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Am. J. Hum. Genet. 51:1201-1212, 1992 Segregation and Manifestations of the mtDNA tRNA'YS A--'GO8344 Mutation of Myoclonus Epilepsy and Ragged-Red Fibers (MERRF) Syndrome Nils-Goran Larsson,* Mar H. TuliniusT Elisabeth Holme,* Anders Oldfors,1 Oluf Andersen,§ Jan Wahistrom, 11 and Jan Aasly# Departments of *Clinical Chemistry, tPediatrics, $Pathology, §Neurology, and IlClinical Genetics, University of Gothenburg, Gothenburg, Sweden; and #Department of Neurology, University of Trondheim, Trondheim, Norway Summary We have studied the segregation and manifestations of the tRNALYS A-)'G(8344) mutation of mtDNA. Three unrelated patients with myoclonus epilepsy and ragged-red fibers (MERRF) syndrome were investigated, along with 30 of their maternal relatives. Mutated mtDNA was not always found in the offspring of women carrying the tRNALYS mutation. Four women had 10%-33% of mutated mtDNA in lymphocytes, and no mutated mtDNA was found in 7 of their 14 investigated children. The presence of mutated mtDNA was excluded at a level of 3:1,000. Five women had a proportion of 43%-73% mutated mtDNA in lymphocytes, and mutated mtDNA was found in all their 12 investigated children. This suggests that the risk for transmission of mutated mtDNA to the offspring increases if high levels are present in the mother and that, above a threshold level of 35%-40%, it is very likely that transmission will occur to all children. The three patients with MERRF syndrome had, in muscle, both 94%-96% mutated mtDNA and biochemical and histochemi- cal evidence of a respiratory-chain dysfunction. Four relatives had a proportion of 61%-92% mutated mtDNA in muscle, and biochemical measurements showed a normal respiratory-chain function in muscle in all cases. These findings suggest that >92% of mtDNA with the tRNALYS mutation in muscle is required to cause a respiratory-chain dysfunction that can be detected by biochemical methods. There was a positive correla- tion between the levels of mtDNA with the tRNALYS mutation in lymphocytes and the levels in muscle, in all nine investigated cases. The levels of mutated mtDNA were higher in muscle than in lymphocytes in all cases. In two of the patients with MERRF syndrome, muscle specimens were obtained at different times. In both cases, biochemical measurements revealed a deteriorating respiratory-chain function, and in one case a progressive increase in the amount of cytochrome c oxidase-deficient muscle fibers was found. Introduction 1985; Wallace et al. 1988). mtDNA is exclusively ma- Myoclonus epilepsy and ragged-red fibers (MERRF) ternally inherited (Giles et al. 1980) and contains the syndrome is a maternally inherited progressive mito- genes for 13 subunits of the respiratory-chain enzyme chondrial encephalomyopathy characterized by myo- complexes, 22 transfer RNA genes, and 2 ribosomal clonic and tonic-clonic seizures, ataxia, dementia, RNA genes (Andersson et al. 1981). The non- muscle weakness, and mitochondrial abnormalities in Mendelian inheritance of MERRF syndrome was ex- skeletal muscle (Fukuhara et al. 1980; Rosing et al. plained when a point mutation that changes a highly conserved adenine to a guanine at nucleotide 8344 in Received May 22, 1992; revision received August 14, 1992. the tRNALYS gene of mtDNA (tRNALYs mutation) was Address for correspondence and reprints: Nils-Goran Larsson, found (Shoffner et al. 1990; Yoneda et al. 1990). In Department of Clinical Chemistry, Sahigren's Hospital, S-413 45 Gothenburg, Sweden. vitro experiments with transmitochondrial cell lines i 1992 by The American Society of Human Genetics. All rights reserved. have demonstrated that the tRNALYS mutation causes 0002-9297/92/5106-0003$02.00 a mitochondrial protein synthesis defect (Chomyn et 1201 1202 Larsson et al. al. 1991). The tRNALYs mutation is found in most II-6, and 111-8) (fig. 1). For the other individuals, data MERRF patients, and there is always heteroplasmy were obtained from interviews with relatives. The with a mixture of normal and mutated mtDNA. The clinical findings are summarized in table 1. proportion of mutated mtDNA varies between differ- Probands. -The first symptom was ataxia in the pro- ent individuals in the same family and even between bands of families A and B, with onset at the age of 0.5 different tissues in the same individual (Shoffner et al. and 5 years, respectively. The first symptoms in the 1990; Noer et al. 1991; Seibel et al. 1991; Zeviani et proband of family C were vision and hearing loss with al. 1991). Patients with MERRF syndrome have a onset at the age of 9 years. The dominating clinical high proportion of mutated mtDNA in muscle, and a findings in all three probands were photosensitive deficiency of the respiratory-chain enzyme complexes myoclonic, generalized tonic-clonic, and akinetic sei- I and IV is frequently found (Shoffner et al. 1990; zures, truncal and limb ataxia, and myoclonic jerks Seibel et al. 1991; Zeviani et al. 1991). Maternal rela- affecting the whole body. The onset ofmyoclonic jerks tives of MERRF patients are often unaffected or have and seizures was at the age of 7, 14, and 11 years in less severe encephalomyopathic manifestations. Large the probands of families A, B, and C, respectively. cervical lipomas have been reported in patients with The probands of families A and C also had dementia, MERRF syndrome and also in otherwise unaffected dysarthria, spastic paraparesis, optic atrophy, and maternal relatives of MERRF patients (Berkovic et al. sensorineural hearing loss. 1989, 1991; Holme et al., submitted). At the age of 10 years the proband offamily A could We have studied the segregation and manifestations still walk and run, but he had poor endurance. Muscle of the tRNALYS mutation. Three unrelated patients weakness was mainly noted in distal muscle groups. with MERRF syndrome and 30 maternal relatives of At the age of 13 years considerable progress of all two of these patients were studied. The correlation symptoms had occurred. He was almost completely between the levels of mtDNA with the tRNALYS muta- wheelchair bound and could only walk short distances tion and clinical manifestations and morphological with support. General muscle weakness and atrophy and biochemical findings in skeletal muscle was stud- were noticed in both the proximal and distal muscle ied in the three patients with MERRF syndrome and groups. At the age of 15 years he was wheelchair in four maternal relatives of two of these patients. In bound and had developed spastic paraparesis with two of the patients with MERRF syndrome, multiple both equinus posture of the feet and contractures ne- muscle biopsies during a 5- and a 3-year period were cessitating bilateral achillotenotomy. performed to study the progression of the disease. At the age of 21 years the proband of family B had severe fatigue, headache, and concentration diffi- culties. He had exercise-induced muscle pain and bi- Material and Methods lateral pes cavus but no spasticity. Muscle weakness was more prominent in proximal than in distal muscle Patients groups. The probands of families A-C had MERRF syn- At the age of 17 years the proband of family C had drome (fig. 1). Maternal relatives of the probands of muscle weakness mainly in proximal muscle groups, families A and B were investigated. Family C declined but he could walk long distances. At the age of 20 further investigation. The probands of families A and years he had severe muscular weakness and atrophy C have been described elsewhere (cases 13 and 8 in of proximal muscle groups, and he could walk only Tulinius et al. 1991a, 1991b). The three probands short distances. and case V-2 of family A were thoroughly investigated Family A. - Celiac disease was suspected in case V-2 according to a protocol described elsewhere (Tulinius at the age of 1 year, because of failure to thrive. He et al. 1 991a). Case IV-21 offamily A and II-5 and III-6 was treated with a gluten-free diet until the age of 4 of family B were extensively investigated to exclude years. He was on a normal diet during age 4-6 years, minor neurological, audiological, cardiological, and but a duodenal biopsy specimen at the age of 6 years ophthalmological signs. A clinical examination was showed subtotal villus atrophy. A gluten-free diet was performed in another 24 members of family A (cases again started and has been continued since. A control II-2, II-4-II-6,. III-1, III-1 1-III-17,9 III-21, III-23 , IV-7,~ duodenal biopsy specimen after 2 years of a gluten-free IV-9-IV-11, IV-13-IV-15, IV-19, and V-3-V-4) and diet showed normal villus structure. At 12 years of in another 5 members of family B (cases I-1, 11-2-II-3, age, case V-2 began to complain of exercise-induced Segregation and Manifestations of tRNALYS Mutation 1203 FamilXA Family S Family C ///* 88% 777 74% 46% 1 2 11 1 2 /s90% III 807 50% 597 Figure I Pedigrees ofthe three investigated families. The arrows indicate the probands. The mean values ofthe proportion ofmtDNA with the tRNALYs mutation in lymphocytes from the investigated individuals are shown. Levels below the detection limit (i.e., 0.3%) of the PCR assay are labeled by 0%. no and 0 = Clinically examined; E andO = carrier ofthe tRNALYs mutation; and * = MERRF syndrome. muscle pain and fatigue. At age 13 years he had minor classical migraine, a slight hearing loss, and decreased concentration difficulties and needed extra assistance vibration sensibility in the lower extremities. Case at school. The results of a neurological examination IV-9 had a slight ataxia in the lower extremities. Cases were normal. The proband's mother, case IV-21, had 11-4-II-6 experienced increasing mental deterioration multiple symmetric lipomas around the neck, with on- with loss of short-term memory that started in their set during her 20s.

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