Late cerebellar ataxia associated with fragile X premutation

• Published in: Revue neurologique 2008-11, Vol.164 (11), p.957
• Main Authors: Chaussenot, A, Borg, M, Bayreuther, C, Lebrun, C
• Format: Article
• Language: fre
• Subjects: Age of Onset; Atrophy; Brain - pathology; Cerebellar Ataxia - etiology; Cerebellar Ataxia - pathology; Cerebellar Ataxia - physiopathology; Disease Progression; Fragile X Syndrome - diagnosis; Fragile X Syndrome - pathology; Fragile X Syndrome - physiopathology; Functional Laterality; Genetic Testing; Humans; Male; Middle Aged
• ISSN: 0035-3787
• DOI: 10.1016/j.neurol.2008.03.022

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects carriers, principally males after 50 years of age, of premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS are an intention tremor and/or a cerebellar ataxia, with or without parkinsonism, cognitive disorders, neuropathy and autonomic dysfunction. MRI shows symmetrical signal abnormalities in the middle cerebellar peduncles and deep cerebellar white matter, typically sparing the dentate nucleus, associated with generalized atrophy. We report a case of FXTAS with isolated cerebellar ataxia. We report the case of a 60-year-old right-handed man with an uneventful personal and familial history. Since 2002, he progressively developed gait ataxia associated with paresthesia in the lower limbs. The physical examination revealed static and kinetic cerebellar ataxia with dysarthria. Exhaustive screening tests (inflammatory, immunological, metabolic, infectious and neoplasic) and the cerebrospinal fluid analysis were normal. The brain MRI T2-weighted sequences showed diffuse increased signal in both cerebellar white matter and middle peduncles suggestive of FXTAS. Functional explorations (evoked somesthesic and visual potentials, electromyogram, and cerebral scintigraphy) confirmed the isolated cerebellar involvement. The FXTAS was suggested and the genotype was explored. Southern Blot revealed an expansion of trinucleotide CGG with 107 repetitions, confirming the diagnosis of FXTAS. In patients with a fragile X premutation, FMR1 protein levels are gradually reduced with increased repeat number, despite elevated FMR1 transcripts levels. Neuropathologic examination reveals eosinophilic intranuclear inclusions in neurons and astrocytes throughout the cortex, subcortical regions, and brain stem. The pathogenic hypothesis would be related to a gain of function with toxic effects of FMR1 messenger RNA on cellular metabolism. Cerebellar ataxia, which may be isolated or not, is the most frequent neurologic manifestation, like many studies showed. FXTAS should be suspected in patients with unexplained late-onset cerebellar ataxia. Typical presentation includes a male in his fifties with progressive ataxia and tremor. Brain MRI with symmetrical cerebellar abnormalities is very suggestive of this diagnosis. Genetic screening and advice for the patient and his family must be proposed in order to detect the fragile X syndrome.