FP.39 An international retrospective early natural history study of LAMA2-related dystrophies

Abstract

<i>LAMA2</i>-related dystrophies (LAMA2-RDs), caused by recessively inherited mutations in the <i>LAMA2</i> gene, represent one of the most common forms of congenital muscular dystrophy and are characterized by a complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RDs presenting congenitally typically have a phenotype of severe weakness, delayed motor milestones, failure to thrive and progressive respiratory insufficiency. While a comprehensive prospective natural history study has been performed in LAMA2-RD patients >5 years, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized. Extracting data from the CMD international registry, we describe a cohort of 62 patients with LAMA2-RD from 10 countries. Data for ages birth-5 years was retrospectively collected from the medical records. Inclusion criteria required that the patients had either two causative <i>LAMA2</i> variants or one confirmed causative <i>LAMA2</i> variant and a supporting clinical phenotype. Initial analyses reveal key findings including significant elevations of creatine kinase during the neonatal period which declined rapidly within the first few months of life. The mean age of first recognition of abnormal brain white matter appearance on MRI was 12.0 months. The first report of failure to thrive was at a mean age of 23.4 months. Noninvasive ventilation was initiated in half the patients by 24 months of age. This data represents the largest multinational retrospective early natural history study of LAMA2-RD which provides data essential for understanding early clinical history, especially as international, prospective early natural history data collection is in progress. Promising therapies in preclinical development for LAMA2-RD may ameliorate the phenotype of LAMA2-RD, particularly when initiated early in the course of the disease, making the comprehensive understanding of early natural history of LAMA2-RD timely and of great importance.