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