TY - JOUR
T1 - Impact of the fragile X mental retardation 1 (FMR1) gene premutation on neuropsychiatric functioning in adult males without fragile X-associated tremor/ataxia syndrome
T2 - A controlled study
AU - Kogan, Cary S.
AU - Turk, Jeremy
AU - Hagerman, Randi J
AU - Cornish, Kim M.
PY - 2008/9/5
Y1 - 2008/9/5
N2 - Fragile X Syndrome is the most common heritable form of mental retardation caused by silencing of the FMR1 gene, which arises from intergenerational trinucleotide repeat expansion leading to full mutation. An intermediary carrier condition, known as the premutation, is characterized by expansion up to 200 repeats without concomitant gene silencing. This prevalent allelic variant was initially thought to be free of phenotypic effects. However, recent reports have identified a degenerative disease, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in older men as well as premature ovarian failure in women. Previously reports are inconsistent regarding the neuropsychiatric phenotype associated with premutation due to small sample sizes, ascertainment bias, lack of adequate control groups, administration of measures with poor psychometric properties, and the confounding effects of FXTAS. We addressed these problems by conducting a controlled study of male carriers (n = 40) of the premutation without manifest symptoms of FXTAS, comparing their responses on specific, reliable, and valid measures of neuropsychiatric functioning to those of individuals with shared family environment (n = 22) and non-carrier comparison males (n = 43). Multivariate analyses revealed that the premutation confers significant risk for working memory difficulties, an associated feature of Attention-Deficit Disorder. Furthermore, both the family controls and men with premutation exhibited higher rates of Alcohol Abuse as compared to non-carrier control men. These findings highlight the importance of recognizing the distinct phenotypic outcomes that characterize the Fragile X premutation and the subtle risk factors that can act as precursors to more significant psychiatric impairment.
AB - Fragile X Syndrome is the most common heritable form of mental retardation caused by silencing of the FMR1 gene, which arises from intergenerational trinucleotide repeat expansion leading to full mutation. An intermediary carrier condition, known as the premutation, is characterized by expansion up to 200 repeats without concomitant gene silencing. This prevalent allelic variant was initially thought to be free of phenotypic effects. However, recent reports have identified a degenerative disease, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in older men as well as premature ovarian failure in women. Previously reports are inconsistent regarding the neuropsychiatric phenotype associated with premutation due to small sample sizes, ascertainment bias, lack of adequate control groups, administration of measures with poor psychometric properties, and the confounding effects of FXTAS. We addressed these problems by conducting a controlled study of male carriers (n = 40) of the premutation without manifest symptoms of FXTAS, comparing their responses on specific, reliable, and valid measures of neuropsychiatric functioning to those of individuals with shared family environment (n = 22) and non-carrier comparison males (n = 43). Multivariate analyses revealed that the premutation confers significant risk for working memory difficulties, an associated feature of Attention-Deficit Disorder. Furthermore, both the family controls and men with premutation exhibited higher rates of Alcohol Abuse as compared to non-carrier control men. These findings highlight the importance of recognizing the distinct phenotypic outcomes that characterize the Fragile X premutation and the subtle risk factors that can act as precursors to more significant psychiatric impairment.
KW - Alcohol abuse
KW - FMRP
KW - Fragile X syndrome
KW - FXTAS
KW - Working memory
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U2 - 10.1002/ajmg.b.30685
DO - 10.1002/ajmg.b.30685
M3 - Article
C2 - 18165971
AN - SCOPUS:51449101409
VL - 147
SP - 859
EP - 872
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
SN - 1552-4841
IS - 6
ER -