Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.

Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.

Expanding the spectrum of neonatal-onset AIFM1-associated disorders.

OBJECTIVES: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. METHODS: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. RESULTS: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. INTERPRETATION: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.

Selected Physical Characteristics and Playing-Related Musculoskeletal Problems in Adolescent String Instrumentalists.

PURPOSE: Music research has investigated the prevalence of playing-related musculoskeletal problems in adults and children, but the prevalence in adolescents has not been established. String instrumentalists report high problem rates, though it is unclear whether rates vary between upper and lower strings in adolescent instrumentalists. Further, there is limited evidence for the association between physical characteristics and playing problems in this group of musicians. METHODS: Seventy-six adolescent string musicians from the West Australian Youth Orchestras were surveyed. Their experience of playing problems, both symptoms (PRMS) and disorders (PRMD), within the last month and measurements of body mass index, hand span, and joint mobility (Beighton scale) were obtained. Prevalence rates were calculated and compared between upper and lower string instrumentalists using a chi-squared test. Logistic regression examined the association of physical measures with playing problems, adjusting for confounding factors. RESULTS: Within the last month, 73.5% participants reported experiencing a PRMS and 26.5percnt; reported experiencing a PRMD. There was no significant difference between the problem rates in upper and lower string instrumentalists. After adjusting for potential confounders, an increasing count of hypermobile joints remained significantly associated with problems (OR 1.76, CI 1.02 to 3.04, p=0.042). CONCLUSIONS: This study found playing problems are common in adolescent string instrumentalists, though rates did not differ between upper and lower string players. Joint hypermobility was associated with playing-related problems in adolescent musicians. Early identification of problems in this group of maturing musicians may help prevent disabling disorders and maximize performance.