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The identification of the m.12207G > A variant in MT-TS2, (NC_012920.1:m.12207G > A) was first reported in 2006. The affected individual presented with developmental delay, feeding difficulty, proximal muscle weakness, and lesions within her basal ganglia, with heteroplasmy levels of 92% in muscle and no evidence of maternal inheritance. Herein, we report a case involving a 16-year-old boy with the same pathogenic variation and different phenotype, including sensorineural deafness, epilepsy, and intellectual disability, without diabetes mellitus (DM). His mother and maternal grandmother had similar but milder symptoms with DM. Heteroplasmy levels of the proband in blood, saliva, and urinary sediments were 31.3%, 52.6%, and 73.9%, respectively, while those of his mother were 13.8%, 22.1%, and 29.4%, respectively. The differences in the symptoms might be explained by the different levels of heteroplasmy. To our knowledge, this is the first familial report of the m.12207G > A variant in MT-TS2 that causes DM. The present case showed milder neurological symptoms than did the former report, and suggests the presence of a good phenotype–genotype correlation within this family.

Abstract Background Mitochondrial DNA depletion syndrome (MTDPS) is part of a group of mitochondrial diseases characterized by a reduction in mitochondrial DNA copy number. Most MTDPS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism. Methods We performed the whole‐exome sequencing of a hepato‐encephalopathy patient with MTDPS and functional analyses to determine the clinical significance of the identified variant. Results Here, whole‐exome sequencing of a patient presenting with hepato‐encephalopathy and MTDPS identified a novel homozygous frameshift variant, c.13_29del (p.Trp6Profs*71) in MICOS13. MICOS13 (also known as QIL1, MIC13, or C19orf70) is a component of the MICOS complex, which plays crucial roles in the maintenance of cristae junctions at the mitochondrial inner membrane. We found loss of MICOS13 protein and fewer cristae structures in the mitochondria of fibroblasts derived from the patient. Stable expression of a wild‐type MICOS13 cDNA in the patients fibroblasts using a lentivirus system rescued mitochondrial respiratory chain complex deficiencies. Conclusion Our findings suggest that the novel c.13_29del (p.Trp6Profs*71) MICOS13 variant causes hepato‐encephalopathy with MTDPS. We propose that MICOS13 is classified as the cause of MTDPS.

Background Enoyl-CoA hydratase short-chain 1 (ECHS1) is an enzyme involved in the metabolism of branched chain amino acids and fatty acids. Mutations in the ECHS1 gene lead to mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, resulting in the accumulation of intermediates of valine. This is one of the most common causative genes in mitochondrial diseases. While genetic analysis studies have diagnosed numerous cases with ECHS1 variants, the increasing number of variants of uncertain significance (VUS) in genetic diagnosis is a major problem. Methods Here, we constructed an assay system to verify VUS function for ECHS1 gene. A high-throughput assay using ECHS1 knockout cells was performed to index these phenotypes by expressing cDNAs containing VUS. In parallel with the VUS validation system, a genetic analysis of samples from patients with mitochondrial disease was performed. The effect on gene expression in cases was verified by RNA-seq and proteome analysis. Results The functional validation of VUS identified novel variants causing loss of ECHS1 function. The VUS validation system also revealed the effect of the VUS in the compound heterozygous state and provided a new methodology for variant interpretation. Moreover, we performed multiomics analysis and identified a synonymous substitution p.P163= that results in splicing abnormality. The multiomics analysis complemented the diagnosis of some cases that could not be diagnosed by the VUS validation system. Conclusions In summary, this study uncovered new ECHS1 cases based on VUS validation and omics analysis; these analyses are applicable to the functional evaluation of other genes associated with mitochondrial disease. [ABSTRACT FROM AUTHOR]

Objective: Neonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis.Design: Retrospective observational study from January 2004 to March 2020.Setting: Population based.Patients: Patients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches.Interventions: None.Main Outcome Measures: Disease types, initial symptoms, biochemical findings, molecular diagnosis and prognosis.Results: Of the 281 patients, multisystem mitochondrial disease was found in 194, Leigh syndrome in 26, cardiomyopathy in 38 and hepatopathy in 23 patients. Of the 321 initial symptoms, 236 occurred within 2 days of birth. Using biochemical approaches, 182 patients were diagnosed by mitochondrial respiratory chain enzyme activity rate and 89 by oxygen consumption rate. The remaining 10 patients were diagnosed using a genetic approach. Genetic analysis revealed 69 patients had nuclear DNA variants in 36 genes, 11 of 15 patients had mitochondrial DNA variants in five genes and four patients had single large deletion. The Cox proportional hazards regression analysis showed the effects of Leigh syndrome (HR=0.15, 95% CI 0.04 to 0.63, p=0.010) and molecular diagnosis (HR=1.87, 95% CI 1.18 to 2.96, p=0.008) on survival.Conclusions: Neonatal-onset mitochondrial disease has a heterogenous aetiology. The number of diagnoses can be increased, and clarity regarding prognosis can be achieved by comprehensive biochemical and molecular analyses using appropriate tissue samples. [ABSTRACT FROM AUTHOR]