SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum

Background and purpose The aim of our study was to describe patients with the p.D12Y variant (previously reported as D11Y) in SOD1 showing heterogeneous clinicopathological features. Methods We performed clinical, electrophysiological, magnetic resonance imaging (MRI) and muscle pathology studies in four SOD1 p.D12Y variant‐positive patients. Results The SOD1 p.D12Y clinical manifestations ranged from a benign phenotype characterized by distal distribution of muscular weakness and long survival to classic forms of amyotrophic lateral sclerosis with poor prognosis. Two patients with the distal clinical phenotype showed MRI and muscle pathology alterations indicating a concurrent muscle involvement. In one of these patients significant myopathic changes were associated with rimmed vacuolar pathology. Conclusions We expand the clinical spectrum of SOD1 p.D12Y variant, including predominant lower motor neuron forms with long survival and classic forms with aggressive course. Some patients may have concomitant distal myopathy without other explanations. Given clinical, MRI and muscle pathology alterations, SOD1 should be considered in the differential diagnosis of molecularly undefined distal myopathies with rimmed vacuoles.