 |
 |
 |
 |
 |
Subject: Tremor-Ataxia Syndrome From Fragile X Premutation (AAN 2003) Date: 4/9/2003 E-MOVE reports from the 55th Annual Meeting of the American Academy of Neurology, held in Honolulu March 29-April 5 2003. Poster numbers, session numbers, and pages are from Neurology 2003;60.Four studies explore the newly described Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS), and its possible association with some cases of MSA. FXTAS occurs in individuals with moderately expanded forms of the gene FMR1, which, when fully expanded, is responsible for fragile X mental retardation syndrome. The normal allele contains a CGG repeat of less than 40 units. The intermediate or “gray zone” length is 41-55 repeats. The premutation length is 50-200 repeats; carriers typically have children with highly expanded alleles (>200) who develop fragile X syndrome. Approximately 20% of male premutation carriers develop FXTAS in late adulthood, marked by intention tremor, ataxia, dementia, parkinsonism, and autonomic dysfunction. 1. Fragile X-associated tremor/ataxia syndrome (FXTAS): A common heritable neuronal inclusion disorder PJ Hagerman, C Iwahashi, B Babineau, D Yasui, CM Greco, M Duncan, S Graw, F Kim, RJ Hagerman P06.078, A469-A470 Brains from 8 males (mean age 74 years) with FXTAS (approximately 70-100 repeats) were examined. Intranuclear inclusions were seen in neurons and glia in cortex, cerebellum, and hippocampus. Inclusions were positive for ubiquitin and proteasome subunits. Normal levels of FMR1 protein, but elevated levels of FMR1 mRNA, were found in patients (approximate average threefold increase over normal). The authors state, “The only known biochemical abnormality associated with the premutation is the presence of elevated mRNA levels, suggesting that inclusion formation, as well as FXTAS, may be caused by a gain of function toxicity due to the excess FMR1 mRNA.” 2. Molecular phenotype and neuropathology in a male with the fragile X premutation F Tassone, CM Greco, EW Khandjian, RJ Hagerman, PJ Hagerman P06.079, A470 Allele size was consistent among 13 brain regions and peripheral blood in a male with 135 repeats. FMR1 mRNA levels varied widely throughout the brain, and were also elevated in blood. Reduced FMR1 protein levels were found in both brain and blood. Inclusions were seen in both neurons and astrocytes, and the cerebellum was atrophied. 3. Two female cases of the fragile X premutation tremor/ataxia syndrome: Cognitive, molecular and radiological studies RJ Hagerman, L Zhang, J Brundberg, D Hessl, S Jacquemont, F Tassone, SW Harris, T Jardini, PJ Hagerman S39.005, A331-A332 Two sisters (ages 67 and 62) developed tremor beginning at ages 32 and 52, respectively, progressing to include ataxia, lower-extremity areflexia, and decreased vibration sense. CGG repeat length was 90 in both, and elevated FMR1 mRNA was seen in both. No cognitive decline was seen in either, unlike their brother, who developed FXTAS with rapidly progressing dementia beginning at age 61. 4. A subtype of multiple system atrophy with cerebellar ataxia (MSA-C): The fragile X-associated tremor/ataxia syndrome (FXTAS) L Zhang, M Leehey, V Wheelock, F Tassone, RH Hagerman, PJ Hagerman P06.080, A470 FXTAS may account for some cases of MSA, according to this study. Nineteen patients diagnosed with MSA-C (n=6) or MSA-P (n=13) were genotyped for FMR1 repeat length. Nine patients had alleles in the “gray zone” of 41-60 repeats, including both MSA-P and MSA-C patients. MRI revealed increased signal intensity of the cerebellar white matter, in keeping with imaging results in FXTAS patients. The authors conclude, “Given the prevalence of 0.2% (males) and 0.5-1% (females) for FMR1 alleles with 40 or more CGG repeats, the finding of 4/10 (males) and 5/9 (females) with gray-zone alleles would be extremely rare in the absence of an association between the expanded alleles and the MSA phenotype.” --- E-MOVE meeting reports are funded in part by unrestricted educational grants from these sponsors: Gold Level: Bertek Pharmaceuticals Silver Level: Amarin Pharmaceuticals Bronze Level: Allergan Inc., Schwarz Pharma E-MOVE Editor: Richard Robinson, NASW, WE MOVE
|
||||
| All contents copyright © WE MOVE 2010. This page last modified 2/25/2009. | ||||