The phenotyping dilemma in VRK1-related motor neuron disease: a Turkish family with young-onset amyotrophic lateral sclerosis caused by a novel mutation

<i>Objective</i>: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. <i>Methods</i>: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. <i>Results</i>: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (<i>p</i> = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). <i>Conclusion</i>: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.