P.184 Defining the pathological natural history of LAMA2 muscular dystrophy

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LAMA2 muscular dystrophy (LAMA2-MD), is an autosomal recessive condition due to pathogenic variants in the <i>LAMA2</i> gene. The <i>LAMA2</i> gene encodes for the alpha 2 subunit of laminin proteins, which act as an important component of the extracellular matrix. Specifically, laminin-211 (Lm-211; merosin) is the major laminin of mature skeletal muscle, acts as an anchor for myofibers in the basement membrane; its laminin subunit composition is alpha2beta1gamma1. Variants in the <i>LAMA2</i> gene and subsequent alterations in laminin-211 protein expression or composition result in a spectrum of clinical manifestations that range from severe, early onset congenital muscular dystrophy (a.k.a. MDC1A) to a milder, later-onset muscular dystrophy (a.k.a. LGMD R23). The pathology of LAMA2-MD in skeletal muscle biopsies includes dystrophic changes (active and chronic degeneration and regeneration), with a decrease in or loss of laminin alpha 2 (merosin) immunostaining. However, the pathological natural history of LAMA2-MD has not been systematically studied and it is unclear what spectrum of altered expression may be seen in other extracellular matrix proteins. In this study, we assessed the histologic and immunofluorescent findings of a cohort of 57 muscle biopsy samples obtained from 50 different LAMA2-MD patients and in comparison, to 9 age-matched patients with normal skeletal muscle histology. The severity of dystrophic disease was established using H&E, Masson trichrome, and developmental myosin stains. Expression of laminins in muscle was assessed through immunostaining for laminin-211, laminin-111, laminin-411, and laminin-511. While analysis is still in progress, the severity of dystrophic pathology will be evaluated in the context of patient age, type of <i>LAMA2</i> mutation, and expression patterns of laminin proteins. Our findings will clarify the pathological spectrum of LAMA2-MD in a manner that will allow the identification of useful pathological endpoints for future human studies.