Clinical phenotypes of a juvenile sibling pair carrying the fragile X premutation

Abstract

Individuals with alleles containing 55–200 CGG repeats in the fragile X mental retardation (FMR1) gene are premutation carriers. The premutation allele has been shown to lead to a number of types of clinical involvement, including shyness, anxiety, social deficits, attention deficit hyperactivity disorder (ADHD) and executive function deficits. Some of these problems could be due to mild deficits of the fragile X protein (FMRP) and a possible developmental effect of the elevated FMR1 mRNA observed in carriers. In addition, two abnormal phenotypes specific to the premutation have been described. Primary ovarian insufficiency (FXPOI), defined by cessation of menses prior to age 40, occurs in 20% of females with the premutation. The other phenotype, fragile X-associated tremor/ataxia syndrome (FXTAS), affects some older adult premutation carriers. Premutation females typically have one expanded allele (≥ 55 CGG repeats) and one normal allele (≤ 54 CGG repeats). This study describes the cognitive, behavioral and molecular profile of a female with two alleles in the premutation range (60 and 67 CGG repeats) in comparison to her brother with a similar premutation size (65 CGG repeats). Both exhibited high IQ scores, anxiety, and some physical features associated with fragile X syndrome. This comparison allows us to examine the effect of the premutation in this male-female pair while controlling for environmental and background genetic factors.

Psychiatric Disorders Associated with FXTAS

“…In a case series of three boys and two girls with the premutation, ages 3 to 10, four had autism and one met criteria for ASD [19]. Basuta et al [20] described two siblings with the premutation (7 year old girl and 8 year old boy) both of whom had social anxiety and obsessive-compulsive symptoms, although the boy had more behavioral problems (attention deficits and hyperactivity). In a more heterogeneous group of 7 male and 43 female carriers ages 5-80, 14% of men and 5% of women met the Autism Diagnostic Observation Schedule-Generic criteria for ASD [21].…”

Towards An Understanding of Neuropsychiatric Manifestations In Fragile X Premutation Carriers

“…In an early cohort study, daughters of carrier fathers, blinded to their father’s carrier status, reported more frequent behaviors related to adult ADHD [16]. This was followed by several case studies reporting ADHD behaviors in child carriers, such as difficulty focusing and sitting still in class [8,12,17] and a case-control study observing increased rates of ADHD in probands compared to non-probands and non-carriers [10]. Additional systematic studies have found a higher prevalence of adult ADHD in carriers compared to non-carriers [18].…”

Neurodegeneration the RNA way

“…While initially thought to be asymptomatic, carriers of a “pre-mutation” range repeat of 55–200 CGGs have a distinct clinical and molecular phenotype (Hagerman et al, 2001). Specifically, FXTAS patients acquire a progressive neurodegenerative disorder characterized by action tremor, gait difficulties, neuropsychiatric symptoms, peripheral neuropathy and dementia after the age of 50 (Hagerman et al, 2001; Basuta et al, 2011). …”