Summary and Introduction
Background: A 76-year-old man presented with an 8-year history of balance problems and a 2-year history of short-term memory loss. He had also been experiencing long-term problems with impotence and episodes of urinary incontinence, and had been managed for hypertension for 25 years. His medical history was otherwise unremarkable. Three of his grandchildren had been diagnosed with fragile X syndrome.
Investigations: Neurological examination, cognitive and neuropsychological testing, nerve conduction studies, MRI, and genetic testing.
Diagnosis: Fragile X-associated tremor/ataxia syndrome (FXTAS) resulting from a premutation (CGG repeat) expansion of the FMR1 gene.
Management: Explanation of the genetic ramifications of premutation carrier status for the FMR1 gene, and symptomatic treatment for the clinical difficulties experienced by the patient.Introduction
A 76-year-old man presented to a movement disorders clinic with a history of gait ataxia that had commenced at the age of 68 years. His wife had noted at that time that his gait would drift to one side, and he began to fall on a regular basis while jogging. He had used a walking stick intermittently since the age of 72 years, from which age he had also noticed a marked reduction in his stamina levels, although he could still walk a mile when necessary. After reaching the age of 74 years, he experienced several falling episodes—two resulting in fractured ribs. When he was aged 75 years, he first noted tremor in his left hand during walking; the tremor did not occur at other times.
Memory problems became increasingly apparent to the patient from the age of 74 years, and he experienced occasional episodes of confusion—for example not knowing whether to move forward at a red traffic light. At the age of 75 years his primary health-care provider commenced him on donepezil 5 mg daily, which the patient felt helped his memory and decreased his episodes of confusion.
In the months before his visit to the clinic, the patient experienced sleep disturbance that was found to improve with the prescription of trazodone 50 mg daily. He also experienced restless leg syndrome, for which his primary care physician prescribed gabapentin 100 mg daily, which appeared to improve his symptoms. The patient had experienced problems with impotence for many years, and during the year before his visit to the clinic he had occasional episodes of urinary frequency and mild urinary incontinence. He also experienced episodes of light-headedness when standing up rapidly; he had had hypertension for 25 years, which was managed with hydrochlorothiazide and atenolol. When questioned, the patient denied any numbness or tingling in his extremities, thyroid disease, diabetes, migraine, weakness, swallowing problems, or bowel incontinence. His past medical history was unremarkable apart from an ongoing high serum cholesterol level that was treated with a statin, and partial loss of hearing.
His family history revealed that two of his three daughters had children; five in total. All three of his granddaughters had full-mutation alleles (>200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene (Online Mendelian Inheritance in Man® [OMIM] 309550; Johns Hopkins University, Baltimore, MD), with mental impairment ranging from learning disabilities to mild mental retardation. Of his two grandsons, one was a carrier of the premutation allele (55–200 CGG repeats) with learning disabilities, and the other was without a fragile X mutation. One of his daughters, the mother of two of the full-mutation children, suffered from premature ovarian failure (POF)—the cessation of menses prior to the age of 40 years. Genetic testing of the patient was subsequently carried out using the standard FMR1 DNA test, which confirmed his status as a premutation carrier (78 CGG repeats).
Neurological examination demonstrated a significant bilateral ataxia on heel-to-shin movements, and a broad-based gait. The patient could not tandem walk, and the pull test was positive. Although the patient had no rest tremor, a mild tremor was present in his left hand while walking, and his walking arm swing was decreased bilaterally, with greater decrease on the left. He displayed no other features of parkinsonism, such as increased tone. Tremor was absent with finger-to-nose testing, but the patient had a slight postural tremor in the left hand. His palmomental reflex and snout reflex were positive. Deep tendon reflexes were symmetrical—2+ in the upper extremities, 3+ at the knees, but barely detectable in the ankles. Vibration sense was absent in the toes and ankles and present in the right knee, but was decreased by 50% in the left knee as well as in the right and left forefingers. Pinprick sensation and temperature and position sense were normal in the upper and lower extremities.
Cognitive testing at the age of 72 years using the Wechsler Adult Intelligence Scale®—Third Edition (WAIS-III; The Psychological Corporation, San Antonio, TX) had demonstrated a full-scale IQ of 111 (verbal 108; performance 113). At the time of the patient's presentation at the age of 76 years, his full-scale IQ was found to have diminished to 103 (verbal, 112; performance, 92). Additional neuropsychological testing at this time revealed memory problems on the Rey Auditory–Verbal Learning Test (RAVLT), with scores ranging from the 6th to the 18th percentiles for age. The patient also demonstrated executive function deficits on the Stroop color–word test with deficits in inhibition (T score of 31), and on the Behavior Dyscontrol Scale 2 (BDS2; score 11 = severely impaired). These results indicated significant deficits in his executive function and short-term memory.
An MRI scan at the age of 72 years had displayed mild brain atrophy, which was found to have progressed to moderate atrophy by the time of the patient's presentation at the age of 76 years. There was an increased T2 signal intensity in the subcortical and periventricular white matter, which was accompanied by characteristic involvement of the deep cerebellar white matter and middle cerebellar peduncles (MCPs) at both age 72 years (Figure 1) and age 76 years.
Figure 1. (click image to zoom)
MRI of the patient at the age of 72 years. (A) Axial T2-weighted image demonstrating symmetric, increased signal within the middle cerebellar peduncles. (B) Axial fluid-attenuated inversion recovery (FLAIR) image revealing increased signal within the periventricular cerebral white matter. (C) Sagittal T1 image demonstrating mild atrophy of the caudal pons, mild cerebral volume loss and thinning of the corpus callosum. Images courtesy of J Brunberg.
Nerve conduction velocity studies showed a slowing of motor conduction velocity across the elbow (40 m/s; normal >48 m/s) and a reduction of sensory nerve action potential amplitude in the right ulnar nerve (2 mV; normal >7 mV) that was consistent with entrapment neuropathy. In the lower extremities, there was evidence of a mild motor and sensory neuropathy as demonstrated by absence of the right sural nerve action potential, temporal dispersion of the compound muscle action potential in the left tibial nerve on proximal nerve stimulation, and bilateral absence of tibial H-reflexes.
The genetic ramifications of premutation carrier status for the FMR1 gene were explained to the patient, and he was continued on his current medications although the dose of his donepezil was increased to 10 mg per day. He was also subsequently offered a trial of amantadine 100 mg twice daily for ataxia. Both the patient and his wife felt that the donepezil was helpful; follow-up has been scheduled to assess improvement in his symptoms with medication. Printer- Friendly Email This