The molecular diagnosis of mitochondrial disorders still remains elusive in a large proportion of patients, but advances in next generation sequencing are significantly improving our chances to detect mutations even in sporadic patients. Syndromes associated with mitochondrial DNA multiple deletions are caused by different molecular defects resulting in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia to multi-systemic disorders of variable severity. The mutations underlying these conditions remain undisclosed in half of the affected subjects. We applied next-generation sequencing of known mitochondrial targets (MitoExome) to probands presenting with adult-onset mitochondrial myopathy and harbouring mitochondrial DNA multiple deletions in skeletal muscle. We identified autosomal recessive mutations in the DGUOK gene (encoding mitochondrial deoxyguanosine kinase), which has previously been associated with an infantile hepatocerebral form of mitochondrial DNA depletion. Mutations in DGUOK occurred in five independent subjects, representing 5.6% of our cohort of patients with mitochondrial DNA multiple deletions, and impaired both muscle DGUOK activity and protein stability. Clinical presentations were variable, including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis in a young female who had received a liver transplant at 9 months of age and adult-onset lower motor neuron syndrome with mild cognitive impairment. These findings reinforce the concept that mutations in genes involved in deoxyribonucleotide metabolism can cause diverse clinical phenotypes and suggest that DGUOK should be screened in patients harbouring mitochondrial DNA deletions in skeletal muscle.

To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase ␥ (POLG2) and a mutation in the OPA1 gene.Design: Clinical examination and morphological, biochemical, and molecular analyses.Setting: Tertiary care university hospitals and molecular genetics and scientific computing laboratory.Patient: A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal.Results: A muscle biopsy specimen showed scattered intensely succinate dehydrogenase-positive and cytochrome-c oxidase-negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those in POLG (polymerase ␥ gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C). Conclusion:Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.

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Mutations in the mitochondrial DNA cytochrome b gene (MTCYB) have been commonly associated with isolated mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders, and only once with a parkinsonism/mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) overlap syndrome. Here, we describe a novel mutation (m.14864 T>C) in MTCYB in a 15-year-old girl with a clinical history of migraines, epilepsy, sensorimotor neuropathy, and strokelike episodes, a clinical picture reminiscent of MELAS. The mutation, which changes a highly conserved cysteine to arginine at amino acid position 40 of cytochrome b, was heteroplasmic in muscle, blood, fibroblasts, and urinary sediment from the patient but absent in accessible tissues from her asymptomatic mother. This case demonstrates that MTCYB must be included in the already long list of mitochondrial DNA genes that have been associated with the MELAS phenotype.

We report an unusual case history of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood due to a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.

To describe the first American patient with a congenital muscle dystrophy characterized by the presence in muscle of gigantic mitochondria displaced to the periphery of the fibers and to stress the potential origin and effects of the mitochondrial changes. Design: Case report and documentation of a novel mutation in the gene encoding choline kinase beta (CHKB). Setting: Collaboration between 2 tertiary care academic institutions. Patient: A 2-year-old African American boy with weakness and psychomotor delay. Interventions: Detailed clinical and laboratory studies, including muscle biopsy, biochemical analysis of the mitochondrial respiratory chain, and sequencing of the CHKB gene. Main Outcome Measures: Definition of unique mitochondrial changes in muscle. Results: This patient had the same clinical and laboratory features reported in the first cohort of patients, but he harbored a novel CHKB mutation and had isolated cytochrome c oxidase deficiency in muscle. Conclusions: Besides confirming the phenotype of CHKB mutations, we propose that this disorder affects the mitochondria-associated membrane and the impaired phospholipid metabolism in the mitochondria-associated membrane causes both the abnormal size and displacement of muscle mitochondria.

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