0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

A New ELOVL4 Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia FREE

Cynthia V. Bourassa, MSc1; Salmo Raskin, MD, PhD2,3; Sérgio Serafini, MD4; Hélio A. G. Teive, MD, PhD5; Patrick A. Dion, PhD1; Guy A. Rouleau, MD, PhD, FRCP(C)1
[+] Author Affiliations
1Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada
2Group for Advanced Molecular Investigation, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Paraná, Brazil
3Genetika–Centro de Aconselhamento e Laboratório de Genética, Curitiba, Paraná, Brazil
4Dermatology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil
5Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil
JAMA Neurol. 2015;72(8):942-943. doi:10.1001/jamaneurol.2015.0888.
Text Size: A A A
Published online

Spinocerebellar ataxia with erythrokeratodermia (SCA34; OMIM 133190) is an autosomal dominant complex form of ataxia. This condition was first described in 1972 with the report of a French-Canadian family with multiple affected individuals.1 Four decades later, a segregating locus was identified through linkage analysis of 32 individuals from this family. Subsequent whole-exome sequencing of 3 individuals revealed a mutation in the elongation of very long-chain fatty acids–like 4 gene (ELOVL4) (NM_022726.3 c.504G>C); this mutation produced a defective protein (p.Leu168Phe).2 We report here the identification of a different ELOVL4 mutation in a single case who had signs consistent with SCA34. To our knowledge, our findings are the first to confirm ELOVL4 as the cause of SCA34.

A man in his 30s developed a progressive gait disorder in his mid-20s. Brain magnetic resonance imaging showed cerebellar and pontine atrophy (Figure 1, A and B). Neurological examination (H.A.G.T.) demonstrated dysarthria; diplopia; and horizontal gaze–evoked nystagmus, bilaterally, with mild bilateral ophthalmoplegia; mild dysmetria in the upper limbs; and gait ataxia, with great difficulty in the tandem gait. The patient had normal reflexes, normal position, and vibration sense, as well as normal pain and light touch sensation. His father had a mild gait disorder. The patient also had erythematous skin lesions on his forearms and legs during adolescence (Figure 1C). A dermatological evaluation (S.S.) suggested the diagnosis of erythrokeratodermia. The clinical diagnosis of Giroux-Barbeau syndrome was made.

Place holder to copy figure label and caption
Figure 1.
Images Supporting the Clinical Diagnosis of Spinocerebellar Ataxia With Erythrokeratodermia

A, Horizontal section of the patient’s brain magnetic resonance image (MRI) showing cerebellar atrophy (arrowhead). B, Sagittal section of the patient’s brain MRI showing cerebellar and pontine atrophy (arrowhead). C, Erythematous skin lesions on the patient’s arm.

Graphic Jump Location

Sanger sequencing was used to screen the proband for the presence of mutation in the ELOVL4 gene. The analysis of all 6 exons, as well as the exon-intron boundaries, identified a heterozygote substitution (NM_022726.3 c.539A>C; Figure 2) that leads to a missense mutation (p.Gln180Pro). This variation was absent from dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) and the Exome Variant Server (http://evs.gs.washington.edu/EVS/). It is predicted to be damaging by PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) and Mutation Taster (http://www.mutationtaster.org/).

Place holder to copy figure label and caption
Figure 2.
Chromatogram of the Mutation Identified

Chromatogram obtained from Sanger sequencing of exon 4 of the elongation of very long-chain fatty acids–like 4 gene and analyzed by Mutation Surveyor version 4.0 (SoftGenetics).

Graphic Jump Location

The ELOVL4 gene encodes a protein responsible for the elongation of very long-chain fatty acids. It contains 5 transmembrane domains, a histidine cluster dideoxy binding motif, and an endoplasmic reticulum retention signal.3 Interestingly, the mutation identified here (p.Gln180Pro) is found in the same transmembrane domain as the previously reported SCA34 mutation. Other diseases have been associated with ELOVL4 mutations; however, the mutations underlying these conditions affect different domains of the protein. For Stargardt-like macular dystrophy, the mutations are clustered in exon 6 and they disrupt the endoplasmic reticulum retention signal.4 In the complex syndrome of ichthyosis, spastic quadriplegia, and mental retardation, which might be considered to be a more severe form of SCA34, the homozygous mutations are in exon 5, which encodes the fourth transmembrane domain.5 Our report supports the notion that SCA34 causative mutations cluster in exon 4 of ELOVL4 where they disrupt the third transmembrane domain. Moreover, the finding of an ELOVL4 mutation in a patient with an SCA34 phenotype suggests that alterations in this gene lead to the same condition in separate populations.

To our knowledge, this is only the second report of ELOVL4 mutations in SCA34, and it is the only gene thus far reported to lead to this phenotype. A member of the same gene family, ELOVL5, was reported to cause SCA38,6 adding another lipid metabolism gene to the list of genes causing spinocerebellar ataxia.

Corresponding Author: Guy A. Rouleau, MD, PhD, FRCP(C), Department of Neurology and Neurosurgery, Montreal Neurological Institute, 3801 University St, Room 636, Montréal, QC H3A 2B4, Canada (guy.rouleau@mcgill.ca).

Author Contributions: Dr Rouleau had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Raskin, Rouleau.

Acquisition, analysis, or interpretation of data: Bourassa, Serafini, Teive, Dion.

Drafting of the manuscript: Bourassa, Serafini, Dion.

Critical revision of the manuscript for important intellectual content: Raskin, Serafini, Teive, Dion, Rouleau.

Obtained funding: Rouleau.

Administrative, technical, or material support: Bourassa.

Study supervision: Raskin, Teive, Dion, Rouleau.

Conflict of Interest Disclosures: Dr Rouleau holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. No other disclosures were reported.

Giroux  JM, Barbeau  A.  Erythrokeratodermia with ataxia. Arch Dermatol. 1972;106(2):183-188.
PubMed   |  Link to Article
Cadieux-Dion  M, Turcotte-Gauthier  M, Noreau  A,  et al.  Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol. 2014;71(4):470-475.
PubMed   |  Link to Article
Bedell  M, Harkewicz  R, Wang  X, Zhang  K.  Focus on molecules: ELOVL4. Exp Eye Res. 2010;90(4):476-477.
PubMed   |  Link to Article
Logan  S, Anderson  RE. Dominant Stargardt macular dystrophy (STGD3) and ELOVL4. In: Ash  JD, Grimm  C, Hollyfield  JG, Anderson  RE, LaVail  MM, Bowes Rickman  C, eds. Retinal Degenerative Diseases. Vol 801. New York, NY: Springer; 2014:447-453.
Mir  H, Raza  SI, Touseef  M,  et al.  A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity. BMC Med Genet. 2014;15(1):25.
PubMed   |  Link to Article
Di Gregorio  E, Borroni  B, Giorgio  E,  et al.  ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet. 2014;95(2):209-217.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Images Supporting the Clinical Diagnosis of Spinocerebellar Ataxia With Erythrokeratodermia

A, Horizontal section of the patient’s brain magnetic resonance image (MRI) showing cerebellar atrophy (arrowhead). B, Sagittal section of the patient’s brain MRI showing cerebellar and pontine atrophy (arrowhead). C, Erythematous skin lesions on the patient’s arm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Chromatogram of the Mutation Identified

Chromatogram obtained from Sanger sequencing of exon 4 of the elongation of very long-chain fatty acids–like 4 gene and analyzed by Mutation Surveyor version 4.0 (SoftGenetics).

Graphic Jump Location

Tables

References

Giroux  JM, Barbeau  A.  Erythrokeratodermia with ataxia. Arch Dermatol. 1972;106(2):183-188.
PubMed   |  Link to Article
Cadieux-Dion  M, Turcotte-Gauthier  M, Noreau  A,  et al.  Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol. 2014;71(4):470-475.
PubMed   |  Link to Article
Bedell  M, Harkewicz  R, Wang  X, Zhang  K.  Focus on molecules: ELOVL4. Exp Eye Res. 2010;90(4):476-477.
PubMed   |  Link to Article
Logan  S, Anderson  RE. Dominant Stargardt macular dystrophy (STGD3) and ELOVL4. In: Ash  JD, Grimm  C, Hollyfield  JG, Anderson  RE, LaVail  MM, Bowes Rickman  C, eds. Retinal Degenerative Diseases. Vol 801. New York, NY: Springer; 2014:447-453.
Mir  H, Raza  SI, Touseef  M,  et al.  A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity. BMC Med Genet. 2014;15(1):25.
PubMed   |  Link to Article
Di Gregorio  E, Borroni  B, Giorgio  E,  et al.  ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet. 2014;95(2):209-217.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

388 Views
1 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
Jobs