Diagnosis of Mitochondrial Diseases: Clinical and Histological Study of Sixty Patients with Ragged Red Fibers

Home , Mitochondrial disease, Mitochondrial myopathy, Pearson syndrome

Original Article

Diagnosis of mitochondrial diseases: Clinical and histological study of sixty patients with ragged red fibers

Sundaram Challa, Meena A. Kanikannan*, Murthy M. K. Jagarlapudi**, Venkateswar R. Bhoompally***, Mohandas Surath*** Departmetns of Pathology and *Neurology, Nizam’s Institute of Medical Sciences, Hyderabad. **Institute of Neurological Sciences, Care Hospital, ***L.V. Prasad Eye Institute, Hyderabad, India.

Background: Mitochondrial diseases are caused by muta- group of patients. tions in mitochondrial or nuclear genes, or both and most Key Words: Mitochondrial disease, Ragged-red fiber, Pro- patients do not present with easily recognizable disorders. gressive external ophthalmoplegia, Kearns-Sayre syndrome, The characteristic morphologic change in muscle biopsy, Myoclonus epilepsy with ragged-red fibers, Heart block. ragged-red fibers (RRFs) provides an important clue to the diagnosis. Materials and Methods: Demographic data, presenting symptoms, neurological features, and investigative findings in 60 patients with ragged-red fibers (RRFs) on muscle biopsy, seen between January 1990 and December Introduction 2002, were analyzed. The authors applied the modified respiratory chain (RC) diagnostic criteria retrospectively to de- Mitochondrial diseases with ragged-red muscle fibers (RRF) termine the number of cases fulfilling the diagnostic criteria as well as some without RRF, are caused by mutations in mi- of mitochondrial disease. Results: The most common clini- tochondrial or nuclear genes, or both, which are normally in- cal syndrome associated with RRFs on muscle biopsy was volved in the formation and maintenance of a functionally in- progressive external ophthalmoplegia (PEO) with or with- tact oxidative phosphorylation system in the mitochondrial out other signs, in 38 (63%) patients. Twenty-six patients inner membrane.1 These disorders present, with bewildering (43%) had only external ophthalmoplegia, 5 (8%) patients array of clinical presentations and are usually dominated by presented with encephalomyopathy. Specific syndromes the involvement of the nervous system and the skeletal mus- were the presenting feature in 8 (13%), Kearns-Sayre syn- cle (hence the term “mitochondrial encephalomyopathies”). drome (KSS) in 4 and myoclonus epilepsy with ragged-red In most cases, myopathy is associated with a cluster of cen- fibers (MERRF) in 4. Myopathy was the presenting feature tral nervous system (CNS) symptoms, suggesting one of the in 5 (8%) and 4 presented with infantile myopathy. Of the 60 well-defined mitochondrial encephalomyopathies. However, the patients, 18 (30%) had proximal muscle weakness. Two encephalomyopathies may be less specific, consisting of one patients with KSS and one patient with myopathy had com- 2- plete heart block necessitating pace making. When the modi- of the CNS symptoms typical of mitochondrial dysfunction. 15 fied RC diagnostic criteria were applied, only 26 (43%) pa- Most of the recent proposed criteria for the diagnosis of tients had one other major criterion in addition to RRFs for mitochondrial diseases include biochemical and molecular ge- 16,17 the diagnosis of mitochondrial diseases. The remaining 34 netic testing. Often these tests are expensive and may not (57%) patients with RRFs on muscle biopsy had only some be available in most medical centers in the developing world. clinical features suggestive of RC disorder but did not fulfill However mitochondrial diseases associated with RRFs can the clinical criteria (of the modified diagnostic criteria) for be diagnosed on muscle biopsy. RRFs are characterized by the diagnosis of mitochondrial diseases. Conclusion: In large proliferations of subsarcolemmal mitochondria and re- patients with clinical features suggestive of RC disorder, placement of some of the contractile elements with demonstration of RRFs on muscle biopsy helps in confirm- intermyofibrillar accumulations of mitochondria. These ap- ing the diagnosis of mitochondrial disease in only a sub- pear red as detected by Gomori-Trichrome staining and can

C. Sundaram Professor of Pathology, Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad - 500 82, India. E-mail: [email protected]

Neurology India September 2004 Vol 52 Issue 3 353

CMYK 353 Challa S, et al: Mitochondrial Diseases also be seen using a stain for succinate dehydrogenase. They Table 1b: Minor diagnostic criteria 18 have a moth-eaten appearance. They may be isolated, infre- Clinical quent or numerous and may involve type 1 fibers often.19 Only Symptoms compatible with a RC defect a few small case series have been reported from India and all Histology 20,21,22 1% - 2% ragged-red fibers if aged 30 – 50 years the case series were based on muscle biopsy. This paper Any ragged-red fibers if < 30 years of age presents the clinical data of 60 patients with RRFs on muscle > 2% subsarcolemmal mitochondrial accumulations in a patient biopsy and discusses the diagnosis of mitochondrial diseases. < 16 years of age Widespread electron microscopic abnormalities in any tissue Enzymology Materials and Methods Antibody based demonstration of a defect in RC complex expression Case files of patients with RRF on muscle biopsy seen between 20% - 30% activity of any RC complex in a tissue 30% - 40% activity of any RC complex in a cell line January 1990 and December 2002 were retrieved from the neuropa- 30% - 40% activity of the same RC complex activity in more thology files, Department of Pathology, of our center. The clinical than two tissues data noted included age, gender, family history, presenting symp- Functional toms and neurological features. Investigative findings included se- Fibroblast ATP synthesis rates 2 – 3 SD below mean rum creatine phosphokinase (CK), electromyoneurographic (EMNG) Fibroblasts unable to grow on media with glucose replaced by findings, and CT and/or MRI features. One patient had muscle analy- galactose sis for mitochondrial respiratory chain studies. None of the patients Molecular Identification of nuclear or mtDNA mutation of probable had molecular genetic testing. The diagnostic criteria applied for the pathogenicity diagnosis of mitochondrial diseases were those proposed by Bernie Metabolic et al17 (Table 1a & b). For categorizing patients into various clinical One or more metabolic indicators of impaired RC function 1 syndromes, the classification proposed by Nordin and Johns, 2001 *Diagnostic criteria proposed by Bernier et al (2002) was adopted. Muscle biopsy was done by open biopsy from left vastus lateralis in also done on cryo-sections. Electron microscopic studies could not be all patients. The biopsy was divided into three parts: one part was done due to its unavailability at our center. snap frozen in isopentane precooled in liquid nitrogen for cryo-sections; one part was fixed in 3% cacodylate buffered glutaraldehyde Results for election microscopy; and one part was fixed in 10% buffered for- malin for routine paraffin embedding sections. Cryo-sections were stained with haematoxyclin and eosin, modified Gomori trichrome Clinical Features stain (MGT), Masson’s trichrome stain, oil red O, periodic acid Schiff The mean age at the time of diagnosis was 29.3 years (range with and without diastase. Enzyme histochemistry with adenosine 1 – 71 years) and there were 35 males and 25 females. The triphosphatase (ATP) at pH 9.4, 4.6 and 4.3, succinic dehydroge- mean age at the onset of the disease was 19.7 years (range: nase (SDH) and NADH-Tetrazolium reductase (NADH-TR) were birth to 59.7 yrs) and the age of the onset in each diagnostic criteria is given in table 1. The disease had a progressive course Table 1a: Proposed major diagnostic criteria for mitochondrial in all the patients. The mean delay between the onset of the * disease diagnosis disease and the diagnosis was 6.7 years (range 2 months to I. Clinical: Clinically complete mitochondrial encephalomyopathy or 30 yrs). Based on the clinical features, patients could be mitochondrial cytopaty defined as fulfilling all three of the following 1 conditions grouped into one of the clinical syndromes proposed. (a) Unexplained combination of multisystemic symptoms that is (Table 2). The most common clinical syndrome associated with essentially pathognomonic for a respiratory chain (RC) RRFs on muscle biopsy was progressive external ophthalmo- disorder (b) Symptoms must include at least three of the organ system plegia (PEO) with or without other signs in 38 (63%) pa- presentations, namely neurologic, muscular, cardiac, renal, tients. Twenty-six patients (43%) had only external ophthal- nutritional, hepatic, endocrine, hematological, otologic, moplegia and 6 had oculopharyngeal weakness. Six patients ophthalmologic, dermatologic or dysmorphic. (c) A progressive clinical course with episodes of with PEO had associated myoclonus. Five (8%) patients pre- exacerbations OR a family history that is strongly indicative sented with cerebellar ataxia, 3 had associated myopathy and

of mtDNA mutation (at least one maternal relative other than 2 had diffuse muscle wasting. Specific syndromes were the the probands whose presentation predicts a probable or presenting feature in 8 (13%), Kearns-Sayre syndrome (KSS) definite RC disorder) (d) Exclusion of other metabolic or non-metabolic disorders in 4 and myoclonus epilepsy with ragged-red fibers (MERRF) Histology in 4. Myopathy was the presenting feature in 5 (8%) and 4 (a) > 2% ragged-red fibers in skeletal muscle presented with infantile myopathy. Of the 60 patients, 18 Enzymology (a) 2% COX-negative fibers if < 50 years of age (30%) had proximal muscle weakness and 4 had clinical and/ (b) 5% COX-negative fibers if > 50 years of age or electrophysiological evidence of neuropathy. Retinitis (c) < 20% activity of any RC complex in a tissue pigmentosa was noted in 8 patients including 4 patients with (d) < 30% activity of any RC complex activity in a cell line (e) < 30% activity of the same RC complex activity in more KSS. than two tissues Associated systemic involvement was noted in 5 patients,

354 Neurology India September 2004 Vol 52 Issue 3 354 CMYK Challa S, et al: Mitochondrial Diseases

Table 2: Mitochondrial diseases – Syndromes with neuromuscular manifestations Clinical syndrome n (%) Mean age at@ (n = 60) onset presentation (in years) Progressive external opthalmoplegia 26 (43) 21.3 24.1 Progressive external opthalmoplegia plus 12 (20) 23.3 34.0 Oculopharyngeal 6 Myopathy 5 Myoneuropathy 1 Myopathy* 5 (8) 35.8 40.0 Infantile myopathy 4 (7) 0.7 2.7 Kearns-Sayre syndrome 4 (7) 10.5 21.5 Myoclonic epilepsy with ragged-red fiber 4 (7) 23.3 28.0 Encephalomyopathy 5 (8) 36.7 39.8 Cerebellar ataxia with myopathy 3 Cerebellar ataxia with muscle atrophy 2 ** One patient with myopathy* and two patients with Kearns-Sayre syndrome had complete heart block @ Age at onset and presentation of clinical syndrome with ragged-red fibers diabetes mellitus in 2 and cardiac involvement in 3. Electro- in 4 (all of them had features of cerebellar ataxia), bilateral cardiogram was done in 35 patients, complete heart block was basal ganglionic calcification in 1, and cortical atrophy was the specific abnormality in 3 patients. Of the 4 patients with noted in 2. KSS, 2 had complete heart block. One of the patients with myopathy had cardiomyopathy and complete heart block. He Pathological Features presented with recurrent syncope. All three required perma- The diagnosis of mitochondrial disease was based on the pres- nent pacing. 2D Echo was done in 5 patients with myopathy, ence of characteristic ragged-red fibers (RRF) in > 2% of 4 patients with KSS, and 4 children with infantile myopathy. muscle fibers in the muscle biopsy.16,17,23,24 All muscle biopsies Positive family history was noted in 3 probands. In one fam- showed subsarcoplasmic red deposits and ragged sarcoplasm ily, father and one of the sons were affected and in the other 2 on MGT stain though the number of fibers showing RRF var- families, one of the brothers and sisters were affected. ied significantly (Figure 1) and also an increase in the intensity of staining for oxidative enzymes on SDH and NADH (Fig- Laboratory Data ure 2, 3). Type grouping suggestive of reinnervation was seen Of the 35 patients in whom serum CK values were avail- in 5 (8.3%) biopsies. ATP staining showed type-1 dominance able, moderately elevated levels were noted in 5 (300 – 700 and type-2 atrophy in 5 each. One patient showed type-1 domi- IU/l) and all of them had clinical evidence of significant proxi- nance and type-2 atrophy. Significant neutral lipid accumula- mal muscle weakness. EMNG data was available in 31 pa- tion was seen in 3 and none showed glycogen excess on PAS tients, myopathic EMG features were seen in 12 patients, one staining. Central nuclei were seen in 2 biopsies (Table 3). had features of denervation, and 4 had evidence of neuropathy. Ragged-Red Fibers – Diagnosis of Mitochondrial CT was the neuroimaging modality in all the patients with Disease encephalopathic features. Cerebellar folial atrophy was noted Of the 60 patients with RRFs on muscle biopsy, 25 (42%)

(1) (2) (3)

Figure: (1) Red-ragged fibers MGT X 40. (2) Increased oxidative enzyme activity SDH X 40. (3) Increased oxidative enzyme activity NADH – TR x 40.

Neurology India September 2004 Vol 52 Issue 3 355

CMYK 355 Challa S, et al: Mitochondrial Diseases patients fulfilled the definite criteria for the diagnosis of mi- Table 5: Mitochondrial Diseases – Specific Syndromes tochondrial disease (Table 3). This included 4 patients with Leigh disease Kearns-Sayre syndrome (KSS), 4 with myoclonus epilepsy Alpers disease with ragged-red fibers (MERRF), 5 patients with Lethal infantile mitochondrial disease Pearson’s syndrome encephalomyopathies, and 12 patients with multisystemic Kearns-Sayre syndrome symptoms that was essentially pathognomonic for respiratory Mitochondrial-encephalomyopathy, lactic acidosis, and stroke like chain (RC) disorder and a progressive clinical course and at episode (MELAS) least three of the organ system involvement (dysmorphic fea- Myolonic epilepsy with ragged-red fiber (MERRF) Neuropathy, ataxia, and retinitis pigmentosa (NARP) tures 5, diabetes mellitus 2, and cardiac involvement 1, and Mitochondrial neuro-gastro-intestinal encephlomyopathy (MNGIE) retinopathy 4). One patient had clinical features suggestive Leber’s hereditary optic neuropathy (LHON) RC disorder on histological and enzymological criteria. While 26 all the remaining 34 patients had symptoms that were essen- ported with a variety of point mutations in DNA. Cardiac tially pathognomonic for RC disorder, with one or two organ conduction blocks are more frequent in patients with KSS. system presentation, and a progressive clinical course (Table 4). Intraventricular conduction defects show an unusually rapid progression to potentially fatal complete atrioventricular block 27,28 Discussion and are an indication for prophylactic cardiac pacing. Clinical investigations only help, to some extent in catego- Mitochondrial diseases can present at any age and include a rizing the mitochondrial disorders into one of the specific combination of multisystemic symptoms. The adult criteria encephalopathic syndromes. Serum CK level may be mildly require muscle or neurologic involvement.16 The presence of elevated in mitochondrial myopathies but are often normal. PEO is very suggestive, as is the presence of CNS dysfunc- Electroneuromyographic features are not pathognomonic and tion such as ataxia, seizures, or sensorineural deafness. In mitochondrial diseases should be in the electrophysiolgic dif- most cases myopathy is present along with a cluster of CNS ferential diagnosis of a patient with myopathic EMG findings 29,30 symptoms suggesting the well-defined syndromes (Table 5).1 and reduced sural sensory response amplitudes. The retina, in particular the retinal pigment epithelium, is Neuroradiologic features suggestive of mitochondrial diseases highly vulnerable to be involved by mtDNA defect, and the include symmetric basal ganglia calcifications, brain infarcts, 31 retinopathy is phenotypically variable and frequently subclini- or cerebral and cerebellar atrophy. cal, depending to some extent on the type or site of mt DNA RRFs on muscle biopsy are observed in a wide variety of defect.25 Peripheral neuropathy is also a frequent association.1 mitochondrial diseases including mtDNA depletion, mtDNA 32 The clinical features of cardiac involvement in mitochondrial deletions, and mitochondrial transfer RNA mutations. RRFs diseases vary in the different subgroups of these disorders. are not seen in disorders due to defects of substrate trans- 32,33 Mitochondrial myopathy with cardiomyopathy has been report, substrate utilization, and the Kreb’s cycle. RRFs are not pathognomonic of mitochondrial diseases, but can also be seen in other conditions like dystrophies, dermatomyositis and Table 3: Mitochondrial Diseases – Histological findings in older individuals31 and also in zidovudine-associated my- Histological findings n (%) 34,35 Ragged-red fiber 60 (100) opathy in HIV-infected patients. However, in these dis- Type – 1 predominance 6 (10) eases, the intensity and the proportion of muscle biopsies show- Type – 2 predominance 6 (10) ing RRFs will be sparse. Presence of more than 2% RRFs in Denervation 5 (8) Lipid 3 (5) skeletal muscle biopsy is taken as one of the criteria for the diagnosis of mitochondrial disease.16,17,19,23,24 Another useful histochemical probe is the stain for Cytochrome c oxidase Table 4: Ragged-Red Fibers on muscle biopsy – Diagnosis of mitochondrial disease (COX) activity. Many studies use Cytochrome c oxidase stain- Definite mitochondrial disease 25 (42%) ing to identify negatively staining fibers. Cytochrome c oxi- (a) Clinical and histology dase identifies complex IV in the respiratory chain. Ragged- Kearns-Sayre syndrome 4 red fibers are often COX-negative. Although COX staining Myoclonic epilepsy with ragged-red fiber 4 Encephalomyopthy 5 may be diffusely abnormal in primary COX deficiencies, most Symptoms with at least three of the organ 12 mitochondrial myopathies show segmental loss of COX stain- system presentation ing in individual muscle fibers.1 In our study we have not used (b) Histological and enzyme studies 1 (1%) Progressive external ophthalmoplegia plus 1 this stain. Unfortunately, most patients with mitochondrial diseases do not show any of the above characteristic muscle Probable or possible mitochondrial disease 34 (57%) changes. Enzymology and molecular genetic studies are often (a) Histological and symptoms with two organ 8 required to establish a definite diagnosis of mitochondrial dis- system presentation 17 (b) Histological and symptoms with one organ 26 eases (Table 1a & b). system presentation Mammalian mtDNA is thought to be strictly maternally

356 Neurology India September 2004 Vol 52 Issue 3 356 CMYK Challa S, et al: Mitochondrial Diseases inherited. In familial cases of disease caused by gene defects essential clinical criteria for the diagnosis of mitochondrial in mtDNA, inheritance is nonmendelian and passes from disease is “symptoms must include at least three of the organ mother to offspring. Families with a mendelian pattern of in- system presentations”. The relevance of such criteria can only heritance of mitochondrial gene defects have been described. be validated by genetic and enzymatic studies in patients with However, these cases appear to be attributable to defects in symptoms of one or two organ system presentation sugges- the nuclear genes that encode proteins responsible for the fi- tive of RC disorder. To determine the sensitivity, both MAC17 delity of mtDNA replication or the maintenance of mitochon- and MDC39 criteria need to be tested prospectively in large drial genomes rather than attributable to direct inheritance cohorts of patients. of defective forms of mtDNA.36 Nuclear DNA mechanisms of Our study also suggests that except for some specific mito- genetic transmission include autosomal dominant, autosomal chondrial encephalomyopathic syndromes, the clinical features recessive genetic imprinting and X-linked transmission. Re- are rarely pathognomonic for the diagnosis of mitochondrial cently Schwartz and Vissing (2002)37 described a patient with disorders. It will be prudent to evaluate such patients with exercise intolerance, lactic acidosis after minimal exertion, and unexplained combination of multisystem symptoms and pro- RRFs. The mitochondrial haplotype in the patient’s muscle gressive clinical course for possible mitochondrial disease. In matched that of his father. The 2 bp deletion causing disease the absence of genetic and enzymatic studies, muscle biopsy was unique to the patient, apparently representing a neq for RRFs is likely to establish the diagnosis of mitochondrial mutation arising in the paternal germ line or during embry- disease in a proportion of such patients. onic development. The family with mendelian pattern of inheritance, autosomal dominant, in this study may be due to References the defects in the nuclear genes. Several diagnostic schemes were proposed to improve the 1. Nardin RA, Johns DR. Mitrochondrial dysfunction and neuromuscular disease. Muscle Nerve 2001;24:170-91. diagnostic sensitivity, as the clinical features are suggestive 2. Shaag A, Saada A, Steinberg A, Navon P, Elpeleg ON. Mitochondrial rather than pathognomonic of mitochondrial diseases. First encephalomyopathy associated with a novel mutation in the mitochondrial tRNA (leu) (UUR) gene (A3243T). Biochem Biophys Res Commun 1997;233:637-9. consensus diagnostic criteria were proposed in 1996 (Adult 3. Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myo- Criteria, AC).16 However non-neurologic manifestations oc- clonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA (Lys) mutation. Cell 1990;61;931-7. 38 cur in over 30% of pediatric patients. A modified version to 4. Silvestri G, Ciafaloni E, Santorelli FM, Shanske S, Servidei S, Graf WD, et al. allow for diagnosis of pediatric cases has recently been sug- Clinical features associated with the A->G transition at nucleotide 8344 of m tDNA (“MERRF mutation”). Neurol 1993;43:1200-6. 17 gested (Modified Adult Criteria, MAC). Both systems in- 5. Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S. A new mtDNA muta- clude clinical, genetic, histopathological, and metabolic crite- tion in the tRNA (Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1992;51:1213-7. ria and also a scoring criterion for the results of biochemical 6. Silvestri G, Servidei S, Rana M, Ricci E. Spinazzola A, Paris E, et al. A novel studies. The latter criteria appear to improve the sensitivity mitochondrial DNA point mutation in the tRNA (Ile) gene is associated with progressive external ophthalmoplegia. Biochem Biophys Res Commun 39 of the adults. Recently Wolf and Smeitink developed a scor- 1996;220:623-7. ing system, Mitochondrial Disease Criteria (MDC). MDC al- 7. Simon LT, Horoupian DS, Dorfman LJ, Marks M, Herrick MK, Wasserstein P, et al. Polyneuropathy, ophthalmoplegia, leukoencephalopathy and intestinal lows more precise definitions of clinical and metabolic items pseudo-obstruction: POLIP syndrome. Ann Neurol 1990;28:349-60. and the independent scoring of muscle biochemical investiga- 8. Simpson MV, Chin CD, Keilbaugh SA, Lin TS, Prusoff WH. Studies on the inhibition of mitochondrial DNA replication by 3’-azido-3’ deoxythymidine and tions other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem Definite diagnosis of mitochondrial disease is defined as the Pharmacol 1989;38:1033-6. 9. Stansbie D, Wallace SJ, Marsac C. Disorders of the pyruvate dehydrogenase identification of either two major criteria or one major plus complex. J Inherit Metab Dis 1986;9:105-19. two minor criteria. A probable diagnosis is defined as either 10. Suomalainen A, Kaukonen J, Amati P, Timonen R, Haltia M, Weissenbach J, et aI. An autosomal locus predisposing to deletions of mitochondrial DNA. Nat one major plus one minor criterion or at least three minor Genet 1995;9:146-51. criteria. A possible diagnosis is defined as either a single ma- 11. Sweeney MG, Bundey S, Brockington M, Poulton KR, Winer JB, Harding AE. Mitochondrial myopathy associated with sudden death in young adults and a jor criterion or two minor criteria, one of which may be clini- novel mutation in the mitochondrial DNA leucine transfer RNA (UUR) gene. cal.17 In our study, only 43% of patients with RRFs fulfilled Q J Med 1993;86:709-13. 12. Taggart RT, Smail D, Apolito C, Vladutiu GD. Novel mutations associated with the definite criteria for the diagnosis of mitochondrial disease. carnitine palmitoyltransferase II deficiency. Hum Mutat 1999;13:210-20. The remaining 34 (57%) patients had histological criteria and 13. Taivassalo T, De Stefano N, Argov Z, Matthews PM, Chen J, Genge A, et al. Effects of aerobic training in patients with mitochondrial myopathies. Neurol two of the three clinical criteria for the diagnosis of mitochon- 1998;50:1055-60. drial diseases and thus they were probable or possible cases of 14. Takeda K, Kawai M, Sakuta M, Takemura T. Paralytic ileus and atonic bladder in a case of mitochondrial encephalomyopathy – electrophysiological, chemical mitochondrial disease. However, it is important to keep in mind and pathological study with evidence of the peripheral nerve involvement. Rinsho that the application of these criteria is based on a detailed Shinkeigaku 1989;29:643-46. 15. Tanaka M, Ino H, Ohno K, Hattori K, Sato W, Ozawa T, et al. Mitochondrial understanding of complex clinical and laboratory information. mutation in fatal infantile cardiomyopathy. Lancet 1990;336:1452. Most patients do not present with easily recognizable disor- 16. Walker UA, Collins S, Byrne E. Respiratory chain encephalopathies: A diagnostic classification. Eur Neurol 1996;36:260-7. ders. Symptoms can be difficult to assimilate into a unifying 17. Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diag- diagnosis as in the case of pediatric patients.17 One of the nostic criteria for respiratory chain disorders in adults and children. Neurol

Neurology India September 2004 Vol 52 Issue 3 357

CMYK 357 Challa S, et al: Mitochondrial Diseases

2002;59:1406-11. involvement in autosomal dominant progressive external ophthalmoplegia with 18. Moraes CT, Ricci E, Petruzzella V, Shanske S, DiMauro S, Schon EA, et al. hypogonadism. Muscle Nerve 1996;19:751-7. Moleular analysis of the muscle pathology associated with mitochondrial DNA 30. Torbergsen T, Stalberg E, Bless JK. Nerve-Muscle involvement in a large fam- deletions. Nat Genet 1992;1:359-67. ily with mitochondrial cytopathy: electrophysiological studies. Muscle Nerve nd 19. Dubowitz:Muscle Biopsy. A practical approach, 2 Ed. Bailliere Tindall 1985. 1991;14:35-41. p. 504-59. 31. Jackson MJ, Schaefer JA, Johnson MA, Morris AA, Turnbull DM, Bindoff 20. Acharya JN, Satishchandra P, Shankar SK. Familial progressive myoclonus epi- LA. Presentation and clinical investigation of mitochondrial respiratory chain lepsy: Clinical and electrophysiologic observations. Epilepsia 1995;36:429-34. disease. A study of 51 patients. Brain 1995;118:339-57. 21. Radhakrishnana VV, Saraswathy A, Radhakrishnan K, et al. Mitrochondrial 32. DiMauro S, Lombes A, Nakase H, Mita S, Fabrizi GM, Tritschler HJ, et al. myopathies: A clinicopathological study. Neurosciences Today 2000;4:145-7. Cytochrome C Oxidase deficiency Pediatr Res 1990;28:536-41. 22. Mehndiratta MM, Agarwal P, Tatke M, Krishnamurthy M. Neurological mito- 33. DiMauro S, Bonilla E, Davidson M, Hirano M, Schon EA, Mitochondria in chondrial cytopathies. Neurol India 2002;50:162-7. neuromuscular disorders Biochim Biophys Acta 1998;1366:199-210. 23. Rifai Z, Welle S, Kamp C, Thornton CA. Ragged red fibers in normal aging 34. Arnaudo E, Dalakas M, Shanske S Moraes CT, DiMauro S, Schon EA, Deple- and inflammatory myopathy. Ann Neurol 1995;37:24-9. tion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced 24. Sengers RC, Stadhouders AM. Secondary mitochondrial pathology. J Inherit myopathy. Lancet 1991;337:508-10. 35. Dalakas MC, Illa I Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mito- Metab Dis 1987;10(Suppl 1):98-104. chondrial myopathy caused by long-term zidovudine therapy. M Engl J Med 25. Isashiki Y, Nakagawa M, Ohba N, Kamimura K, Sakoda Y, Higuchi I, et al. 1990;322:1098-105. Retinal manifestations in mitochondrial diseases associated with mitochondrial 36. Zeviani M, Servidie S, Gellera C, Bertini E, DiMauro S, DiDonato S. An auto- DNA mutation. Acta Ophthalmol Scand 1998:76:6-13. somal dominant disorder with multiple deletions of mitochondrial DNA start- 26. Anan R, Nakagawa M, Miyata M, Higuchi I, Nakao S, Suehara M, et al. Car- ing at the D loop region. Nature 1989;339:309-11. diac involvement in mitochondrial diseases. A study on 17 patients with docu- 37. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J mented mitochondrial DNA defects. Circulation 1995;91:955-61. Med 2002;347:576-80. 27. Charles R, Holt S, Kay JM, Epstein EJ, Rees JR. Myocardial ultrastructure 38. Munnich A, Rotig A, Chretien D, Cormier V, Bourgeron T, Bonnefont JP, et al. and the development of atrioventricular block in Kearns-Sayre syndrome. Cir- Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab culation 1981;63:214-9. Dis 1996;19:521-7. 28. Kakura H, Tachibana Y, Nakamura K, Tanaka Y, Sanada J, Arima T. Mito- 39. Wolf NI, Smeitink JA. Mitochondrial disorders: A proposal for consensus diag- chondrial encephalomyopathy (Kearns-Sayre syndrome) with complete atriov- nostic criteria in infants and children. Neurol 2002;59:1402-5. entricular block: A case report. Jpn Circ J 1998;62:623-5. 29. Melberg A, Lundberg PO, Henriksson KG, Olsson Y, Stalberg E. Muscle-nerve Accepted on 28.12.2003.

358 Neurology India September 2004 Vol 52 Issue 3 358 CMYK