Friedreich Ataxia

Sanjay I Bidichandani, Martin B Delatycki, Margaret P Adam, Holly H Ardinger, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen Stephens, Anne Amemiya

PMID: 20301458

Abstract:

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 ECG, 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP63981226	Nitrofurantoin Related Compound A		63981-22-6	Price