An expanded repeat region in the ataxin-2 gene causes spinocerebellar ataxia or boosts risk for amyotrophic lateral sclerosis, leading scientists to believe it was only a matter of time before they would find both diseases in a single family. In the JAMA Neurology online August 19, researchers from Columbia University in New York report the first instance of just such a kindred. Sheng-Han Kuo and colleagues describe a woman with spinocerebellar ataxia type 2 (SCA2) and her uncle, who died of ALS. Both shared the ataxin-2 expansion. This finding supports previous papers suggesting that the one mutation can lead to both diseases.

Though both conditions can immobilize patients, researchers had little reason to suspect a relationship between SCA2 and ALS until the 2010 report linking ALS to the ataxin-2 repeats (see ARF related news story). Most people have 22 or 23 polyglutamine repeats in the gene; 34 or more repeats cause SCA2 with near-100 percent penetrance. While precise cutoffs remain uncertain, several groups have confirmed that 27-33 repeats increase risk for ALS (see Lee et al., 2011, Lahut et al., 2012, Conforti et al., 2012).

Kuo, senior author on the new study, met the woman with SCA2 in an ataxia support group. She asserted that her uncle’s ALS must be related to her condition, but until the 2010 report Kuo could not explain why that might be. He obtained a DNA sample from the woman and her uncle, who had also been treated at Columbia and died at the age of 64. He had given the sample and consent for its use in research. First author Sirinan Tazen, since moved to Kaiser Permanente in Bakersfield, California, and colleagues discovered the woman carried 40 repeats, the uncle 39. The pedigree indicates the woman’s father, (the uncle’s brother), must have carried the expansion, as well. He died at age 62 of diabetes, but might have developed ALS or ataxia if he had lived longer, noted Rosalind Chuang of Stanford University in Palo Alto, California. In fact, if he had difficulty walking, doctors might have blamed it on sensory neuropathy associated with the diabetes without looking for another cause, suggested Chuang, who was not involved in the study. The father’s mother did have ataxia, when she died of a heart attack at age 62.

Though it remains possible that the uncle’s ALS was coincidental and unrelated to his ataxin-2 genotype, Kuo doubts it. He was negative for mutations in two other ALS genes, superoxide dismutase 1 and an expansion in C9ORF72. Philip Van Damme of VIB Leuven, Belgium, agreed with Kuo. Van Damme wrote in an email to Alzforum that the known relationship between ALS and ataxin-2 provides good circumstantial evidence that the uncle’s disease was due to the same expansion as his niece’s. Van Damme was not involved in the JAMA report.

The study addresses an open question, commented Guy Rouleau of the Montréal Neurological Institute in Canada, who was not involved in the current work. Do cases like this uncle, with a SCA2-length expansion but symptoms of ALS, represent true ALS or misdiagnosed ataxia? Rouleau has observed ALS cases with more than 32 repeats, as have others (Daoud et al., 2011, Van Damme et al., 2011 ). “These people really had ALS; they did not have other signs of SCA2,” Rouleau said. In controls, instances of 32 or more repeats are rare, he added, but, one study did count 31-33 repeats in healthy controls. In that cohort, nine out of 4,877 healthy controls (0.2 percent) carried 31-33 repeats, though six of these were younger than the usual age of onset for ALS at the time (Ross et al., 2011). This indicates that this length does not always cause ALS and that the presence of the expansion may be coincidental.

Rouleau believes the data support a spectrum of disease containing both ALS and SCA2 due to ataxin-2 expansion. He suggested neurologists re-examine their SCA2-carrying families for signs of ALS, and also look for cases with pathology in between classic ALS and standard SCA2. A few such mixed case have been reported (Van Langenhove et al., 2012, Nanetti et al., 2009).

This kind of disease spectrum would not be new, noted Aaron Gitler of Stanford University in an email to Alzforum. Mutations in valosin-containing protein cause a variety of conditions—including ALS, frontotemporal dementia, inclusion body myopathy and Paget’s disease of bone—within the same family, he noted (see ARF related news story). Similarly, mutations in senataxin have been linked to both juvenile ALS (Chen et al., 2004) and ataxia (Nanetti et al., 2013). “It tallies with the concept that ALS is a clinical syndrome with heterogeneous etiologies, rather than a distinct disease entity,” wrote Van Damme.

Chuang, who is a neurologist, has seen ataxin-2 expansions cause parkinsonism and dystonia, as well as ataxia. Parkinsonism and Parkinson’s disease, in particular, have been reported to appear alongside SCA2 (Gispert et al., 2012, Gellera et al., 2012, Furtado et al., 2004, Infante et al., 2004, Gwinn-Hardy et al., 2000, Charles et al., 2007). Another study linked the expansion to progressive supranuclear palsy (Ross et al., 2011). Doctors may miss cases of ALS in family histories, Chuang suggested, because they assume a relative was wheelchair-bound due to ataxia and not motor neuron disease. Determining whether a patient has ALS or ataxia could be important for prognosis, she said, suggesting that electromyography might help doctors distinguish the two.

Knowing that SCA2 and ALS due to ataxin-2 expansion can co-occur in the same family should help doctors order genetic testing, Kuo said. There are more than 50 mutations that could explain a person’s SCA2, but if the doctor knows of ALS in the family tree, ataxin-2 should rise to the top of the list, he suggested. Chuang noted that this testing might then leave genetic counselors wondering how to advise patients, given that the penetrance of disease from intermediate-length carriers remains in question. Future research should help clarify the answer to this question.—Amber Dance


  1. These are puzzling cases indeed. Do these patients have ALS or a different clinical presentation of SCA2? How should we classify such patients? Intermediate repeat expansions have been identified as a genetic risk factor for ALS, while true (longer) expansions are encountered in rare sporadic and familial ALS cases and probably should be considered as a rare true cause of ALS. Thus, disease presentations of SCA and ALS within the same family are possible. That tallies with the concept that ALS is a clinical syndrome with heterogeneous etiologies, rather than a distinct disease entity.

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News Citations

  1. ALS—A Polyglutamine Disease? Mid-length Repeats Boost Risk
  2. Adding ALS to the Manifestations of VCP Mutations

Paper Citations

  1. . Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet. 2011 May 1;20(9):1697-700. PubMed.
  2. . ATXN2 and its neighbouring gene SH2B3 are associated with increased ALS risk in the Turkish population. PLoS One. 2012;7(8):e42956. PubMed.
  3. . Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis. Neurology. 2012 Dec 11;79(24):2315-20. PubMed.
  4. . Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch Neurol. 2011 Jun;68(6):739-42. PubMed.
  5. . Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011 Jun 14;76(24):2066-72. PubMed.
  6. . Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet. 2011 Aug 15;20(16):3207-12. PubMed.
  7. . Ataxin-2 polyQ expansions in FTLD-ALS spectrum disorders in Flanders-Belgian cohorts. Neurobiol Aging. 2012 May;33(5):1004.e17-20. PubMed.
  8. . Rare association of motor neuron disease and spinocerebellar ataxia type 2 (SCA2): a new case and review of the literature. J Neurol. 2009 Nov;256(11):1926-8. PubMed.
  9. . DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. PubMed.
  10. . The modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis. 2012 Jan;45(1):356-61. PubMed.
  11. . ATAXIN2 CAG-repeat length in Italian patients with amyotrophic lateral sclerosis: risk factor or variant phenotype? Implication for genetic testing and counseling. Neurobiol Aging. 2012 Aug;33(8):1847.e15-21. PubMed.
  12. . Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). Mov Disord. 2004 Jun;19(6):622-9. PubMed.
  13. . Spinocerebellar ataxia type 2 with Levodopa-responsive parkinsonism culminating in motor neuron disease. Mov Disord. 2004 Jul;19(7):848-52. PubMed.
  14. . Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese. Neurology. 2000 Sep 26;55(6):800-5. PubMed.
  15. . Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?. Neurology. 2007 Nov 20;69(21):1970-5. PubMed.

Further Reading


  1. . De Novo Mutations in Ataxin-2 Gene and ALS Risk. PLoS One. 2013;8(8):e70560. PubMed.
  2. . TDP-43 pathology in polyglutamine diseases: With reference to amyotrphic lateral sclerosis. Neuropathology. 2013 Jul 29; PubMed.
  3. . Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis. Hum Mol Genet. 2013 Feb 15;22(4):717-28. PubMed.
  4. . Spinocerebellar Ataxia Type 2: Clinical Presentation, Molecular Mechanisms, and Therapeutic Perspectives. Mol Neurobiol. 2012 Sep 21; PubMed.
  5. . Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. Acta Neuropathol. 2012 Aug;124(2):221-30. PubMed.
  6. . Amyotrophic lateral sclerosis and spinocerebellar ataxia 2. Neurology. 2011 Jun 14;76(24):2050-1. PubMed.

Primary Papers

  1. . Amyotrophic Lateral Sclerosis and Spinocerebellar Ataxia Type 2 in a Family With Full CAG Repeat Expansions of ATXN2. JAMA Neurol. 2013 Aug 19; PubMed.