Fragile X-associated tremor/ataxia syndrome

Overview

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder that primarily affects older male carriers of a premutation in the FMR1 gene on the X chromosome. Unlike Fragile X Syndrome, which is caused by a full mutation, FXTAS results from a smaller expansion known as a premutation. FXTAS is characterized by progressive tremor, ataxia (balance and coordination problems), cognitive decline, and brain atrophy. It typically begins after the age of 50 and is more common in men, though some female carriers may also develop milder symptoms.

Causes

FXTAS is caused by a premutation in the FMR1 gene, defined by 55 to 200 CGG trinucleotide repeats. This premutation leads to elevated levels of abnormal FMR1 mRNA, which is thought to be toxic to neurons and contributes to the development of FXTAS. Unlike Fragile X Syndrome, which is caused by a full mutation (over 200 repeats) leading to silencing of the gene, FXTAS involves overproduction of an abnormal gene product.

Symptoms

FXTAS is a progressive disorder, and symptoms generally worsen over time. Common signs and symptoms include:

Neurological Symptoms

• Intention tremor: Shaking that occurs during purposeful movement (e.g., reaching for an object)

• Gait ataxia: Unsteady walking and balance problems

• Parkinsonism: Symptoms similar to Parkinson's disease, such as stiffness and slowness of movement

• Peripheral neuropathy: Numbness, tingling, or pain in the limbs

• Dysautonomia: Issues with blood pressure regulation, bladder control, or other autonomic functions

Cognitive and Psychiatric Symptoms

• Memory loss and executive function decline

• Mood disorders (e.g., depression, anxiety)

• Personality changes

• Social withdrawal

Diagnosis

Diagnosis of FXTAS is based on clinical findings and genetic testing. Key steps include:

• Genetic testing: Confirming the presence of an FMR1 premutation (55–200 CGG repeats)

• Neurological evaluation: Assessing tremor, gait, reflexes, and cognitive function

• MRI of the brain: Often shows white matter lesions, particularly in the middle cerebellar peduncles (“MCP sign”), and generalized brain atrophy

• Neuropsychological testing: To evaluate cognitive and behavioral symptoms

Treatment

There is no cure for FXTAS, and treatment is supportive and symptom-focused. Management involves a multidisciplinary approach and may include:

Medication

• Beta-blockers or primidone: For managing tremor

• Levodopa or dopamine agonists: For parkinsonian symptoms (though with limited response)

• Antidepressants or anxiolytics: For mood and anxiety disorders

• Pain management: For neuropathic symptoms

Therapeutic Support

• Physical therapy: To maintain mobility and balance

• Occupational therapy: To assist with daily activities

• Cognitive therapy: To address memory and executive dysfunction

• Speech therapy: If communication or swallowing is affected

Family and Genetic Counseling

• Important for informing relatives about the genetic risk and carrier status

• Particularly relevant for family planning and early intervention in younger generations

Prognosis

FXTAS is a progressive and debilitating condition. Symptoms typically worsen over time, leading to significant impairment in mobility, cognitive ability, and daily functioning. Life expectancy may be reduced in advanced cases, often due to complications such as falls, aspiration pneumonia, or other neurological deterioration. However, symptom progression varies widely, and supportive care can improve quality of life. Early recognition and intervention can help slow functional decline and provide better management of symptoms.