Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy

AbstractIn Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

Abstract Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6‐months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease