Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease

Nguyen, Thy; Biliciler, Suur; Wiszniewski, Wojciech; Sheikh, Kazim A.

doi:10.1097/cnd.0000000000000096

Cited by 37 publications

(44 citation statements)

References 8 publications

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“…The clinical presentation was characterized by an older onset age compared with previously reported VRK1 neuropathy patients, who usually manifest in childhood through early adulthood, but not later than the end of the third decade . No upper motor neuron signs, cognitive impairment, abnormal brain imaging findings, or microcephaly were noted in our patients, in contrast to other reported cases of VRK1 mutations . However, mild sensory symptoms (probably related to small fiber loss) and respiratory insufficiency were present in one.…”

Section: Discussioncontrasting

confidence: 52%

“…Schematic illustration of the VRK1 protein and the mutations identified within it (wide arrow denotes the currently reported mutation) . Protein domains and their positions are shown below…”

Section: Discussionmentioning

confidence: 99%

“…To date, only limited number of cases with adult‐onset motor neuropathy attributed to VRK1 have been published . Herein, we describe two patients with adult‐onset motor neuropathy from two unrelated consanguineous families of Moroccan Jewish descent.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in the vaccinia‐related kinase 1 ( VRK1 ) gene cause a wide spectrum of recessive phenotypes with variable age of onset, usually characterized by motor neuropathy, and occasionally also non‐lower motor neuron involvement or structural brain changes. Among these are motor neuron disease (including SMA) in children with or without pontocerebellar hypoplasia, motor and sensory axonal neuropathy plus microcephaly, dHMN and dHMN associated with upper motor neuron signs, early onset amyotrophic lateral sclerosis, and adult‐onset dSMA . In other cases, pontocerebellar hypoplasia with intellectual disability, primary micocephaly or brain abnormalities in the prenatal setting were reported.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

et al. 2020

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Background Adult‐onset hereditary motor neuropathies are caused by mutations in multiple genes. Mutations within the vaccinia‐related kinase 1 (VRK1) gene were associated with a wide spectrum of recessively inherited motor neuropathies, characterized by childhood to early adulthood age of onset and an occasionally non‐lower motor neuron involvement. Methods We describe two patients with adult‐onset (aged 48 and 40 years) length‐dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent. One also demonstrated mild nocturnal respiratory difficulty and sensory symptoms. Whole‐exome sequencing (WES) was performed. Results A homozygous mutation in VRK1 (c.1160G>A (p.Arg387His)), shared by both patients, was identified. This rare mutation segregated with the disease in the two families, and was absent in 120 controls of Jewish Moroccan origin. Conclusions Our findings support VRK1 as a causative gene for adult‐onset distal hereditary motor neuropathy, and indicate its relevance for evaluation of individuals with similar motor impairment.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

et al. 2020

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“…Recessive mutations in ALS5/SPG11/KIA8140 typically cause recessive hereditary spastic paraplegia with thin corpus callosum and axonal neuropathy, but can now also cause recessive CMT2 [19]. Finally, recessive mutations in VRK1 , a rare cause of the usually fatal condition ponto-cerebellar hypoplasia and spinal muscular atrophy may also cause HMN [20]. …”

Section: Introductionmentioning

confidence: 99%

Recent advances in the genetic neuropathies

Rossor

Tomaselli

Reilly

2016

Current Opinion in Neurology

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Purpose of review Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neuromuscular diseases with a population prevalence of 1 in 2500. This review will cover recent advances in the genetics and pathomechanisms of CMT and how these are leading to the development of rational therapies. Recent findings Pathomechanistic and therapeutic target advances in CMT include the identification of the ErbB receptor signalling pathway as a therapeutic target in CMT1A and pharmacological modification of the unfolded protein response in CMT1B. In CMT2D, due to mutations in GARS, VEGF-mediated stimulation of the Nrp1 receptor has been identified as a therapeutic target. Preclinical advances have been accompanied by the publication of large natural history cohorts and the identification of a sensitive biomarker of disease (muscle MRI) that is able to detect disease progression in CMT1A over one year. Summary Advances in next generation sequencing technology, cell biology and animal models of CMT are paving the way for rational treatments. The combination of robust natural history data and the identification of sensitive biomarkers mean that we are now entering an exciting therapeutic era in the field of the genetic neuropathies.

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Motor neuron diseases caused by a novel VRK1 variant – A genotype/phenotype study

Sedghi

Moslemi

Olivé

et al. 2019

Ann Clin Transl Neurol

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Background: Motor neuron disorders involving upper and lower neurons are a genetically and clinically heterogenous group of rare neuromuscular disorders with overlap among spinal muscular atrophies (SMAs) and amyotrophic lateral sclerosis (ALS). Classical SMA caused by recessive mutations in SMN1 is one of the most common genetic causes of mortality in infants. It is characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy. Non-SMN1-related spinal muscular atrophies are caused by variants in a number of genes, including VRK1, encoding the vaccinia-related kinase 1 (VRK1). VRK1 variants have been segregated with motor neuron diseases including SMA phenotypes or hereditary complex motor and sensory axonal neuropathy (HMSN), with or without pontocerebellar hypoplasia or microcephaly. Results: Here, we report an association of a novel homozygous splice variant in VRK1 (c.1159 + 1G>A) with childhood-onset SMA or juvenile lower motor disease with brisk tendon reflexes without pontocerebellar hypoplasia and normal intellectual ability in a family with five affected individuals. We show that the VRK1 splice variant in patients causes decreased splicing efficiency and a mRNA frameshift that escapes the nonsensemediated decay machinery and results in a premature termination codon. Conclusions: Our findings unveil the impact of the variant on the VRK1 transcript and further support the implication of VRK1 in the pathogenesis of lower motor neuron diseases.

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Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease

Cited by 37 publications

References 8 publications

Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

Recent advances in the genetic neuropathies

Motor neuron diseases caused by a novel VRK1 variant – A genotype/phenotype study

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