquis V. Cerebral infarction associated with Kearns-Sayre oxidase deficiency. J Neurol Neurosurg Psychiatry 1989;52:122-125 syndrome. Neurology 1997;49:308 67. Morten KJ, Cooper JM, Brown GK, Lake BD, Pike D, Poulton J. A new 46. Seigel RS, Seeger JF, Gabrielsen TO, Allen RJ. Computed tomography point mutation associated with mitochondrial encephalomyopathy. in oculocraniosomatic disease (Kearns-Sayre syndrome). Radiology Hum Mol Genet 1993;2:2081-2087 1979;130:159-164 68. Papadimitiou A, Hadjigeorgiou GM, Divari R, Papagalanis N, Comi G, 47. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. Bresolin N. Influence of coenzyme Q10 on total serum calcium White matter involvement in mitochondrial diseases. Mol Genet Metab concentration in two patients with Kearns-Sayre syndrome and 2005;84:127-136 hypoparathyroidism. Neuromusc Disord 1996;6:49-53 48. Chu BC, Terae S, Takahashi C, Kikuchi Y, Miyasaka K, Abe S, Minowa K, 69. Tengan CH, Kiyomoto BH, Rocha MS, Tavares VLS, Gabbai AA, Moraes CT. Sawamura T. MRI of the brain in the Kearns-Sayre syndrome: report of Mitochondrial encephalomyopathy and hypoparathyroidism associated four cases and a review. Neuroradiology 1999;41:759-764 with a duplication and a deletion of mitochondrial deoxyribonucleic 49. De Volder A, Ghilain S, de Barsy T, Goffinet AM. Brain metabolism acid. J Clin Endocrinol Metab 1998;83:125-129 in mitochondrial encephalomyopathy: a PET study. J Comput Assist 70. Simpoulus AP, Delea CS, Bartler FC. Neurodegenerative disorders and Tomogr 1988;12:854-857 hyperaldosteronism. J Pediatr 1971;79:633-641 50. Frackowiak RS, Herold S, Petty RK, Morgan-Hughes JA. The cerebral 71. North K, Korson MS, Krawiecki N, Shoffner JM, Holm IA. Oxidative metabolism of glucose and oxygen measured with positron tomography phosphorylation defect associated with primary adrenal insufficiency. in patients with mitochondrial diseases. Brain 1988;111:1009-1024 J Pediatr 1996;128:688-692 51. Barbiroli B, Montagna P, Martinelli P, Lodi R, Iotti S, Cortelli P, 72. De Block CEM, De Leeuw IH, Maassen JA, Ballaux D, Martin J J. A novel Funicello R, Zaniol P. Defective brain energy metabolism shown by 7301-bp deletion in mitochondrial DNA in a patient with Kearns-Sayre in vivo 31 PLEASE CHECK P MR spectroscopy in 28 patients with syndrome, diabetes mellitus, and primary amenorrhoea. Exp Clin Endocrinol Diabetes 2004;112:80-83 mitochondrial cytopathies. J Cereb Blood Flow Metab 1993;13:469-474 73. Mori K, Narahara K, Ninomiya S, Goto Y, Monaka I. Renal and skin 52. Molnar MJ, Valikovics A, Molnar S, Tron L, Dioszeghy P, Mechler F, involvement in a patient with complete Kearns-Sayre syndrome. Am J Gulyas B. Cerebral blood flow and glucose metabolism in mitochondrial Med Genet 1991;38:583-587 disorders. Neurology 2000;55:544-548 74. Rotig A, Bessis JL, Romero N, Cormier V, Saudubray JM, Narcy P, 53. Rango M, Bozalli M, Prelle A, Scarlato G, Bresolin N. Brain activation Lenoir G, Rustin P, Munnich A. Maternally inherited duplication of the in normal subjects and in patients affected by mitochondrial disease mitochondrial genome in a syndrome of proximal tubulopathy, diabetes without clinical central nervous system involvement: a phosphorus mellitus, and cerebellar ataxia. Am J Hum Genet 1992;50:364-370 magnetic resonance spectroscopy study. J Cereb Blood Flow Metab 75. Berio A, Piazzi A. Kearns-Sayre syndrome associated with de Toni- 2001;21:85-91 Debre-Fanconi syndrome due to cytochrome-c-oxidase (COX) 54. Kartsounis LD, Troung DD, Morgan-Hughes JA, Harding AE. The deficiency. Panminerva Med 2001;43:211-214 neuropsychological features of mitochondrial myopathies and 76. Rogounovitch T, Saenko V, Yamashita S. Mitochondrial DNA and human encephalomyopathies. Arch Neurol 1992;49:158-160 thyroid diseases. Endocrine J 2004;51:265-277 55. Lang CJG, Brenner P, Heuss D, Engelhardt A, Reichmann H, Seibel P, 77. Isotani H, Fukumoto Y, Kawamura H, Furukawa K, Ohsawa N, Goto Y, Neundorfer B. Neuropsychological status of mitochondrial Nishino I, Nonaka I. Hypoparathyroidism and insulin-dependent diabetes encephalomyopathies. Eur J Neurol 1995;2:171-176 mellitus in a patient with Kearns-Sayre syndrome harboring a mitochondrial 56. Turconi AC, Benti R, Castelli E, Pochintesta S, Felisari G, Comi G, deletion. Clin Endocrinol (Oxf) 1996;45:637-641 Gagliardi C, Del Piccolo L, Bresolin N. Focal cognitive impairment 78. Cormier V, Rotig A, Tardieu M, Colonna M, Saudubray JM, Munnich A. in mitochondrial encephalomyopathies: a neuropsychological and Autosomal dominant deletions of the mitochondrial genome in a case neuroimageing study. J Neurol Sci 1999;170:57-63 of progressive encephalopathy. Am J Hum Genet 1991;48:643-648

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 37 Clinical and Molecular Review of KSS

79. Wilichowski E, Grüters A, Kruse K, Rating D, Beetz R, Korenke GC, 101. Dunbar DR, Moonie PA, Swingler RJ, Davidson D, Roberts R, Holt IJ. Ernst BP, Christen HJ, Hanefeld F. Hypoparathyroidism and deafness Maternally transmitted partial direct tandem duplication of mitochondrial associated with pleioplasmic large scale rearrangements of the DNA associated with diabetes mellitus. Hum Mol Genet 1993;2:1619-1624 mitochondrial DNA: a clinical and molecular genetic study of four 102. Maassen J, Kadowaki T. Maternally inherited diabetes and deafness: a children with Kearns-Sayre syndrome. Pediatr Res 1997;41:193-200 new diabetes subtype. Diabetologia 1996;39:375-382 80. Abramowicz MJ, Cochaux P, Cohen LH, Vamos E. Pernicious anaemia 103. Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DA, and hypoparathyroidism in a patient with Kearns-Sayre syndrome with Wallace DC. Maternally transmitted diabetes and deafness associated mitochondrial DNA duplication. J Inher Metab Dis 1996;19:109-111 with a 10.4 kb mitochondrial DNA deletion. Nat Genet 1992;1:11-15 81. Poulton J, Deadman ME, Bindoff L, Morten K, Land J, Brown G. 104. Ballinger SW, Shoffner JM, Gebhart S, Koontz DA, Wallace DC. Families of mtDNA re-arrangements can be detected in patients with Mitochondrial diabetes revisited. Nature Genet 1994;7:458-459 mtDNA deletions: duplications may be a transient intermediate form. 105. Alcolado JC, Alcolado R. Importance of maternal history of non-insulin Hum Mol Genet 1993;2:23-30 dependent diabetic patients. Br Med J 1991;302:1178-1180 82. Bordarier C, Duyckaerts C, Robain O, Ponsot G, Laplane D. Kearns- 106. Soejima A, Inoue K, Takai D, et al. Mitochondrial DNA is required Sayre Syndrome. Two clinico-pathological cases. Neuropediatrics for regulation of glucose-stimulated insulin secretion in a mouse 1990;21:106-109 pancreatic beta cell line, MIN6. J Biol Chem 1996;271:26194-26199 107. Alcolado JC, Majid A, Brockington M, Sweeney MG, Morgan R, Rees A, 83. Poulton J, Morten KJ, Weber K, Brown GK, Bindoff L. Are duplications Harding AE, Barnett AH. Mitochondrial gene defects in patients with of mitochondrial DNA characteristic of Kearns-Sayre syndrome? Hum NIDDM. Diabetologia 1994;37:372-376 Mol Genet 1994;3:947-951 108. Feinsmith BM, Liebesman WP, Guibor P. Steroid danger in Kearns-Sayre 84. Carboni P, Giacanelli M, Porro G, Sideri G, Paolella A. Kearns- Syndrome (KSS). N J Med 1988;85:659-663 Sayre syndrome. A case of the complete syndrome with encephalic 109. Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda F, leukodystrophy and calcification of basal ganglia. Ital J Neurol Sci Kasuga M. Diabetes mellitus carrying a mutation in the mitochondrial 1981;3:263-268 PLEASE CHECK tRNALeu(UUR) gene. Diabetologia 1995;38:193-200 85. Goto Y, Itami N, Kajii N, Tochimaru H, Endo M, Horai S. Renal tubular 110. Oexle K, Oberle J, Finckh B, Kohlschutter A, Nagy M, Seibel P, involvement mimicking Bartter syndrome in a patient with Kearns- Seissler J, Hubner C. Islet cell antibodies in diabetes mellitus Sayre syndrome. J Pediatr 1990;116:904-910 associated with a mitochondrial tRNA (Leu (UUR)) gene mutation. 86. Simopoulos AP, Delea CS, Bartter FC. Neurodegenerative disorders and Exp Clin Endocrinol Diabetes 1996;104:212-217 hyperaldosteronism. J Pediatr 1971;79:633-641 111. Oka Y, Katagiri H, Yakazi Y, Murase Y, Kobayashi T. Mitochondrial gene 87. Horwitz SJ, Roessmann U. Kearns-Sayre syndrome with mutation in islet-cell antibody-positive patients who were initially hypoparathyroidism. Ann Neurol 1978;3:513-518 non-insulin-dependent diabetics. Lancet 1993;342:527-528 88. Spiro AJ, Prineas JW, Moore CJ. A new mitochondrial myopathy in a 112. Coulter DL, Allen RI. Acute deterioration in children with Kearns-Sayre patient with salt craving. Arch Neurol 1970;22:259-269 syndrome. Arch Neurol 1981;38:247-250 89. Wong L-JC, Senadheera D. Direct detection of multiple point mutations 113. Tanabe Y, Miyamoto S, Kimoshita I, Yamada K, Sasaki N, Makino E, in mitochondrial DNA. Clin Chem 1997;43:1857-1861 Nakajima H. Diabetes mellitus in Kearns-Sayre syndrome. Eur Neurol 90. Drachman DA. Ophthalmoplegia plus. The neurodegenerative disorders 1988;28:34-38 associated with progressive external ophthalmoplegia. Arch Neurol 114. Franzese A, Del Giudice E, Santoro L, De Filippo G, Argenziano A. 1968;18:654-674 Diabetes mellitus in Kearns-Sayre Syndrome: a case with a 10-year 91. Butler IJ, Gadoth N. Review of multisystem disorders of children and follow-up. Diabetes Res Clin Pract 1995;30:233-235 young adults. Arch Intern Med 1997;136:1290-1293 115. Piccolo G, Aschei M, Ricordi A, Banfi P, Lo Corto F, Frattino P. Normal 92. Carrol PV, Umpleby AM, Albany E, Jackson NC, Morgan-Hughes JA, insulin receptors in mitochondrial myopathies with ophthalmoplegia. J Sonksen PH, Russel-Jones DL. Growth hormone therapy may benefit Neurol Sci 1989;94:163-172 protein metabolism in mitochondrial encephalopathy. Clin Endocrinol 116. Curless RG, Flynn J, Backynski B, Gregorios JB, Benke P, Cullen R. 1997;47:113-117 Fatal metabolic acidosis and coma after steroid therapy for KSS. 93. Matsuuzaki M, Izumi T, Shishikura K, Suzuki H, Hirayama Y. Hypothalamic Neurology 1986;36:872-873 growth hormone deficiency and supplementary GH therapy in two 117. Martens ME, Peterson PL, Lee CP, Nigro MA, Hart Z, Glasberg M, patients with mitochondrial myopathy, encephalopathy, lactic acidosis Hatfield JS, Chang CH. Kearns-Sayre syndrome: Biochemical studies of and stroke-like episodes. Neuropediatrics 2002;33:271-273 mitochondrial metabolism. Ann Neurol 1988;24:630-637 94. Egger J, Lake BD, Wilson J. Mitochondrial cytopathy. A multisystem 118. Katagiri H, Asano T, Ishihara H, Inukai K, Anai M, Yamanouchi T, disorder with ragged red fibres on muscle biopsy. Arch Disease in Tsukuda K, Kikuchi M, Kitaoka H, Ohsawa N, et al. Mitochondrial Childhood 1981;56:741-752 diabetes mellitus: prevalence and clinical characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese 95. Barberi S, Bozzola E, Berardinelli A, Meazza C, Bozzola M. Long- patients. Diabetologia 1994;37:504-510 term growth hormone therapy in mitochondrial cytopathy. Horm Res 119. Maassen JA. Mitochondrial diabetes, pathophysiology, clinical 2004;62:103-106 presentation and genetic analysis. Am J Med Genet 2002;115:66-70 96. Russel-Jones DL, Weissberger AJ, Bowes SB, Kelly JM, Thomason M, 120. Mandrup-Poulsen T, Helqvist S, Wogensen LD, Moving J, Pociot F, Umpleby AM, Jones RH, Sönkesen PH. The effects of growth hormone Johannesen J, Nerup J. Cytokines and free radicals as effector on protein metabolism in adult growth hormone deficient patients. molecules in the destruction of pancreatic β-cells. Curr Top Microbiol Clin Endocrinol 1993;38:427-431 Immunol 1990;164:169-193 97. Mohri I, Taniike M, Fujimura H, Matsuoka T, Inui K, Nagai T, Okada S. 121. Anderson S, Bankier AT, Barrell BG, de Bruijn MHL, Coulson AR, A case of Kearns-Sayre syndrome showing a constant proportion of Drouin J, Eperon IC, Nielich DP, Roe BA, Sanger F, Schreier PH, Smith deleted mitochondrial DNA in blood cells during 6 years of follow-up. J AJH, Staden R, Young IG. Sequence and organization of the human Neurol Sci 1998;158:106-109 mitochondrial genome. Nature 1981;290:457-465 98. Gerbitz K-D, van den Ouweland JMW, Maasen JA, Jaksch M. Mitochondrial 122. Tzagoloff A, Myers AM. Genetics of mitochondria biogenesis. Annu Rev diabetes: a review. Biochem Biophys Acta 1995;1271:253-260 Biochem 1986;55:249-285 99. Poulton J, O’Rahilly S, Morten KJ, Clark A. Mitochondrial DNA, diabetes 123. Graeber MB, Muller U. Recent developments in the molecular genetics and pancreatic pathology in Kearns-Sayre syndrome. Diabetologia of mitochondrial disorders. J Neurol Sci 1998;153:251-263 1995;38:868-871 124. Schon EA. Mitochondria. In: DiMauro S, Wallace DC, eds. Mitochondrial 100. Poulton J, Deadman ME, Gardiner RM. Tandem direct duplications of DNA in human pathology. New York: Raven Press 1993;1-7 mitochondrial DNA in mitochondrial myopathy: analysis of nucleotide 125. Clayton DA. Replication and transcription of vertebrate mitochondrial sequence and tissue distribution. Nucleic Acids Res 1989;17:10223-10229 DNA. Annu Rev Cell Biol 1992;7:453-478

38 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS

126. Wallace DC. Mitochondrial DNA sequence variation in human evolution 150. Bresolin N, Moggio M, Bet L, Gallanti A, Prelle A, Nobile-Orazio E, and disease. Proc Natl Acad Sci USA 1994;91:8739-8746 Adobbati L, Ferrante C, Pellegrini G, Scarlato G. Progressive cytochrome 127. Wallace DC. Mitochondrial DNA variation in human evolution, c oxidase deficiency in a case of Kearns-Sayre syndrome: morphological, degenerative disease, and ageing. Am J Hum Genet 1995;57:201-223 immunological, and biochemical studies in muscle biopsies and autopsy 128. Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem tissues. Ann Neurol 1987;21:564-572 1992;61:1175-1212 151. Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulinius M. Progressive 129. Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial increase of the mutated mitochondrial DNA fraction in Kearns-Sayre decay in ageing. Proc Natl Acad Sci USA 1994;91:10771-10778 syndrome. Pediatr Res 1990;28:131-136 130. Wallace DC, Melov S. Radicals r’ageing. Nat Genet 1998;19:105-106 152. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle 131. Wallace DC. Mitochondrial diseases – genotype versus phenotype. mitochondrial DNA in mitochondrial myopathies: sequence analysis Trends Genet 1993;9:128-133 and possible mechanisms. Nucleic Acids Res 1989;17:4465-4469 132. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. 153. Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S. A direct Mitochondrial DNA deletions in human brain: regional variability and repeat is a hotspot for large-scale deletion of human mitochondrial increase with advanced age. Nature Genet 1992;2:324-329 DNA. Science 1989;244:346-349 133. Cortopassi G, Arnheim N. Detection of mitochondrial DNA deletion in 154. Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC. tissues of older humans. Nucleic Acids Res 1990;18:6927-6933 Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome 134. Melov S, Shoffner JM, Kaufman A, Wallace DC. Marked increase in the associated with a mitochondrial DNA deletion: a slip-replication model number and variety of mitochondrial DNA rearrangements in ageing and metabolic therapy. Proc Natl Acad Sci USA 1989;86:7952-7956 human skeletal muscle. Nucleic Acids Res 1995;23:4122-4126 155. Cortopassi GA, Shibata D, Soong NW, Arnheim N. A pattern of 135. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, McKee AC, Beal MF, accumulation of a somatic deletion of mitochondrial DNA in ageing Graham BH, Wallace DC. Marked changes in mitochondrial DNA deletion human tissues. Proc Natl Acad Sci USA 1992;89:7370-7374 levels in Alzheimer brains. Genomics 1994;23:471-476 156. Moslemi A-R, Melberg A, Holme E, Oldfors A. Autosomal dominant 136. Hamblet NS, Castora FJ. Elevated levels of the Kearns-Sayre syndrome progressive external ophthalmoplegia: distribution of multiple mitochondrial DNA deletion in temporal cortex of Alzheimer’s patients. mitochondrial DNA deletions. Neurology 1999;53:79-84 Mutat Res 1997;379:253-262 157. Mita S, Rizzuto R, Moraes CT. Recombination via flanking direct repeats 137. Corral-Debrinski M, Shoffner JM, Lott MT, Wallace DC. Association of is a major cause of large-scale deletions of human mitochondrial DNA. mitochondrial DNA damage with ageing and coronary atherosclerotic Nucleic Acids Res 1990;18:561-567 heart disease. Mutat Res 1992;275:169-180 158. Buroker NE, Brown JR, Gilbert TA, O’Hara PJ, Beckenbach AT, Thomas WK, 138. Santorelli FM, Sciacco M, Tanji K, Shanske S, Vu TH, Golzi V, Griggs RC, Smith MJ. Length heteroplasmy of sturgeon mitochondrial DNA: an illegitimate Mendell JR, Hays AP, Bertorini TE, Pestronk A, Bonilla E, DiMauro S. elongation model. Genetics 1990;124:157-163 Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: 159. Rocher C, Letellier T, Copeland WC, Lestienne P. Base composition a study of 56 patients. Ann Neurol 1996;39:789-795 at mtDNA boundaries suggests a DNA triple helix model for human 139. Blume G, Pestronk A, Frank B, Johns DR. Polymyositis with cytochrome mitochondrial DNA large-scale rearrangements. Mol Genet Metab oxidase negative muscle fibres. Early quadriceps weakness and poor 2002;76:123-132 response to immunosuppressive therapy Brain 1997;120:39-45 160. Blok RB, Thorburn DR, Thompson GN, Dahl H-HM. A topoisomerase II 140. Brierley EJ, Johnson MA, Lightowlers RN, James OFW, Turnbull DM. cleavage site is associated with a novel mitochondrial DNA deletion. Role of mitochondrial DNA mutations in human ageing: implications for Hum Genet 1995;95:75-81 the central nervous system and muscle. Ann Neurol 1998;43:217-223 161. Schroder R, Vielhaber S, Wiedemenn FR, Kornblum C, 141. Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, Papassotiropoulos A, Broich P, Zierz S, Elger CE, Reichmann H, Seibel P, Taylor RW, Bindoff LA, Turnbull DM. The epidemiology of pathogenic Klockgether T, Kunz WS. New insights into the metabolic consequences mitochondrial DNA mutations. Ann Neurol 2000;48:188-193 of large-scale mtDNA deletions: a quantitative analysis of biochemical, 142. Zeviani M, Di Donato S. Mitochondrial disorders. Brain 2004;127:2153-2172 morphological, and genetic findings in human skeletal muscle. J 143. Remes AM, Majamaa-Voltti K, Karppa M, Moilanen JS, Uimonen S, Neuropathol Exp Neurol 2000;59:353-360 Helander H, Rusanen H, Salmela PI, Sorri M, Hassinen IE, Majamaa K. 162. Mazat JP, Letellier T, Bedes F, Malgat M, Korzeniewski B, Jouaville LS, Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish Morkuniene R. Metabolic control analysis and threshold effect in oxidative population. Neurology 2005;64:976-981 phosphorylation: implications for mitochondrial pathologies. Mol Cell 144. Wallace DC, Lott MT, Torroni A, Brown MD, Shoffner JM. Report of the Biochem 1997;174:143-148 committee on human mitochondrial DNA. In: Cuticchia AJ, Pearson PL, 163. Rossignol R, Malgat M, Mazat JP, Letellier T. Threshold effect and eds. Human gene mapping. Baltimore Johns Hopkins University Press tissue specificity. Implication for mitochondrial cytopathies. J Biol 1994;813-845 Chem 1999;274:33426-33432 145. Nakase H, Moraes CT, Rizzuto R, Lombes A, DiMauro S, Schon EA. 164. Goto Y, Koga Y, Horai S, Nonaka I. Chronic progressive external Transcription and translation of deleted mitochondrial genomes in ophthalmoplegia: a correlative study of mitochondrial DNA deletions Kearns-Sayre syndrome: implications for pathogenesis. Am J Hum and their phenotypic expression in muscle biopsies. J Neurol Sci Genet 1990;46:418-427 1990;100:63-69 146. DiMauro S, Moraes CT, Shanske S, Lombes A, Nakase H, Mita S, 165. Yamamoto M, Clemens PR, Engel AG. Mitochondrial DNA deletions in Tritschler HJ, Bonilla E, Miranda AF, Schon EA. Mitochondrial mitochondrial cytopathies: observations in 19 patients. Neurology encephalomyopathies: biochemical approach. Rev Neurol 1991;41:1822-1828 1991;147:443-449 166. Wong L-JC. Recognition of mitochondrial DNA deletion syndrome 147. Hayashi J, Ohta S, Kikuchi A, Takemitsu M, Goto Y, Nonaka I. with non-neuromuscular multisystemic manifestations. Genet Med Intoduction of disease related mitochondrial DNA deletions into HeLa 2001;3:399-404 cells lacking mitochondrial DNA results in mitochondrial dysfunction. 167. Rasmussen UF, Rasmussen HN, Krustrup P, Quistorff B, Saltin B, Proc Natl Acad Sci USA 1991;88:10614-10618 Bangsbo J. Aerobic metabolism of human quadriceps muscle: in vivo 148. Porteous WK, James AM, Sheard PW, Porteous CM, Packer MA, data parallel measurements on isolated mitochondria. Am J Physiol Hyslop SL, Melton JV, Pang CY, Wei YH, Murphy MP. Bioenergetic Endocrinol Metab 2001;280:E301-E307 consequences of accumulating the common 4977-bp mitochondrial 168. Gellerich FN, Deschauer M, Chen Y, Muller T, Neudecker S, Zierz S. DNA deletion. Eur J Biochem 1998;257:192-201 Mitochondrial respiratory rates and activities of respiratory chain 149. Vielhaber S, Kudin A, Schroder R, Elger CE, Kunz WS. Muscle fibres: complexes correlate linearly with heteroplasmy of deleted mtDNA applications for the study of the metabolism consequences of enzyme without threshold and independently of deletion size. Biochim Biophys deficiencies in skeletal muscle. Biochem Soc Trans 2000;28:159-164 Acta 2002;1556:41-52

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 39 Clinical and Molecular Review of KSS

169. Wong L-JC, Perng CL, Hsu CH, Bai RK, Schelley S, Vladutiu GD, Vogel 188. Chen X, Prosser R, Simonetti S, Sadlock J, Jagiello G, Schon EA. H, Enns GM. Compensatory amplification of mtDNA in a patient with Rearranged mitochondrial genomes are present in human oocytes. Am a novel deletion/duplication and high mutant load. J Med Genet J Hum Genet 1995;57:239-247 2003;40:e125 189. Hirano M, Marti R, Ferreiro-Barros C, Vila MR, Tadesse S, NishigakiY, 170. Fassati A, Bordoni A, Amboni P, Fortunato F, Fagiolari G, Bresolin N, Prelle A, Nishino I, Vu TH. Defects of intergenomi communication: autosomal Comi G, Scarlato G. Chronic progressive external ophthalmoplegia: a correlative disorders that cause multiple deletions and depletion of mitochondrial study of quantitative molecular data and histochemical and biochemical profile. DNA. Semin Cell Dev Biol 2001;12:417-427 J Neurol Sci 1994;123:140-146 190. Spinazzola A, Zeviani M. Disorders of nuclear-mitochondrial 171. Houshmand M, Gardner A, Hallstrom T, Muntzing K, Oldfors A, Holme E. intergenomic signaling. Gene 2005;354:162-168 Different tissue distribution of a mitochondrial DNA duplication 191. Moraes CT, Shanske S, Tritschler HJ, Aprille JR, Andreetta F, Bonilla E, and the corresponding deletion in a patient with a mild mitochondrial Schon EA, DiMauro S. MtDNA depletion with variable tissue expression: encephalomyopathy: deletion in muscle, duplication in blood. Neuromuscular a novel genetic abnormality in mitochondrial diseases. Am J Hum Disord 2004;14:195-201 Genet 1991;48:492-501 172. Manfredi G, Vu T, Bonilla E, Schon EA, DiMauro S, Arnaudo E, 192. Poulton J, Morten K, Freeman-Emmerson C, Potter C, Sewry C, Zhang L, Rowland LP, Hirano M. Association of myopathy with Dubowitz V, Kidd H, Stephenson J, Whitehouse W, Hansen FJ. large-scale mitochondrial DNA duplications and deletions: which is Deficiency of the human mitochondrial transcription factor h-mtTFA in pathogenic? Ann Neurol 1997;42:180-188 infantile mitochondrial myopathy is associated with mtDNA depletion. 173. Poulton J, Morten KJ, Marchington D, Weber K, Brown KG, Rotig A, Hum Molec Genet 1994;3:1763-1769 Bindoff L. Duplications of mitochondrial DNA in Kearns-Sayre syndrome. 193. Spelbrink JN, Li FY, Tiranti V, PLEASE MENTION FULL NAMES et Muscle Nerve 1995;3:S154-S158 al. Human mitochondrial DNA deletions associated with mutations in 174. Martin-Negrier ML, Coquet M, Moretto BT, Lacut JY, Dupon M, Bloch B, the gene encoding Twinkle, a phage T7 gene 4-like protein localized Lestienne P, Vital C. Partial triplication of mtDNA in maternally transmitted in mitochondria. Nat Genet 2001;28:223-231 (Erratum, Nat Genet diabetes mellitus and deafness. Am J Hum Genet 1998;63:1227-1232 2001;29:100) 175. Hammans SR, Morgan-Hughes JA. Mitochondrial myopathies: clinical 194. Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C, features, investigation, treatment and genetic counseling. In: Schapira Mutation of POLG is associated with progressive external ophthalmoplegia AHV, DiMauro S, eds. Mitochondrial disorders in neurology. Oxford characterized by mtDNA deletions. Nat Genet 2001;28:211-212 Butterworth-Heinemann 1994;49-74 195. Napoli L, Bordoni A, Zeviani M, Hadjigeorgiou GM, Sciacco M, Tiranti V, 176. Marzuki S, Berkovic SF, Noer AS, Kapsa RMI, Kalnins RM, Byrne E, Terentiou A, Moggio M, Papadimitriou A, Scarlato G, Comi GP. A novel Sasmono T, Sudoyo H. Developmental genetics of deleted mtDNA in missense adenine translocator-1 gene mutation in Greek adPEO family. mitochondrial oculomyopathy. J Neurol Sci 1997;145:155-162 Neurology 2001;57:2295-2298 177. Puoti G, Carrara F, Sampaolo S, De Caro M, Vincitorio CM, Invernizzi F, 196. Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei A, Zeviani M. Identical large scale rearrangement of mitochondrial DNA Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M. causes Kearns-Sayre syndrome in a mother and her son. J Med Genet Mutations of mitochondrial DNA polymerase gammaA are a frequent cause 2003;40:858-863 of autosomal dominant or recessive progressive external ophthalmoplegia. 178. Shoffner JM, Wallace DC. Oxidative phosphorylation diseases. Ann Neurol 2002;52:211-219 In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic 197. Ponomarev MV, Longley MJ, Nguyen D, Kunkel TA, Copeland WC. Active and molecular bases of inherited disease. New York McGraw-Hill site mutation in DNA polymerase gamma associated with progressive Information Services company 1995;1535-1610 external ophthalmoplegia cases error-prone DNA synthesis. J Biol 179. Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, DiDonato S. An Chem 2002;277:15225-15228 autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 1989;339:309-311 198. Hirano M, Silvestri B, Blake DM, Lombes A, Minetti C, Bonilla E, 180. Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, PLEASE FILL THE NAMES et al. Mitochondrial neurogastrointestinal Keranen S, Peltonen L, Suomalainen A. Role of adenine nucleotide encephalomyopathy (MNGIE): clinical, biochemical, and genetic translocator I in mtDNA maintenance. Science 2000;289:782-785 features of an autosomal recessive mitochondrial disorder. Neurology 181. Zeviani M, Gellera C, Pannacci M, Uziel G, Prelle A, Servidei S, 1994;44:721-727 DiDonato S. Tissue distribution and transmission of mitochondrial DNA 199. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene deletions in mitochondrial myopathies. Ann Neurol 1990;28:94-97 mutations in MNGIE, a human mitochondrial disorder. Science 182. Cormier V, Rotig A, Quartino AR, Forni GL, Cerone R, Maier M, 1999;283:689-692 Saudubray JM, Munnich A. Widespread multi-tissue deletions of the 200. Nishino I, Spinazzola A, Papadimitiou A, Hammans S, Steiner I, mitochondrial genome in the Pearson marrow-pancreas syndrome. J Hahn CD, PLEASE FILL THE NAMES et al. Mitochondrial Pediatr 1990;117:599-602 neurogastrointestinal encephalomyopathy: an autosomal recessive 183. Rotig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, disorder due to thymidine phosphorylase mutations. Ann Neurol Schmitz J, Rustin P, Fischer A, Saudubray J-M, Munnich A. Pearson’s 2000;47:792-800 marrow-pancreas syndrome: a multisystem mitochondrial disorder in 201. Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant infancy. J Clin Invest 1990;86:1601-1608 mitochondrial thymidine kinase in mitochondrial DNA depletion 184. McShane MA, Hammans SR, Sweeney M, Holt IJ, Beattie TJ, Brett EM, myopathy. Nat Genet 2001;29:342-344 Harding AE. Pearson syndrome and mitochondrial encephalomyopathy 202. Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, in a patient with a deletion of mitochondrial DNA. Am J Hum Genet Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N. The deoxyguanosine 1991;48:39-42 kinase gene is mutated in individuals with depleted hepatocerebral 185. Muraki K, Nishimura S, Goto Y, Nonaka I, Sakura N, Ueda K. The mitochondrial DNA. Nat Genet 2001;29:337-341 Erratum in: Nat Genet association between haematological manifestation and mtDNA 2001;29:491 deletions In Pearson syndrome. J Inherit Metab Dis 1997;20:697-703 203. Spinazzola A, Marti R, Nishino I, Andreu AL, Naini A, Tadesse S, Pela I, 186. De Vries DD, Buzing CJM, Ruitenbeek W, van der Wouw MPME, Sperl W, Zammarchi E, Donati MA, Oliver JA, Hirano M. Altered thymidine metabolism Sengers RCA, Trijbels JMF, van Oost BA. Myopathology and a mitochondrial due to defects of thymidine phosphorylase. J Biol Chem 2002;277:4128-4133 DNA deletion in the Pearson marrow and pancreas syndrome. Neuromusc 204. Kapellar P, Fazekas F, Offenbacher H, Stollberger R, Schmidt R, Disord 1992;2:185-195 Bergloff J, Radner H, Fazekas G, Schafhalter-Zoppoth I. Magnetic 187. Bourgeron T, Chretien D, Rotig A, Munnich A, Rustin P. Fate and resonance imageing and spectroscopy of progressive cerebral expression of the deleted mitochondrial DNA differ between human involvement in Kearns-Sayre syndrome. J Neurol Sci 1996;135:126-130 heteroplasmic skin fibroblast and Epstein-Barr virus-transformed 205. Demange P, Gia HP, Kalifa G, Sellier N. MR of Kearns-Sayre syndrome. lymphocyte cultures. J Biol Chem 1993;268:19369-19376 Am J Neuroradiol 1989;10:S91

40 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 Clinical and Molecular Review of KSS

206. Lamont PJ, Surtees R, Woodward CE, Leonard JV, Wood NW, Harding AE. 226. Kornblum C, Schroder R, Muller K, Vorgerd M, Eggers J, Bogdanow M, Clinical and laboratory findings in referrals for mitochondrial DNA analysis. Papassotiropoulos A, Fabian K, Klockgether T, Zange J. Creatine has Arch Dis Child 1998;79:22-27 no beneficial effect on skeletal muscle energy metabolism in patients 207. Reichmann H, Vogler L, Seibel P. Ragged red or ragged blue fibers. Eur with single mitochondrial DNA deletions: a placebo-controlled, Neurol 1996;36:98-102 double blind 31 PLEASE CHECK P-MRS crossover study. Eur J Neurol 208. Hayes DL, Hyberger LK, Hodge DO. Incidence of conduction system 2005;12:300-309 disease and need for permanent pacemaker in patients with Kearns- 227. Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial Sayre syndrome. PACE 2001;24(4 part II):576 of creatine monohydrate in patients with mitochondrial cytopathies. 209. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Muscle Nerve 1997;20:1502-1509 Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, 228. Tarnopolsky MA, Martin J. Creatine monohydrate increases strength in Winters SL, Gibbons RJ, Antman EM, Alpert JS, Gregoratos G, patients with neuromuscular disease. Neurology 1999;52:854-857 Hiratzka LF, Faxon DP, Jacobs AK, Fuster V, Smith SC Jr. ACC/ 229. Klopstock T, Querner V, Schmidt F, Gekeler F, Walter M, Hartard M, AHA/NASPE 2002 guideline update for implantation of cardiac Henning M, Gasser T, Pongratz D, Straube A, Dieterich M, Muller-Felber W. pacemakers and antiarrhythmia devices: summary article. A report A placebo-controlled crossover trial of creatine in mitochondrial diseases. of the American College of Cardiology/American Heart Association Neurology 2000;55:1748-1751 Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to 230. Komura K, Hobbiebrunken E, Wilichowski EK, Hanefeld FA. Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145- Effectiveness of creatine monohydrate in mitochondrial 2161 encephalomyopathies. Pediatr Neurol 2003;28:53-58 210. Morgan PG, Hoppel CL, Sedensky MM. Mitochondrial defects and 231. Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwang JQ, Guy J, Schon EA. Rescue anaesthetic sensitivity. Anesthesiology 2002;96:1268-1270 of a deficiency in ATP synthesis by transfer of MTA TP6, a mitochondrial 211. Finsterer J, Haberler C, Schmiedel J. Deterioration of Kearns-Sayre DNA-encoded gene, to the nucleus. Nat Genet 2002;30:394-399 syndrome following articaine administration for local anesthesia. Clin 232. Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Neuropharmacol 2005;28:148-149 Hauswirth WW, Lewin AS. Resque of a mitochondrial deficiency causing 212.Taivassalo T, De Stefano N, Argov Z, Matthews PM, Chen J, Leber Hereditary Optic Neuropathy. Ann Neurol 2002;52:534-542 Genge A, Karpati G, Arnold DL. Effects of aerobic training 233. Tanaka M, Borgeld HJ, Zhang J, Muramatsu S, Gong JS, Yoneda M, in patients with mitochondrial myopathies. Neurology Maruyama W, Naoi M, Ibi T, Sahashi K, Shamoto M, Fuku N, Kurata M, 1998;50:1055-1060 Yamada Y, Nishizawa K, Akao Y, Ohishi N, Miyabayashi S, Umemoto H, 213. Santra S, Gilkerson RW, Davidson M, Schon EA. Ketogenic treatment Muramatsu T, Furukawa K, Kikuchi A, Nakano I, Ozawa K, Yagi K. Gene reduces deleted mitochondrial DNAs in cultured human cells. Ann therapy for mitochondrial disease by delivering restriction endonuclease Neurol 2004;56:662-669 SmaI into mitochondria. J Biomed Sci 2002;9:534-541 234. Seibel P, Trappe J, Villani G, Klopstock T, Papa S, Reichmann H. 214. Shoubridge EA, Johns T, Karpati G. Complete restoration of a wild- Transfection of mitochondria: strategy towards gene therapy of type mtDNA genotype in regenerating muscle fibres in a patient with a mitochondrial DNA diseases. Nucleic Acids Res 1995;23:10-17 tRNA point mutation and mitochondrial encephalomyopathy. Hum Mol 235. Mahata B, Bhattacharyya SN, Mukherjee S, Adhya S. Correction Genet 1997;6:2239-2242 of translational defects in patient-derived mutant mitochondria 215. Clark KM, Bindoff LA, Lightowlers RN, Andrews RM, Griffiths PG, by complex-mediated import of a cytoplasmic tRNA. J Biol Chem Johnson MA, Brierley EJ, Turnbull DM. Reversal of a mitochondrial DNA 2005;280:5141-5144 defect in human skeletal muscle. Nat Genet 1997;16:222-224 236. Srivastava S, Moraes CT. Manipulating mitochondrial DNA heteroplasmy 216. Shoffner JM, Wallace DC. Oxydative phosphorylation diseases and by a mitochondrial targeted endonuclease. Hum Mol Genet mitochondrial DNA mutations: diagnosis and treatment. Annu Rev Nutr 2001;10:3093-3099 1994;14:535-568 237. Taylor RW, Wardell TM, Connolly BA, Turnbull DM, Lightowlers RN. 217. Ogasahara S, Yorifuji S, Nishikawa Y, Takahashi M, Wada K, Hazama T, Linked oligodeoxynucleotides show binding cooperativity and can Nakamura Y, Hashimoto S, Kono N, Tarui S. Improvement of abnormal selectively impair replication of deleted mitochondrial DNA templates. pyruvate metabolism and cardiac conduction defect with coenzyme Nucleic Acids Res 2001;29:3404-3412 Q10 in Kearns-Sayre syndrome. Neurology 1985;35:372-377 238. Irwin W, Fontaine E, Agnolucci L, Penzo D, Betto R, Bortolotto 218. Berio A, Piazzi A. Improvement of Kearns-Sayre syndrome with S, PLEASE FILL FULL NAMES et al. Bupivacaine myotoxicity is controlled carbohydrate intake and Coenzyme Q10 therapy. mediated by mitochondria. J Biol Chem 2002;277:12221-12227 Ophthalmologica 1994;208:342-343 239. Taylor RW, Chinnery PF, Turnbull DM, Lightowlers RN. Selective 219. Nakamura Y, Takahashi M, Kitaguchi M, Yorifuji S, Nishikawa Y, Imaoka H, inhibition of mutant human mitochondrial DNA replication in vitro by Tarui S. Abnormal evoked potentials of Kearns-Sayre syndrome. Electromyogr peptide nucleic acids. Nat Genet 1997;15:212-215 Clin Neurophysiol 1995;35:365-370 240. Poulton J, Deadman ME, Ramacharan S, Gardiner RM. Germ-line 220. Choi C, Sunwoo IN, Kim HS, Kim DI. Transient improvement of pyruvate deletions of mtDNA in mitochondrial myopathy. Am J Hum Genet metabolism after coenzyme Q therapy in Kearns-Sayre syndrome: MRS 1991;48:649-653 study. Yonsei Med J 2000;41:676-679 241. Bernes SM, Bacino C, Prezant TR, Pearson MA, Wood TS, Fournier P, 221. Ogasahara S, Nishikawa Y, Yorifuji S, Soga F, Nakamura Y, Takahashi M, Fischel-Ghodsian N. Identical mitochondrial DNA deletion in mother Hashimoto S, Kono N, Tarui S. Treatment of Kearns-Sayre syndrome with progressive external ophthalmoplegia and son with Pearson with coenzyme Q10. Neurology 1986;36:45-53 marrow-pancreas syndrome. J Pediatr 1993;123:598-602 222. Bresolin N, Bet L, Binda A, Moggio M, Comi G, Nador F, Ferrante C, Carenzi A, 242. Shanske S, Tang Y, Hirano M, Nishigaki Y, Tanji K, Bonilla E, Sue C, Krishna S, Scarlato G. Clinical and biochemical correlations in mitochondrial myopathies Carlo JR, Willner J, Schon EA, DiMauro S. Identical mitochondrial DNA deletion treated with coenzyme Q10. Neurology 1988;38:892-899 in a woman with ocular myopathy and in her son with Pearson syndrome. Am 223. Peterson PL. The treatment of mitochondrial myopathies and J Hum Genet 2002;71:679-683 encephalomyopathies. Biochim Biophys Acta 1995;1271:275-280 243. Larsson NG, Eiken HG, Boman H, Holme E, Oldfors A, Tulinius MH. Lack 224. Matthews PM, Ford B, Dandurand RJ, Eidelman DH, O’Connor D, of transmission of deleted mtDNA from a woman with Kearns-Sayre Sherwin A, Karpati G, Andermann F, Arnold DL. Coenzyme Q10 with syndrome to her child. Am J Hum Genet 1992;50:360-363 multiple vitamins is generally ineffective in treatment of mitochondrial 244. Marchington DR, Macaulay V, Hartshorne GM, Barlow D, Poulton J. disease. Neurology 1993;43:884-890 Evidence from human oocytes for a genetic bottleneck in an mtDNA 225. Artuch R, Pavia C, Playan A, Vilaseca MA, Colomer J, Valls C, Rissech M, disease. Am J Hum Genet 1998;63:769-775 Gonzalez MA, Pou A, Briones P, Montoya J, Pineda M. Multiple endocrine 245. Graff C, Wredenberg A, Silva JP, Bui TH, Borg K, Larsson NG. Complex involvement in two pediatric patients with Kearns-Sayre syndrome. genetic counseling and prenatal analysis in a woman with external Horm Res 1998;50:99-104 ophthalmoplegia and deleted mtDNA. Prenat Diagn 2000;20:426-431

Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006 41 Clinical and Molecular Review of KSS

246. Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, 255. Matthews PM, Hopkin J, Brown RM, Stephenson JB, Hilton-Jones D, Carrara F, Lombes A, Laforet P, Oqier H, Jaksch M, Lochmuller H, Brown GK. Comparison of the relative levels of 3243 (A→G) mtDNA Horvath R, Deschauer M, Thorburn DR, Bindoff LA, Poulton J, Taylor mutation in heteroplasmic adult and fetal tissues. J Med Genet RW, Matthiews JNS, Turnbull DM. Risk of developing a mitochondrial 1994;31:41-44 DNA deletion disorder. Lancet 2004;364:592-596 256. Blok RB, Gook DA, Thorburn DL, Dahl H-HM. Skewed segregation of the 247. Chinnery PF. Inheritance of mitochondrial disorders. Mitochondrion mtDNA nt 8993 (T→G) mutation in human oocytes. Am J Hum Genet 2002;2:149-155 1997;60:1495-1501 248. Barritt JA, Brenner CA, Cohen J, Matt DW. Mitochondrial DNA rearrangements in human oocytes and embryos. Mol Hum Reprod 257. Thorburn DR, Dahl H-HM. Mitochondrial disorders: genetics, 1999;10:927-933 counseling, prenatal diagnosis and reproductive options. Am J Med 249. Brenner CA, Wolny YM, Barritt JA, Matt DW, Munne S, Cohen J. Genet 2001;106:102-114 Mitochondrial DNA deletion in human oocytes and embryos. Mol Hum 258. Ikebe S-I, Tanaka M, Ohno K, Sato W, Hattori K, Kondo T, Mizuno Y, Ozawa T. Reprod 1998;4:887-892 Increase of deleted mitochondrial DNA in the striatum in Parkinson’s disease 250. Hauswirth WW, Laipis PJ. Rapid segregation of heteroplasmic bovine and senescence. Bioch Biophys Res Comm 1990;170:1044-1048 mitochondria. Nucleic Acids Res 1989; 17:7325-7331 259. Shoffner JM, Watts RL, Juncos JL, Torroni A, Wallace DC. Mitochondrial 251. Poulton J, Macaulay V, Marchington DR. Is the bottleneck cracked? Am oxidative phosphorylation defects in Parkinson’s disease. Ann Neurol J Hum Genet 1998;62:752-757 1991;30:332-339 252. Chinnery PF, Thorburn DR, Samuels DC, White SL, Dahl H-HM, Turnbull DM, 260. Shoffner JM, Brown MD, Torroni A, Lott MT, Cabell MF, Mirra SS, Beal Lightowlers RN, Howell N. The inheritance of mitochondrial DNA heteroplasmy: MF, Yang CC, Gearing M, Salvo R, PLEASE FILL FULL NAMES et random drift, selection or both? Trends Genet 2000;16:500-505 253. Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. Genetic al. Mitochondrial DNA variants observed in Alzheimer disease and counseling and prenatal diagnosis for mtDNA disease. Am J Hum Genet Parkinson disease patients. Genomics 1993;17:171-184 1998;63:1908-1910 261. Cavelier L, Jazin EE, Eriksson I, Prince J, Bave U, Oreland L, 254. Harding AE, Holt IJ, Sweeney MG, Brockington M, Davis MB. Prenatal Gyllensten U. Decreased cytochrome-c oxidase activity and lack of diagnosis of mitochondrial DNA89938993 T→G PLEASE CHECK disease. age-related accumulation of mitochondrial DNA deletions in the brains Am J Hum Genet 1992;50:629-633 of schizophrenics. Genimics 1995;29:217-224

42 Pediatric Endocrinology Reviews (PER) n Volume 4 n No. 2 n December 2006