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  • Updated 02.25.2021
  • Released 09.25.2004
  • Expires For CME 02.25.2024

Fragile X-associated tremor/ataxia syndrome

Introduction

Overview

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset triplet repeat disorder that leads to dementia, ataxia, tremor, and neuropathy. Its cause is a restricted triplet repeat expansion mutation in the fragile X mental retardation gene (FMR1), whereas a larger expansion results in fragile X syndrome A in children. Fragile X-associated tremor/ataxia syndrome affects less than 20% of female and about 50% of male carriers. In this article, the authors focus on fragile X-associated tremor/ataxia syndrome and its relation to fragile X syndrome A. Fragile X-associated tremor/ataxia syndrome illustrates the importance of obtaining a comprehensive family history that is not limited to clinical question of the patient in question. Fragile X-associated tremor/ataxia syndrome is in the differential diagnosis in patients with various combinations of the above symptoms with or without a family history of mental retardation. Some estimates suggest that as many as 1 in 3000 men above 50 years of age may develop fragile X-associated tremor/ataxia syndrome; such numbers would signify a great impact on healthcare costs. The pathomechanistic evidence of mitochondrial and RNA dysfunction and of a neurodevelopmental component to fragile X-associated tremor/ataxia syndrome is discussed.

Key points

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset triplet repeat disorder that leads to dementia, ataxia, tremor, and neuropathy.

• Normal individuals have 6 to 50 CGG repeats, carriers of the premutation have 55 to 200 repeats, and fragile X syndrome A patients have 200 to 1500 repeats with methylation at the cytosine within the CGG repeat leading to silencing of the gene.

• Impairment of executive functioning with relative preservation of language and visuospatial skills is the hallmark of dementia.

• Fragile X-associated tremor/ataxia syndrome affects less than 20% of female and about 50% of male carriers.

• MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum.

Historical note and terminology

Researchers first began to look for a connection between fragile X syndrome A and the neurologic symptoms in elderly men when mothers of affected children noted that their children’s grandfathers became forgetful, had frequent falls, and other neurologic problems. This resulted in the recognition of a syndrome originally referred to as “intention tremor, parkinsonism, and generalized brain atrophy in male carriers of a fragile X premutation” (21).

In fragile X syndrome A, a cytosine-guanine-guanine (CGG) triplet repeat expansion in excess of 200 repeats leads to silencing of the FMR1 gene and its protein product, fragile X mental retardation protein, whereas fragile X-associated tremor/ataxia syndrome patients have a triplet repeat expansion of 55 to 200 CGG repeats.

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