ClinVar Genomic variation as it relates to human health

Testicular torsion (present) , Specific learning disability (present) , Short stature (present) , Pes cavus (present) , Optic atrophy (present) , Lipoma (present) , Hypothyroidism (present) , Hyperlipidemia (present) , Hepatic steatosis (present) , Hand tremor (present) , Generalized tonic-clonic seizures (present) , Gait disturbance (present) , Focal seizures (present) , Elevated serum alanine aminotransferase (present) , Dystonia (present) , Dysarthria (present) , Delayed gross motor development (present) , Celiac disease (present) (less)

In patients with the MERRF syndrome (545000), Shoffner et al. (1990) and Yoneda et al. (1990) identified an A-to-G transition at nucleotide 8344 that altered a conserved nucleotide in the tRNA(lys) gene (MTTK) and was heteroplasmic. The mutation was found in 3 independent pedigrees with the disease, while 75 controls did not have the mutation. Treatment with CoQ at 300 mg/day resulted in marked improvement of the phenotype. The same mutation was reported by Berkovic et al. (1991), Seibel et al. (1991), Shih et al. (1991), Tanno et al. (1991), and Zeviani et al. (1991). In all 3 patients with the MERRF syndrome, Noer et al. (1991) found the A-to-G substitution of nucleotide 8344 in the tRNA-lys gene. There was evidence that the mutations had arisen independently in these patients. Boulet et al. (1992) studied the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the skeletal muscle of 4 patients with myoclonus epilepsy and ragged-red fibers. The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase. The great majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wildtype clones. Approximately 15% wildtype mtDNAs restored translation and COX activity to near-normal levels. The results showed that the A-to-G substitution is functionally a recessive mutation that can be rescued by intraorganellar complementation. Proteins of the complex I and VI subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Among 9 affected members of a MERRF family, Suomalainen et al. (1993) showed that the mutated nucleotide 8344 comprised from 9 to 72% of the total mtDNA in the leukocytes. They made use of a solid-phase minisequencing technique which, in addition to identifying the A8344G mutation permitted simultaneous determination in the same assay from one blood sample of the relative amount of mutated mtDNA. Lertrit et al. (1992) studied 6 tissues from a patient with MERRF caused by the 8344 mutation. Heteroplasmy was observed in all: cerebellum, cerebrum, pancreas, liver, muscle, and heart. Thus, the mutated population of mitochondria must have existed before the formation of the 3 primary embryonic layers. The patient had no family history of a CNS disorder. Lertrit et al. (1992) found a lack of correlation between the degree of mtDNA heteroplasmy and clinical symptoms related to a particular organ and suggested that this indicated the presence of tissue-specific nuclear factors that modify the phenotypic expression of the 8344 mutation. Perhaps rather than a specific nuclear factor there are merely tissue differences in the requirements for the particular element of the respiratory chain involved. Shoffner and Wallace (1992) estimated that the MTTK*MERRF8334 mutation accounts for 80 to 90% of MERRF cases. Penisson-Besnier et al. (1992) described a family with MERRF and the point mutation at 8344. The mutation was found in all the maternal lineage with a relatively narrow range of variation in the percentage of mutant mitochondrial genomes with one exception represented by a set of dizygotic twins; one was clinically affected and showed a high proportion of mutant mitochondrial DNAs in blood cells, while the other was asymptomatic and showed very small amounts of mutant mtDNA in blood and skin. This suggests that the mitochondria are segregated at an early stage in oogenesis. In a study of 150 patients, most of them with diagnosed or suspected mitochondrial disease, Silvestri et al. (1993) found a high correlation between the A-to-G transition at position 8344 and the MERRF syndrome, but they also showed that this mutation can be associated with other phenotypes, including Leigh syndrome (256000), myoclonus or myopathy with truncal lipomas, and proximal myopathy. Furthermore, the absence of the 8344 mutation in 4 typical MERRF patients suggested that other mutations in the MTTK gene or elsewhere in the mitochondrial genome can produce the same phenotype. Hammans et al. (1993) studied 7 patients with the A8344-to-G mutation and their relatives. In 1 family, the mutation was deduced to be present in 4 generations. The index cases showed the core clinical features of MERRF, namely, myoclonus, ataxia, and seizures. Among other features, progressive external ophthalmoplegia, Leigh syndrome, and stroke-like episodes were observed, well recognized features in mitochondrial myopathies but novel manifestations of this genotype. Analyses for the proportion of mutant mtDNA, using an oligonucleotide hybridization technique, indicated that the proportion of mutant mtDNA in blood was significantly greater in symptomatic than in asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. In a Chinese family living in Taiwan, Fang et al. (1994) described MERRF caused by the A8344-to-G mutation in 6 persons, including the grandmother, 2 sibs, and 3 grandchildren. Action myoclonus was seen in 5; short stature, muscle weakness, and mental retardation in 4; lactic acidosis, hearing impairment, and ataxia in 2; and seizures in 1. Muscle biopsy from 2 affected sibs showed ragged-red fibers and abundant subsarcolemmal mitochondria with paracrystalline inclusions. Enriquez et al. (1995) studied the pathogenic mechanism of the A8344G mutation by comparing mtDNA-less cells which were transformed with either the mutant MTTK gene or the wildtype MTTK. A decrease of 50-60% in the specific tRNA-lys aminoacylation capacity per cell was found in mutant cells. Furthermore, several lines of evidence revealed that the severe protein synthesis impairment in MERRF mutation-carrying cells was due to premature termination of translation at each or near each lysine codon, with the deficiency of aminoacylated tRNA-lys being the most likely cause of this phenomenon. Borner et al. (2000) generated conflicting results, using an assay that combines tRNA oxidation and circularization. The authors determined the relative amounts and states of aminoacylation of mutant and wildtype tRNAs in tissue samples from patients with MELAS syndrome (540000) and MERRF syndrome. In most biopsies from MELAS patients carrying the 3243A-G substitution in the mitochondrial tRNALeu(UUR) gene (590050), the mutant tRNA was underrepresented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the 8344A-G substitution, neither the relative abundance nor the aminoacylation of the mutated tRNA was affected. The authors concluded that whereas the 3243A-G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNALeu, the 8344A-G mutation does not affect tRNALys function in MERRF patients in the same way. A specific mutation in mitochondrial DNA was first demonstrated by Shoffner et al. (1990); this was a missense mutation in the MTTK gene. The A-to-G mutation at nucleotide 8344 accounted for 80 to 90% of MERRF cases (Shoffner and Wallace, 1992). Biochemically, the mutation produced multiple deficiencies in the enzyme complexes of the respiratory chain, consistent with a defect in translation of all mtDNA-encoded genes. Chomyn et al. (1991) showed that transfer of mtDNAs carrying the mutation to human cell lines lacking their own mitochondrial DNA resulted in a severe defect in mitochondrial translation in the recipient cells, independent of nuclear background, implying that the tRNA mutation itself is sufficient to cause the disease. See 545000 for a discussion of the MERRF syndrome (myoclonus epilepsy associated with ragged-red fibers). In a study of 67 Australian cases labeled Leigh syndrome from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features, Rahman et al. (1996) identified 11 patients with mitochondrial DNA point mutations. Two mutations were in the MTATP6 gene (8993T-G, 516060.0001; 8993T-C, 516060.0002), and one was the common MERRF mutation in the MTTK gene (8344A-G). Chomyn (1998) reviewed the new insights into human mitochondrial function and genetics by study of the 8344A-G mutation in the gene encoding mitochondrial lysyl-tRNA. Holme et al. (1993) reported a woman with multiple symmetric lipomas (MSL; see 151800) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. Gamez et al. (1998) identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with MSL. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss. Horvath et al. (2007) reported a 66-year-old German man with the 8344A-G mutation who presented with an 8-year history of parkinsonism (556500). Symptoms included bradykinesia, resting tremor, and asymmetric rigidity. He also had proximal muscle weakness, hyporeflexia, decreased distal sensation, and bilateral hearing loss. Serum creatine kinase was elevated. He showed good response to levodopa. Skeletal muscle biopsy showed ragged-red fibers, fiber size variability, centrally placed nuclei, and atrophic and necrotic fibers. There was a mild decrease in some respiratory chain enzymes. The 8344A-G mutation was homoplasmic in muscle and 80% in leukocytes. A brother with progressive hearing loss since age 10 had 70% heteroplasmy in blood. Biancheri et al. (2010) identified the 8344A-G mutation in a child with severe cavitating leukoencephalopathy. The infant had congenital cataracts, but developed normally until age 17 months when he showed psychomotor and neurologic regression. Symptoms included nystagmus, irritability, hypertonia, extensor plantar responses, and swallowing and feeding difficulties. Brain MRS showed increased lactate; muscle biopsy showed ragged-red fibers and decreased activity of mitochondrial complexes I+III and II+III (about 30% residual activity). Patient tissues showed high levels of mutant mtDNA that was not detected in the mother's tissues. Biancheri et al. (2010) noted the unusual early presentation in this patient and emphasized the characteristic cystic degenerative pattern of the brain imaging which is suggestive of a mitochondrial disorder. Using mutant and control cybrids, Yen et al. (2016) found that the 8344A-G mutation in MTTK suppressed maturation of COQ5 (616359) and disrupted a COQ5-containing mitochondrial protein complex, concomitant with reduction in mitochondrial membrane potential, oxygen consumption, and ATP production. (less)

Cerebellar ataxia (present) , Dysarthria (present) , Frequent falls (present) , Progressive muscle weakness (present) , Gowers sign (present) , Paresthesia (present) , Difficulty climbing stairs (present) , Peripheral neuropathy (present) (less)

In patients with the MERRF syndrome (545000), Shoffner et al. (1990) and Yoneda et al. (1990) identified an A-to-G transition at nucleotide 8344 that altered a conserved nucleotide in the tRNA(lys) gene (MTTK) and was heteroplasmic. The mutation was found in 3 independent pedigrees with the disease, while 75 controls did not have the mutation. Treatment with CoQ at 300 mg/day resulted in marked improvement of the phenotype. The same mutation was reported by Berkovic et al. (1991), Seibel et al. (1991), Shih et al. (1991), Tanno et al. (1991), and Zeviani et al. (1991). In all 3 patients with the MERRF syndrome, Noer et al. (1991) found the A-to-G substitution of nucleotide 8344 in the tRNA-lys gene. There was evidence that the mutations had arisen independently in these patients. Boulet et al. (1992) studied the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the skeletal muscle of 4 patients with myoclonus epilepsy and ragged-red fibers. The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase. The great majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wildtype clones. Approximately 15% wildtype mtDNAs restored translation and COX activity to near-normal levels. The results showed that the A-to-G substitution is functionally a recessive mutation that can be rescued by intraorganellar complementation. Proteins of the complex I and VI subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Among 9 affected members of a MERRF family, Suomalainen et al. (1993) showed that the mutated nucleotide 8344 comprised from 9 to 72% of the total mtDNA in the leukocytes. They made use of a solid-phase minisequencing technique which, in addition to identifying the A8344G mutation permitted simultaneous determination in the same assay from one blood sample of the relative amount of mutated mtDNA. Lertrit et al. (1992) studied 6 tissues from a patient with MERRF caused by the 8344 mutation. Heteroplasmy was observed in all: cerebellum, cerebrum, pancreas, liver, muscle, and heart. Thus, the mutated population of mitochondria must have existed before the formation of the 3 primary embryonic layers. The patient had no family history of a CNS disorder. Lertrit et al. (1992) found a lack of correlation between the degree of mtDNA heteroplasmy and clinical symptoms related to a particular organ and suggested that this indicated the presence of tissue-specific nuclear factors that modify the phenotypic expression of the 8344 mutation. Perhaps rather than a specific nuclear factor there are merely tissue differences in the requirements for the particular element of the respiratory chain involved. Shoffner and Wallace (1992) estimated that the MTTK*MERRF8334 mutation accounts for 80 to 90% of MERRF cases. Penisson-Besnier et al. (1992) described a family with MERRF and the point mutation at 8344. The mutation was found in all the maternal lineage with a relatively narrow range of variation in the percentage of mutant mitochondrial genomes with one exception represented by a set of dizygotic twins; one was clinically affected and showed a high proportion of mutant mitochondrial DNAs in blood cells, while the other was asymptomatic and showed very small amounts of mutant mtDNA in blood and skin. This suggests that the mitochondria are segregated at an early stage in oogenesis. In a study of 150 patients, most of them with diagnosed or suspected mitochondrial disease, Silvestri et al. (1993) found a high correlation between the A-to-G transition at position 8344 and the MERRF syndrome, but they also showed that this mutation can be associated with other phenotypes, including Leigh syndrome (500017), myoclonus or myopathy with truncal lipomas, and proximal myopathy. Furthermore, the absence of the 8344 mutation in 4 typical MERRF patients suggested that other mutations in the MTTK gene or elsewhere in the mitochondrial genome can produce the same phenotype. Hammans et al. (1993) studied 7 patients with the A8344-to-G mutation and their relatives. In 1 family, the mutation was deduced to be present in 4 generations. The index cases showed the core clinical features of MERRF, namely, myoclonus, ataxia, and seizures. Among other features, progressive external ophthalmoplegia, Leigh syndrome, and stroke-like episodes were observed, well recognized features in mitochondrial myopathies but novel manifestations of this genotype. Analyses for the proportion of mutant mtDNA, using an oligonucleotide hybridization technique, indicated that the proportion of mutant mtDNA in blood was significantly greater in symptomatic than in asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. In a Chinese family living in Taiwan, Fang et al. (1994) described MERRF caused by the A8344-to-G mutation in 6 persons, including the grandmother, 2 sibs, and 3 grandchildren. Action myoclonus was seen in 5; short stature, muscle weakness, and mental retardation in 4; lactic acidosis, hearing impairment, and ataxia in 2; and seizures in 1. Muscle biopsy from 2 affected sibs showed ragged-red fibers and abundant subsarcolemmal mitochondria with paracrystalline inclusions. Enriquez et al. (1995) studied the pathogenic mechanism of the A8344G mutation by comparing mtDNA-less cells which were transformed with either the mutant MTTK gene or the wildtype MTTK. A decrease of 50-60% in the specific tRNA-lys aminoacylation capacity per cell was found in mutant cells. Furthermore, several lines of evidence revealed that the severe protein synthesis impairment in MERRF mutation-carrying cells was due to premature termination of translation at each or near each lysine codon, with the deficiency of aminoacylated tRNA-lys being the most likely cause of this phenomenon. Borner et al. (2000) generated conflicting results, using an assay that combines tRNA oxidation and circularization. The authors determined the relative amounts and states of aminoacylation of mutant and wildtype tRNAs in tissue samples from patients with MELAS syndrome (540000) and MERRF syndrome. In most biopsies from MELAS patients carrying the 3243A-G substitution in the mitochondrial tRNALeu(UUR) gene (590050), the mutant tRNA was underrepresented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the 8344A-G substitution, neither the relative abundance nor the aminoacylation of the mutated tRNA was affected. The authors concluded that whereas the 3243A-G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNALeu, the 8344A-G mutation does not affect tRNALys function in MERRF patients in the same way. A specific mutation in mitochondrial DNA was first demonstrated by Shoffner et al. (1990); this was a missense mutation in the MTTK gene. The A-to-G mutation at nucleotide 8344 accounted for 80 to 90% of MERRF cases (Shoffner and Wallace, 1992). Biochemically, the mutation produced multiple deficiencies in the enzyme complexes of the respiratory chain, consistent with a defect in translation of all mtDNA-encoded genes. Chomyn et al. (1991) showed that transfer of mtDNAs carrying the mutation to human cell lines lacking their own mitochondrial DNA resulted in a severe defect in mitochondrial translation in the recipient cells, independent of nuclear background, implying that the tRNA mutation itself is sufficient to cause the disease. See 545000 for a discussion of the MERRF syndrome (myoclonus epilepsy associated with ragged-red fibers). In a study of 67 Australian cases labeled Leigh syndrome from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features, Rahman et al. (1996) identified 11 patients with mitochondrial DNA point mutations. Two mutations were in the MTATP6 gene (8993T-G, 516060.0001; 8993T-C, 516060.0002), and one was the common MERRF mutation in the MTTK gene (8344A-G). Chomyn (1998) reviewed the new insights into human mitochondrial function and genetics by study of the 8344A-G mutation in the gene encoding mitochondrial lysyl-tRNA. Holme et al. (1993) reported a woman with multiple symmetric lipomas (MSL; see 151800) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. Gamez et al. (1998) identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with MSL. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss. Horvath et al. (2007) reported a 66-year-old German man with the 8344A-G mutation who presented with an 8-year history of parkinsonism (556500). Symptoms included bradykinesia, resting tremor, and asymmetric rigidity. He also had proximal muscle weakness, hyporeflexia, decreased distal sensation, and bilateral hearing loss. Serum creatine kinase was elevated. He showed good response to levodopa. Skeletal muscle biopsy showed ragged-red fibers, fiber size variability, centrally placed nuclei, and atrophic and necrotic fibers. There was a mild decrease in some respiratory chain enzymes. The 8344A-G mutation was homoplasmic in muscle and 80% in leukocytes. A brother with progressive hearing loss since age 10 had 70% heteroplasmy in blood. Biancheri et al. (2010) identified the 8344A-G mutation in a child with severe cavitating leukoencephalopathy. The infant had congenital cataracts, but developed normally until age 17 months when he showed psychomotor and neurologic regression. Symptoms included nystagmus, irritability, hypertonia, extensor plantar responses, and swallowing and feeding difficulties. Brain MRS showed increased lactate; muscle biopsy showed ragged-red fibers and decreased activity of mitochondrial complexes I+III and II+III (about 30% residual activity). Patient tissues showed high levels of mutant mtDNA that was not detected in the mother's tissues. Biancheri et al. (2010) noted the unusual early presentation in this patient and emphasized the characteristic cystic degenerative pattern of the brain imaging which is suggestive of a mitochondrial disorder. Using mutant and control cybrids, Yen et al. (2016) found that the 8344A-G mutation in MTTK suppressed maturation of COQ5 (616359) and disrupted a COQ5-containing mitochondrial protein complex, concomitant with reduction in mitochondrial membrane potential, oxygen consumption, and ATP production. (less)

In patients with the MERRF syndrome (545000), Shoffner et al. (1990) and Yoneda et al. (1990) identified an A-to-G transition at nucleotide 8344 that altered a conserved nucleotide in the tRNA(lys) gene (MTTK) and was heteroplasmic. The mutation was found in 3 independent pedigrees with the disease, while 75 controls did not have the mutation. Treatment with CoQ at 300 mg/day resulted in marked improvement of the phenotype. The same mutation was reported by Berkovic et al. (1991), Seibel et al. (1991), Shih et al. (1991), Tanno et al. (1991), and Zeviani et al. (1991). In all 3 patients with the MERRF syndrome, Noer et al. (1991) found the A-to-G substitution of nucleotide 8344 in the tRNA-lys gene. There was evidence that the mutations had arisen independently in these patients. Boulet et al. (1992) studied the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the skeletal muscle of 4 patients with myoclonus epilepsy and ragged-red fibers. The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase. The great majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wildtype clones. Approximately 15% wildtype mtDNAs restored translation and COX activity to near-normal levels. The results showed that the A-to-G substitution is functionally a recessive mutation that can be rescued by intraorganellar complementation. Proteins of the complex I and VI subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Among 9 affected members of a MERRF family, Suomalainen et al. (1993) showed that the mutated nucleotide 8344 comprised from 9 to 72% of the total mtDNA in the leukocytes. They made use of a solid-phase minisequencing technique which, in addition to identifying the A8344G mutation permitted simultaneous determination in the same assay from one blood sample of the relative amount of mutated mtDNA. Lertrit et al. (1992) studied 6 tissues from a patient with MERRF caused by the 8344 mutation. Heteroplasmy was observed in all: cerebellum, cerebrum, pancreas, liver, muscle, and heart. Thus, the mutated population of mitochondria must have existed before the formation of the 3 primary embryonic layers. The patient had no family history of a CNS disorder. Lertrit et al. (1992) found a lack of correlation between the degree of mtDNA heteroplasmy and clinical symptoms related to a particular organ and suggested that this indicated the presence of tissue-specific nuclear factors that modify the phenotypic expression of the 8344 mutation. Perhaps rather than a specific nuclear factor there are merely tissue differences in the requirements for the particular element of the respiratory chain involved. Shoffner and Wallace (1992) estimated that the MTTK*MERRF8334 mutation accounts for 80 to 90% of MERRF cases. Penisson-Besnier et al. (1992) described a family with MERRF and the point mutation at 8344. The mutation was found in all the maternal lineage with a relatively narrow range of variation in the percentage of mutant mitochondrial genomes with one exception represented by a set of dizygotic twins; one was clinically affected and showed a high proportion of mutant mitochondrial DNAs in blood cells, while the other was asymptomatic and showed very small amounts of mutant mtDNA in blood and skin. This suggests that the mitochondria are segregated at an early stage in oogenesis. In a study of 150 patients, most of them with diagnosed or suspected mitochondrial disease, Silvestri et al. (1993) found a high correlation between the A-to-G transition at position 8344 and the MERRF syndrome, but they also showed that this mutation can be associated with other phenotypes, including Leigh syndrome (500017), myoclonus or myopathy with truncal lipomas, and proximal myopathy. Furthermore, the absence of the 8344 mutation in 4 typical MERRF patients suggested that other mutations in the MTTK gene or elsewhere in the mitochondrial genome can produce the same phenotype. Hammans et al. (1993) studied 7 patients with the A8344-to-G mutation and their relatives. In 1 family, the mutation was deduced to be present in 4 generations. The index cases showed the core clinical features of MERRF, namely, myoclonus, ataxia, and seizures. Among other features, progressive external ophthalmoplegia, Leigh syndrome, and stroke-like episodes were observed, well recognized features in mitochondrial myopathies but novel manifestations of this genotype. Analyses for the proportion of mutant mtDNA, using an oligonucleotide hybridization technique, indicated that the proportion of mutant mtDNA in blood was significantly greater in symptomatic than in asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. In a Chinese family living in Taiwan, Fang et al. (1994) described MERRF caused by the A8344-to-G mutation in 6 persons, including the grandmother, 2 sibs, and 3 grandchildren. Action myoclonus was seen in 5; short stature, muscle weakness, and mental retardation in 4; lactic acidosis, hearing impairment, and ataxia in 2; and seizures in 1. Muscle biopsy from 2 affected sibs showed ragged-red fibers and abundant subsarcolemmal mitochondria with paracrystalline inclusions. Enriquez et al. (1995) studied the pathogenic mechanism of the A8344G mutation by comparing mtDNA-less cells which were transformed with either the mutant MTTK gene or the wildtype MTTK. A decrease of 50-60% in the specific tRNA-lys aminoacylation capacity per cell was found in mutant cells. Furthermore, several lines of evidence revealed that the severe protein synthesis impairment in MERRF mutation-carrying cells was due to premature termination of translation at each or near each lysine codon, with the deficiency of aminoacylated tRNA-lys being the most likely cause of this phenomenon. Borner et al. (2000) generated conflicting results, using an assay that combines tRNA oxidation and circularization. The authors determined the relative amounts and states of aminoacylation of mutant and wildtype tRNAs in tissue samples from patients with MELAS syndrome (540000) and MERRF syndrome. In most biopsies from MELAS patients carrying the 3243A-G substitution in the mitochondrial tRNALeu(UUR) gene (590050), the mutant tRNA was underrepresented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the 8344A-G substitution, neither the relative abundance nor the aminoacylation of the mutated tRNA was affected. The authors concluded that whereas the 3243A-G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNALeu, the 8344A-G mutation does not affect tRNALys function in MERRF patients in the same way. A specific mutation in mitochondrial DNA was first demonstrated by Shoffner et al. (1990); this was a missense mutation in the MTTK gene. The A-to-G mutation at nucleotide 8344 accounted for 80 to 90% of MERRF cases (Shoffner and Wallace, 1992). Biochemically, the mutation produced multiple deficiencies in the enzyme complexes of the respiratory chain, consistent with a defect in translation of all mtDNA-encoded genes. Chomyn et al. (1991) showed that transfer of mtDNAs carrying the mutation to human cell lines lacking their own mitochondrial DNA resulted in a severe defect in mitochondrial translation in the recipient cells, independent of nuclear background, implying that the tRNA mutation itself is sufficient to cause the disease. See 545000 for a discussion of the MERRF syndrome (myoclonus epilepsy associated with ragged-red fibers). In a study of 67 Australian cases labeled Leigh syndrome from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features, Rahman et al. (1996) identified 11 patients with mitochondrial DNA point mutations. Two mutations were in the MTATP6 gene (8993T-G, 516060.0001; 8993T-C, 516060.0002), and one was the common MERRF mutation in the MTTK gene (8344A-G). Chomyn (1998) reviewed the new insights into human mitochondrial function and genetics by study of the 8344A-G mutation in the gene encoding mitochondrial lysyl-tRNA. Holme et al. (1993) reported a woman with multiple symmetric lipomas (MSL; see 151800) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. Gamez et al. (1998) identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with MSL. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss. Horvath et al. (2007) reported a 66-year-old German man with the 8344A-G mutation who presented with an 8-year history of parkinsonism (556500). Symptoms included bradykinesia, resting tremor, and asymmetric rigidity. He also had proximal muscle weakness, hyporeflexia, decreased distal sensation, and bilateral hearing loss. Serum creatine kinase was elevated. He showed good response to levodopa. Skeletal muscle biopsy showed ragged-red fibers, fiber size variability, centrally placed nuclei, and atrophic and necrotic fibers. There was a mild decrease in some respiratory chain enzymes. The 8344A-G mutation was homoplasmic in muscle and 80% in leukocytes. A brother with progressive hearing loss since age 10 had 70% heteroplasmy in blood. Biancheri et al. (2010) identified the 8344A-G mutation in a child with severe cavitating leukoencephalopathy. The infant had congenital cataracts, but developed normally until age 17 months when he showed psychomotor and neurologic regression. Symptoms included nystagmus, irritability, hypertonia, extensor plantar responses, and swallowing and feeding difficulties. Brain MRS showed increased lactate; muscle biopsy showed ragged-red fibers and decreased activity of mitochondrial complexes I+III and II+III (about 30% residual activity). Patient tissues showed high levels of mutant mtDNA that was not detected in the mother's tissues. Biancheri et al. (2010) noted the unusual early presentation in this patient and emphasized the characteristic cystic degenerative pattern of the brain imaging which is suggestive of a mitochondrial disorder. Using mutant and control cybrids, Yen et al. (2016) found that the 8344A-G mutation in MTTK suppressed maturation of COQ5 (616359) and disrupted a COQ5-containing mitochondrial protein complex, concomitant with reduction in mitochondrial membrane potential, oxygen consumption, and ATP production. (less)