collaboration via my good friend Martin D. !!
Friedreich Ataxia
Synonym: FRDA
Sanjay I Bidichandani, MBBS, PhD and Martin B Delatycki, MBBS, FRACP, PhD.
Author Information
Initial Posting: December 18, 1998; Last Update: July 24, 2014.
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Summary
Clinical characteristics.
Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with mean onset between age ten and 15 years and usually before age 25 years. FRDA is typically associated with dysarthria, muscle weakness, spasticity 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 suspected based on clinical findings and confirmed by detection of biallelic pathogenic variants in FXN. The most common type of variant, which is observed on both alleles in more than 90% 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 in one allele and another intragenic pathogenic variant in the other allele.
Management.
Treatment of manifestations: 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 insertion for cardiac disease; dietary modification, oral hypoglycemic agents or insulin for diabetes mellitus; antispasmodics for bladder dysfunction; psychological support, both pharmacologic and counseling.
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.
Therapies under investigation: Idebenone, deferiprone, erythropoietin, histone deacetylase inhibitors, EPI-743, PPAR gamma agonists, nicotinamide, resveratrol.
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 diagnosis are possible if both FXN pathogenic variants have been identified in an affected family member.
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Diagnosis
Suggestive Findings
Diagnosis of Friedrich ataxia (FRDA) should be suspected in individuals with a combination of the following findings:
Progressive ataxia of gait and limbs
Dysarthria; decrease in/loss of position sense and/or vibration sense in lower limbs; muscle weakness
Absent muscle stretch reflexes in the legs (In atypical cases, reflexes may be preserved; see Atypical Presentations, FRDA with retained reflexes.)
Onset before age 25 years (In atypical cases, onset may be delayed; see Atypical Presentations, Late-onset FRDA and very late-onset FRDA.)
Family history consistent with autosomal recessive inheritance
Especially if these additional findings are present:
Pyramidal weakness of the legs, extensor plantar responses
Scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathy
Glucose intolerance, diabetes mellitus, optic atrophy, or deafness
Note: Before the identification of FXN, clinical diagnostic criteria for Friedreich ataxia (FRDA) were established by Geoffroy et al [1976] and refined by Harding [1981]. Following identification of FXN, studies have shown that up to 25% of individuals with GAA expansions in both FXN alleles exhibit clinical findings that differ from the previously established clinical diagnostic criteria [Filla et al 2000].
Establishing the Diagnosis
full article at https://www.ncbi.nlm.nih.gov/books/NBK1281/