Friedrich's Ataxia (FRDA) Flashcards
What is FRDA?
- Neurodegenerative disorder that primarily affects the spinal cord and cerebellum.
- Characterised by degenerative atrophy of the posterior columns of the spinal cord leading to progressive ataxia, sensory loss, and muscle weakness
Who discovered FRDA?
Nikolaus Friedreich (1863)
What causes FRDA?
GAA trinucleotide repeat expansion in the first intron of the Frataxin gene on chromosome 9
Typical repeats vs repeats in FRDA:
- Normal individuals have 5–30 repeats, but people with FRDA have hundreds to thousands of repeats.
- More repeats generally correlate with earlier onset and more severe disease progression
How is FRDA inherited?
Autosomal recessive (both copies of FXN gene must be mutated).
Pathophysiology of FRDA:
- Reduced Frataxin Protein Production leads to mitochondrial dysfunction.
- Frataxin is crucial for iron metabolism in mitochondria. Low frataxin leads to oxidative stress. This damages mitochondrial function, reducing ATP (energy) production and impairing nerve and muscle function.
- Neurodegeneration: dorsal root ganglia, spinal cord, and cerebellum are affected. Leads to progressive loss of proprioception, coordination, and voluntary motor control.
When is the onset of FRDA commonly?
Childhood
What types of ataxia are present in FRDA?
- Sensory ataxia: loss of balance and coordination.
- Cerebellar ataxia: wide-based, unsteady gait and difficulty with precise movements.
What pathways are affected?
- Posterior columns (DCML)
- Corticospinal (pyramidal) tract
- Ventral/dorsal spinocerebellar tracts
Epidemiology of FRDA
- Most common hereditary ataxia
- Approximately 50% of all ataxia cases
- Approximately 75% in patients less than 25 years of age
- Prevalence: 1 in 29,000-50,000
- Carrier rate: 1 in 60-120
Neurological clinical features of FRDA (SCARED)
- Slowly progressive ataxia
- Coordination issues: unsteady, broad-based gait
- Arch deformities: high arches (pes cavus)
- Reflex loss: absent DTRs, but upgoing plantar reflexes (Babinski +)
- Extreme sensory loss: proprioception & vibration lost first, then pain & temperature
- Degeneration of dorsal root ganglia
Systemic clinical features of FRDA (CASH-D)
- Cardiomyopathy (Dilated)
- Ability to walk lost in 10–15 years
- Scoliosis
- Hearing loss (sensorineural)
- Diabetes
Speech and swallowing in FRDA:
- Dysarthria: slow, jerky speech with sudden utterances, progresses to near-unintelligibility
- Swallowing: liquid dysphagia in advanced disease, choking risk, modified foods or feeding tubes often used
Current treatments for FRDA:
- Antioxidants e.g. Omaveloxolone
- Energy metabolism enhancers
- Iron chelators
- Erythropoietin (EPO) and Histone Deacetylase (HDAC) inhibitors
- Immune modulators
- Repeat-targeted Nucleic Acid Therapies
What does Omaveloxolone do in FRDA?
- Antioxidant that enhances energy and metabolism, and slows down degeneration.
- Currently only for over 16s.
What do iron chelators do in FRDA?
Reduce oxidative stress
What do Erythropoietin (EPO) and Histone Deacetylase (HDAC) inhibitors do in FRDA?
Increase amount of frataxin
What do repeat-targeted nucleic acid therapies do in FRDA?
target these expanded repeats to restore frataxin expression
What is the life expectance for FRDA?
into 40s
Within how many years will people with FRDA lose the ability to walk?
Within 15 years post-onset
What is the major cause of death in FRDA?
Cardiac dysfunction: congestive heart failure or arrhythmia
Evaluation of FRDA:
- Relies on history and physical examination.
- Check glucose levels: diabetes
- Vitamin E levels: normal in FRDA
- EMG: usually normal or show mild abnormalities since FRDA primarily affects sensory nerves, not the muscles directly.
- Nerve conduction studies: in FRDA there are absent or reduced amplitude sensory nerve action potentials (SNAPs)
- Genetic testing: the only disease with pathological GAA repeats.
- MRI of the brain and spinal cord, which will show atrophy of the cervical/thoracic spinal cord and cerebellum.
