Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant.

Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mitochondrial DNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4 and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G > A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.

Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism.

Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck. Uncertainty surrounding this process limits our ability to address inherited mtDNA diseases. We produce a new, physically motivated, generalisable theoretical model for mtDNA populations during development, allowing the first statistical comparison of proposed bottleneck mechanisms. Using approximate Bayesian computation and mouse data, we find most statistical support for a combination of binomial partitioning of mtDNAs at cell divisions and random mtDNA turnover, meaning that the debated exact magnitude of mtDNA copy number depletion is flexible. New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. We analytically solve a mathematical description of this mechanism, computing probabilities of mtDNA disease onset, efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing a quantitative and experimentally-supported stochastic theory of the bottleneck.

A common mitchondrial DNA variant is associated with thinness in mothers and their 20-yr-old offspring.

A common mitochondrial (mt)DNA variant that is maternally inherited, the 16189 variant, is associated with type 2 diabetes and thinness at birth. To elucidate the association of the variant with thinness, we studied the 16189 variant in a well-characterized Australian cohort (n = 161) who were followed up from birth to age 20 yr. PCR analysis and mtDNA haplotyping was carried out on DNA from 161 offspring from consecutive, normal, singleton pregnancies followed from birth to age 20 yr. The 16189 mtDNA variant was present in 14 of the 161 20 yr olds (8.7%). Both the mothers with the 16189 variant and their 20-yr-old offspring were thinner than those without. Median (interquartile range) BMI was 21.9 kg/m(2) (20.4 to 22.9) in mothers with the variant compared with 23.5 (21.4 to 26.6) in those without (P = 0.013) and 22.2 (21.1 to 23.8) in 20 yr olds with the variant compared with 22.7 (20.8 to 25.6) in those without (P = 0.019). The 16189 variant was also associated with a high placental weight and high placental-to-birth weight ratio (P = 0.051 and P = 0.0024, respectively). Insulin sensitivity was normal in 20 yr olds with the 16189 variant. This contrasts with 20 yr olds who did not have the variant but who had been thin or small at birth and who had normal BMI and normal placental-to-birth weight ratio, but were insulin resistant. This study suggests that the 16189 mtDNA variant is associated with maternally inherited thinness in young adults. This may be mediated by effects on mtDNA replication and, thence, placental function. Further research is required to confirm these hypotheses.