Bi-allelic mutations (homozygous or compound heterozygous) mutations in the VRK1gene cause neurological disease that can have congenital and/or post-natal progressive manifestations. Inheritance is autosomal recessive.
VRK1mutations were first described in patients with spinal muscular atrophy (SMA) and pontocerebellar hypoplasia type 1 (PCH1; OMIM #607596), presenting with severe congenital microcephaly. Some, but not all, patients have structural brain abnormalities, which are commonly associated with delayed development and ultimate intellectual disability.
Motor-neuron disease is the most consistent feature of VRK1-associated disease, with widely variable age of onset and severity. The spectrum of motor neuron disease is wide, including childhood-onset SMA, juvenile/early-onset amyotrophic lateral sclerosis (ALS) or SMA, and adult-onset, distal hereditary motor neuropathy (dHMN), with lower extremity predominant, progressive weakness, with upper and lower motor neuron signs. Sensory peripheral neuropathy has also been described.
VRK1-associated disease is rare. Fewer than 30 cases have been reported as of 2020, in individuals from various countries and ethnicities. Notably, in Ashkenazi Jews there is a founder mutation (VRK1R358X, rs137853063), with a heterozygote carrier frequency of ~ 1/230 in this ethnic group. This nonsense mutation is associated with a severe phenotype including severe congenital microcephaly and childhood onset SMA. In general, missense mutations, which are the majority of VRK1mutations described, have been associated with motor and sensory neuropathy without CNS involvement.
VRK1