- Ataxia: abnormal, uncoordinated movements
- Hereditary ataxias: a heterogeneous group of inherited conditions that have ataxia as a cardinal symptom, generally secondary to injury or dysfunction of the cerebellum
- Friedreich’s ataxia (FA): an autosomal recessive disorder characterized by spinocerebellar degeneration
Genetics and pathophysiology
- A mutation in the FXN gene on chromosome 9 results in a guanine-adenine-adenine (GAA) trinucleotide repeat expansion.
- Normally, the GAA sequence within the FXN gene is repeated 7–34 times.
- In FA, the sequence is repeated approximately 70–1,300 times.
- This triple-repeat expansion causes gene silencing and reduces the production of a protein called frataxin to 5%–35% of normal.
- Frataxin is a mitochondrial protein and a key part of adenosine triphosphate (ATP) production.
- Frataxin deficiency leads to cell damage through different mechanisms.
- Cells most frequently damaged by frataxin deficiency include neurons, myocardial cells, and pancreatic beta cells.
- The major neuronal pathogenesis is a distal to proximal neuron death, known as the “dying back phenomenon.”
- The primary sites of neural involvement include peripheral nerves, the dorsal columns, the corticospinal tract, and the lateral and ventral spinocerebellar tracts.
- Most common autosomal recessive ataxia (50% of cases)
- Incidence in the United States: 1 in 40,000
- More common in Caucasians
- Onset of symptoms usually < 20 years of age
- Triad (highly suggestive): ataxia + areflexia + extensor plantar reflexes
- Gait ataxia:
- Usually the presenting symptom in adolescence
- Affects both lower limbs
- Progressively worsening slow and clumsy gait after normal walking has developed
- A combination of 2 types of gait:
- Cerebellar: wide-based, constant shifting of position to maintain balance
- Sensory deficit: exacerbates wide-base gate, steppage gait
- Other symptoms include:
- Motor weakness
- Loss of vibration and position sense; eventual loss of light touch, pain, and temperature sensations
- Loss of deep tendon reflexes
- Extensor plantar reflexes
- Ataxia of trunk and arm
- Tremor in facial and arm muscles
- Dependence on a wheelchair in the 1st to 2nd decade of life
- Dysarthria and dysphagia
- Kyphoscoliosis (up to 80%)
- Hypertrophic cardiomyopathy (> 50%): signs of ventricular hypertrophy such as systolic ejection murmurs
- Diabetes mellitus (approximately 10%)
- Pes cavus (hollow foot) and/or pes equinovarus (clubfoot)
- Visual and hearing loss
- Mild cognitive impairment
- Confirms the diagnosis
- Prenatal diagnosis for parents with an affected child
- Any patient suspected of having the disease
- Magnetic resonance imaging (MRI) (imaging of choice):
- Atrophy of the cervical spinal cord with minimal evidence of cerebellar atrophy
- Cerebellar atrophy is a late finding.
- Electrocardiogram (ECG) and echocardiography to look for signs of hypertrophic cardiomyopathy
- Serum glucose testing for diabetes mellitus
- Nerve conduction studies may show mild reduction in velocity.
- No definitive treatment
- Multidisciplinary intervention (e.g., neurology, physical medicine, cardiology, orthopedics, endocrinology)
- Early enactment of occupational therapy and physical therapy helps preserve function.
- Mean age of death is 37.
- Higher numbers of GAA repeats are associated with earlier onset of disease and a higher chance of cardiomyopathy and diabetes.
- Cardiomyopathy is the most frequent cause of death.
- Females have a significantly better prognosis.
The differential diagnosis for FA includes the following conditions:
- Hereditary ataxia-telangiectasia (AT): degenerative cerebellar ataxia with oculocutaneous vascular malformations (telangiectasia) and café-au-lait macules. Genetically inherited, and transmitted in an autosomal recessive pattern. Patients present with unusual narrow-based gaits, unlike in FA, where gait is broad-based. There is an elevated incidence of cancer in patients with AT (primarily leukemia and lymphoma). There are no curative treatments and prognosis is poor. The median age of death for patients with AT is 25.
- Charcot-Marie-Tooth disease (CMT): a spectrum of genetically inherited conditions affecting peripheral nerves. Common clinical symptoms include progressive peripheral neuropathy, distal weakness, and muscular atrophy. Genetic testing and electromyography are important diagnostic tools to detect this condition. Treatment is supportive. While becoming wheelchair-bound is common, most patients retain ambulatory capacity and life expectancy is not shortened.
- Ataxia with vitamin E deficiency: while often seen in patients with dietary deficiencies, there is a genetic form of this condition that is caused by mutations in the alpha-tocopherol transfer protein gene. This mutation is inherited in an autosomal recessive pattern, much like FA. Similarly to FA, it can present with neuropathy and loss of normal gait. In addition, the condition has cutaneous findings such as retinitis pigmentosa. Treatment with high doses of vitamin E is curative in these patients.
- Warner, W. C., & Sawyer, J. R. (2017). Scoliosis and kyphosis. In F. M. Azar MD, J. H. Beaty MD & S. T. Canale MD (Eds.), Campbell’s operative orthopaedics (pp. 1897–2120.e26). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323374620000446
- Palau Martínez, F. (2016). Enfermedades monogénicas raras. In C. Rozman Borstnar, & F. Cardellach López (Eds.), Farreras Rozman. medicina interna (pp. 1170–1182). .00148-4 https://www.clinicalkey.es/#!/content/3-s2.0-B9788490229965001484
- Warner, W. C., & Sawyer, J. R. (2017). Neuromuscular disorders. In F. M. Azar MD, J. H. Beaty MD & S. T. Canale MD (Eds.), Campbell’s operative orthopaedics (pp. 1392–1422.e5). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323374620000355
- Rosenberg, R. N. (2018). Ataxic disorders. In J. L. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo & J. Loscalzo (Eds.), Harrison’s principles of internal medicine, 20e (). New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1164415673
- Garg, M., Kulkarni, S. D., Shah, K. N., & Hegde, A. U. (2017). Diabetes Mellitus as the Presenting Feature of Friedreich’s Ataxia. Journal of neurosciences in rural practice, 8(Suppl 1), S117–S119.
- Genetics Home Reference. Friedreich Ataxia. Retrieved September 8, 2020, from https://ghr.nlm.nih.gov/condition/friedreich-ataxia#diagnosis