bims-cytox1 2019-06-09 papers

Issue of 2019–06–09
three papers selected by
Gavin McStay, Staffordshire University

J Clin Med. 2019 Jun 04. pii: E789. [Epub ahead of print]8(6):

A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia.

Charlotte M Zierz, Karen Baty, Emma L Blakely, Sila Hopton, Gavin Falkous, Andrew M Schaefer, Marios Hadjivassiliou, Ptolemaios G Sarrigiannis, Yi Shiau Ng, Robert W Taylor.

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A>G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxia.

Keywords: cerebellar ataxia; heteroplasmy; isolated COX deficiency; mitochondrial DNA; single fibre segregation studies

DOI: https://doi.org/10.3390/jcm8060789

Genet Med. 2019 Jun 07.

Biparental inheritance of mitochondrial DNA in humans is not a common phenomenon.

Rocio Rius, Mark J Cowley, Lisa Riley, Clare Puttick, David R Thorburn, John Christodoulou.

PURPOSE: A recent report has raised the possibility of biparental mitochondrial DNA (mtDNA) inheritance, which could lead to concerns by health-care professionals and patients regarding investigations and genetic counseling of families with pathogenic mitochondrial DNA variants. Our aim was to examine the frequency of this phenomenon by investigating a cohort of patients with suspected mitochondrial disease.
METHODS: We studied genome sequencing (GS) data of DNA extracted from blood samples of 41 pediatric patients with suspected mitochondrial disease and their parents.
RESULTS: All of the mtDNA variants in the probands segregated with their mother or were apparently de novo. There were no variants that segregated only with the father and none of these families showed evidence of biparental inheritance of their mtDNA.
CONCLUSION: Paternal mitochondrial transmission is unlikely to be a common occurrence and therefore at this point we would not recommend changes in clinical practice.

Keywords: genetic counseling; genetic testing; mitochondrial diseases; mitochondrial genome; paternal inheritance

DOI: https://doi.org/10.1038/s41436-019-0568-0

Ann Neurol. 2019 Jun 02.

COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.

Michio Inoue, Shumpei Uchino, Aritoshi Iida, Satoru Noguchi, Shinichiro Hayashi, Tsutomu Takahashi, Katsunori Fujii, Hirofumi Komaki, Eri Takeshita, Ikuya Nonaka, Yukinori Okada, Takuya Yoshizawa, Leentje Van Lommel, Frans Schuit, Yu-Ichi Goto, Masakazu Mimaki, Ichizo Nishino.

OBJECTIVE: Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms.
METHODS: Whole exome sequencing was performed in two unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology. We assessed the COX6A2 variants using measurements of enzymatic activities and assembly of mitochondrial respiratory chain complexes in the samples from the patients and knockout mice.
RESULTS: Both patients presented muscle weakness and hypotonia in four limbs along with facial muscle weakness. One patient had cardiomyopathy. Neither patient exhibited involvement from other organs. Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart. The variants detected were homozygous c.117C>A (p.Ser39Arg) and compound heterozygous c.117C>A (p.Ser39Arg) and c.127T>C (p.Cys43Arg). We found specific reductions in complex IV activities in the skeletal muscle of both individuals. Assembly of complex IV and its supercomplex formation were impaired in the muscle.
INTERPRETATION: This study indicates that biallelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency. This article is protected by copyright. All rights reserved.

Keywords: congenital myopathy; cytochrome c oxidase deficiency; mitochondrial

DOI: https://doi.org/10.1002/ana.25517