Handbook of Genetic Counseling/Friedreich Ataxia

Friedreich Ataxia

Contracting

• Acknowledge prior contact
• What do they know about Friedreich Ataxia?
• Do they have any questions?

Etiology

• Slowly progressive ataxia with onset usually during adolescence
• Autosomal recessive inheritance
• Majority of cases caused by mutations in X25/FRDA gene
  • Found on chromosome 9q13
  • <1% of patients who meet the clinical diagnostic criteria do not have an identifiable mutation in this gene
  • 96% of patients with FRDA1 are homozygous for a GAA expansion in the X25 gene
    • Normal alleles have 7-38 repeats
    • Premutation alleles have 34-60 repeats
    • Disease-causing alleles 66-1700 triplets
    • GAA repeat length is unstable during germ line transmission:
      • Maternal transmission gives both contractions and expansions
      • Paternal transmission usually contracts repeat size but premutation alleles may expand in size
    • Larger expansion size correlates with earlier onset of disease
• X25 gene codes for a protein called frataxin
  • Found in inner mitochondrial membrane
  • Putative iron transporter to regulate mitochondrial iron content

Incidence and Carrier Frequency

• Population frequency of 2-4 per 100,000
• Carrier frequency is 1/60-1/100

Clinical Features

• Obligatory diagnostic criteria:
  • Progressive ataxia of gait and limbs
  • Absent reflexes in legs
  • Dysarthria
  • Decrease in position sense and/or vibration in lower limbs
  • Muscle weakness
  • Motor nerve conduction velocity of >40 m/s with reduced or absent sensory nerve action potential
• Additional findings:
  • Scoliosis
  • Pes cavus
  • Cardiomyopathy (66%)
    • Usually in later stages of disease but may precede ataxia
    • 2/3 of patients have abnormal EKG
  • Optic nerve atrophy (25%)
  • Sensorineural hearing loss (10%)
  • Diabetes mellitus (10%) or glucose intolerance (20%)

Natural history

• Ataxia usually develops in childhood or early teens
• Rate of progression is variable
  • Mean age of loss of ambulation is 25 years
  • Death usually occurs in 30's
    • Cardiomyopathy
    • Diabetes
    • Pneumonia due to dysphagia
• 25% of patients have atypical findings
  • Late-onset FRDA (LOFA)
    • Approximately 15% of patients with FRDA
    • Age of onset greater than 25 years of age
    • Usually have repeat size smaller than 500
  • FRDA with retained reflexes (FARR)
    • 12% of patients with FRDA
    • Show brisk tendon reflexes for up to 10 years after disease onset
  • FRDA with slowly progressive disease
    • Disease progression slower in Acadian patients
    • Age on onset and neurological manifestations similar

Testing

• Molecular genetic testing can be used to identify mutations in X25/FRDA
  • Shortest repeat length causing disease has not yet been determined for sure
  • <1% of patients who satisfy clinical diagnostic criteria have no identifiable mutation
• Carrier testing
  • Can be offered if two disease-causing mutations are identified in proband
  • Alleles in premutation range may be transmitted unchanged or may expand
• Prenatal testing
  • Clinically available for couples at 25% risk for having child with FRDA1 if both disease causing mutations are known
  • DNA from amniocentesis at 16-18 weeks or CVS at 10-12 weeks can be analyzed

Management

• No therapy is known to stop, delay, or reverse disease progression
• Future therapies may include:
  • Drug therapy
  • Gene therapy
  • Other pathophysiology-based treatments
• Support
  • Psychological support
  • Prostheses, walking aids, and wheelchairs may help patients maintain an active lifestyle
  • Physical therapy
  • Speech therapy
  • Orthopedic intervention for scoliosis and foot deformities
  • Treatment of cardiac disease and diabetes

Differential Diagnosis

• Demyelinating form of hereditary motor and sensory neuropathy type I (HMSNI or CMT1)
  • Childhood symptoms may be similar
  • Nerve conduction studies or DNA testing can determine definitively
• Vitamin E deficiency
  • Should be considered in cases that don't show a GAA expansion
  • Fulfill diagnostic criteria for FRDA but often have titubation and hyperkinesia
  • Treated with Vitamin E supplements
• Other early onset ataxias present with different clinical findings

Psychosocial Issues

• Feelings of guilt, anxiety
• Pregnancy issues: preimplantation genetic diagnosis, prenatal testing, possible pregnancy termination
• Discussion with other family members about risk, inheritance
• Disruption of work, school, social life for those affected

Resources

• National Ataxia Foundation

Phone: 763-553-0020

Email: naf@ataxia.org

• Muscular Dystrophy Association

Phone: 520-529-5300 or 8-572-1717

Email: mda@mdausa.org

Web: www.mdausa.org

• International Network of Ataxia Friends (INTERNAF)

Web: internaf.org

Resources

Geneclinics. "Friedreich Ataxia" Web: www.geneclinics.org Online Mendelian Inheritance in Man. "Friedreich Ataxia" Web: www.ncbi.nlm.nih.gov

Notes

The information in this outline was last updated in 2001.