Cognitive Dysfunction in FMR1 Premutation Carriers

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.

Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series

“…Cognitive function, which has been reported to be impaired once ataxia is detected [13], also compromises mobility [19]. Another important feature in FXTAS is a deficit in executive function [20], which is demonstrated in our three cases by their low BDS-2 scores. It has even been suggested that executive dysfunction is the primary cognitive deficit in patients with FXTAS and that it mediates the other cognitive deficits [21].…”

“…Here, we highlighted the importance of suspecting FXTAS in patients presenting with gait deficits or ataxia as the initial symptom of neurodegeneration, as up to 20% of patients with FXTAS can develop ataxia without concomitant tremor [2]. It is equally important to suspect FXTAS when the patient presents with cognitive decline and gait abnormalities because approximately 40% of patients with FXTAS develop dementia in advanced stages of the disease [20]. Exposure to toxins, chemotherapy, chemical agents, chronic substance use, and general anesthesia have been associated with disease progression, as exemplified in one of our cases.…”

Fragile X spectrum disorders

“…Not clinically referred children typically do not show differences compared to controls, particularly in girls (97). Probands who presented clinically usually have cognitive deficits compared to controls (97,98).…”

“…Not clinically referred children typically do not show differences compared to controls, particularly in girls (97). Probands who presented clinically usually have cognitive deficits compared to controls (97,98). ADHD is increased in carriers compared to controls (97) and in adulthood these symptoms can persist or present as executive function deficits (34,99,100).…”

“…Probands who presented clinically usually have cognitive deficits compared to controls (97,98). ADHD is increased in carriers compared to controls (97) and in adulthood these symptoms can persist or present as executive function deficits (34,99,100). Myers et al (2001), in a small study of 14 children with the premutation found a trend towards lower performance IQ (101).…”