Abstract
BackgroundMotor neuron disorders involving upper and lower neurons are a genetically and clinically heterogenous group of rare neuromuscular disorders with overlap among spinal muscular atrophies (SMAs) and amyotrophic lateral sclerosis (ALS). Classical SMA caused by recessive mutations in SMN1 is one of the most common genetic causes of mortality in infants. It is characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy. Non‐SMN1‐related spinal muscular atrophies are caused by variants in a number of genes, including VRK1, encoding the vaccinia‐related kinase 1 (VRK1). VRK1 variants have been segregated with motor neuron diseases including SMA phenotypes or hereditary complex motor and sensory axonal neuropathy (HMSN), with or without pontocerebellar hypoplasia or microcephaly.ResultsHere, we report an association of a novel homozygous splice variant in VRK1 (c.1159 + 1G>A) with childhood‐onset SMA or juvenile lower motor disease with brisk tendon reflexes without pontocerebellar hypoplasia and normal intellectual ability in a family with five affected individuals. We show that the VRK1 splice variant in patients causes decreased splicing efficiency and a mRNA frameshift that escapes the nonsense‐mediated decay machinery and results in a premature termination codon.ConclusionsOur findings unveil the impact of the variant on the VRK1 transcript and further support the implication of VRK1 in the pathogenesis of lower motor neuron diseases.
Highlights
Hereditary lower motor neuron diseases are a genetically and clinically heterogenous group of rare neuromuscular disorders within the spectrum spinal muscular atrophy/ hereditary motor neuropathy
Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association
Variants in VRK1, encoding the vaccinia-related kinase 1 (VRK1) which is widely expressed in human tissues and has a vital role in embryonic cortical neuronal proliferation,[6] have been reported in patients with SMAPCH or hereditary complex motor and sensory axonal neuropathy (HMSN) with microcephaly.[7,8,9]
Summary
Hereditary lower motor neuron diseases are a genetically and clinically heterogenous group of rare neuromuscular disorders within the spectrum spinal muscular atrophy/ hereditary motor neuropathy. They are characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy.[1] Clinical course varies depending on the type of SMA. Classical SMA caused by recessive mutations in SMN1 is one of the most common genetic causes of mortality in infants It is characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy. Conclusions: Our findings unveil the impact of the variant on the VRK1 transcript and further support the implication of VRK1 in the pathogenesis of lower motor neuron diseases
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