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Spinocerebellar ataxia 17 (SCA 17) is a rare cause of ataxia and maybe underdiagnosed in late-onset cases without a family history. The phenotype can vary greatly with recognized clinical features including chorea, dementia, parkinsonism, dystonia, and psychiatric disturbance. We present a patient with a late onset ataxia mimicking Multiple System Atrophy — Cerebellar type (MSA-C) attributed to an intermediate range expansion of the CAG/CAA repeat of the TATA-binding protein (TBP) gene following thorough exclusion of other possible causes.

Case Report

  1. Top of page
  2. Case Report
  3. Discussion
  4. Legend to the Video
  5. Author roles
  6. Full Financial Disclosures of all Authors for the Past year
  7. Acknowledgements
  8. References
  9. Supporting Information

A 61-year old right-handed man presented to a tertiary referral Movement Disorders Clinic with a 2-year history of slurring of speech that tended to be worse in the evening. His family observed that he was less steady on his feet and he admitted having occasional stumbles and falls. He was born in Zimbabwe of European descent and moved to the United Kingdon at the age of 15 years; there was no family history of similar problems or neurological disorder. He had worked as a logistics manager and drank modest amounts of alcohol. He admitted to recent erectile dysfunction to which sildenafil had limited effect. He denied having any urinary frequency, bowel disturbance or orthostatic symptoms. His wife gave a history of very occasional violent nocturnal movements possibly suggestive of REM sleep behaviour disorder (RBD).

On examination he had a slurring cerebellar dysarthria and jerky pursuit eye movements. There was poly-mini-myoclonus and dysdiadochokinesis worse on the right. He walked unsteadily with a wide base and could not perform tandem gait unsupported. Tone, power, reflexes and sensation were normal and there was no bradykinesia. MRI of brain the preceding year (1 year from onset) showed cerebellar atrophy (Fig. 1A) and a diagnosis of MSA-C was considered.

image

Figure 1. Sequential MRI & DAT SPECT imaging at years 1 (A), 2 (B,D) and 4 (C,E,F) from symptom onset. Sagittal (top) and axial (bottom) sections at 1 year from symptom onset (A), 2 years from symptoms onset (B) and 4 years from onset (C). Cerebellar volume loss is evident on the sagittal imaging throughout. Axial imaging through the pons shows the evolution of the cruciform sign, which becomes clearer with time (C). DAT SPECT imaging at 2 years from onset (D) and 4 years from onset (E) remained normal. There was no evidence of the “slit-like void sign” or “hyperintense putaminal rim” at the level of the lenticular nucleus (F).(A-C top images: T1 weighted, A-C bottom images & F: T2-weighted).

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Routine blood tests including thyroid profile were normal. Autonomic function tests were unremarkable (no orthostatic hypotension, preserved pressor responses) and he had a normal anal sphincter EMG. Repeat MRI brain (2 years from onset) showed some progression of cerebellar atrophy and a possible early “hot cross bun” sign (Fig. 1B), but a DaTscan revealed normal tracer uptake into both striata (Fig. 1D). DNA analysis for SCA 1, 2, 3, 6, 7, 17, DRPLA, FRDA (Friedreich's ataxia) and FMR1 (fragile X premutation) were negative. Serum alpha fetoprotein, anti-transglutaminase antibody and vitamin E and B12 levels were normal.

Four years after the first symptoms he reported 2–3 falls per week and was now using a stick for support. Examination revealed a full range of jerky pursuit eye movements, there was no nystagmus and saccades were of normal initiation, speed and range with occasional undershooting (hypometric) or overshooting (hypermetric). There was a pronounced slurring dysarthria but tongue movements were normal. There was no axial or appendicular rigidity and no bradykinesia (video). Repeat structural imaging showed a more conspicuous hot cross bun sign (Fig. 1C) but no evidence of a hyperintense putaminal rim (“the slit like void sign”) (Fig. 1F). Five years from onset he complained of urinary frequency and occasional episodes of urinary incontinence at night. He reported jerky tremor of his hands and legs when standing and a feeling of “giddiness” when walking up the stairs. There had been no episodes of syncope. On examination there was bilateral dysmetria but no postural blood pressure drop. As he now fulfilled the diagnostic criteria for probable MSA[1] (autonomic failure with urinary incontinence and erectile dysfunction plus a cerebellar syndrome) with a supportive structural marker on imaging, functional imaging was repeated but was again normal (Fig. 1E). On review of his earlier investigations mutational analysis of his SCA 17 locus revealed CAG/CAA repeat sizes of 38 and 41. Usually caused by triplet repeat expansions of more than 44, a new report was issued stating that a CAG/CAA repeat sizes of 41–44 could have a penetrance of 50%. Family history was revisited but there was only a suggestion of possible ataxic signs in one family member, his mother who died at the age of 84 years. She was born with inequality of leg length and underwent an operation at a young age which left her with an abnormal gait. In her later years (70+) she may have developed slurred speech and a hand tremor and was felt to have dementia in her last few years of life. The patient's one younger brother (aged 54) was in good health and his father (aged 90) was in good health apart from ischaemic heart disease. On the scale for assessment and rating of ataxia (SARA) he scored 18.5/40 scoring highly on gait, speech, and heel-shin slide. He had no signs of parkinsonism (bradykinesia or rigidity), no pyramidal signs, no chorea, myoclonus or dystonia. He scored 29/30 on MMSE. Given the battery of other negative results and prominent ataxic phenotype a diagnosis of SCA 17 related ataxia was made.

Discussion

  1. Top of page
  2. Case Report
  3. Discussion
  4. Legend to the Video
  5. Author roles
  6. Full Financial Disclosures of all Authors for the Past year
  7. Acknowledgements
  8. References
  9. Supporting Information

This is only the second reported case of ataxia due to SCA17 with an allele of 41 repeats.[2] Progressive late onset cerebellar ataxia in the absence of family history, a history of alcohol abuse or other toxic insult may be due to MSA-C and several features in this case are suggestive of that diagnosis. Erectile dysfunction is often an early feature of autonomic disturbance in MSA and can sometimes be the presenting symptom in males, but autonomic features are also recognized in various spinocerebellar ataxias[3] including SCA 17.[4] Clinically RBD is very suggestive of an underlying synucleinopathy with Boeve and colleagues reporting 94% of their RBD cases having this pathology at post mortem.[5] However, RBD has been reported in conjunction with both SCA 2 and 3.[6] The hot cross bun sign is common but not specific for MSA and it is recognized in various spinocerebellar ataxias (SCAs 2, 3, 7, 8[7] and recently SCA 17[4]).

The lack of rigidity or bradykinesia 5 years into the disease and absence of the “slit-like void sign” on MR imaging (a more specific marker of MSA than he hot cross bun sign,[8] although more specific for the striatonigral degeneration or Parkinsonian variant of MSA[9] and sometimes only a late finding in MSA-C[10]) all militate against but do not absolutely exclude MSA-C. Normal anal sphincter EMG is highly unusual in pathologically proven MSA with Paviour and colleagues reporting only one normal study out of 30 MSA cases who had undergone this investigation antemortem (24 had abnormal studies and 5 were borderline).[11] The normal dopamine transporter imaging is also against a diagnosis of MSA, even the cerebellar type in which most cases have evidence of subclinical nigrostriatal dopaminergic denervation,[12] it is unhelpful regards the diagnosis of SCA 17 in which abnormal DAT imaging is frequently reported.[4, 13-16]

The relatively late age of onset, lack of dementia and restricted phenotype (an absence of chorea or dystonia) may reflect our patients reduced penetrance allele and together with the previously reported cases may suggest a more benign or limited disease in those with restricted expansions at the SCA 17 locus.[2, 16, 17] MSA-C remains a possibility we cannot exclude without pathological examination but on balance we feel the clinical, imaging and genetic findings are more supportive of SCA 17. Low-range expansions of SCA 17 have been previously reported in connection with Parkinson's disease and MSA[16] and this case highlights the need to consider such a mutation in the differential diagnosis of MSA-C.

Legend to the Video

  1. Top of page
  2. Case Report
  3. Discussion
  4. Legend to the Video
  5. Author roles
  6. Full Financial Disclosures of all Authors for the Past year
  7. Acknowledgements
  8. References
  9. Supporting Information

Video 1: Clinical features at four years from symptom onset. The video demonstrates a slurring dysarthria, normal tongue movements, polyminimyoclonus, ataxia of finger-to-nose and heel-shin testing, an absence of bradykinesia (no decrement in speed or amplitude of finger taps), slightly unsteady gait with impairment on tandem walking and the pull test.

Full Financial Disclosures of all Authors for the Past year

  1. Top of page
  2. Case Report
  3. Discussion
  4. Legend to the Video
  5. Author roles
  6. Full Financial Disclosures of all Authors for the Past year
  7. Acknowledgements
  8. References
  9. Supporting Information

KMD has been the beneficiary of a Reta Lila Weston Scholarship. TTW has received grants from NHS Innovations, Brain Research Trust and CHDI. AJL has consulted for Genus and sat on the advisory boards for Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan and Orion. He has received honoraria from Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan and Orion. AJL has received grants from the PSP Association and the Weston Trust - The Reta Lila Howard Foundation.

References

  1. Top of page
  2. Case Report
  3. Discussion
  4. Legend to the Video
  5. Author roles
  6. Full Financial Disclosures of all Authors for the Past year
  7. Acknowledgements
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Case Report
  3. Discussion
  4. Legend to the Video
  5. Author roles
  6. Full Financial Disclosures of all Authors for the Past year
  7. Acknowledgements
  8. References
  9. Supporting Information

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