# 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.