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. Author manuscript; available in PMC: 2014 May 30.
Published in final edited form as: JAMA Neurol. 2013 Oct;70(10):1302–1304. doi: 10.1001/jamaneurol.2013.443

Amyotrophic Lateral Sclerosis and Spinocerebellar Ataxia Type 2 in a Family with Full CAG Repeat Expansions of ATXN2

Sirinan Tazen 1, Karla Figueroa 2, Justin Y Kwan 3, Jill Goldman 1, Ann Hunt 4, Jacinda Sampson 1, Laurie Gutmann 5, Stefan Pulst 2, Hiroshi Mitsumoto 1, Sheng-Han Kuo 1
PMCID: PMC4039635  NIHMSID: NIHMS589302  PMID: 23959108

Abstract

Importance

To report a family with coexistence of spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS).

Observations

The intermediate or full CAG repeat expansions of ATXN2 are associated with ALS. However, no coexistence of SCA2 and ALS in a family has been reported in the literature. We are reporting a 47 year-old woman with an 11-year history of ataxia and her paternal uncle with ALS who was evaluated at Columbia University Medical Center since July 2006. Both ataxia and ALS patient have full pathological CAG repeat expansions of ATXN2.

Conclusions and Relevance

This report highlights the diverse clinical phenotypes of ATXN2 CAG expansions and its coexistence in a single family. Also, the value of this report is to help clinicians consider the genetic diagnosis of SCA2 when encountering an ataxia patient with a family history of ALS.

Keywords: spinocerebellar ataxia type 2, amyotrophic lateral sclerosis, ATXN2, CAG repeats, TDP-43

INTRODUCTION

Full expansion of the CAG repeat (>34) in ATXN2 is a known cause of spinocerebellar ataxia type 2 (SCA2).1 More recently, an intermediate expansion of CAG repeat (between 27 and 33) has been associated with amyotrophic lateral sclerosis (ALS).2–9 Full CAG repeat expansions in ATXN2 can also occur in rare cases of ALS.3–7 The co-existence of SCA2 and ALS with full CAG repeat expansions in ATXN2 within a family has not been reported. We report a family with SCA2 and ALS and the detail phenotypic description of the affected individuals.

REPORT

A forty-seven year-old woman developed gait difficulty at the age of 36, slurred speech at the age of 37, and loss of hand dexterity at the age of 41. She did not have swallowing difficulty. Neurological examination revealed clinical signs typical for SCA2 including slow saccadic eye movements, truncal titubation, and hyporeflexia (Video 1). She was able to walk without a walker with a wide based gait and marked staggering (3 points on SARA, scale for the assessment and rating of ataxia). She was able to stand only with intermittent support (4 points on SARA score). She had a slight sway while sitting (1 point on SARA score). She had scanning speech and occasionally was difficult to understand (3 points on SARA score). She had mild dysmetria on finger chase (1 point on SARA score bilaterally), moderate intention tremor on nose-finger test (2 points on SARA score bilaterally), and an abnormal heel-shin slide test (2 points on SARA score bilaterally). She had normal fast alternating movements (0 point on SARA score). Her total SARA score was 16 (Video 1). She also had jaw opening dystonia, facial myokymia and shoulder muscle fasciculations, but did not have spasticity, muscle weakness, bradykinesia, rest tremor, or rigidity. Magnetic resonance imaging showed marked cerebellar atrophy. Her electromyography showed fasciculations and myokymia in the mentalis muscle without denervation. Her genetic testing showed an expanded CAG repeat of 40/22 in ATXN2. She had no expanded hexanucleotide repeats of C9orf72 (2/5).

She had a paternal uncle who developed difficulty walking at the age of 62 (Figure 1). Within 9 months of his symptom onset, he had loss dexterity in his hands, worse on the left side. He did not have imbalance. His neurological examination showed muscle atrophy and fasciculation in all four extremities. His muscle strength grading using the Medical Research Council grading scale was 4+/5 in the neck flexor and right upper extremity muscles, 4−/5 in the left upper extremity muscles, and 4–5/5 in both lower extremities. He also had increased tone in all limbs, hyperreflexia, and a spastic gait. Sensory examination was normal. He also had a mild postural tremor but there were no other clinical signs of cerebellar dysfunction. He had normal saccadic eye movements. His electromyography showed diffuse denervation and the transcranial magnetic stimulation study showed prolonged central motor conduction time, consistent a disorder affecting the cortical and spinal motor neurons. His brain MRI revealed no cerebellar atrophy. His cervical, thoracic, and lumbar spine MRI did not show cord compression. Thyroid and hepatic function, parathyroid hormone, Lyme titer, rapid plasma reagin, rheumatoid factor, serum protein electrophoresis with immunofixation were normal. He was diagnosed with ALS. He did not have superoxide dismutase 1 mutation or expanded hexanucleotide repeats in C9orf72 (2/9). He had 39/22 CAG repeat expansions on ATXN2. He required a percutaneous endoscopic gastrostomy tube placement 18 months after the initial symptom and he died 5 months later.

Figure 1.

Figure 1

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Family pedigree.

COMMENT

Intermediate CAG repeat expansion in ATXN2 is associated with an increased risk for ALS.2–10 Full expansions of CAG repeats in ATXN2 (repeat range 34–39) have been reported in ten ALS patients.3–7 We report two members in one family diagnosed with ALS and SCA2, and both individuals have full CAG repeat expansions. To our knowledge, this is the first description of co-existing ALS and SCA2 in a single family. ALS patients with CAG repeat expansions in ATXN2 have a younger age of onset and early spinal motor neuron involvement, 2, 4, 7 similar to our reported case. Interestingly, our SCA2 patient had fasciculations but did not have weakness or spasticity, whereas her paternal uncle who had ALS had postural tremor without other signs of cerebellar dysfunction, indicating a wide range of phenotypic variability in CAG repeat expansions in ATXN2. The SCA2 patient has both maternal and paternal family history of ALS but she inherited the expanded ATXN2 allele from the paternal side of the family, given the history of her paternal grandmother having ataxia and paternal uncle having ALS, and a full CAG repeat expansions in ATXN2. The fact that the maternal great aunt has ALS seems to be coincidental.

In pathologic studies, TAR DNA binding protein 43 (TDP-43) is abnormally localized in SCA2 and ATXN2 is abnormally localized in spinal cord neurons in ALS suggesting a relationship between these two disorders.2, 11 In animal and cellular models, ATXN2 is a modifier for TDP-43 toxicity.2, 12 Furthermore, TDP-43 directly interacts with ATXN2,2 and intermediate expanded CAG repeats in ATXN2 can increase the pathological form of TDP-43 by enhancing C-terminal cleavage and phosphorylated TDP-43.13

This report provides insights into the variability of neurological presentation of CAG repeat expansions in ATXN2, which include Parkinson's disease,10 SCA2, and ALS. Members in the same family carrying a mutation in ATXN2 can have different phenotypes. Genetic test for CAG repeat expansions in ATXN2 should be considered when encountering an ataxia patient with a family history of ALS.

Supplementary Material

Video 1

A forty-seven year old woman with 40/22 CAG repeat expansions of ATXN2 developed ataxia. She had slow saccadic eye movements, dysmetria on finger chase test, finger-chin test, and heel-shin slide test. While walking, she had wide based gait with a variable stride length and good heel strike. She had truncal titubation both at sitting and standing. She also had jaw opening dystonia.

Download video file (5.5MB, m4v)

Acknowledgments

Funding: American Academy of Neurology Research Fellowship and Parkinson's Disease Foundation.

Authors role: Writing the first draft: Tazen, Kwan, Kuo; Genetic test of patients and interpreting the results: Figueroa, Pulst, Critical review of the manuscript: Goldman, Hunt, Sampson, Mitsumoto, Gutmann.

Footnotes

Disclosure: The authors have reported no conflict of interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Video 1

A forty-seven year old woman with 40/22 CAG repeat expansions of ATXN2 developed ataxia. She had slow saccadic eye movements, dysmetria on finger chase test, finger-chin test, and heel-shin slide test. While walking, she had wide based gait with a variable stride length and good heel strike. She had truncal titubation both at sitting and standing. She also had jaw opening dystonia.

Download video file (5.5MB, m4v)

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