OVERVIEW: What every practitioner needs to know

Are you sure your patient has Freidreich ataxia? What are the typical findings for this disease?

Freidreich ataxia (FRDA) is a slowly progressive gait ataxia with onset between ages 10 and 25 years. It is accompanied by dysarthria and leg spasticity. Loss of lower limb reflexes, bladder dysfunction, loss of position sense (positive Romberg sign), and loss of vibration sense also occur.

Cardiomyopathy is seen in 75% of affected individuals.

Diabetes mellitus is seen in 30% of affected individuals.

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What other disease/condition shares some of these symptoms?

Hereditary sensory motor neuropathies: Charcot-Marie-Tooth [CMT] types 1 and 2 can present in childhood with clumsiness and areflexia. Note CMTs that mimic FRDA are usually inherited in an autosomal dominant fashion, so family history is helpful.

Ataxia with vitamin E deficiency: This condition should be differentiated from FRDA by testing for serum concentration of vitamin E.

What caused this disease to develop at this time?

FRDA is inherited in an autosomal recessive pattern with homozygosity for the
FRDA gene. The disease-causing gene has expanded trinucleotide GAA repeats. Disease-causing expanded alleles have greater than 66 repeats (normal is 5-33; premutation is 34-65). Most affected individuals are homozygous for expanded alleles with greater than 100 repeats. Trinucleotide repeats are common. In certain genes, these repeats are unstable and may expand. If they are located in exons, the expansion may alter the protein’s function, as in Huntington disease. In FRDA, the GAA expansion is in an intron and results in decreased transcription of the gene.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Clinical testing to confirm the diagnosis is through targeted mutation analysis of the GAA repeat length in the FRDA-causing gene FXN. Ninety-eight percent of cases have an expansion. About 2% of cases may have an expansion on one allele and an intragenic point mutation on the other allele.

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging of the brain and spine may be normal early. In late disease, cerebellar and cervical spinal cord atrophy may be seen.

An echocardiogram should be obtained, with referral to cardiology

Confirming the diagnosis

The diagnosis of nervous system degenerative diseases is complex and expensive. In the case of FRDA, a peripheral neuropathy is in the differential diagnosis and therefore nerve conduction testing/electromyography (NCV/EMG) may also be considered, which is a specialized, expensive, and sometimes painful test. Therefore, the most effective diagnostic strategy may be to refer the patient to a child neurologist specializing in movement disorders or neuromuscular disorders.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Management should be considered through a neurology or neuromuscular specialty clinic or a Muscular Dystrophy Association clinic. Management will include neurologic assessments, physical therapy and occupational therapy evaluations, speech/swallowing assessments, electrocardiographic assessments, scoliosis evaluation by an orthopedic surgeon, assessment of sleep, bladder function testing if symptomatic, endocrine testing, and psychologic assessment. A multidisciplinary approach is recommended.

Treatments may include walking aids, occupational therapy interventions for school/work/home, dietary modification, treatment of cardiac disease with antiarrhythmic agents, anticoagulants, anti–heart failure medication, hearing aids, treatment of diabetes, bladder antispasmodic agents, continuous positive airway pressure for sleep apnea, and psychological support.

What are the possible outcomes of Freidreich ataxia?

Patients with FRDA generally progress to needing a wheelchair within 10-20 years after clinical presentation. Heart disease may be the most common cause of death. Patients with milder diesease may survive past age 60 years.

What causes this disease and how frequent is it?

Prevalence is 2-4/100,000. The cause of the disease is homozygosity for trinucleotide GAA expansion in the FRDA gene.

How do these pathogens/genes/exposures cause the disease?

The result of these expansions is functional deficiency of the protein frataxin. This causes abnormal accumulation of iron in the mitochondria, interferes with mitochondrial function, and results in overabundance of oxygen free radicals with oxidant-induced intracellular damage.

Other clinical manifestations that might help with diagnosis and management

There are cases of late onset or very late onset FRDA, presenting in adulthood.

What complications might you expect from the disease or treatment of the disease?

Cardiac, endocrine, airway, and orthopedic complications are all possible.

How can Freidreich ataxia be prevented?

The disease is genetic. Genetic counseling is recommended. There is no preventive treatment.

What is the evidence?

There is little objective evidence for FRDA management, which mainly derives from experience in multidisciplinary clinics. Antioxidant therapy (idebenone, coenzyme Q10) improves cardiac function.

Fogel, BL, Perlman, S. “Clinical features and molecular genetics of autosomal recessive cerebellar ataxias”. Lancet Neurol. vol. 6. 2007. pp. 245-57. (An outstanding clinical and scientific review describing and comparing autosomal recessive cerebellar ataxias.)

Ribai, P, Pousset, F, Tanguy, ML. “Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up”. Neurology. vol. 64. 2007. pp. 558-64. (A large and well-described case series of patients with FRDA.)

Di Prospero, NA, Baker, A, Jeffries, N. “Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial”. Lancet Neurol. vol. 6. 2007. pp. 878-86. (A randomized controlled trial. Previous studies had shown benefit only for cardiomyopathy; however, larger doses in this study show some promise for neurological symptoms.)

Lynch, DR, Perlman, SL, Meier, T. “A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia”. Arch Neurol. vol. 67. 2010. pp. 941-7. (A subsequent study which did not show benefit for neurological manifestations.)