https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312944-sup-v001.htm
Fragile X tremor/ataxia syndrome (FXTAS) is an X‐linked syndrome that classically presents with intention tremor, ataxia, and executive dysfunction (secondary to disruption of frontal networks1), predominantly in older males with or without associated parkinsonism and peripheral neuropathy.2 There is, however, increasing awareness of a number of protean manifestations FXTAS.3 For example, there are reports of FXTAS presenting with spastic paraparesis,4 severe psychiatric disorder,5 and rapidly progressive dementia.6 The variability of presentation is thought in part to relate to the pathophysiology of the syndrome, associated with expansion of the fragile X mental retardation 1 (FMR1) gene such that 55‐200 CGG repeats (the FXTAS premutation range) causes gain‐of‐function toxicity.7 This is in contrast to the childhood presentation of fragile X syndrome, which is caused by >200 CGG repeats, leading to silencing of the gene and the associated phenotype of developmental delay, behavioral features, facial features, and seizures.8 The “gray zone” of 40‐55 CGG repeats is now also recognized to cause symptoms in some carriers.9 We present an atypical case of a man with generalized chorea in addition to ataxia and cognitive impairment with FMR1 expansion within the premutation range of FXTAS, which to our knowledge has not been previously reported.
Case Report
A 78‐year‐old man with a 3‐year history of recurrent falls and progressive gait unsteadiness was found to have generalized choreiform movements at presentation that had developed during the previous 6 months. His only medication was a statin, and he had no history of exposure to neuroleptics, dopaminergic medications, stimulants, or toxins. His medical history was notable for dyslipidemia, gastroesophageal reflux disease, and hypertension. He did not drink alcohol regularly or take recreational drugs.
Family history was significant for a nephew with young‐onset dementia of unclear cause (diagnosed at age 58) and a great niece and great nephew who reportedly had Friedreich's ataxia, which unfortunately could not be verified. His balance had deteriorated to the point of multiple falls daily. There was no history extrapyramidal motor or nonmotor features. Cognitive complaints were minor but included memory impairment, attentional deficit, and reduced speed of processing that did not impair function.
His dominant findings on examination were chorea with some asymmetric ataxia (Video S1). Upper and lower limb chorea were worse on the left. He had head and neck choreic movements with minor facial involvement. He had mild upper and lower limb dysmetria (worse on the left), and tandem gait was impaired. There was no tremor or rigidity, and he had only subtle slowing of movement on the left without decrement. The rest of the examination was unremarkable, including eye movements, primitive reflex testing, and sensory examination. In particular, there were no features of peripheral neuropathy. A video of pertinent features following partially successful treatment with tetrabenazine is included (Video S1). Cognitive screening using the Montreal Cognitive Assessment (total score of 24/30) showed deficits in executive function, including impaired verbal fluency, speed of processing, and memory retrieval (delayed recall 2/5, improved with cueing).
Laboratory tests were normal, including full blood count; renal, liver, and thyroid functions; serum glucose; syphilis serology; vitamin B12; and electrolytes with the exception of mild elevation of bilirubin (31; reference range < 20). Magnetic resonance imaging of the brain showed diffuse cerebral atrophy with normal caudate volume and an absence of significant iron accumulation. T2 hyperintensity of the middle cerebellar peduncles was seen (middle cerebellar peduncle sign10; Fig. 1) Magnetic resonance imaging of the cervical spine was unremarkable. Genetic testing for Huntington's disease; spinocerebellar ataxia (SCA) 1, 3, and 17; and dentatorubral‐pallidoluysian atrophy were negative. Testing for the FMR1 mutation was performed in the setting of the magnetic resonance imaging changes described, presentation with ataxia, and cognitive decline as well as a family history of neurodegenerative disease and ataxia. This returned showing 95 CGG repeats, putting him in the premutation range consistent with FXTAS.7
Figure 1.
Magnetic resonance imaging of the brain showing generalized atrophy and T2 hyperintensities in the middle cerebellar peduncles.
Discussion
We describe an atypical case of FXTAS presenting with generalized chorea within 3 years of symptom onset. It would be worth considering this diagnosis in patients with chorea particularly in the setting of a family history of neurodegenerative disease with associated ataxia, tremor, or cognitive decline. Genetic testing for the FMR1 premutation may be pertinent in addition to a traditional diagnostic work‐up for chorea. Testing for FXTAS in these settings is prudent not only for the patient but also for females in the family of childbearing age as the implications include ovarian insufficiency but also potentially preventable cases of the more debilitating fragile X syndrome in offspring.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
F.I.: 1C, 2A
W.L.: 1C, 2B
Disclosures
Ethical Compliance Statement
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained from the patient.
Funding Sources and Conflict of Interest
No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the previous 12 months
No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Supporting information
Video S1. Patient examination features including chorea, dysmetria, and gait ataxia. Video demonstrates mild residual chorea after treatment with tetrabenazine. Eye movements are shown as well as lack of dysdiadochokinesis. Mild dysmetria and impaired tandem gait are also shown.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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Supplementary Materials
Video S1. Patient examination features including chorea, dysmetria, and gait ataxia. Video demonstrates mild residual chorea after treatment with tetrabenazine. Eye movements are shown as well as lack of dysdiadochokinesis. Mild dysmetria and impaired tandem gait are also shown.