P.6.7 Wide phenotypic spectrum of SMA with lower limbs predominance due to mutations in the tail domain of DYNC1H1 gene: A case series

A relatively common neurogenic condition is the autosomal dominant congenital Spinal Muscular Atrophy, mainly affecting the lower limbs (SMA-LED). A proportion of patients with SMA-LED carry mutations in the tail domain of the Cytoplasmic Dynein Heavy Chain 1 (DYNC1H1). Mutations located in the same DYNC1H1 domain have also been described in a family with Charcot–Marie–Tooth, while mutations located in other domains have been described in 2 patients with mental retardation and variable neuronal migration defects but no obvious SMA. To expand the clinical and imaging phenotype of SMA-LED due to DYNC1H1 mutations. We report a series of 10 cases from 7 families, carrying mutations in the tail domain of DYNC1H1, mostly with autosomal dominant inheritance, characterized by congenital/very early onset and similar clinical presentation, frequent association with cognitive impairment and variable clinical severity. In some of these cases imaging of the brain (MRI) and the muscles (lower limbs MRI) was obtained. In most cases with cognitive impairment the brain MRI showed neuronal migration defects resulting in polymicrogyria or cortical dysplasia. In all cases the muscle MRI showed distinctive features characterized by selective sparing and relative hypertrophy of the adductor longus and of the semitendinosus muscles at the thigh level, while at the calf level there was diffuse involvement with relative sparing of the anterior muscles. We describe for the first time a series of cases with both congenital SMA-LED and neuronal migration defects coexisting as a result of a mutation in DYNC1H1. Furthermore we confirm a specific pattern of muscular involvement in this condition, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. Further studies are necessary to clarify whether the location and nature of the DYNC1H1 mutations play a role in the wide phenotypic spectrum that is emerging for this condition.