Friedreich’s Ataxia

Friedreich’s ataxia is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder characterized by progressive spinocerebellar degeneration. It presents in the 1st to 2nd decades of life with progressive gait ataxia, weakness, tremor, dysarthria, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy, and/or diabetes. Patients eventually become bedridden. Diagnosis is confirmed by genetic testing showing trinucleotide repeat expansion in the FXN gene. Treatment is supportive and most patients die of heart disease in the 4th or 5th decade of life.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definitions

  • 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 Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum
  • Friedreich’s ataxia (FA): an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder characterized by spinocerebellar degeneration

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics and pathophysiology

  • A mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 734 times.
    • In FA, the sequence is repeated approximately 701,300 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.

Epidemiology

  • Most common autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceataxia (50% of cases)
  • Incidence in the United States: 1 in 40,000
  • More common in Caucasians
  • Onset of symptoms usually < 20 years of age

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Clinical Presentation

Neurologic features

  • 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and temperature sensations 
    • Loss of deep tendon reflexes
    • Extensor plantar reflexes
    • Ataxia of trunk and arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm
    • Tremor in facial and arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm muscles
    • Dependence on a wheelchair in the 1st to 2nd decade of life
    • Dysarthria and dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia

Non-neurologic features

  • Kyphoscoliosis (up to 80%)
  • Hypertrophic cardiomyopathy (> 50%): signs of ventricular hypertrophy such as systolic ejection murmurs
  • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (approximately 10%)
  • Pes cavus (hollow foot) and/or pes equinovarus (clubfoot)
  • Visual and hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
  • Mild cognitive impairment
Lateral curvature of the spine and round shoulders in friedreich ataxia

Example of severe kyphoscoliosis, a common finding in Friedreich’s ataxia

Image: “Lateral curvature of the spine and round shoulders ” by Lovett, Robert W. License: Public Domain

Diagnosis

Genetic testing

  • Confirms the diagnosis
  • Indications:
    • Prenatal diagnosis for parents with an affected child
    • Any patient suspected of having the disease

Imaging

  • Magnetic resonance imaging (MRI) (imaging of choice):
    • Atrophy of the cervical spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord with minimal evidence of cerebellar atrophy
    • Cerebellar atrophy is a late finding.
  • Electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG)) and echocardiography to look for signs of hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy
  • Serum glucose testing for diabetes mellitus
  • Nerve conduction studies may show mild reduction in velocity.
Mri friedreich ataxia

MRI of a patient with Friedreich’s ataxia: notice the thinning of the cervical spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord

Image: “Figure 6” by Rajith Nilantha de Silva et al. License: CC BY 4.0

Management

  • No definitive treatment 
  • Multidisciplinary intervention (e.g., neurology, physical medicine, cardiology, orthopedics, endocrinology)
  • Early enactment of occupational therapy and physical therapy helps preserve function.
  • Prognosis:
    • 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 Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies is the most frequent cause of death.
    • Females have a significantly better prognosis.

Differential Diagnosis

The differential diagnosis for FA includes the following conditions:

  • Hereditary ataxia-telangiectasia Ataxia-telangiectasia Ataxia-telangiectasia, also known as Louis-Bar syndrome, is a neurocutaneous syndrome, which involves multiple systems but mainly affects the neurological system. Ataxia-telangiectasia is an autosomal recessive genetic disorder caused by a mutation in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene). Ataxia-telangiectasia (AT): degenerative cerebellar ataxia with oculocutaneous vascular malformations (telangiectasia) and café-au-lait macules. Genetically inherited, and transmitted in an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancepattern. 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is inherited in an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancepattern, 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.

References

  1. 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. 18972120.e26). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323374620000446
  2. Palau Martínez, F. (2016). Enfermedades monogénicas raras. In C. Rozman Borstnar, & F. Cardellach López (Eds.), Farreras Rozman. medicina interna (pp. 11701182). .00148-4 https://www.clinicalkey.es/#!/content/3-s2.0-B9788490229965001484
  3. 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. 13921422.e5). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323374620000355
  4. 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
  5. 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.
  6. Genetics Home Reference. Friedreich Ataxia. Retrieved September 8, 2020, from https://ghr.nlm.nih.gov/condition/friedreich-ataxia#diagnosis

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