Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series

Abstract

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed by cerebellar ataxia. Ataxia can be the only symptom in approximately 20% of the patients. FXTAS has a slow progression, and patients usually experience advanced deterioration 15 to 25 years after the initial diagnosis. Common findings in brain imaging include substantial brain atrophy and white matter disease (WMD). We report three cases with an atypical clinical presentation, all presenting with gait problems as their initial manifestation and with ataxia as the dominant symptom without significant tremor, as well as a faster than usual clinical progression. Magnetic resonance imaging (MRI) was remarkable for severe brain atrophy, ventriculomegaly, thinning of the corpus callosum, and periventricular WMD. Two cases were diagnosed with definite FXTAS on the basis of clinical and radiological findings, with one individual also developing moderate dementia. Factors such as environmental exposure and general anesthesia could have contributed to their clinical deterioration. FXTAS should be considered in the differential diagnosis of patients presenting with ataxia, even in the absence of tremor, and FMR1 DNA testing should be sought in those with a family history of fragile X syndrome or premutation disorders.

Molecular epidemiology of hereditary ataxia in Finland

“…Mitochondrial defects have previously been found in > 20% of ataxia patients, especially in those with a syndromic phenotype [ 23 ]. Single patients were found to harbour mutations in ATM , SAMD9L , or FMRI that have occasionally been reported as a cause of inherited ataxia [ 24 – 26 ]. The mutation in ATM was found in exome sequencing, but the genetic cause remained unclear in the seven other patients that were analyzed for 562 ataxia-causing genes.…”

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome

“…Peripheral neuropathy is common in FXTAS (3) and can be a presenting feature of the syndrome (8). Musculoskeletal pain is common; back pain (9) and general muscle pain can often lead to the diagnosis of fibromyalgia (10), especially in women where the prevalence of fibromyalgia has been found as high as 43% (11). In the general population, fibromyalgia typically ranges between 2.4 and 6.8% among women (12).…”

Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers

“…This aspect of our study design allowed us to assess FXTAS during early or more mild stages, but also suggests that patients’ gait impairments may not have manifested yet at the joint level. Furthermore, musculoskeletal weakness (e.g., reductions in deep tendon reflexes and somatosensation) contributing to the control of lower limb joint movement has been reported primarily in male premutation carriers [ 1 , 35 , 36 , 37 ]. Our sample consisted of 68.4% female carriers, suggesting that neurodegeneration affecting joint movements may be specific to males with FXTAS [ 17 , 27 ].…”

“…Based on previous studies of walking in FMR1 premutation carriers [ 17 , 26 , 27 , 33 ], we hypothesized that individuals with FXTAS would show a reduced stride length, decreased stride velocity, and increased percentage of double support time (i.e., percent of stride time spent with both feet in contact with the ground), as well as increased variability of stride length and cadence relative to healthy controls and asymptomatic carriers. As musculoskeletal weakness has been consistently documented in individuals with FXTAS [ 1 , 34 , 35 , 36 , 37 ], we also predicted that patients would show reduced knee flexion of the swing leg at toe-offs and reduced knee extension and ankle dorsiflexion of the ipsilateral leg at heel strikes. For tests of reaching, we hypothesized that premutation carriers would show jerkier joint movement relative to healthy controls, reflective of reduced multi-joint coordination that is often observed in cerebellar patients [ 30 , 38 , 39 , 40 ].…”