Novel VRK1 Deletion and Missense Variants Associated With Non-5q Spinal Muscular Atrophy (SMA)
Alyssa Thallemer1, Yu-Ting Chen2
1School of Medicine, Creighton University, 2Neurology, Immanuel Neurological Institute
Background:
Vaccinia-related kinase 1 (VRK1) mutations impair kinase activity, leading to a spectrum of autosomal recessive neuromuscular and neurodegenerative disorders. Reported neuromuscular phenotypes include SMA, distal hereditary motor neuropathy, and Chaco-Marrie-Tooth type 2. These SMA cases usually present with predominant distal weakness, with or without pontocerebellar hypoplasia.
Results:
We report the case of a 34-year-old man with infantile-onset, progressive muscle weakness. Around age 21, he began using forearm crutches in public and an electric wheelchair at home. He also has hypoxia and hypercapnia respiratory failure, managed with non-invasive ventilation. Neurological examination, limited by a telemedicine visit, revealed severe proximal and distal weakness in upper and lower extremities, with Medical Research Council (MRC) scale of 3/5 in the upper and 2/5 in the lower limbs. Serum creatine kinase was 1066U/L. Electrodiagnostic studies demonstrated a diffuse chronic and active neurogenic process affecting motor neurons or motor nerves, characterized by small compound muscle action potential (CMAP) amplitudes, normal sensory nerve action potentials (SNAP), and severe diffuse chronic reinnervation with ongoing denervation in proximal and distal muscles in the upper and lower extremities and thoracic paraspinal muscle. Negative inspiratory force was -31 cmH₂O and vital capacity was 1200 mL. A biopsy of the left quadriceps muscle showed end-stage muscle tissue atrophy. Whole genome sequencing revealed a likely pathogenic heterozygous 11.24 kb deletion at 14q32.2q32.2 in VRK1, along with an in-trans VRK1 variant of uncertain significance(c791A>G, p.Asn264Ser).
Conclusions:
We report two novel VRK1 mutations associated with non-5q SMA, including the first pathogenic deletion mutation reported in VRK1 gene. Previously described VRK1-related disorders are predominantly associated with nonsense point mutations. The point mutation reported here c.791A>G (p.Asn264Ser), has also not been previously documented. Furthermore, the clinical presentation differs from prior reports, showing significant proximal muscles involvement and respiratory failure rather than the typical distal-predominant presentation.
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