Friedreich Ataxia

Friedreich Ataxia is a rare condition.

This is the most common hereditary neurodegenerative ataxic disorder.

Friedreich Ataxia results in degeneration of the dorsal root ganglia, posterior columns, spinocerebellar and corticospinal tracts, and large sensory peripheral neurons.

Epidemiology & Demographics

Incidence (In U.S.)

Estimated incidence of Friedreich Ataxia – at 1 in 30,000 Caucasians

Prevalence (In U.S.)

2 to 4 per 100,000.

Carrier rate 1:120 to 1:160; lower prevalence in people of Asian or African descent

Which Gender is most commonly affected by Friedreich Ataxia

Friedreich Ataxia affects the Males and females equally

Peak Incidence

The peak incidence of 8 to 15 years

Genetics

Autosomal recessive; 96% of affected patients are homozygous and 4% are compound heterozygous (two different mutations). Trinucleotide repeat expansion accounts for 94% to 98% of cases, whereas point mutations account for 2% to 6% of cases.

What are the symptoms of Friedreich Ataxia?

Always present Symptoms

Gait ataxia

Very Common Symptoms

Babinski sign
Dysarthria
Gait imbalance
Hand muscle atrophy
Impaired proprioception
Limb ataxia

Common Symptoms

Abnormal saccadic eye movements
Abnormality of the foot
Areflexia of lower limbs
Cardiomyopathy
Cervical spinal cord atrophy
Dysmetria
Falls
Impaired visually enhanced vestibulo-ocular reflex
Intention tremor
Muscle weakness
Nystagmus
Optic atrophy
Pes cavus
Poor fine motor coordination
Scoliosis
Sensory axonal neuropathy
Urinary bladder sphincter dysfunction

Occasional Symptoms

Chorea
Decreased motor nerve conduction velocity
Diabetes mellitus
Dysphagia
Dystonia
Hearing impairment
Inability to walk
Incomprehensible speech
Reduced visual acuity
Spasticity

Physical Findings & Clinical Features

•Onset of progressive appendicular and gait ataxia, with absent muscle stretch reflexes in the lower extremities
•With disease progression (within 5 yr): Dysarthria, distal loss of position and vibration sense, pyramidal leg weakness, areflexia in all four limbs, and extensor plantar responses
•Common findings: Progressive scoliosis, distal atrophy, pes cavus, and cardiomyopathy (symmetric concentric hypertrophic form in most cases)
•Insulin-requiring diabetes mellitus may occur in 10% of patients with glucose intolerance occurring in an additional 10% to 20%

What causes Friedreich Ataxia?

•Genetic: Frataxin gene is localized to the centromeric region of chromosome 9q13.
•Normal sequence has 6 to 27 repeats; abnormal sequence has 120 to 1700 GAA repeats.
•Frataxin deficiency leads to impaired mitochondrial iron homeostasis.

What part of the spinal cord does Friedreichs ataxia involve?

Friedreich’s ataxia is an autosomal recessive disorder that arises from triplet expansion of the frataxin gene.

It affects the cerebellum, spinal cord, peripheral nerves, and heart. In the spinal cord, the following tracts are affected: the dorsal columns, lateral corticospinal tracts, and the anterior and posterior spinocerebellar tracts.

Friedreich Ataxia typically presents with ataxia.

Differential Diagnosis

•Charcot-Marie-Tooth disease type 2
•Abetalipoproteinemia
•Severe vitamin E deficiency with malabsorption
•Early-onset cerebellar ataxia with retained reflexes
•Autosomal-dominant cerebellar ataxia (spinocerebellar ataxia)

How is this diagnosed?

•Specific gene testing for the expanded GAA trinucleotide repeat (only required test). Other tests, listed below, support the diagnosis but are not specific like genetic testing.
•Diagnostic criteria include electrophysiologic evidence for a generalized axonal sensory or sensorimotor neuropathy.
•ECG may show widespread T-wave inversion and evidence of left ventricular hypertrophy. ECG abnormalities are present in 65% of patients.
•Sural nerve biopsy shows loss of large myelinated fibers.

Laboratory Tests

•Genetic testing
•Electromyography or nerve conduction study
•ECG and echocardiogram
•Peripheral blood smear for acanthocytes
•Lipid profile
•2-hour glucose tolerance test
•Vitamin E levels (if necessary)

Imaging Studies

MRI of the spinal cord may demonstrate spinal cord atrophy with essentially normal cerebrum, brainstem, and cerebellum.

How is this treated?

Nonpharmacologic Therapy

•Surgical correction of scoliosis and foot deformities in selected patients
•Prosthetic devices as required (e.g., ankle-foot orthosis for footdrop)
•Physical therapy
•Communication devices for patients with severe dysarthria

Acute General Treatment

None established.

•An antioxidant, idebenone (short-chain analogue of coenzyme Q10), administered orally at 5 to 20 mg/kg/day with or without vitamin E has demonstrated inconsistent effects on neurologic, cardiac, and psychosocial outcome measures in clinical trials.
•Further research with various antioxidants and iron chelators is ongoing. An open-label pilot study of antioxidants (coenzyme Q10, 400 mg/day, and vitamin E, 2100 U/day) in a small cohort demonstrated slowing in progression of generalized ataxia and kinetic dysfunction and significant improvement in cardiac function with unaltered deterioration in posture, gait, and hand dexterity.

Chronic Treatment

Chronic management of congestive heart failure is required.

Cardiac arrhythmias will warrant pacemaker implantation.

Disposition

•Loss of ambulation typically occurs within 15 yr of symptom onset, and 95% are wheelchair bound by age 45 yr.
•Life expectancy is reduced, particularly if heart disease is present.

Referral

•Neurologist for evaluation and diagnosis
•Genetic counseling (recommended if available)
•Cardiologist to manage cardiomyopathy and electrophysiologic abnormalities

Important Pearls

Friedreich ataxia should be considered in all preadolescent and adolescent children presenting with progressive ataxia.

Early recognition of cardiac failure and arrhythmias and institution of appropriate therapy helps prolong survival.

Friedreich Ataxia