Aging in individuals with the FMR1 mutation.

Area of Science:

• Neurogenetics
• Geriatric Neurology
• Molecular Genetics

Background:

• Fragile X mental retardation 1 (FMR1) premutation (55-200 CGG repeats) typically does not cause Fragile X syndrome.
• A subset of older males with the FMR1 premutation develop a distinct neurological disorder.
• This disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), highlights aging in FMR1 mutation carriers.

Purpose of the Study:

• To review the clinical experience with FXTAS in male carriers of the FMR1 premutation.
• To elucidate the association between FMR1 premutation and late-onset neurological deficits.
• To summarize the characteristics and implications of FXTAS.

Main Methods:

• Review of clinical data and observations of male patients with FMR1 premutation.
• Analysis of neurological symptoms including tremor, ataxia, and Parkinsonism.
• Examination of molecular correlates, such as elevated mRNA levels and intranuclear inclusions.

Main Results:

• FXTAS typically manifests between ages 50-70 in affected males.
• Key symptoms include progressive intention tremor, ataxia (balance issues, falls), and Parkinsonian features (masked facies, rigidity, tremor).
• Pathological findings include intranuclear inclusions in neurons and astrocytes, linked to elevated FMR1 mRNA.

Conclusions:

• FXTAS is a significant neurological syndrome affecting aging males with the FMR1 premutation.
• The FMR1 premutation influences the aging process, leading to neurodegeneration in susceptible individuals.
• Understanding FXTAS is crucial for managing neurological health in FMR1 premutation carriers.