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Título

Biallelic pathogenic variants in vaccinia related kinase-1 gene is a cause of motor neuronopathy with upper motor neuron signs

Resumo

Background: Recessive mutations in VRK1 (human vaccinia-related kinase 1) gene have been reported in a small number of patients with spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH). More recently, a pure axonal neuropathy has been reported in association with VRK1 mutations. Objective: To describe clinical, neurophysiological and image findings in cohort of patients with VRK1-related disorder. Methods: Clinical, MRI and electrophysiological data were collected in predefined preform from patients with with genetic diagnosis. Results: Six affected patients from 5 different families were included. Four were female, and there was history of consanguinity in just one family. All cases presented in the first decade of live with difficulty walking or frequent falls, and no patient had sensory abnormalities. One patient presented with fasciculation, and all patients presented with brisk reflexes. Brain and spinal MRI was normal in all cases. Involvement of the posterior compartment of the leg was greater then the anterior compartment in four cases detected by clinical examination and confirmed by lower limb MRI. One case has a homozygous missense variant and other cases were compound heterozygous carring one missense variant in association with a loss of function mutation. When available, analysis of parental DNA showed the mutations were on separate alleles. Discussion: This study expands the clinical spectrum of VRK1-related disorders, and suggests that mutations in VRK1 should be considered in patients with motor neuropathy. We propose that missense mutations in VRK1 manifest a milder phenotype compared to nonsense mutation characterized by a combination of upper and lower motor neuron signs mostly confined to the lower limbs, with normal brain development.

Palavras Chave

VRK1, motor neuronopathy, upper motor neuron signs