Case reports: adult spinal muscular atrophy associated with VRK1 gene variations in Hispanic patients

Variations in the vaccine-related kinase 1 gene (VRK1) can lead to adult Hispanic adult spinal muscular atrophy (SMA) without pontocerebellar atrophy, according to 2 case reports and a review of the literature published in Neurology.

Although SMA is typically secondary to a variation in the survival motor neuron 1 gene (SMN1) on chromosome 5q, variations at other loci, such as the VRK1 gene, can lead to different 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 of 2 Hispanic patients with adult SMA without pontocerebellar atrophy were reported in the current analysis as part of an effort to better understand the clinical phenotypes associated with VRK1 gene variations.

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The first case was a 51-year-old Hispanic male with weakness that increased over two decades, mainly in the lower extremities, along with muscle cramps and lower back pain. During the physical exam, the patient had the usual arm strength, bilateral calf atrophy, 4 + / 5 strength in hip and plantar flexion, and 3 + / 5 strength in dorsiflexion.

Nerve conduction tests showed normal sensory nerve conduction, low amplitude motor responses, and neurogenic motor units in the lower extremities, consistent with motor neuron disease. Magnetic resonance imaging (MRI) of the brain was reported to be normal and the genetic test for SMN1 gene deletion was negative. Sequencing of the entire exome 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. Over the years she developed a limp followed by bilateral foot lift and hand grip weakness. Physical examination revealed distal atrophy in the arms and legs. The force was 1/5 in dorsiflexion / plantar flexion, 2/5 in hip flexion, and 4/5 in the deltoids and biceps.

Nerve conduction tests 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 the 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 SMA and milder clinical symptoms. In addition, the patients showed no evidence of pontocerebellar hypoplasia or cognitive symptoms.

Data from these cases, along with previous reports, suggest that VRK1 gene variants with SMA can occur in adulthood without pontocerebellar atrophy.

“We reported 2 cases with VRK1 [gene variants] Present as an adult [SMA] without pontocerebellar hypoplasia. Genetic testing in patients like ours is important to better understand the clinical spectrum of this disease, ”the researchers concluded.


Sung A, Moretti P, Shaibani A. Spinal muscular atrophy in adulthood due to mutations in the VRK1 gene. Neurol Genet. Published online June 22, 2021. doi: 10.1212 / NXG.0000000000000599

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