Variations in the vaccine-related kinase 1 (VRK1) gene may result in adult-onset spinal muscular atrophy (SMA) without pontocerebellar atrophy in Hispanic adults, according to 2 case reports and a literature review published in Neurology.
Although SMA is typically secondary to a variation in the survival motor neuron 1 (SMN1) gene on chromosome 5q, variations in other loci, such as the VRK1 gene, may lead to various clinical phenotypes of the disease. Previous research has shown that the VRK1 gene encodes a serine kinase that is ubiquitously expressed, including in the fetal and adult brain and cerebellum.
The clinical and molecular data from 2 Hispanic patients with adult-onset SMA without pontocerebellar atrophy was reported in the current analysis as part of the effort to better understand the clinical phenotypes associated with VRK1 gene variations.
The first case was a 51-year-old Hispanic man with worsening weakness over 2 decades, mainly in the lower extremities, along with muscle cramps and low back pain. During physical examination, the patient had usual strength in the arms, bilateral calf atrophy, 4+/5 strength in hip flexion and plantar flexion, and 3+/5 strength in dorsiflexion.
Nerve conduction testing showed normal sensory nerve conductions, low-amplitude motor responses, and neurogenic motor units in the lower extremities, consistent with a motor neuron disease. Brain magnetic resonance imaging (MRI) was reported to be normal and genetic testing for SMN1 gene deletion was negative. Whole-exome sequencing identified a homozygous variant in the VRK1 gene (c.C961T, p.R321C).
The second case was a 55-year-old Hispanic woman with progressive lower extremity weakness since the age of 16 years. Over the years, she developed a limp, followed by bilateral foot drop and weakness of hand grips. On physical examination, distal atrophy in the arms and legs was noted. Strength was 1/5 in dorsiflexion/plantar flexion, 2/5 in hip flexion, and 4/5 in the deltoids and biceps.
Nerve conduction testing showed low-amplitude motor responses, and widespread active and chronic denervation in the upper and lower extremities. Brain MRI was reported to be normal and whole-exome sequencing identified compound heterozygous (c.G706A, p.V236M and c.C961T, p.R321C) pathogenic variants in the VRK1 gene.
Both patients had clinical features of lower motor neuron disease consistent with adult-onset SMA and milder clinical symptoms. Furthermore, the patients did not show evidence of pontocerebellar hypoplasia or cognitive symptoms.
Data from these cases, along with previous reports, suggest that VRK1 gene variants may present with adult-onset SMA without pontocerebellar atrophy.
“We reported 2 cases with VRK1 [gene variants] presenting as adult-onset [SMA] without pontocerebellar hypoplasia. Genetic testing in patients like ours is important to expand understanding of the clinical spectrum of this disorder,” the researchers concluded.
Sung A, Moretti P, Shaibani A. Adult-onset spinal muscular atrophy due to mutations in the VRK1 gene. Neurol Genet. Published online June 22, 2021. doi:10.1212/NXG.0000000000000599