A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course.

The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.

Early MRI in neonatal hypoxic-ischaemic encephalopathy treated with hypothermia: Prognostic role at 2-year follow-up.

UNLABELLED: The prognostic role of early MRI (≤ 6 days of life) is still uncertain in hypoxic-ischaemic encephalopathy (HIE) treated with hypothermia. OBJECTIVE: To compare the prognostic value of early (≤ 6 days) and late MRIs (≥ 7 days) in predicting adverse outcome at 2 years old in asphyxiated term neonates treated with hypothermia. METHODS: This retrospective study included all asphyxiated neonates eligible for hypothermia treatment between November 2009 and July 2012. Two MRI scans were performed at a median age of day 4 (early MRI) and day 11 (late MRI). Two radiologists analysed independently each MRI. Imaging was classified as normal/subnormal or abnormal, using a visual analysis. Apparent diffusion coefficient (ADC) values were measured within predefined areas and posterior limb of internal capsule (PLIC) signal intensity was analysed. Neurodevelopmental outcome was assessed at 18-41 months (median age 24 months) as favourable or adverse. RESULTS: Of the 38 neonates followed up, 8 had an adverse outcome, all related to abnormal MRIs. Twenty-nine neonates had both MRIs sequentially. Both early and late MRIs yielded 100% sensitivity for adverse outcome by using the visual analysis. Early MRI had a higher specificity than late MRI (96.3% versus 89.3%). ADC measurements did not provide further information than visual analysis. PLIC signal abnormalities were a good predictor of adverse outcome on both MRIs. CONCLUSION: Early MRI (≤ 6 days) was a good predictor of neurodevelopmental outcome at 2 years old. It could reliably guide intensive care decisions after the end of hypothermia treatment.