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

Abstract

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.

Figure 1

Molecular genetic data. (A) Individual dot plot showing the age of disease onset in patients harboring 5 common MT‐ATP6 pathogenic variants. Grey circles represent individual patient data, the red squares represent the median blood heteroplasmy level for LS, and the blue triangles indicate the median blood heteroplasmy level for non‐LS. *p < 0.05 (Wilcoxon test). (B) Individual dot plot showing the variations in blood mutant heteroplasmy levels in 3 phenotypic categories (asymptomatic carriers, LS, and non‐LS) and MT‐ATP6 pathogenic variants. Grey circles represent individual patient data, green circles represent the median blood heteroplasmy level in asymptomatic carriers, the red squares represent the median blood heteroplasmy level for LS, and the blue triangles indicate the median blood heteroplasmy level for non‐LS. *p < 0.05 (Wilcoxon test). We have examined the correlation of mutant heteroplasmy level and age of disease onset for each of the common MT‐ATP6 pathogenic variants. There is no statistical significant correlation identified in any variants. (C) Individual dot plot showing the difference in mutant heteroplasmy levels across different MT‐ATP6 variants. Grey circles represent individual patient data, and the blue triangles indicate the median difference of heteroplasmy level. B‐Bu = difference in the heteroplasmy level between blood and buccal samples; B‐M = difference in the heteroplasmy level between blood and muscle samples; B‐U = difference in the heteroplasmy level between blood and urine samples; LS = Leigh syndrome.

Figure 2

Risk of disease manifestation and blood heteroplasmy level. Estimated probability of being clinically affected based on the blood heteroplasmy level for 4 MT‐ATP6 pathogenic variants (m.8993T>C, m.8993T>G, m.9176T>C, and m.9185T>C) is illustrated. For instance, for an estimated probability of 0.5 being clinically affected, the mutant heteroplasmy appears to be the lowest in the m.8993T>G variant (54%), compared to 3 other variants m.8993T>C, m.9176T>C, and m.9185T>C (73%–78%).