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

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin

Incentivizing the Dynamic Workforce: Learning Contracts in the Gig-Economy

In principal-agent models, a principal offers a contract to an agent to perform a certain task. The agent exerts a level of effort that maximizes her utility. The principal is oblivious to the agent's chosen level of effort, and conditions her wage only on possible outcomes. In this work, we consider a model in which the principal is unaware of the agent's utility and action space. She sequentially offers contracts to identical agents, and observes the resulting outcomes. We present an algorithm for learning the optimal contract under mild assumptions. We bound the number of samples needed for the principal obtain a contract that is within $\epsilon$ of her optimal net profit for every $\epsilon>0$

Hypomyelination and Congenital Cataract Broadening the Clinical Phenotype

Objective: To further delineate the clinical spectrum of hypomyelination and congenital cataract (HCC), a rare autosomal recessive white matter disorder due to deficiency of a membrane protein, hyccin, encoded by FAM126A

Treatment outcome of creatine transporter deficiency: international retrospective cohort study.

To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1-3 = mild; 4-6 = moderate; and 7-9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females