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Duchenne muscular dystrophy (DMD) is a genetic disorder that leads to progressive loss of motor, respiratory function, and cardiomyopathy; cardiac involvement is an important cause of mortality in DMD patients, despite that, DMD cardiac management remains highly variable and the evidence of disease modifying therapies on cardiac function is still scarce. Ataluren is a dystrophin restorative therapy for nonsense mutations in the DMD gene (nmDMD), although its therapeutic efficacy on cardiac function has not been properly assessed, longitudinal case-series suggest a beneficial effect. We present the cardiac outcomes of 23 nmDMD non-ambulatory Colombian patients treated with ataluren, 12 patients also received cardioprotective treatment prescribed by their cardiologists. 17 patients lost ambulation (LoA) during the treatment and 6 patients started therapy after LoA; patients had a median age of 14 years (10y-26y) and a median exposure to ataluren of 44 months at data cut-of, the median Left Ventricle Ejection Fraction (LVEF) at baseline was 67%. Patients reached an overall increase in the LVEF during the first year, followed by a decrease in LVEF during the second year of follow-up; we found that patients receiving cardioprotective treatment presented higher increases and lower decreases in their LVEF, achieving better cardiac function, thus supporting the need to improve the preventive management of cardiomyopathy in DMD patients. We observed a slow decline of LVEF in our patients and a high variability in cardiac function; only 4 patients presented with left ventricular systolic dysfunction at a mean age of 18.25 years, and 3 patients even showed a significant improvement in their LVEF (≥5%) compared to baseline. Although the evidence of ataluren efficacy on cardiac function is limited, our findings suggest that the treatment with ataluren and cardioprotective drugs could have a positive impact on cardiac function in nmDMD patients. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a genetic disease which leads to progressive muscular weakness, loss of ambulation and decline in cardio-pulmonary function; the latter being the major cause of morbidity and mortality in DMD. Natural history studies indicate that an early loss of ambulation (LoA) correlates with a faster pulmonary decline. Ataluren is a dystrophin restorative therapy for DMD patients with nonsense mutations (nmDMD) that has showed to delay the decline of pulmonary function, even in non-ambulatory patients. We collected data of pulmonary function from 20 mnDMD non-ambulatory patients treated with ataluren plus the standard of care during a 3-year follow-up period. 11 patients lost ambulation during the treatment and the remaining 9 started therapy after LoA; patients had a median age of 14 years (11y-26y) and a median exposure to ataluren of 45 months at data cut-off, the median FVC% baseline was 74%. We found that decline to predicted FVC <80% occurred in patients at 13 years, and by 20 years they still had a predicted FVC >30%, with an outlier predicted FVC <30% at 14 years due to a severe phenotype. Patients were assigned into two subgroups according to the age of LoA (>10yo and ≤10yo); we observed a slower yearly decline for FVC% in patients with LoA >10yo (average FVC% 3-year decline -1.13%) compared to patients with LoA ≤10yo (average FVC% 3-year decline -4.55%), being significant in both subgroups compared to natural history studies. We noticed a significantly higher preservation of pulmonary function in patients that started treatment with Ataluren before LoA (95% CI; p=0.035), supporting the recommendation to continue treatment after LoA. These results show a possible beneficial effect on the use of modifying therapies such as Ataluren in non-ambulatory DMD patients and a direct impact in the quality of life and the requirement of ventilatory support in these patients. [ABSTRACT FROM AUTHOR]

Aim: Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2-4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes., Methods: Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in São Paulo, Brazil, in October 2018., Results: Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified., Conclusion: Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy., (© 2020 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

NDUFV1 mutations have been related to encephalopathic phenotypes due to mitochondrial energy metabolism disturbances. In this study, we report two siblings affected by a diffuse leukodystrophy, who carry the NDUFV1 c.1156C>T (p.Arg386Cys) missense mutation and a novel 42-bp deletion. Bioinformatic and molecular analysis indicated that this deletion lead to the synthesis of mRNA molecules carrying a premature stop codon, which might be degraded by the nonsense-mediated decay system. Our results add information on the molecular basis and the phenotypic features of mitochondrial disease caused by NDUFV1 mutations., (Copyright © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)