Based on their findings, the researchers urged for the inclusion of a VRK1 gene analysis in the diagnostic workup of patients who present with predominant calf muscle weakness.
Researchers are detailing multiple cases of distal spinal muscular atrophy (dSMA) caused by vaccinia-related kinase 1 (VRK1) variants.
Based on their findings, coming from 4 patients with adult-onset disease caused by compound heterozygous VRK1 variants, the researchers urged for the inclusion of a VRK1 gene analysis in the diagnostic workup of patients who present with predominant calf muscle weakness.
All 4 patients received next-generation sequencing, which revealed multiple gene variants, including several novel variants. In patient 1, c.607C>T (p.Arg203Trp) and c.858G>T (p.Met286Ile) variants in the VRK1 gene were identified. His brother, patient 2, carried the same variants.
A known variant in the VRK1 gene, c.583T>G (p.Leu195Val), and c.701A>G (p.Asn234Ser) were identified in patient 3, and patient 4 had 2 variants: the known c.583T>G (p.Leu195Val) variant and a novel c.197C>G (p.Ala66Gly) variant.
The researchers note that while their findings support the pathogenicity of VRK1 variants, the drivers behind the phenotypic variability in these patients remains unclear.
“Of the five genetic variants we found in our patients with dSMA, four have been reported in ClinVar though with unclear phenotypic associations, except for c.197C>G (p.Ala66Gly),” detailed the researchers. “Algorithms developed to predict the pathogenic effect of variants on protein structure and function (SIFT, PolyPhen-2, Mutation Taster) all suggest the p.Arg203Trp variant disruptive, while the predictions for p.Met286Ile and p.Asn234Ser variants are contradictory. However, the segregation analysis concluding a compound heterozygous state for patients 1 and 2 suggests p.Met286Ile to be pathogenic as well.”
The researchers highlighted the similar phenotype among the patients, noting onset of disease in their twenties, slow progression of distal weakness with visible calf muscle involvement, and mild elevation of CK. These patients also had neurogenic needle EMG findings without sensory involvement, as well as similar muscle radiological features. MRI findings among the patients were similar, with pronounced atrophy in the posterior lower leg compartment.
Symptoms included difficulties walking on toes, inability to stand, and reduced ankle reflexes. A muscle biopsy of patient 1, a 59-year-old man, suggested denervation atrophy, with an increase in fiber size variation and small groups of atrophic fibers of either histochemical type. Patient 2, the bother of patient 1, had similar findings, with symmetrical atrophy and fatty replacement of the soleus and medial gastrocnemius revealed by a muscle MRI.
The muscle MRI of patient 3, a 36-year-old, showed atrophy and modest asymmetrical fatty changes in his lower leg muscles, mainly involving the posterior compartment. In patient 4, muscle biopsy showed a slight increase in fiber size variation, an increase in the number of fibers with internalized nuclei, and several dispersed atrophic fibers.
“While the grouped atrophic muscle fibers of either histochemical type in the muscle biopsy of patient 1 suggested a neurogenic aetiology, the gastrocnemius biopsy in patient 4 showed mixed myopathic and neurogenic changes,” explained the researchers. “This however is not surprising as gastrocnemius is particularly prone to develop myopathic changes as secondary phenomenon to a neurogenic process. This adds complexity in distinguishing neurogenic from myopathic diseases in patients with distal weakness, and highlights the limitation of calf muscle biopsies in patients with distal weakness.”
Outside of the 4 patients seen by the researchers, the group identified 30 others, all of which harbored 2 variants in VRK1. According to the researchers, VRK1 variants are associated with a range of neurological phenotypes, including neurodevelopmental disorders and dSMA.
Demaegd K, Brilstra E, Hoogendijk J, et al. Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease – Case series and review. Neuromuscul Disord. 2022;32(6):P527-532. doi:10.1016/j.nmd.2022.04.007