Following the identification of the mutation, it became clear that the patients shared many clinical features, but it would have been difficult to separate them clinically from the rest of the cohort. After an unremarkable perinatal history, onset of slow, progressive, neurodegenerative features and/or static encephalopathy ensued by 6 months of age. Clinical features included failure to develop gross or fine motor skills, absent or delayed speech, progressive spasticity and spontaneous epileptic seizures (Table 1 and Table S1). Brain MRI demonstrated mild atrophy of the cerebellum, pons and corpus callosum (Figure 1B), together with progressive microcephaly. Electromyography, while initially normal at a young age, demonstrated age-dependent muscle fibrillations and high amplitude motor unit potentials in one patient, indicating progressive spinal motor neuron loss. Extensive testing for known metabolic or degenerative diseases was negative, suggesting a here-to-fore unknown condition.
