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).