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Internal Medicine

Friedreich’s ataxia (FRDA)

Spinocerebellar ataxia caused by trinucleotide (GAA) expansion due to FXN (fraxatin) gene mutation characterized by the progressive loss of voluntary muscular coordination (ataxia) and heart enlargement (hypertrophic cardiomyopathy).

Introduction

Friedreich’s ataxia is a disorder where there’s a buildup of iron that damages various organ systems – in particular, the nervous system gets damaged which causes ataxia, which is when the muscles don’t move in a coordinated way.

Spinocerebellar ataxia caused by trinucleotide (GAA) expansion due to FXN (fraxatin) gene mutation characterized by the progressive loss of voluntary muscular coordination (ataxia) and heart enlargement (hypertrophic cardiomyopathy).

  • Autosomal recessive (AR)
  • M/C inherited ataxia
  • M/C autosomal recessive ataxia
frda

History

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Nikolaus Friedreich (1825 – 1882) was a German pathologist and neurologist, and a third-generation physician in the Friedreich family.

Nikolaus Friedreich first described Friedreich ataxia in a series of 5 papers published from 1863 to 1877. Friedreich recognized many of the main features of the disorder subsequently named after him, including an onset most often occurring in adolescence, ataxia, sensory neuropathy, scoliosis, foot deformity, and cardiomyopathy. During the next 100 years, precisely what comprises the clinical spectrum of Friedreich ataxia was the subject of some confusion and debate. With discovery of the causative gene in 1996,6 FXN (previously called X25 and FRDA), rapid and accurate diagnosis of Friedreich ataxia can now be made in most instances.


Pathophysiology

Frataxin (FXN) gene mutation (chromosome 9)
(homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion)

Frataxin deficiency

Impaired intracellular antioxidant defences
Dysregulation of iron-sulfur cluster proteins
Depression of aerobic electron transport chain respiration
Massive mitochondrial dysfunction

Cell death
(brain, spinal cord and heart)

jnc12303-fig-0001-m
Schematic representation of the biological pathways altered in Friedreich’s ataxia (FRDA) as consequences of frataxin deficiency in mitochondria. There is a representation of the three major organs involved in the pathogenesis of FRDA, that is, nervous system, heart and pancreas. | González-Cabo, P., & Palau, F. (2013). Mitochondrial pathophysiology in Friedreich’s ataxia. Journal of Neurochemistry, 126(s1), 53–64. https://doi.org/10.1111/jnc.12303
jnc12303-fig-0002-m
Schematic drawing of axonal pathology in peripheral and central nervous systems. Dying‐back sensory axonal neuropathy is represented by loss of large myelinated axons (dashed black line) and abnormal myelinization (loss of the black line in the myelin), in association with loss of large proprioceptive neurons in the dorsal root ganglia (DRG). Involvement of central axons is indicated by dashed black lines in the spinal cord that represent abnormal medial lemniscus and dendrite connections. Degenerated fasciculi and tracts are indicated in white. Motor neurons, interneurons and motor nerves axons and myelin are normal. | González-Cabo, P., & Palau, F. (2013). Mitochondrial pathophysiology in Friedreich’s ataxia. Journal of Neurochemistry, 126(s1), 53–64. https://doi.org/10.1111/jnc.12303

Clinical features

Typically presents prior to 25 years, with the average age of symptom onset occurring in the early to mid-teen years

  • Scoliosis and foot deformity (pes cavus) (early signs and may precede ataxia)

Neuromuscular manifestations:

Nearly all patients become paraplegic and require wheelchairs (over ½ are wheelchair-bound 16 years after onset)
  • Gait ataxia
  • Dysmetria of arms and legs (type of ataxia featuring lack of coordination of movement typified by the undershoot/overshoot of intended position with the hand, arm, leg, or eye)
  • Dysarthria (motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes)
  • Head titubation (essential tremor, characterised by uncontrollable, rhythmic shaking)
  • Atrophy and weakness of distal extremities
  • Absence of muscle stretch reflexes
  • Babinski signs
  • Loss of joint and vibratory senses
  • Superimposed stocking-and-glove type sensory neuropathy
  • Variable muscle tone in legs (normal in arms)
    • Spasticity and hyperreflexia present

Major clinical features of FRDA and their frequency from 3 studies:

SymptomHarding1Durr2Delatycki3
Ataxia99100100
Dysarthria979195
Absent lower limb reflexes998774
Scoliosis796078
Pes cavus (high-arch)555574
Swallowing disturbance27
Sphincter disturbance2341
Reduced vision1813
Hearing impairment813
Cardiomyopathy on echocardiogram6365
Diabetes/abnormal glucose tolerance10328
  1. Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104:589–620.
  2. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335:1169–1175.
  3. Delatycki MB, Paris DB, Gardner RJ, et al. Clinical and genetic study of Friedreich ataxia in an Australian population. Am J Med Genet. 1999;87:168–174.

Atypical Friedreich ataxia:

Does not meet classical criteria.
  • Friedreich ataxia with retained reflexes (9% cases): Often presents with brisk lower limb reflexes, particularly knee jerks
  • Late-onset Friedreich ataxia (14% cases): Onset after 25 years
  • Very late-onset Friedreich ataxia: Onset after 40 years (very rare)

Complications

  • Cardiomyopathy (early sign in some cases)
  • Diabetes mellitus (invariably delayed in the course of the illness)
  • Optic atrophy (uncommon but some patients become blind)
  • Nystagmus
  • Auditory neuropathy/dyssynchrony (1% cases)
    • Problems with speech perception despite normal pure-tone audiometry
  • Vestibular dysfunction
nihms275352f1
Ages of onset and death as a function of GAA trinucleotide repeat expansions (short alleles) in 30 patients with autopsy-confirmed FRDA. (a) Age of onset vs. GAA trinucleotide repeats; (b) age of death vs. GAA trinucleotide repeats. The patient identified by the arrows (onset at 50, death at 83) was not diagnosed during life. | Koeppen, A. H. (2011). Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. Journal of the Neurological Sciences, 303(1–2), 1–12. https://doi.org/10.1016/j.jns.2011.01.010

Diagnosis

Genetic testing:

  • Homozygosity for GAA trinucleotide repeat expansion in intron 1 of FXN (98% cases)
  • Other 2% cases:
    • Compound heterozygosity for GAA expansion
    • Point mutation or deletion

Management

ldx034f01
Flow chart for the diagnosis and management of Friedreich’s ataxia. | Cook, A., & Giunti, P. (2017). Friedreich’s ataxia: clinical features, pathogenesis and management. British Medical Bulletin, 124(1), 19–30. https://doi.org/10.1093/bmb/ldx034

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