Handbook of Genetic Counseling/Friedreich Ataxia
Friedreich Ataxia
Contracting
edit- Acknowledge prior contact
- What do they know about Friedreich Ataxia?
- Do they have any questions?
Etiology
edit- 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
edit- Population frequency of 2-4 per 100,000
- Carrier frequency is 1/60-1/100
Clinical Features
edit- 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
edit- 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
- Late-onset FRDA (LOFA)
Testing
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
editGeneclinics. "Friedreich Ataxia" Web: www.geneclinics.org Online Mendelian Inheritance in Man. "Friedreich Ataxia" Web: www.ncbi.nlm.nih.gov
Notes
editThe information in this outline was last updated in 2001.