Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.
ABSTRACT Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling.
The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score <or=123 on the MDRS.
Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p<0.01 and p<0.03 for logistic and survival model, respectively) role in cognitive impairment. The estimated penetrance of marked cognitive impairment in our sample (adjusted for the mean age 63.4 years and mean education level 9.7 years) for midsize/large (70-200 CGG) and small (55-69 CGG) premutation alleles was 33.3% (relative risk (RR) 6.5; p = 0.01) and 5.9% (RR 1.15; p = 0.9) respectively. Penetrance in the control group was 5.1%.
Male carriers of midsize to large premutation alleles had a sixfold increased risk of developing cognitive decline and the risk increases with allele size. In addition, it was observed that cognitive impairment may precede motor symptoms. These data provide guidance for genetic counselling although larger samples are required to refine these estimates.
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Article: Erratum: Emerging topics in FXTAS.Journal of Neurodevelopmental Disorders 01/2015; 7(1):13. DOI:10.1186/s11689-015-9108-7 · 3.71 Impact Factor
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ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a premutation CGG-repeat expansion in the 5'UTR of the fragile X mental retardation 1 (FMR1) gene. The classical clinical manifestations include tremor, cerebellar ataxia, cognitive decline and psychiatric disorders. Other less frequent features are peripheral neuropathy and autonomic dysfunction. Cognitive decline, a form of frontal subcortical dementia, memory loss and executive function deficits are also characteristics of this disorder. In this review, we present an expansion of recommendations for genetic testing for adults with suspected premutation disorders and provide an update of the clinical, radiological and molecular research of FXTAS, as well as the current research in the treatment for this intractable complex neurodegenerative genetic disorder.Journal of diarrhoeal diseases research 11/2014; 3(4):101-109. DOI:10.5582/irdr.2014.01029
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ABSTRACT: Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.Current Psychiatry Reviews 02/2013; 9(1):78-84. DOI:10.2174/157340013805289635