J. Chad Hoyle, MD
DESCRIPTION
Friedreich's ataxia (FRDA) is an autosomal recessive disorder that classically presents with progressive ataxia, lower extremity areflexia, pyramidal signs, proprioceptive/vibratory sensory loss, and dysarthria before the age of 25.
EPIDEMIOLOGY
Incidence
No data available. See prevalence.
Prevalence
- Although rare, FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia, and North Africa. Cases are not encountered in Southeast Asia, sub-Saharan Africa, or among Native Americans. Mexico also has a lower than average prevalence.
- The statistical prevalence is about 1 in every 30,000–50,000 people with no gender predilection.
- The average age of onset of symptomatology is 10–15 years old, classically with an age of onset less than 25 years old, though late onset disease occurs in 15% of patients. “Late onset FRDA” is defined as age of onset between 26 and 39 years old and “Very late onset FRDA” is defined as age of onset at age 40 and older.
- Acadians may have a milder phenotype.
RISK FACTORS
Genetics
- Autosomal recessive linked to chromosome 9q13 affecting the frataxin gene.
- Homozygous GAA trinucleotide repeat expansion (95–98% of cases) with remainder having GAA repeat expansion on one allele and a point mutation or other intragenic mutation on the other allele (no homozygous point mutations have been observed).
- Above mutations silence the frataxin gene.
- Though the length of the repeat does correlate to a degree with disease severity, there are exceptions and prognosis cannot be made solely on the basis of repeat size.
Pregnancy Considerations
- Genetic counseling and carrier testing should be made available for FRDA patients for family planning discussions.
- In a milder disease cohort of FRDA patients with an average age of onset of 24.4, pregnancy complications did not appear to be increased and despite the mothers’ neurological deficits, nearly 4/5 births were still vaginal.
- Counseling for psychosocial aspects of childrearing for FRDA patients should be offered.
GENERAL PREVENTION
No reports available. See treatment.
PATHOPHYSIOLOGY
Frataxin protein deficiency causes pathological changes with a predilection for certain tissues, including the dorsal root ganglia dorsal column, spinocerebellar tracts, and corticospinal tracts. The cerebellum is affected to a milder degree (i.e., dentate nuclei). Systemic involvement of the heart and pancreas relate to the hypertrophic cardiomyopathy and diabetes.
ETIOLOGY
- The excessive GAA triplet repeats in FRDA impede transcription structurally and through heterochromatin formation. This reduces the level of frataxin protein.
- Deficiency of frataxin protein appears to be associated with mitochondrial dysfunction, iron dysregulation, and oxidate stress.
- Homozygous symptomatic patients have frataxin protein levels of 5–30% of normal.
- As carriers are asymptomatic, theoretically frataxin protein levels only need to be >50% of normal to avert disease, and thus investigative approaches to increase frataxin levels are an active area of research.
COMMONLY ASSOCIATED CONDITIONS
HISTORY
- The first symptom typically is gait unsteadiness followed by limb incoordination, difficulty with fine motor movements, and dysarthria. Gait unsteadiness is worse in the dark.
- Rarely scoliosis or cardiomyopathy may precede gait incoordination on presentation.
- Loss of ambulation typically occurs 10–15 years after diagnosis of classic FRDA, though late onset cases have a slower progression and less secondary skeletal abnormalities.
PHYSICAL EXAM
- Classic findings are gait ataxia, limb dysmetria, absent lower extremity reflexes, upgoing plantar responses, decreased vibratory/proprioceptive loss, and dysarthria.
- Lower extremity weakness develops as the disease progresses.
- Muscle atrophy of the hand intrinsics and legs becomes apparent with disease progression.
- Nystagmus is not typical, though square wave jerks can be a common eye movement finding.
- Common systemic musculoskeletal exam findings include scoliosis and pes cavus. Optic atrophy on fundoscopic exam or decreased hearing would be less common exam findings.
- An uncommon finding would include retained or exaggerated deep tendon reflexes (known as FRDA with retained reflexes, which tends to be later onset with a lower incidence of secondary skeletal involvement and cardiomyopathy).
- Very rare finding of isolated spastic paraparesis with ataxia developing later.
- Chorea also would be a very rare variant exam correlate.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- GAA repeat testing to confirm homozygous trinucleotide repeat expansion. If only one allele with GAA repeat expansion, then perform sequence testing to evaluate other allele for possible point mutation or other intragenic frataxin mutation.
- A vitamin E level as deficiency can mimic the FRDA clinical phenotype closely.
Follow-Up & Special Considerations
In unclear cases of ataxia, one could perform a very wide range of labs depending on age and time course of symptom onset, including routine labs, b12, thyroid studies, ammonia, celiac antibodies, GAD antibodies, paraneoplastic panel, metabolic labs for inborn errors of metabolism, mitochondrial studies, further genetic testing, among other possibilities given clinical clues.
Imaging
Initial Approach
MRI of the brain/cervical spine recommended to rule out other pertinent pathology.
Follow-Up & Special Considerations
In FRDA, imaging is negative other than spinal cord atrophy and much less commonly mild cerebellar atrophy (not of the hemispheres).
Diagnostic Procedures/Other
- EKG commonly demonstrates T-wave inversions, axis deviation, and other changes.
- An echocardiogram commonly demonstrates hypertrophic changes. Cardiac MRI might offer higher quality surveillance for early and pertinent changes.
- EMG may have absent sensory responses related to polyneuropathy (dorsal root ganglia pathology) with motor amplitudes less affected.
Pathological Findings
No reports available.
DIFFERENTIAL DIAGNOSIS
- Vitamin E deficiency most closely mimics FRDA. (Autosomal recessive [AR] disorders, such as ataxia with isolated vitamin E deficiency and abetalipoproteinemia should be considered with significant vitamin E deficiency)
- Other AR ataxias could present similarly, as well, though would typically be associated with more significant cerebellar atrophy and other clues per individual disorder (ataxia with oculomotor apraxia, ataxia telangiectasia, spastic ataxia of Charlevoix Saguenay, and spinocerebellar ataxia with axonal neuropathy)
- Spinocerebellar ataxia
- Vitamin B12 deficiency
- Mitochondrial disorders and POLG mutations
- Ataxic presentation of primary coenzyme Q10 deficiency (associated with cerebellar atrophy)
- Other structural, metabolic, toxic, or acquired disorders in general presenting with ataxia
- Of note, isolated “sporadic ataxia” presentations (defined by progressive ataxia with onset after age 20, no family history, no other clinical symptoms, and no established cause), may test positive for FRDA in about 4% of cases
MEDICATION
First Line
- There are no proven or FDA-approved disease modifying therapies for FRDA.
- Symptomatic medication therapy can be utilized. Baclofen is utilized for spasticity if needed. Start at roughly 5 mg PO t.i.d. and titrate slowly to a maximum of 60–80 mg PO total daily dosing as needed and depending on age.
Second Line
- Idebenone supplementation (coenzyme Q10 analog with antioxidant properties) without definitive benefit but some trends of decreasing cardiac hypertrophy of uncertain clinical significance. Also, possible dose-dependent trend toward improvement in neurological symptoms at high dose. As no significant side effects, some still consider treatment (low dose 5–10 mg/kg/day versus high dose 35–45 mg/kg/day).
- Further therapies listed below are in an investigational stage and are NOT recommended outside of a clinical trial at this point.
- Agents that increase the level of frataxin have been identified. Erythropoietin (EPO) raises frataxin levels through a posttranscriptional mechanism and histone deacetylase inhibitors (HDAC inhibitors) raise frataxin levels through decreasing heterochromatin silencing of the frataxin gene. EPO has shown mild initial clinical encouragement in an open label study but has concerns of increasing hematocrit requiring phlebotomy and HDAC inhibitors have yet to be tested clinically.
- Iron chelation therapy with deferiprone also demonstrated possible mild initial encouragement in an open label study, though there were side effect concerns of possible agranulocytosis.
- Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) γ-agonist that involves another pathway being studied in FRDA.
ADDITIONAL TREATMENT
General Measures
No reports available.
Issues for Referral
- Cardiology to monitor cardiomyopathy and treat as appropriate.
- Orthopedics for surgical consideration of significant scoliosis cases (typically >40 degrees/significant progression of curve). Less commonly orthopedic surgery consultation for significant foot deformity.
- Endocrinology for diabetes.
Additional Therapies
- At discretion of cardiologist, stationary cycling for 20–25 minutes at 70–85% of maximum heart rate, as measured with a graded exercise test, is recommended.
- Physical/occupational therapy evaluation for assistive or adaptive devices.
- Orthoses for scoliosis or foot deformities as needed.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
Some recommend supplementation with idebenone as antioxidant therapy. See treatment section.
SURGERY/OTHER PROCEDURES
Orthopedic surgery considerations in select cases of significant scoliosis or severe foot deformities (see issues for referral).
IN-PATIENT CONSIDERATIONS
No reports available.
Nursing
No reports available.
Discharge Criteria
No reports available.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Yearly EKG and ECHO surveillance in patient initially without cardiac disease. Cardiac MRI might be a promising alternative to ECHO.
- Plain films to assess scoliosis roughly yearly with emphasis during periods of growth and during transition to wheelchair.
- Glucose monitoring yearly.
- Hearing assessment every 2–3 years.
DIET
Diet is at the discretion of cardiologist.
PATIENT EDUCATION
Friedreich's Ataxia Research Alliance: www.curefa.org or contact office at 484-879-6160 or 484-875-3105.
PROGNOSIS
Average mortality is roughly 36 years past the initial onset of symptoms (older than previous estimate of 37 years old).
COMPLICATIONS
Mortality is most often related to heart failure, arrhythmia, or aspiration and pneumonia.
ICD9
334.0 Friedreich's ataxia