Friedreich ataxia

Friedreich ataxia (FDRA) is an autosomal recessive disorder involving trinucleotide repeat expansion that leads to progressive neurodegeneration. It affects multiple spinal cord tracts, causing muscle weakness and impaired coordination of all limbs. A staggering gait in childhood is the resulting main symptom. Other features include skeletal abnormalities, cardiomyopathy, and diabetes. The clinical course is mainly determined by the extent of the loss of mobility and cardiac involvement. Diagnosis requires confirmation with genetic tests. Because there is no curative therapy available, the prognosis is poor.

• The most common autosomal recessive ataxia ^[1]
• Peak incidence: 8–15 years (most cases < 25 years) ^[2][3]
• Affects individuals of Central and Northern European descent ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Trinucleotide repeat expansion (of the nucleotide triplet GAA) in the FXN gene on chromosome 9; → deficiency of frataxin (an iron-binding protein) → intramitochondrial accumulation of iron and ; dysregulation of cellular antioxidant defense due to mitochondrial dysfunction → oxidative damage and degeneration of CNS and PNS

References: ^[2][4]

• Neurological
  • Progressive ataxia (impaired coordination of muscles) of all limbs ; due to damage to the spinocerebellar tracts (often a presenting feature)
    • Gait ataxia
      • Bilateral lower limbs equally affected
      • Wide-based gait with frequent falling
      • Titubation while standing or sitting
    • Arms: action and intention tremors
    • Associated symptoms
      • Impaired proprioception and vibration sense (pallhypesthesia) due to damage to the dorsal columns
      • Loss of deep tendon reflexes due to degeneration of the dorsal root ganglia
  • Spastic paralysis due to degeneration of the lateral corticospinal tract
  • Nystagmus
  • Dysarthria and dysphagia (may be accompanied by uncoordinated breathing)
  • Bladder dysfunction
  • Hearing loss
• Skeletal deformities
  • Secondary scoliosis (kyphoscoliosis): usually occurs in childhood
  • Foot deformity: foot inversion (talipes equinovarus) and/or high-arched foot (pes cavus) with hammertoes
• Other features
  • Concentric hypertrophic cardiomyopathy: palpitations, arrhythmias, dyspnea, exercise intolerance ^[5]
  • Diabetes mellitus
  • Personality changes (e.g., emotional lability)

Individuals with FRiedreich ATAXia have ATAXic GAAit due to the expansion of the triplet GAA in the FRATAXin gene.

• A specific trinucleotide repeat expansion assay should be performed in all suspected cases.
• ECG: T-wave inversion and ventricular hypertrophy
• Echocardiography: symmetric, concentric ventricular hypertrophy
• Nerve conduction studies
  • Sensory: absent or reduced sensory nerve action potentials (SNAP)
  • Motor: normal until advanced stages
• MRI brain and spinal cord: cervical spine atrophy (minimal cerebellar atrophy)

References:^[4]

• No curative treatment available
• Multidisciplinary supportive care: genetic counseling, physiotherapy, and speech and language therapy
• Treatment of cardiologic, orthopedic, and metabolic (i.e., diabetes) features of the disease

References:^[4]

• Nonambulation is common by age 20–30.
• Average age at death: 37 years
• Causes of death
  • Most common: heart failure due to hypertrophic cardiomyopathy
  • Respiratory complications

References:^[6]

• Carrier testing of relatives
• Prenatal testing: Genetic counseling is recommended for parents with one affected child.

References:^[6]