Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning

Abstract

Objectives To clarify the neuropsychiatric phenotype of fragile X-associated tremor/ataxia syndrome (FXTAS), and assess the extent to which it is mediated by the dysexecutive syndrome that is a major feature of the disorder. Methods We examined the prevalence of clinically meaningful psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, in comparison with men with a normal allele. Measures included the Neuropsychiatric Inventory (NPI), Symptom Checklist-90-R (SCL-90-R), and the Behavioral Dyscontrol Scale (BDS), a measure of executive functioning. Between-group differences were evaluated using logistic regression, followed by a mediation analysis with ordinary least squares regression to assess the contribution of dysexecutive syndrome to the observed psychiatric domains. Results Men with FXTAS showed higher rates of clinically significant symptoms overall and in specific domains: somatization, obsessive-compulsive, depression, anxiety, psychoticism, agitation/aggression, apathy/indifference, irritability, and nighttime behavior problems. Post hoc analyses suggested that findings of psychoticism among men with FXTAS may be associated with participants’ accurate acknowledgement of cognitive and physical dysfunction, rather than reflecting psychosis. Asymptomatic carriers showed no evidence of clinically significant psychiatric symptoms, but when all carriers were compared with men having a normal FMR1 allele, executive function deficits were found to mediate scores in several domains on both NPI and SCL-90-R. Conclusions Building on prior research, the results provide evidence that the psychiatric phenotype for men includes clinically meaningful depression, hostility, and irritability, in association with behavioral and attentional disinhibition. It is likely that these problems reflect the effects of impaired executive functioning.

Síndrome de Tremor Ataxia y Falla Ovárica Prematura en portadora de la premutación del gen FMR1

“…The prevalence of FMR1 premutation is 11.7 per 10,000 males (95% CI: 6.0-18.7) and 34.4 per 10,000 females (95% CI: 6.3-83.3), corresponding to 1 for every 855 males and 1 for every 291 females 8 , 9 . There are no data on the prevalence of allelic variants of the FMR1 gene in Columbia.…”

“…The phenotype of those affected by the MC of the FMR1 gene is completely different and does not have the classic features of FXS such as mild to moderate intellectual disability (ID), autistic spectrum disorders, elongated face, prognathism, large winged ears, joint hypermobility, macroorchidism, language deficit, anxiety and aggression. In females, the phenotype is usually less severe 11 .…”

“…FXTAS is a progressive neurodegenerative disorder characterized by neurological deficits that include progressive intention tremor, cerebellar ataxia, cognitive deficit, parkinsonism, neuropathies, autonomic dysfunction and dementia. This syndrome occurs in 40% of male carriers at age 60 and in 75% at age 80 and occurs in 20% of females 3 , 4 , 9 . In the general population, the estimated prevalence is 1 in 4,000 males older than 55 years and 1 in 7,800 in females 3 .…”

Placebo Response in Fragile X‐associated Tremor/Ataxia Syndrome

“…FXTAS includes parkinsonism as a motor feature and could reasonably be added to the list of movement disorders to hold to this standard. However, the neuropsychiatric profiles of PD and FXTAS are quite different, with cognitive impairment occurring earlier in the disease course and characterized by more prominent executive dysfunction in FXTAS than in PD …”

“…However, the neuropsychiatric profiles of PD and FXTAS are quite different, with cognitive impairment occurring earlier in the disease course and characterized by more prominent executive dysfunction in FXTAS than in PD. 20 Abnormal executive functioning is associated with inaccurate self-report of functional impairment, even in otherwise healthy adults. 21 It is therefore not surprising that patients with PD and HD differ in self-awareness for abnormal movements.…”