A recurrent de novo DYNC1H1 tail domain mutation causes spinal muscular atrophy with lower extremity predominance, learning difficulties and mild brain abnormality

•De novo missense mutation c.751C>T in DYNC1H1 gene is a pathogenic mutation causing SMALED.•The mutation has a high phenotypic-genotypic correlation in 4 unrelated patients.•Leg muscle MRI findings are highly specific in DYNC1H1-related SMALED.•Muscle biopsy findings are variable and non-specific so has limited use in DYNC1H1-related SMALED. We describe four unrelated patients with the same de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene. We found a high phenotype-genotype correlation with all four patients having early childhood-onset predominant lower limb muscle weakness and wasting which was slowly progressing and later-onset mild upper extremities proximal weakness. All four patients presented minor cognitive dysfunction with learning difficulty and developmental behavioural comorbidities with mild abnormalities in the brain MRI. The leg muscle MRI findings are highly consistent in DYN1CH1-related spinal muscular atrophy with lower limb predominance (SMALED) with relative sparing of biceps femoris and semitendinosus, and hypertrophy of adductor longus in the thighs; and sparing the anterior and medial muscles in the calves. This report provides important clinical evidence indicating the de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene is pathogenic causing SMALED. Muscle MRI is more specific than muscle biopsy in the diagnosis of SMALED.