Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

Distinct clinical syndromes have been associated with pathogenic MT‐ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty‐one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT‐ATP6–related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310–315

[1]  Marni J. Falk,et al.  MT‐ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases , 2019, Human mutation.

[2]  D. Turnbull,et al.  Mitochondrial donation: from test tube to clinic , 2018, The Lancet.

[3]  Robert W. Taylor,et al.  MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load , 2018, EBioMedicine.

[4]  Robert W. Taylor,et al.  Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors , 2018, Annals of clinical and translational neurology.

[5]  Robert W. Taylor,et al.  Recent Advances in Mitochondrial Disease. , 2017, Annual review of genomics and human genetics.

[6]  Joanna Poulton,et al.  Pathogenic Mitochondrial tRNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease , 2013, Human mutation.

[7]  R. Rodenburg,et al.  A guide to diagnosis and treatment of Leigh syndrome , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[8]  G. Comi,et al.  Phenotypic heterogeneity of the 8344A>G mtDNA “MERRF” mutation , 2013, Neurology.

[9]  Jacqueline A Palace,et al.  Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease , 2012, Neurology.

[10]  I. D. de Coo,et al.  PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring. , 2012, Human reproduction update.

[11]  Robert W. Taylor,et al.  Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[12]  D. Turnbull,et al.  The determination of complete human mitochondrial DNA sequences in single cells: implications for the study of somatic mitochondrial DNA point mutations. , 2001, Nucleic acids research.

[13]  S. Dimauro,et al.  Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation , 1999, Journal of Inherited Metabolic Disease.

[14]  D. Turnbull,et al.  Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA , 1999, Nature Genetics.

[15]  S. Dimauro,et al.  Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. , 1999, American journal of human genetics.

[16]  M. Zeviani,et al.  Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families , 1997, Journal of neurology, neurosurgery, and psychiatry.

[17]  J. Christodoulou,et al.  Leigh syndrome: Clinical features and biochemical and DNA abnormalities , 1996, Annals of neurology.

[18]  J. Christodoulou,et al.  Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. , 1992, American journal of human genetics.

[19]  A. Harding,et al.  A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. , 1990, American journal of human genetics.