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IMPORTANCE Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease. OBJECTIVE To determine the molecular basis of multiple respiratory chain complex deficiencies. DESIGN, SETTING, AND PARTICIPANTS We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. RESULTS Presumptive causal variants were identified in 28 patients (53%; 95% Cl, 39%-67%) and possible causal variants were identified in 4 (8%; 95% Cl, 2%-18%). Together these accounted for 32 patients (60% 95% Cl, 46%-74%) and involved 18 different genes. These included recurrent mutations in RMND1, AARS2, and MT01, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1, and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1 and cardiomyopathy with AARS2 and MT01. However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations and no cardiomyopathy with founder SC02 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% Cl, 26%-54%). CONCLUSIONS AND RELEVANCE Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods. [ABSTRACT FROM AUTHOR]

Objective: To explore myelin components and mitochondrial changes within the central nervous system in patients with well-characterized mitochondrial disorders due to nuclear DNA or mitochondrial DNA (mtDNA) mutations. Design: Immunohistochemical analysis, histochemical analysis, mtDNA sequencing, and real-time and longrange polymerase chain reaction were used to determine the pathogenicity of mtDNA deletions. Setting: Department of Clinical Pathology, Columbia University Medical Center, and New castle Brain Tissue Resource. Patients: Seventeen patients with mitochondrial disorders and 7 controls were studied from August 1, 2009, to August 1, 2010. Main Outcome Measure: Regions of myelinassociated glycoprotein (MAG) loss. Results: Myelin-associated glycoprotein loss in Kearns-Sayre syndrome was associated with oligodendrocyte loss and nuclear translocation of apoptosis-inducing factor, whereas inflammation, neuronal loss, and axonal injury were minimal. In a Kearns-Sayre syndrome MAG loss region, high levels of mtDNA deletions together with cytochrome-c oxidase-deficient cells and loss of mitochondrial respiratory chain subunits (more prominent in the white than gray matter and glia than axons) confirmed the pathogenicity of mtDNA deletions. Conclusion: Primary mitochondrial respiratory chain defects affecting the white matter, and unrelated to inflammation, are associated with MAG loss and central nervous system demyelination. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial diseases are characterized by wide phenotypic and genetic variability, but presentations in adults with akinetic rigidity and hyperkinetic movement disorders are rare. Objectives: To describe clinically a subject with progressive neurodegeneration characterized by psychosis, dementia, and akinesia-rigidity, and to associate this phenotype with a novel mitochondrial transfer RNAPhe (tRNAPhe) (MTTF) mutation. Design, Setting, and Patient: Case description and detailed laboratory investigations of a 57-year-old woman at a university teaching hospital and a specialist mitochondrial diagnostic laboratory. Results: Histopathological findings indicated that an underlying mitochondrial abnormality was responsible for the subject's progressive neurological disorder, with mitochondrial genome sequencing revealing a novel m.586G>A MTTF mutation. Conclusions: The clinical phenotypes associated with mitochondrial disorders may include akinesia-rigidity and psychosis. Our findings further broaden the spectrum of neurological disease associated with mitochondrial tRNAPhe mutations. [ABSTRACT FROM AUTHOR]

Background: Pathogenic mutations of the human mitochondrial genome are associated with well-characterized, progressive neurological syndromes, with mutations in the transfer RNA genes being particularly prominent. Objective: To describe a novel mitochondrial transfer RNAPro gene mutation in a woman with a myoclonic epilepsy with ragged-red fibers-like disease. Design, Setting, and Patient: Case report of a 49-year-old woman presenting with a myoclonic epilepsy with ragged-red fibers-like disease comprising myoclonic jerks, cerebellar ataxia, and proximal muscle weakness. Results: Histochemical analysis of a muscle biopsy revealed numerous cytochrome-c oxidase-deficient, ragged-red fibers, while biochemical studies indicated decreased activity of respiratory chain complex I. Molecular investigation of mitochondrial DNA revealed a new heteroplasmic mutation in the TφC stem of the mitochondrial transfer RNAPro gene that segregated with cytochrome-c oxidase deficiency in single muscle fibers. Conclusions: Our case serves to illustrate the everevolving phenotypic spectrum of mitochon drial DNA disease and the importance of performing comprehensive mitochondrial genetic studies in the absence of common mitochondrial DNA mutations. [ABSTRACT FROM AUTHOR]

Objective: To describe an unusual clinical phenotype in an adult harboring 2 compound heterozygous polymerase γ (POLG) mutations. Design: Case report. Setting: University-based outpatient neurology clinic and pathology and genetics laboratory. Patient: A 27-year-old man presenting with isolated distal myopathy of the upper extremities in the absence of sensory disturbances. Results: Histochemical analysis of a muscle biopsy specimen showed numerous cytochrome c oxidase-deficient fibers. Molecular analysis revealed marked depletion of muscle mitochondrial DNA in the absence of multiple mitochondrial DNA deletions. Sequence analysis of the POLG gene revealed heterozygous sequence variants in compound c.1156C>T (p.R386C) and c.2794C>T (p.H932Y) segregating with clinical disease in the family. The p.R386C change appears to be a novel mutation. Conclusion: Our case broadens the phenotypic spectrum of disorders associated with POLG mutations and highlights the complex relationship between genotype and phenotype in POLG-related disease. [ABSTRACT FROM AUTHOR]