PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. Sep 11, 2012; 79(11): 1181–1182.
PMCID: PMC3525304
Oculomotor and visual axis systems sparing in spinocerebellar ataxia type 13R420H
Michael F. Waters, MD, PhD,corresponding author
Scientific Advisory Boards:
  • NONE
Gifts:
  • NONE
Funding for Travel or Speaker Honoraria:
  • NONE
Editorial Boards:
  • NONE
Patents:
  • NONE
Publishing Royalties:
  • NONE
Employment, Commercial Entity:
  • NONE
Consultancies:
  • NONE
Speakers’ Bureaus:
  • NONE
Other Activities:
  • NONE
Clinical Procedures or Imaging Studies:
  • NONE
Research Support, Commercial Entities:
  • NONE
Research Support, Government Entities:
  • NIH NINDS (NS054715-01A1) PI 12/07-12/12
Research Support, Academic Entities:
  • NONE
Research Support, Foundations and Societies:
  • NONE
Stock/Stock Options/Board of Directors Compensation:
  • NONE
License Fee Payments, Technology or Inventions:
  • NONE
Royalty Payments, Technology or Inventions:
  • NONE
Stock/Stock Options, Research Sponsor:
  • NONE
Stock/Stock Options, Medical Equipment & Materials:
  • NONE
Legal Proceedings:
  • NONE
Sankarasubramoney H. Subramony, MD,
Scientific Advisory Boards:
  • NONE
Gifts:
  • NONE
Funding for Travel or Speaker Honoraria:
  • NONE
Editorial Boards:
  • Handbook of Clinical Neurology, volume editor, 2011 Speakers’ Bureaus: Athena Diagnostics
Patents:
  • NONE
Publishing Royalties:
  • NONE
Employment, Commercial Entity:
  • NONE
Consultancies:
  • NONE
Speakers’ Bureaus:
  • NONE
Other Activities:
  • NONE
Clinical Procedures or Imaging Studies:
  • NONE
Research Support, Commercial Entities:
  • NONE
Research Support, Government Entities:
  • 2009-2011:Clinical Research Consortium for Spinocerebellar Ataxias (Co-investigator. T Ashizawa M.D. PI). NINDS
Research Support, Academic Entities:
  • NONE
Research Support, Foundations and Societies:
  • 2010-2011Clinical outcome measures in Friedreich Ataxia (Friedreich Ataxia Research Alliance): Site principal investigator 2009-2012New Initiatives in Ataxia Research. National Ataxia Foundation (Principal Investigator)
Stock/Stock Options/Board of Directors Compensation:
  • NONE
License Fee Payments, Technology or Inventions:
  • NONE
Royalty Payments, Technology or Inventions:
  • NONE
Stock/Stock Options, Research Sponsor:
  • NONE
Stock/Stock Options, Medical Equipment & Materials:
  • NONE
Legal Proceedings:
  • NONE
Joel Advincula, MD,
Scientific Advisory Boards:
  • NONE
Gifts:
  • NONE
Funding for Travel or Speaker Honoraria:
  • NONE
Editorial Boards:
  • NONE
Patents:
  • NONE
Publishing Royalties:
  • NONE
Employment, Commercial Entity:
  • NONE
Consultancies:
  • NONE
Speakers’ Bureaus:
  • NONE
Other Activities:
  • NONE
Clinical Procedures or Imaging Studies:
  • NONE
Research Support, Commercial Entities:
  • NONE
Research Support, Government Entities:
  • NONE
Research Support, Academic Entities:
  • NONE
Research Support, Foundations and Societies:
  • NONE
Stock/Stock Options/Board of Directors Compensation:
  • NONE
License Fee Payments, Technology or Inventions:
  • NONE
Royalty Payments, Technology or Inventions:
  • NONE
Stock/Stock Options, Research Sponsor:
  • NONE
Stock/Stock Options, Medical Equipment & Materials:
  • NONE
Legal Proceedings:
  • NONE
Susan Perlman, MD,
Scientific Advisory Boards:
  • NONE
Gifts:
  • NONE
Funding for Travel or Speaker Honoraria:
  • NONE
Editorial Boards:
  • NONE
Patents:
  • NONE
Publishing Royalties:
  • NONE
Employment, Commercial Entity:
  • NONE
Consultancies:
  • NONE
Speakers’ Bureaus:
  • NONE
Other Activities:
  • NONE
Clinical Procedures or Imaging Studies:
  • NONE
Research Support, Commercial Entities:
  • Edison Pharmaceuticals for a compassionate drug trial in one patient. Company provided funding for lab work required in study.
Research Support, Government Entities:
  • NONE
Research Support, Academic Entities:
  • NONE
Research Support, Foundations and Societies:
  • National Ataxia Foundation for maintenance of the web- based database being used in a different study.
Stock/Stock Options/Board of Directors Compensation:
  • NONE
License Fee Payments, Technology or Inventions:
  • NONE
Royalty Payments, Technology or Inventions:
  • NONE
Stock/Stock Options, Research Sponsor:
  • NONE
Stock/Stock Options, Medical Equipment & Materials:
  • NONE
Legal Proceedings:
  • NONE
and Tetsuo Ashizawa, MD
Scientific Advisory Boards:
  • Myotonic Dystrophy Foundation 2011, 2012; NIH 2011, 2012; National Ataxia Foundation 2011, 2012
Gifts:
  • NONE
Funding for Travel or Speaker Honoraria:
  • NONE
Editorial Boards:
  • Editorial Boards:; PLoS ONE: Associate Editor, 2011, 2012
Patents:
  • DNA test for SCA10, US Patent 6855497 [Issued February 15, 2005]; PVA or PEG conjugates of peptides for epitope specific immunosuppression, US Patent 6048529 [Issued April 11, 2000]; METHODS AND COMPOSITIONS INVOLVING NUCLEOTIDE REPEAT DISORDERS, Pub. No.: WO/2007/121272 [Publication Date October 25, 2007]
Publishing Royalties:
  • NONE
Employment, Commercial Entity:
  • NONE
Consultancies:
  • NONE
Speakers’ Bureaus:
  • NONE
Other Activities:
  • NIH study section, 2011; NIH special emphasis panel, 2012; Muscular Dystrophy Association Grant Review, 2012; Association Francaise contre les Myopathie Grant Review, 2011, 2012
Clinical Procedures or Imaging Studies:
  • NONE
Research Support, Commercial Entities:
  • NONE
Research Support, Government Entities:
  • NINDS, RC1 NS068897-01 [PI], 2011, 2012
Research Support, Academic Entities:
  • NONE
Research Support, Foundations and Societies:
  • NONE
Stock/Stock Options/Board of Directors Compensation:
  • NONE
License Fee Payments, Technology or Inventions:
  • DNA test for SCA10, Baylor College of Medicine
Royalty Payments, Technology or Inventions:
  • NONE
Stock/Stock Options, Research Sponsor:
  • NONE
Stock/Stock Options, Medical Equipment & Materials:
  • NONE
Legal Proceedings:
  • NONE
From the Departments of Neurology (M.F.W., S.H.S., T.A.) and Neuroscience (M.F.W.), University of Florida College of Medicine, Gainesville; Western Visayas State University Medical Center (J.A.), Iloilo City, Philippines; and Department of Neurology (S.P.), UCLA Medical Center, Los Angeles, CA.
corresponding authorCorresponding author.
Study funding: Supported in part by NIH NINDS (NS054715-01A1) (M.F.W.).
Correspondence & reprint requests to Dr. Waters: mwaters/at/neurology.ufl.edu
Received January 20, 2012; Accepted April 6, 2012.
Spinocerebellar ataxia type 13 (SCA13) has been described to have both neurodevelopmental and neurodegenerative phenotypes. Three distinct mutations, all occurring in the KCNC3 voltage-gated potassium channel, have been shown in vitro to have unique biophysical properties.1 The p.Phe448Lys and p.Arg423His mutant alleles share a profound developmental phenotype with delayed motor milestones, mental retardation, and epilepsy.
In contrast, p.Arg420His shows a neurodegenerative phenotype reminiscent of other SCAs. Onset ranges from the second to fourth decade. Once clinical symptoms declare, there is a slow though relentless progression with prominent truncal and appendicular ataxia, gait instability, and dysarthria. The electrophysiologic properties of this mutant allele are consistent with a null mutation. Coexpression with wild-type Shaw alleles demonstrates a subtype-specific dominant negative effect.1
The description of SCA types has grown considerably in the last decade, as have their attendant etiologies. Though many SCAs are trinucleotide repeat diseases, several are now attributable to point mutations. Historically, the differential diagnosis of these disorders has been difficult. There is considerable phenotypic overlap among the SCAs and clinical heterogeneity within single genotypes.24 Often, patients presenting for evaluation are so advanced as to mask subtle phenotypic features obfuscating identifying characteristics of particular subtypes. Though molecular diagnostics are available, pan screening is prohibitively expensive. Though no current effective treatments exist, accurately identifying each SCA is imperative in designing clinical trials toward treatment development.
We examined a Filipino kindred harboring the SCA13R420H mutation to investigate phenotypic features that may assist in differentiating this disease from other SCAs.
Methods.
Forty-one members of a 3-generation Filipino kindred segregating the KCNC3R420H allele were comprehensively examined. Of these individuals, 21 were affected and 20 were unaffected. The affected individuals ranged in age from 10 to 82 years old. Of this group, 7 were presymptomatic, 2 were minimally affected with a Scale for the Assessment and Rating of Ataxia (SARA) score5 of 1–1.5 and Functional Stage6 of 0.5–1, and the remainder had SARA scores ranging from 4 to 32.5, Functional Stages from 2 to 5, and a disease duration ranging from 5 to 48 years. Due to examination conditions, formal direct-current electro-oculography including horizontal opticokinetic nystagmus drum and vestibulo-ocular reflex testing were not performed, allowing that electrophysiologic examinations may have revealed more subtle findings. However, particular attention was given to oculomotor pathologies as well as other defining characteristics along the visual axis representative of what would be available to a community-based neurologist. This examination included assessments for gaze-evoked horizontal/vertical nystagmus, slow/hypometric/hypermetric saccades, fragmented smooth pursuit, square wave jerks on fixation, horizontal/vertical ophthalmoplegia, diplopia, abnormal visual acuity, and optic nerve atrophy.
Standard protocol approvals, restrictions, and patient consents.
University of Florida institutional review board approval for this study and signed informed consents for all patients examined have been retained.
Results.
The 20 unaffected individuals in this pedigree demonstrated no clinical signs of oculomotor abnormalities. Surprisingly, of the 21 affected individuals, 14 of whom were symptomatic, marked oculomotor abnormalities were also absent. This was observed in spite of the fact that 10 of these individuals had SARA scores ≥8. The 2 most severely affected individuals (SARA 29 and 32.5) were also spared.
Two patients did demonstrate slight delay in initiation of ballistic saccades, 1 showing increased eye-blink during this delay. These patients were at a median regarding disease severity and duration with SARA scores of 8 and 10.5 and Functional Staging of 2 and 3. Disease duration in this subgroup was 10 and 23 years. This finding is of unclear significance as none of the other affected individuals, including the most severe, exhibited this finding.
Discussion.
The modified Harding classification of ADCAs broadly sorts SCAs into 4 groups.2 All of these designations allow for cerebellar ataxia where oculomotor abnormalities are nearly uniformly seen. Virtually all patients with SCA display gaze-evoked nystagmus and abnormalities of the slow visual-tracking systems which localize to the posterior vermis, flocculus, and paraflocculus.7 These deficits are seen in ataxias due to both expanded repeats and point mutations.
The importance of accurate clinical classification of the various SCAs is increasing, as clinical trials are currently under way in an effort to finally provide relief in these debilitating conditions. Ultimately, molecular diagnoses will provide the genetic anchors allowing us to classify patients into homogeneous groups. However, this remains costly, forcing an appropriate step-wise approach when presented with a patient with acquired ataxia. The challenge for the clinician is prudence in ordering molecular testing which can be further economized by thoughtful consideration of the appropriate potential mutations. In evaluating the patient with clinical symptomatology of a spinocerebellar ataxia, the absence of striking oculomotor features may be consistent with the p.Arg420His allelic form of SCA13.
Footnotes
Author contributions: Dr. Waters participated in the clinical examinations and wrote the manuscript. Dr. Subramony conducted the clinical examinations and contributed to the intellectual content of the manuscript. Dr. Advincula participated in the clinical examinations. Dr. Perlman conducted the clinical examinations and contributed to the intellectual content of the manuscript. Dr. Ashizawa conducted the clinical examinations and contributed to the intellectual content of the manuscript.
Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
1. Waters MF, Minassian NA, Stevanin G, et al. Mutations in the voltage-gated potassium channel KCNC3 cause degenerative and developmental CNS phenotypes. Nat Genet 2006;38:447–451. [PubMed]
2. Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet 1983;21:1151–1155. [PubMed]
3. Schelhaas HJ, Ippel PF, Beemer FA, et al. Similarities and differences in the phenotype, genotype, and pathogenesis of different spinocerebellar ataxias. Eur J Neurol 2000;7:309–314. [PubMed]
4. Fogel BL, Perlman S. An approach to the patient with late-onset cerebellar ataxia. Nat Clin Pract 2006;2:629–635. [PubMed]
5. Schmitz-Hübsch T, Tezenas du Montcel S, et al. Scale for the assessment and rating of ataxia: development of a new scale. Neurology 2006;66:1717–1720. [PubMed]
6. Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology 2005;64:1261–1262. [PubMed]
7. Buttner N, Geschwind D, Jen JC, et al. Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol 1998;55:1353–1357. [PubMed]
Articles from Neurology are provided here courtesy of
American Academy of Neurology