High apolipoprotein E4 allele frequency in FXTAS patients

Abstract

Original research articleFragile X-associated tremor/ataxia syndrome (FXTAS, OMIM no. 300623) is a late-onset neuropsychiatric degenerative disorder that occurs in FMR1 premutation carriers . Clinical symptoms, which appear in patients in their 50s or later, include action tremor, progressive cerebellar ataxia, peripheral neuropathy, autonomic dysfunction, cognitive decline, and dementia. [1][2][3][4] Magnetic resonance imaging in patients with FXTAS demonstrates mild to moderate cerebellar and brain atrophy, as well as white matter hyperintensities. In addition, hyperintensities in the middle cerebellar peduncles on T2 have been described as a characteristic finding in patients with FXTAS and therefore constitute a major diagnostic feature of the disorder.3,5 It has been estimated that at least one-third of all FMR1 premutation carriers will develop an FXTAS syndrome, although there is significant variability in the progression of neurological dysfunction. 2,6,7 Apolipoprotein E (ApoE) is a lipoprotein that transports cholesterol and other lipids and lipid-soluble molecules into the central nervous system. [8][9][10][11] ApoE also modulates the inflammatory response to cellular damage in the brain.12 The human ApoE gene shows polymorphic variation, and three alleles, designated as ApoE ε2, ε3, and ε4, are common in the general population. 13 Variant distribution of these alleles has been shown to be associated with a number of age-related diseases including atherosclerosis, cardiovascular disease, and neurodegenerative disorders.14-16 Although the pathogenic mechanism involving ApoE in these diseases is still unclear, it has been demonstrated that the ApoE ε4 allele is a well-established genetic risk factor for neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease, and other disorders in which dementia is present. [17][18][19] On the basis of this observation, we have evaluated the ApoE genotypes and allelic distribution among a FMR1 premutation carrier cohort presenting with FXTAS. These data might contribute to uncover a new genetic risk factor for FXTAS and might be useful to identify new genes involved in the disease onset and progression. METHODS SubjectsA total of 44 unrelated FMR1 premutation carriers (22 presenting with FXTAS symptoms and 22 without FXTAS clinical symptoms) were included. Samples from subjects belong to the Hospital Clinic of Barcelona and were molecularly diagnosed in the genetics laboratory of the same hospital. All participants were enrolled from families with members known to be affected with fragile X syndrome, and all of them are of Caucasian ethnicity. A classification on the basis of the gender and the age of the participants is summarized in Table 1. Although clinical data is scarce for some of the patients and we did not diagnose dementia in all of them, none of the cases included in the study had a diagnosis of AD. Overall, FXTAS encompasses patients who meet criteria in any of the three categories of involvement: definite, probable, and possible.3 ...

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms

“…Third, although little is known regarding the basis for partial penetrance of FXTAS in the aging premutation population, genetic background effects are doubtless influencing the appearance and severity of the disorder. In this regard, it is interesting that risk factors for related neurodegenerative disorders may also influence risk for FXTAS (e.g., APOE4 allelotype, [143]) or related adult clinical involvement (e.g., corticotrophin releasing hormone receptor 1 polymorphisms, [91]). Fourth, one puzzling feature of clinical involvement in FXTAS is the greater frequency of associated medical findings, such as hypothyroidism and fibromyalgia [134,29], in women with FXTAS relative to males of similar age and stage of neurological involvement.…”

Epigenetic considerations of the APOE gene

“…alzgene.org/). Besides AD and CVD, genetic studies have also connected APOE and its ε2/ε3/ε4 alleles to multiple physiological conditions and disorders, including aging (18,19), diabetes (20), dysbetalipoproteinemia (21), frontotemporal dementia (22), fragile X-associated ataxia (23), glomerulopathy (24), Lewy body dementia (25), metabolic syndrome (26), retinal-related disorders (27) disease (28), posttraumatic stress disorder (29), primary progressive aphasia (30), schizophrenia (31), stroke (32), traumatic brain injury (33), and vascular dementia (34).…”

Towards An Understanding of Neuropsychiatric Manifestations In Fragile X Premutation Carriers

“…Critically, the development of one of these premutation disorders such as FXPOI does not necessarily predispose a carrier to FXTAS [51]. FXTAS also clusters in families so that if a patient has relatives with FXTAS, this will increase the premutation carrier patient’s risk for FXTAS with age, presumably because of background genetic factors associated with FXTAS such as APO E4 alleles [84]. …”