Arch Dis Child 1999;81:209–215 209 Multiple presentation of mitochondrial disorders Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from

Andreea Nissenkorn, Avraham Zeharia, Dorit Lev, Aviva Fatal-Valevski, Varda Barash, Alisa Gutman, Shaul Harel, Tally Lerman-Sagie

Abstract The most severely aVected organs in mito- The aim of this study was to assess the chondrial disorders are those depending on heterogeneous clinical presentations of high rate aerobic metabolism—for example, children with mitochondrial disorders the brain, skeletal and cardiac muscle, the sen- evaluated at a metabolic neurogenetic sory organs, and the kidney.125 We aimed to clinic. The charts of 36 children with describe the great variety of symptomatology in highly suspected mitochondrial disorders patients with mitochondrial disorders in Israel, were reviewed. Thirty one children were and to compare this with the common clinical diagnosed as having a mitochondrial dis- presentations in other countries. order, based on a suggestive clinical pres- entation and at least one of the accepted Patients and methods laboratory criteria; however, in five chil- Thirty six consecutive patients (20 boys and 16 dren with no laboratory criteria the diag- girls) were evaluated at the paediatric neurol- nosis remained probable. All of the ogy clinic, Dana Children’s Hospital from patients had nervous system involvement. August 1994 to August 1996 and at the meta- Twenty seven patients also had dysfunc- bolic neurogenetic clinic, Wolfson Medical tion of other systems: sensory organs in 15 Center from September 1996 to June 1998 for patients, cardiovascular system in five, suspected mitochondrial disorders. Table 1 gastrointestinal system in 20, urinary sys- summarises the demographic characteristics of tem in four, haematopoietic system in the study group. four, and endocrine system in nine. The The diagnosis of a mitochondrial disorder clinical presentation was compatible with was based on accepted clinical presentations an established syndrome in only 15 chil- and at least one of the following: (1) deficiency dren. Severe lactic acidosis or ragged red of respiratory chain enzymes or pyruvate utili- muscle fibres were encountered in very sation enzymes in muscle or fibroblasts; (2) few patients. These results suggest that evidence of mutations or deletions in mt-DNA; Pediatric Neurology mitochondrial disorders should be evalu- (3) characteristic changes, such as ragged red Unit and Metabolism muscle fibres on trichrome Gomori stain, or http://adc.bmj.com/ Clinic, Wolfson ated in children presenting with a complex neurological picture or multisystem in- decreased succinate dehydrogenase or cyto- Medical Center, chrome C oxidase staining in muscle biopsy; Holon, Israel 58100 volvement. (4) evidence of abundant abnormal ultrastruc- A Nissenkorn (Arch Dis Child 1999;81:209–215) D Lev ture of mitochondria; (5) excretion of abnor- T Lerman-Sagie Keywords: mitochondrial disorders; mitochondrial mal organic acids in urine characteristic of a DNA; respiratory chain; pyruvate dehydrogenase known mitochondrial syndrome (for example, Department of 3-methyl glutaconic acid); (6) a family member Pediatrics C, with a proven mitochondrial disease. on September 26, 2021 by guest. Protected copyright. Schneider Children’s Mitochondrial disorders, once thought to be Hospital, Beilinson The respiratory chain enzymes and/or the Campus, Petah Tikva, relatively rare, are now thought to be the most PDH complex were assessed in 24 children (20 1 Israel prevalent metabolic disease. They form a het- in muscle biopsy, three in fibroblasts alone, and A Zeharia erogeneous group of diseases with multisystem one in both fibroblasts and liver biopsy). Mus- presentations that aVect mitochondrial ATP cle homogenates were prepared according to Child Development production.2–5 The defect in energy production Birch-Machin and colleagues11 and electron Center and Pediatric Neurology Unit, Dana may be caused by abnormalities in substrate transport activities were measured 12 13 Children’s Hospital, transport or use (such as pyruvate dehydroge- spectrophotometrically. Citrate synthase, Tel-Aviv, Israel nase complex deficiency), Krebs cycle, oxida- PDH complex activity,14 and protein content15 A Fatal-Valevski tive phosphorylation, and defects of inter- were assayed. S Harel genomic signalling.46 Most of these enzymes We assessed mt-DNA for mutations or are encoded by nuclear genes, and are therefore deletions according to the clinical presentation Department of Clinical 16 Biochemistry, transmitted by Mendelian inheritance, usually in 16 patients. Total DNA extraction Hadassah University autosomal recessive.478 Pyruvate dehydroge- Hospital, Jerusalem, nase (PDH) E1á deficiency is X-linked and Table 1 Demographic characteristics of the study group Israel recently an autosomal dominant defect of Present age (years) 8.2 (range, 0.6–22) V Barash 46 A Gutman intergenomic signalling has been described. Age at presentation (years) 2.5 (range, 0–14) Thirteen polypeptides of the respiratory chain Age at diagnosis (years) 5.2 (range, 0.3–16) Patients who died 3 of 36 Correspondence to: as well as all 22 mitochondrial tRNAs are Consanguineous families 5 of 28 Dr Lerman-Sagie. encoded by mitochondrial DNA (mt-DNA) Ethnic background: Jewish/Arab 33/3 email: [email protected] and, therefore, defects in their genes are trans- Sex ratio: male/female 20/16 Families with several members aVected 9 Accepted 18 May 1999 mitted by maternal inheritance.4 7–10 210 Nissenkorn, Zeharia, Lev, Fatal-Valevski,Barash, Gutman, et al Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from Table 2 Diagnostic criteria in the 31 patients with proved mitochondrial disorders

Abnormal Suggestive Clinical OXPHOS/PDH Mt-DNA Muscle electron organic Patient syndrome deficiency mutation histopathology microscopy aciduria AZicted sibling 1 Leigh Complex V T8993G 2 Leigh PDH E1 3 Leigh Generalised 4 Leigh Complex I 3-MGA 5 NARP T8993G Patient 6 6 NARP T8993G Patient 5 7 MiMyCa Complex I RRF Yes 8 MiMyCa RRF 9 Barth 3-MGA 10 LHON 3460 11 E3 deficiency PDH E3 12 E3 deficiency PDH E3 13 CosteV 3-MGA 14 CosteV 3-MGA Patient 15 15 CosteV 3-MGA Patient 16 16 Anaemia + myopathy Complex I + IV Yes 17 IPO + NB Complex IV No COX Patients 18,19 staining 18 IPO+NB Patients 17,19 19 IPO+NB Patients 17,18 20 Encephalopathy Complex I 21 Encephalopathy Complex I 22 Encephalopathy Complex I Patient 23 23 Encephalopathy Patient 22 24 Encephalopathy Complex I 25 Encephalopathy Complex I + III + IV Yes 26 Encephalopathy Complex I 27 Encephalopathy Complex I 28 Encephalopathy Complex I Yes 29 Encephalopathy Complex II 3-MGA 30 Encephalopathy Complex I 31 Encephalopathy PDH E1 + generalised

Generalised refers to a generalised deficiency of all respiratory chain enzymes. COX, cytochrome C oxidase (complex IV); IPO + NB, intestinal pseudo-obstruction and neurogenic bladder; LHON, Leber’s hereditary optic neuropathy; 3-MGA, 3-methylglutaconic aciduria; MiMyCa, maternally inherited myopathy and cardiomyopathy; Mt-DNA, mitochondrial DNA; NARP, neuropathy, ataxia, retinitis pigmentosa; PDH, pyruvate dehydrogenase; OXPHOS, oxida- tive phosphorylation or respiratory chain enzymes; RRF, ragged red muscle fibres.

from muscle, mt-DNA probes, and Southern and cardiomyopathy), whereas absent staining blot analysis were performed.17 18 We per- of a rectal biopsy for complex IV was found in formed the polymerase chain reaction using a girl with complex IV deficiency and gastro- mt-DNA primers.19 We analysed the currently intestinal dysmotility. Abundant ultrastructur- known point mutations causing MELAS ally abnormal mitochondria were present in

(mitochondrial encephalopathy, lactic acidosis, four of six children. 3-Methylglutaconic http://adc.bmj.com/ and stroke-like episodes), NARP (neuropathy, aciduria was found in six children: one patient ataxia, and retinitis pigmentosa), MERRF with Barth syndrome, three with CosteV (myoclonic epilepsy and ragged red muscle fibres), LHON (Leber’s hereditary optic neu- 12 ropathy), cardiomyopathy, and deafness.20 Polymerase chain reaction products were gel 10 purified and sequenced directly using the 10 deoxy terminator on Applied Biosystem Model on September 26, 2021 by guest. Protected copyright. 373 DNA sequencing system.21 We evaluated muscle histopathology in 22 8 patients. Six children also had electron micros- copy studies. We evaluated blood lactate, pyru- vate, and amino acids and urinary organic acids 6 in most children.

4 4 Results Number of patients A firm diagnosis of a mitochondrial disorder 3 was made in 31 children, based on the criteria 2 mentioned previously (table 2). 2 Deficiencies in the respiratory chain en- 1 1 1 1 1 zymes and/or PDH were found in 20 of 24 children, half of them with complex I defi- 0 E3 ciency (fig 1). Mutations in mt-DNA were PDH present in four of 16 patients: three with the Complex I T8993G mutation (two siblings with NARP ComplexComplex II Complex IV V and one infant with Leigh syndrome), and one Multiple defects Normal enzymes with complicated LHON with the 3460 muta- tion. Ragged red fibres on trichrome Gomori PDH + multiple complexes were present in two of 22 patients, both of them Figure 1 Respiratory chain enzyme and/or pyruvate with MiMyCa (maternally inherited myopathy dehydrogenase (PDH) deficiencies. Multiple presentation of mitochondrial disorders 211 Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from 23 24 25 18 syndrome (four), NARP (two), MiMyCa 26 27 16 (two), Barth syndrome (one), and LHON 16 (one).28 In addition, we diagnosed CosteV syn- 14 drome in Iraqi Jews (three) (optic atrophy and choreoathetosis)29–31; a new syndrome in Per- 12 sian Jews with sideroblastic anaemia and myopathy (one)32; intermittent hepatic dys- 10 function, encephalopathy, and lactic acidosis as 8 a result of lipoamide dehydrogenase (E3) defi- ciency in Ashkenazi Jews (two)33; sensorineural 6 deafness and myopathy (one)22; and intestinal Number of patients 4 4 dysmotility, neurogenic bladder, and complex 3 3 2 2 2 IV deficiency (three). The clinical presentation 2 1 1 1 1 of the remaining patients did not fit into well defined syndromes (fig 2). 0 E3 The nervous system was involved in all chil- Leigh NARP Barth LHON dren: static mental retardation (11), acute MiMyCa Costeff IPO + NB encephalopathy followed by mental deteriora- tion (six), chronic progressive encephalopathy

Encephalo(myo)pathy (nine), acute intermittent metabolic decom- Deafness + myopathy pensation with encephalopathy (six), spastic paraparesis (two), hypotonia (17), increased Sideroblastic anaemia + myopathy muscle tone (10), seizures (10), stroke-like epi- Figure 2 The clinical presentation according to described sodes (two), headache (three), ataxia (eight), symptoms. IPO + NB, intestinal pseudo-obstruction and extrapyramidal movements (six), autistic fea- neurogenic bladder; LHON, Leber’s hereditary optic tures (two), central apnoea (four), myopathy neuropathy; MiMyCa, maternally inherited myopathy and cardiomyopathy; NARP,neuropathy, ataxia, and retinitis (six), neuropathy (one), autonomic dysfunc- pigmentosa. tion (nine), external ophthalmoplegia (two), microcephaly (12), and macrocephaly (one) syndrome, one with Leigh syndrome and (fig 3). Only 12 children had normal intelli- complex I deficiency, and one with complex II gence. deficiency and encephalopathy. Serum lactic Sensory organ involvement was encountered acid was increased above twice the normal in 15 patients: retinitis pigmentosa (three), concentration in seven patients, mildly in- optic atrophy (five), cataract (one), alternating creased in eight, and normal in 15. anisocoria (two), exophthalmus (one), and Five patients with a highly suggestive clinical sensorineural deafness (five). presentation did not fulfill any of the above cri- Five patients had cardiovascular involve- teria, and therefore remained in the category of ment: cardiomyopathy (three), intracardiac http://adc.bmj.com/ “suspected mitochondrial disorder”. One had conduction defects (three), autonomic dys- sensorineural hearing loss and myopathy, but regulation of blood pressure and cardiac evaluation for known mt-DNA mutations causing deafness16 22 and muscle biopsy for res- rhythm (one). piratory chain enzymes were normal. Three Twenty children had gastrointestinal dys- siblings had stroke-like episodes with hemiple- function: impaired liver function (three), cyclic gia, seizures, and a maternal grandmother with vomiting (two), dysphagia (four), chronic diar- rhoea (one), failure to thrive (14, necessitating

a neurodegenerative disorder, but in a muscle on September 26, 2021 by guest. Protected copyright. biopsy, mt-DNA mutations specific for an insertion of a feeding gastrostomy in two), MELAS16 were not found. The fifth patient is and intestinal pseudo-obstruction (three, one hemiplegic and had severe lactic acidosis in of whom required resection of the colon). infancy that later became normal. This course is suggestive of transient complex IV deficiency or benign infantile mitochondrial myopathy.2 External ophthalmoplegia 2 Neuropathy 1 After the diagnosis of a mitochondrial dis- Autonomic involvement 9 order most of our patients were treated with Myopathy 6 Macrocephaly 1 coenzyme Q (5 mg/kg) and antioxidants. Pa- Microcephaly 12 tients with complex I deficiency received ribo- Apnoea 4 Autistic features 2 flavin and treatment with pantothenic acid was Extrapyramidal movements 6 attempted in patients with 3-methylglutaconic Ataxia 8 Headache 3 aciduria. However, because there is no clear Stroke-like episodes 2 Myoclonic seizures 5 proof of the yield of these treatments in Generalised tonic-clonic seizures 10 ameliorating symptoms or preventing compli- Increased muscle tone 10 Hypotonia 17 cations, we emphasised symptomatic treatment Spastic paraparesis 2 (physiotherapy, antiepileptic drugs, and muscle Acute intermittent encephalopathy 6 Chronic progressive encephalopathy 9 relaxants) and early detection of multisystem Acute encephalopathy + regression 6 involvement by yearly screening of heart, eyes, Static mental retardation 11 hearing, and routine blood and urine investiga- Normal intelligence 12 tions. 024 6 8 10 12 14 16 18 The specific syndromes encountered in our Number of patients patients were the previously described Leigh Figure 3 Nervous system involvement. 212 Nissenkorn, Zeharia, Lev, Fatal-Valevski,Barash, Gutman, et al Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from Three patients had urinary tract involvement and Leigh syndrome) present with chronic manifesting as neurogenic bladder. Recurrent progressive or acute intermittent neurological infections of the urinary tract were present in deterioration, we found 12 children with four. normal intelligence and 11 with static mental The haematopoietic system was aVected in retardation. However, all of them also had four patients: anaemia with ring sideroblasts either a complex neurological picture or multi- (one), spherocytic anaemia (one), neutropenia system involvement. Interestingly, the auto- (one, as part of Barth syndrome), leucocytosis nomic nervous system was involved in nine (one). patients, with neurogenic bladder, intestinal Recurrent infections of the respiratory tract dysmotility, cardiovascular dysregulation, and were encountered in six patients, and severe anisocoria. inspiratory stridor was present in two infants Even though mitochondrial disorders are (without any anatomical or physiopathological frequently called encephalomyopathies, we basis in one of them). found myopathic changes in only six patients Endocrine involvement was present in nine (out of 22 who underwent a muscle biopsy), patients: hypoglycaemia (eight), impaired glu- despite the frequent finding of hypotonia. This cose tolerance (two), partial central diabetes finding is consistent with observation of Tulin- insipidus (one), and central precocious puberty ius et al that patients with complex IV (one). deficiency usually present with myopathy, as Dysmorphic features were present in four opposed to those with complex I deficiency, children, three of them with a combined who present with encephalopathy.35 In our enzyme deficiency. series there was only one family with an Brain imaging findings specific for mito- isolated complex IV deficiency compared with chondrial disorders such as bilateral symmetric 10 with complex I deficiency. lesions of the basal ganglia and midbrain were External ophthalmoplegia, the hallmark of found in four children, and two patients had a mitochondrial disorders in adults,36 was en- non-specific leucodystrophy. An abnormal countered in only two children, probably electroencephalogram was found in eight because of the young age of our patients. patients, characterised by slowing of the back- Although all of our patients had some degree ground and/or epileptic discharges. of nervous system involvement, 27 children also had dysfunction of other organs, and in 12 the presenting symptoms were non- neuromuscular. These findings are similar to Discussion 34 The primary function of the mitochondria is those reported by Munnich et al, and support energy production. Because all organs are the observation that mitochondrial disorders dependent on ATP, mitochondrial disorders can no longer be regarded as primary neuro- can aVect any system and present muscular disorders and the name mitochon- heterogeneously.1–5 34 These eVects include: drial encephalomyopathies should probably be + In the central nervous system: acute or abandoned. http://adc.bmj.com/ intermittent encephalopathy, mental retar- Our study was conducted in a paediatric dation or progressive dementia, ataxia, clinic. The mean age at presentation was 2.5 extrapyramidal movements, seizures, para- years, but the mean age at diagnosis was 5.2 paresis, and stroke-like episodes years, the lag varying from several weeks to 10 In the peripheral nervous system: general- years. A similar lag time was also found by + 35 ised myopathy, external ophthalmoplegia, Tulinius et al. A prolonged diagnostic lag may be attributed to decreased awareness of the

and neuropathy (both sensorimotor and on September 26, 2021 by guest. Protected copyright. autonomic) many possible presentations of mitochondrial + In the sensory organs: optic nerve atrophy, disorders, as well as to widespread misconcep- tapeto-retinal degeneration, cataract, or sen- tions about these disorders, such as the sorineural deafness mandatory presence of lactic acidosis or a neu- + In the heart: cardiomyopathy and conduc- rodegenerative course. tion defects The diagnostic criteria for mitochondrial + In the gastrointestinal tract: liver abnormali- disorders are not well established. We used a ties, pancreatic insuYciency or intestinal modification of the criteria suggested by Tulin- pseudo-obstruction, chronic diarrhoea, and ius and colleagues35 37 and Jackson et al.36 We villous atrophy added a supplementary criterion: a proven + In the urinary tract: tubular dysfunction and mitochondrial disorder in a sibling with a simi- neurogenic bladder lar clinical presentation. We felt that in these + In the bone marrow: sideroblastic anaemia, cases there was no need for a full diagnostic neutropenia, or pancytopenia evaluation. Nevertheless, one should not ex- + In the endocrine glands: hypoglycaemia, pect the same age of appearance, severity, or diabetes mellitus, diabetes insipidus, growth clinical presentation in siblings.38 hormone deficiency, hypoparathyroidism, According to our criteria, the diagnosis of a and delayed puberty. mitochondrial disorder was established in 31 In our study, we found involvement of all children (table 2). However, we believe that the systems. The nervous system was involved in absence of positive criteria does not rule out a all patients (fig 3). Although it is customary to mitochondrial disorder and such a diagnosis presume that mitochondrial disorders (such as remains highly probable, based on clinical MELAS, MERRF, Kearn-Sayre syndrome, features. Multiple presentation of mitochondrial disorders 213 Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from In 20 children we found abnormal respira- tory chain enzymes or PDH complex activity. Key messages The most prevalent deficiency was in complex I (half of the deficiencies), similar to the obser- + A full mitochondrial evaluation is war- vations of Munnich and colleagues34 and ranted in children with a complex neuro- 35 37 logical picture or a single neurological Tulinius et al, but unlike them we found that isolated complex IV deficiency was rare. Inter- symptom and other system involvement estingly, we encountered a combined decrease + When the presentation is classic for a of PDH and respiratory chain enzyme activity maternally inherited mitochondrial (complexes I, III, and IV) in one patient, with a syndrome—for example, mitochondrial severe presentation since the perinatal period. encephalopathy, lactic acidosis, and This association has been described only stroke-like episodes (MELAS), myo- rarely.39 40 The patients usually present early in clonic epilepsy and ragged red muscle life and are more severely aVected than patients fibres (MERRF), Leber’s hereditary with isolated complex deficiencies. A defect in optic neuropathy (LHON), appropriate mitochondrial protein import or assembly—for mitochondrial DNA studies should be example, the heat shock protein 60, is obtained first assumed.39 + When the clinical picture is classic for a Mutations in mt-DNA were found in only nuclear DNA inherited syndrome and four patients, three of them with T8993G and the gene or the linkage is known—for one with the 3460 mutation. The phenotypic example, MNGIE (mitochondrial neuro- heterogeneity as a result of mutation abun- gastrointestinal encephalopathy) or DID- dance is seen here, because both patients with MOAD (diabetes insipidus, diabetes Leigh disease and NARP presented with the mellitus, optic atrophy, and deafness), 8993 mutation.23–25 Ragged red muscle fibres proceed with genetic studies indicate a mutation in mitochondrial t-RNA, + When the clinical picture is non-specific so their presence in two patients, both with but highly suggestive of a mitochondrial cardiomyopathy and maternal involvement, disorder, start with serum and/or cere- proves maternal inheritance, despite the ab- brospinal fluid lactic acid and urinary sence of the described mt-DNA mutations.16 26 organic acids and proceed with muscle Other mutations in t-RNA genes are probably biopsy and assessment of the respiratory responsible for this syndrome. The infrequent chain enzymes occurrence of mt-DNA mutations or ragged + Normal serum or cerebrospinal fluid lac- red muscle fibres might be because most mito- tic acid does not exclude a mitochondrial chondrial disorders in children are caused by disorder mutations in nuclear DNA.1 Ultrastructurally abnormal mitochondria were present in four of the six patients drial disorder. Evaluation of respiratory chain evaluated. It was the sole diagnostic criterion in enzymes had the highest diagnostic yield one patient with encephalopathy, hypotonia, (83%). We found that assessment of urinary http://adc.bmj.com/ and macrocephaly, as well as a borderline com- organic acids was useful, because raised plex I deficiency and suspected maternal urinary lactate or certain organic acids fre- inheritance. This emphasises the importance of quently associated with mitochondrial disor- electron microscopic evaluation even in pa- ders (such as 3-methyl glutaconic, dicarboxy- tients with normal muscle histology. lic, and glutaric acids) could be found. Serum lactic acid was greatly increased in In 21 patients, the inheritance pattern was

only a minority of patients and was normal in suggestive: maternal in 10 (six with known on September 26, 2021 by guest. Protected copyright. 15 patients (including three children with maternally inherited syndromes and four with Leigh syndrome). Therefore, normal lactic a family history of maternal lineage involve- acid concentrations do not preclude a diagno- ment), X-linked recessive in one (Barth sis of a mitochondrial disorder. Munnich and syndrome), and autosomal recessive in 10 (five colleagues534 explain the lack of sensitivity of with consanguinity and five with established evaluation of the plasma redox status in the autosomal recessive syndromes). In the rest of following ways: (1) proximal tubulopathy the children the inheritance was not clear, thus might lower blood lactate; (2) tissue specific precluding accurate genetic counselling. isoforms might be selectively impaired; (3) the Known syndromes were diagnosed in less defect might be generalised but partial; or (4) than half of our patients (15 of 36), in contrast the defect might be confined to complex II, to the series of Tulinius and colleagues35 and which only slightly alters the redox status. Jackson et al.36 A plausible explanation is the Therefore, they suggest that when the basic high index of suspicion for possible mitochon- screen is inconclusive, provocative tests, such drial disorders in children presenting with a as a glucose loading test, screening for organic complex neurological picture and/or multisys- acids, and determining the lactate/pyruvate tem involvement in our paediatric metabolic ratio in cerebrospinal fluid, should be per- neurogenetic clinic. formed. Widely acknowledged mitochondrial syn- In our experience, the clinical presentation dromes were found in only 10 children, four of of a complex neurological picture (not neces- them with Leigh disease. Zeviani and colleagues1 sarily progressive) or the involvement of seem- identified this disease in 23 of 36 paediatric ingly unrelated organs and systems was the mitochondrial patients, whereas other mito- most sensitive finding suggesting a mitochon- chondrial syndromes were quite rare. 214 Nissenkorn, Zeharia, Lev, Fatal-Valevski,Barash, Gutman, et al Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from We found nine patients with syndromes that 10 Moraes C, Shanske S, Tritschler HJ, et al. MtDNA depletion with variable expression: a novel genetic abnor- are specific for the diverse ethnic background mality in mitochondrial diseases. Am J Hum Genet of Israeli Jews (our clinic is located in the 1991;48:492–501. 11 Birch-Machin MA, Shepherd IM, Watmough NJ, et al. Fatal Tel-Aviv metropolitan area and serves a popu- lactic acidosis in infancy with a defect of complex III of the lation with a disproportionately small number respiratory chain. Pediatr Res 1989;25:553–9. 12 Rustin P, Chretien D, Bourgeron T, et al. Biochemical and of Arabs). molecular investigations in respiratory chain deficiencies. Two patients with E3 deficiency presented Clin Chim Acta 1994;228:35–51. 13 Sherrat HS, Watmough MA, Johnson MA, Turnbull DM. with intermittent liver failure and encephalopa- Methods for study of normal and abnormal skeletal muscle thy, cyclic vomiting, and normal intelligence. mitochondria. Methods Biochem Anal 1988;33:243–335. 14 Sheu KF, Hu CW, Utter MF. Pyruvate dehydrogenase com- Thus, their description fits a new syndrome of plex activity in normal and deficient fibroblasts. J Clin E3 deficiency described by Elpeleg et al in Invest 1981;67:1463–71. 33 15 Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein Ashkenazi Jews of Hungarian descent. measurement with Folin phenol reagent. J Biol Chem 1951; Three Iraqi Jewish patients had optic atrophy 193:265–75. 16 Zeviani M, Tiranti V, Piantadosi C. Mitochondrial disor- and choreoathetosis, typical of a unique ders. Medicine 1998;77:59–72. syndrome described in Israel by CosteV et al in 17 Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, 29 DiDonato S. An autosomal dominant disorder with multi- 1989, and later found to be associated with ple deletions of mitochondrial DNA starting at the D-loop raised urinary 3-methylglutaconic acid by region. Nature 1989;339:309–11. 30 18 ShoVner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan Zeharia et al. This syndrome is assumed to be DA, Wallace DC. Spontaneous Kearns-Sayre/chronic mitochondrial in origin.31 Recently, Nystuen external ophthalmoplegia plus syndrome associated with 41 a mitochondrial deletion: a slip-replication model and and colleagues showed a linkage to 19q13.2– metabolic therapy. Proc Natl Acad Sci USA 1989;86: q13.3. 7952–6. 19 ShoVner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, One patient, the child of consanguineous Wallace DC. Myoclonic epilepsy and ragged-red fibers dis- Persian Jews, presented with sideroblastic ease (MERRF) is associated with a mitochondrial DNA tRNAlys mutation. Cell 1990;61:931–7. anaemia, myopathy, mental retardation, short 20 Goto Y, Nonaka I, Horai S. A mutation in the tRNA- stature, microcephaly, and dysmorphic fea- (Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348: tures. His mitochondrial investigations re- 651–3. vealed low activity of complexes I and IV, 21 Seibel P, Lauber J, Klopstock T, Marsac C, Kadenbach B, Reichmann H. Chronic progressive external ophthalmo- ultrastructurally abnormal mitochondria, but plegia is associated with a novel mutation in the mitochon- no deletions or mutations of mt-DNA. This drial tRNA(Asn) gene. Biochem Biophys Res Commun 1994; patient is similar to those described recently by 200:938–42. 32 22 Fischel-Ghodsian N, Prezant TR, Fournier P, Stewart IA, another Israeli group, and might represent a Maw M. Mitochondrial mutation associated with nonsyn- new mitochondrial syndrome with sideroblas- dromic deafness. Am J Otolaryngol 1995;16:403–8. 23 Santorelli FM, Shanske S, Macaya A, DeVivo DC, tic anaemia in Persian Jews. DiMauro S. The mutation at nt8993 of mitochondrial Three siblings of non-consanguineous DNA is a common cause of Leigh syndrome. Ann Neurol 1993;34:827–34. Ashkenazi Jewish origin presented with intesti- 24 Di Mauro S, De Vivo D. Genetic heterogeneity in Leigh nal pseudo-obstruction and neurogenic bladder syndrome. Ann Neurol 1996;40:5–7. 25 Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A of variable severity, low complex IV concentra- new mitochondrial disease associated with mitochondrial tions on muscle biopsy, and no central nervous DNA heteroplasmy. 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FETAL AND NEONATAL EDITION September issue

The following articles—being published in the September 1999 issue of the Fetal and Neonatal edition of the Archives of Disease in Childhood—may be of general interest to paediatricians. Parental visiting, communication, and participation in ethical decisions: a comparison of neonatal unit policies in Europe M Cuttini, M Rebagliato, P Bortoli, G Hansen, R de Leeuw, S Lenoir, J Persson, M Reid, M Schroell, U de Vonderweid, M Kaminski, H Lenard, M Orzalesi, R Saracci Abnormal cerebral haemodynamics in perinatally asphyxiated neonates related to outcome Judith H Meek, Clare E Elwell, David C McCormick, A David Edwards, Janice P Townsend, Ann L Stewart, John S Wyatt Cranial magnetic resonance imaging and school performance in very low birth weight infants in adolescence R W I Cooke, L J Abernethy

Pyridoxine dependent epilepsy: a suggestive electroclinical pattern http://adc.bmj.com/ R Nabbout, C SouZet, P Plouin, O Dulac Neonatal neuroblastoma J Moppett, I Haddadin, A B M Foot, on behalf of the United Kingdom Children Cancer Study Group Trends and social patterning of birthweight in SheYeld, 1985–94 N J Spencer, S Logan, L Gill on September 26, 2021 by guest. Protected copyright. EVect of fortification on the osmolality of human milk M De Curtis, M Candusso, C Pieltain, J Rigo

ETHICS Children of the 90s: ethical guidance for a longitudinal study S E Mumford