Clinical characteristics: Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years (mean age at onset: 10-15 yrs). FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes.
Diagnosis/testing: The diagnosis of FRDA is established in a proband by detection of biallelic pathogenic variants in FXN. The most common type of variant, which is observed on both alleles in approximately 96% of individuals with FRDA, is an abnormally expanded GAA repeat in intron 1 of FXN. The remaining individuals with FRDA are compound heterozygotes for an abnormally expanded GAA repeat in the disease-causing range on one allele and another intragenic pathogenic variant on the other allele.
Management: Treatment of manifestations: Clinical management guidelines have been published. Prostheses; walking aids and wheelchairs for mobility; speech, occupational, and physical therapy; pharmacologic agents for spasticity; orthopedic interventions for scoliosis and foot deformities; hearing devices for auditory involvement; dietary modifications and placement of a nasogastric tube or gastrostomy for dysphagia; antiarrhythmic agents, anti-cardiac failure medications, anticoagulants, and pacemaker for cardiac disease; dietary modification, oral hypoglycemic agents or insulin for diabetes mellitus; antispasmodics for bladder dysfunction; continuous positive pressure for obstructive sleep apnea; psychological support, both pharmacologic and counseling.
Prevention of secondary manifestations: Active management of spasticity to prevent permanent contractures; aggressive treatment of scoliosis to prevent cardiopulmonary complications; treatment of diabetes to avoid complications related to inadequate treatment; treatment of cardiac complications to avoid arrhythmias; treatment of sleep apnea to present neurologic and cardiopulmonary complications of untreated sleep apnea.
Surveillance: At least annual assessment of overall status; examination for complications including spasticity, scoliosis, and foot deformity; annual EKG, echocardiogram, and fasting blood sugar to monitor for diabetes mellitus; hearing assessment every two to three years; a low threshold for sleep study to investigate for obstructive sleep apnea.
Agents/circumstances to avoid: Environments that place an individual at risk for falls such as rough surfaces for ambulant individuals; excessive use of alcohol, which can increase ataxia; medications (e.g., isoniazid, nitrofurantoin) that are known to cause nerve damage.
Therapies under investigation: Idebenone, histone deacetylase inhibitors, EPI-743, PPAR gamma agonists, nicotinamide, resveratrol, thiamine.
Genetic counseling: FRDA is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of having no pathogenic variant. Carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if both FXN pathogenic variants have been identified in an affected family member.
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