Share

August 2021; 7 (4) ArticleOpen Access

Adult-Onset Spinal Muscular Atrophy due to Mutations in the VRK1 Gene

Angela Sung, Paolo Moretti, Aziz Shaibani
First published June 22, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000599
Full PDF
Citation
Permissions

Make Comment

See Comments

Downloads
471

Share

Abstract

Objective To expand our knowledge of the range of clinical phenotypes associated with vaccinia-related kinase 1 (VRK1) gene mutations.

Methods We present clinical and molecular data of 2 individuals with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy without pontocerebellar atrophy.

Results Genetic testing revealed likely pathogenic variants in the VRK1 gene in both subjects. One individual carried homozygous p.R321C (c.961 C>T), likely pathogenic variants. The other carried compound heterozygous p.V236M (c.706 G>A) and p.R321C (c.961 C>T), likely pathogenic variants. Notably, both patients were of Hispanic descent.

Conclusions We report 2 cases with VRK1 mutations presenting as adult-onset spinal muscular atrophy without pontocerebellar hypoplasia and review the current literature of similar cases. Our report expands the clinical spectrum of neurologic disorders associated with VRK1 mutations.

Glossary

gnomAD=
Genome Aggregation Database;
NCS=
nerve conduction study;
SMA=
spinal muscular atrophy;
SMN1=
survival motor neuron 1;
VRK1=
vaccinia-related kinase 1;
WES=
whole-exome sequencing

The spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by degeneration of the anterior horn cells, resulting in progressive muscle weakness and atrophy. Although the classic form of SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q, there are a host of rare non-5q spinal muscular atrophies with varying clinical phenotypes. The vaccinia-related kinase 1 (VRK1) gene is a gene located on chromosome 14q32 that was fairly recently identified as associated with SMA, particularly a phenotype of SMA with pontocerebellar hypoplasia. The initial case report described infantile onset with clinical features of microcephaly, upper limb ataxia, hyperreflexia, intellectual disability, and motor and sensory neuropathy with cerebellar hypoplasia on imaging.1

Since identification, several other cases of VRK1 mutation have been identified with clinical features including congenital/infantile-onset progressive sensorimotor neuropathy with microcephaly,2 as well as reports of adult-onset progressive weakness with features consistent with amyotrophic lateral sclerosis3 or adult-onset distal hereditary motor neuropathy4 without brain abnormalities. The previously reported VRK1mutations and associated clinical phenotypes are summarized in the table. Despite these reports of new phenotypes, the Online Mendelian Inheritance in Man database still lists pontocerebellar hypoplasia type 1A as the single phenotype associated with VRK1 pathogenic variants. Here, we report 2 cases of VRK1 mutations resulting in an adult-onset SMA-like phenotype without pontocerebellar hypoplasia.

View this table:
Table

Summary of Previously Reported VRK1 Mutations

Methods

Clinical evaluation of patients was performed at the Nerve and Muscle Center of Texas. Verbal consent for publication was obtained from the patients. Diagnostic workup included brain MRI, EMG, and nerve conduction studies (NCSs), and whole-exome sequencing (WES). NextGen whole-exome sequencing was performed on an Illumina system with 100 base pairs or greater paired-end reads. Depth of coverage ranged between 121× maximum and 10× minimum and 98.7% of the exome was surveyed. Hundred percent of the VRK1 coding region was covered at a minimum of 10×.

Standard Protocol Approvals, Registrations, and Patient Consents

Verbal consent for publication was obtained from the patients.

Data Availability

Anonymized data will be shared by request from any qualified investigator.

Case 1

A 51-year-old Hispanic man presented for evaluation of worsening weakness over 20 years. He reported weakness mainly in the lower extremities, resulting in difficulty with climbing stairs and rising from a deep chair. In addition, he experienced muscle cramps and low back pain but no myalgias, dysarthria, dysphagia, or double vision. On examination, he had bilateral calf atrophy and 4+/5 strength in hip flexion and plantar flexion and 3+/5 strength in dorsiflexion as rated on the Modified Research Council grading scale. He had normal strength in the arms. Reflexes were normal except for absent ankle reflexes. The rest of the neurologic examination, including mental status, speech, sensation, and coordination, was unremarkable.

EMG/NCSs showed normal sensory nerve conductions, low-amplitude motor responses, and neurogenic motor units predominantly in the lower extremities. This was consistent with a picture of motor neuron disease. Creatine kinase was elevated at 3,400 IU/L. Brain MRI was normal (figure 1). Genetic testing for SMN1 gene deletion was not detected. WES identified a homozygous, likely pathogenic variant in the VRK1 gene (c.C961T, p.R321C).

Figure 1
Figure 1 Brain MRI of Patient 1

(A) Axial T2 fluid-attenuated inversion recovery through the pons and cerebellum and (B) sagittal T1 through the brainstem and cerebellar vermis without any evidence of pontocerebellar atrophy.

Case 2

A 55-year-old Hispanic woman presented for evaluation of progressive lower extremity weakness. She had noticed symptoms since age 16 years when she had difficulty marching in the band, and 2–3 years later, she began walking with a limp. Gradually, she developed bilateral foot drop and weakness of hand grips. She reported twitching in the thigh muscles and poor balance. She denied sensory symptoms, dysphagia, dysarthria, visual symptoms, and muscle cramps. On examination, she was noted to have distal atrophy in the arms and legs without fasciculations. Strength was 1/5 in dorsiflexion/plantar flexion, 2/5 in hip flexion, and 4/5 in the deltoids and biceps. She had absent ankle reflexes, but otherwise normal reflexes. The rest of the neurologic examination was unremarkable.

EMG/NCSs showed normal sensory nerve conductions, low-amplitude motor responses, and widespread active and chronic denervation in the upper and lower extremities proximally and distally. Brain MRI was normal (figure 2). WES identified compound heterozygous (c.G706A, p.V236M and c.C961T, p.R321C) pathogenic variants in the VRK1 gene.

Figure 2
Figure 2 Brain MRI of Patient 2

(A) Axial T2 fluid-attenuated inversion recovery through the pons and cerebellum and (B) sagittal T1 through the brainstem and cerebellar vermis without any evidence of pontocerebellar atrophy.

Discussion

The VRK1 gene encodes a serine kinase that is ubiquitously expressed, including in the fetal and adult brain and cerebellum. The serine/threonine-protein kinase VRK1 has been shown to phosphorylate a number of substrates, including p53, in an autoregulatory loop that is important for the development and maintenance of the nervous system.5,6 Although the survival motor neuron protein is also known to interact with p53, whether disease mechanisms are shared between SMN1- and VRK1-related disorders is currently not known.

We identified 2 individuals with clinical features of lower motor neuron disease consistent with adult-onset spinal muscular atrophy. Compared with previous SMA cases reported in the literature, these 2 cases demonstrate later onset of disease with milder clinical symptoms. Unlike most of the previously reported cases, there was no evidence of pontocerebellar hypoplasia or cognitive symptoms.

Of all current VRK1 variants identified in individuals with neurologic disease, only p.R358X is currently reported in ClinVar as pathogenic. Increasing our understanding of VRK1 variants in neurologic disease in different populations is an important goal. Both of our subjects were found to carry the R321C sequence variant. In the first case, the variant was found in the homozygous state, and in the second subject, it was in a compound heterozygous state with V236M. VRK1 R321C was previously reported as a compound heterozygous variant with H119R in an individual with adult-onset amyotrophic lateral sclerosis.3 VKR1 V236M was previously reported as a compound heterozygous variant with R89Q in 2 siblings with rapidly progressive sensorimotor polyneuropathy and microcephaly.2

VRK1 residues 321 and 236 are evolutionarily conserved from fruit flies to humans, and the variants identified are predicted to be deleterious (figure 3). Of interest, both variants are present at very low frequency in control individuals of European, African, and Asian descent in the Genome Aggregation Database (gnomAD).7 In contrast, allele frequency of R321C and V236M is higher in the Latino population (0.095% and 0.015%, respectively). It is important that no homozygous individuals for either of these 2 variants are found in gnomAD, suggesting that despite the heterozygote frequency in the Latino population, these variants are likely pathogenic. As a comparison, R358X, an established VRK1 pathogenic variant, is found at higher frequency in individuals of Ashkenazi Jewish descent in gnomAD (0.14%) compared with other populations and is also not observed in the homozygous state in this database.

Figure 3
Figure 3 Serine/Threonine-Protein Kinase VRK1 Conservation Across Evolution

Multiple protein alignments highlight the high degree of evolutionary conservation of valine at position 236 (A) and arginine at position 321 (B) of the human amino acid sequence. The numbers on the right side of each sequence correspond to the last amino acid depicted. Dm = Drosophila melanogaster; Dr = Danio rerio; Hs = Homo sapiens; Mm = Mus musculus.

Our 2 cases, combined with the previous reports by Nguyen and Greenbaum, suggest that VRK1 variants may present with adult-onset motor neuron disease without pontocerebellar atrophy. In addition, our data suggest a role in pathogenicity for both VRK1 R321C and V236M. Identification of R321C in the homozygous state in an affected individual (case 1) and its absence in homozygosity in control populations, despite the presence of this variant in heterozygosity in a large percentage of normal individuals, argues for a pathogenic role of R321C. Moreover, our data show that disease caused by R321C and V236 may be more common in Latinos compared with other populations.

Spinal muscular atrophy related to mutations in the VRK1 gene is a relatively recently identified association. We reported 2 cases with VRK1 mutations presenting as adult-onset spinal muscular atrophy without pontocerebellar hypoplasia. Genetic testing in patients like ours is important to expand understanding of the clinical spectrum of this disorder.

Study Funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Received June 7, 2020.
  • Accepted in final form March 23, 2021.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Renbaum P,
    2. Kellerman E,
    3. Jaron R, et al
    . Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet. 2009;85(2):281-289.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Gonzaga-Cauregui C,
    2. Lotze T,
    3. Jamal L, et al
    . Mutations in VKR1 associated with complex motor and sensory axonal neuropathy plus microcephaly. JAMA Neurol. 2013;70(12):1491-1498.
    OpenUrl
  3. 3.↵
    1. Nguyen TP,
    2. Biliciler S,
    3. Wiszneiwski W,
    4. Sheikh K
    . Expanding phenotype of VRK1 mutations in motor neuron disease. J Clin Neuromuscul Dis. 2015;17(2):69-71.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Greenbaum L,
    2. Barel O,
    3. Nikitin V, et al
    . Identification of a homozygous VRK1 mutation in two patients with adult-onset distal hereditary motor neuropathy. Muscle Nerve. 2020;61(3):395-400.
    OpenUrl
  5. 5.↵
    1. Young PJ,
    2. Day PM,
    3. Zhou J,
    4. Androphy EJ,
    5. Morris GE,
    6. Lorson CL
    . A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. J Biol Chem. 2002;277(4):2852-2859.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Valbuena A,
    2. Vega FM,
    3. Blanco S, et al
    . p53 downregulates its activating vaccinia-related kinase 1, forming a new autoregulatory loop. Mol Cell Biol. 2006;26(13):4782-4793.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Lek M,
    2. Karczewski KJ,
    3. Minikel EV, et al
    . Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285-291.
    OpenUrlCrossRefPubMed
  8. 8.
    1. Najmabadi H,
    2. Hu H,
    3. Garshasbi M, et al
    . Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478(7367):57-63.
    OpenUrlCrossRefPubMed
  9. 9.
    1. Stoll M,
    2. Teoh H,
    3. Lee J, et al
    . Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia. Neurology. 2016;87(1):65-70.
    OpenUrl
  10. 10.
    1. Reches A,
    2. Hiersch L,
    3. Simchoni S, et al
    . Whole-exome sequencing in fetuses with central nervous system abnormalities. J Perinatol. 2018;38(10):1301-1308.
    OpenUrl
  11. 11.
    1. Feng SY,
    2. Li LY,
    3. Feng SM,
    4. Zou ZY
    . A novel VRK1 mutation associated with recessive distal hereditary motor neuropathy. Ann Clin Transl Neurol. 2018;6(2):401-405.
    OpenUrl
  12. 12.
    1. Sedghi M,
    2. Moslemi AR,
    3. Olive M, et al
    . Motor neuron diseases caused by a novel VRK1 variant: a genotype/phenotype study. Ann Clin Transl Neurol. 2019;6(11):2197-2204.
    OpenUrl
  13. 13.
    1. Yamaura G,
    2. Higashiyama Y,
    3. Kusama K, et al
    . Novel VRK1 mutations in a patient with childhood-onset motor neuron disease. Intern Med. 2019;58(18):2715-2719.
    OpenUrl
  14. 14.
    1. Li N,
    2. Wang L,
    3. Sun X, et al
    . A novel mutation in VRK1 associated with distal spinal muscular atrophy. J Hum Genet. 2019;64(3):215-219.
    OpenUrl
  15. 15.
    1. Silva DP,
    2. Soeiro E Sá M,
    3. Silveira F, et al
    . VRK1 variants in two Portuguese unrelated patients with childhood-onset motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener. 2020;3(2):1-5.
    OpenUrl

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
Advertisement

Related Articles

  • No related articles found.

Alert Me