Friedreich Ataxia (FA)

http://neuropathology-web.org/chapter9/images9/9-FRDA.jpg

Section of spinal cord stained to demonstrate classic lesions in the dorsal columns and spinocerbellar tracts in Friedreich Ataxia.  http://neuropathology-web.org/chapter9/images9/9-FRDA.jpg

 

Introduction

Friedreich Ataxia (FA) is the most common hereditary ataxia, occurring in 1/50,000 Caucasians.  Onset of symptoms occurs prior to the age of 10, with the disease primarly impacting the CNS (brain and spinal cord) peripheral nerves, heart, and pancreas.

 

Pathogenesis

  • Typically due to loss of function mutation in frataxin (FXN) gene on chromosome 9
    • Frataxin is a mitochondrial protein involved in iron regulation
    • Frataxin silencing results in mitochondrial accumulation of iron, resulting in oxidative stress injury
  • Gene silencing occurs secondary to trinucleotide (GAA) repeats >66
    • More repeats lead to earlier presentation
  • Somatic expansion of repeats can occur as cells undergo miosis, especially in dorsal root ganglia, resulting in disease progression
  • Typically autosomal recessive, but compound heterozygotes who undergo somatic expansion may exhibit symptoms or have delayed presentation
  • Evidence of genetic heterogeneity - not all patients with FA have FXN mutations

 

Presenting Symptoms

  • Progressive ataxia - typically first symptom
  • Kyphoscoliosis - may predate ataxia
  • Progressive leg weakness
  • Impaired sensation and position sense, especially in feet
  • Loss of deep tendon reflexes in legs

 

Click HERE for a video of a patient with FA and their gait.

 

Complications

  • CNS:    Degeneration of posterior column and spinocerebellar tracts
               +/- cerebellar atrophy leading to:
               
    • Wheelchair confinement (95%, typically 11-25 yrs)
    • Cerebellar dysarthria
    • Impaired swallowing
    • Bladder dysfunction
    • Eye movement (nystagmus), vision loss (5-15%)
    • Loss of position and vibration sense (posterior column degeneration)
    • Distal weakness (UMN degeneration)
    • Movement disorders- tremors, dystonia, chorea1 
                
  • PNS: degeneration of large sensory cells in dorsal root ganglion
          
    • Sensory neuropathy
    • Loss of deep tendon reflexes in all extremeties
    • Hearing loss (5-10%)
  • Musculoskeletal
               
    • Foot deformities (pes cavus - see photo below, hammer toes) and foot ulcers

http://www.thetagoeclinic.co.uk/pages/files/images/pes.jpg

http://www.thetagoeclinic.co.uk/pages/files/images/pes.jpg

 

  • Hand muscle atrophy
  • Scoliosis
  • Muscle atrophy

 

  • Cardiac (91%)
          
    • Hypertrophic cardiomyopathy leading to arrhythmia (ST-T wave abnormalities) and heart failure
                 
      • Most frequent cause of death
    • Fatty degeneration with interstitial fibrosis, cardiomyocyte hypertrophy, and eosinophilic and lymphocytic infiltrates
  • Pancreas:
    • Diabetes mellitus (33%) - secondary to insulin resistance
                      

Diagnosis

  • Clinical diagnosis
  • Should be confirmed with genetic testing
  • MRI shows spinal cord degeneration +/- cerebellar atrophy (left)

https://scientificearthconscientious6.files.wordpress.com/2012/07/new-gene-therapy-strategy-boosts-levels-of-deficient-protein-in-friedreichs-ataxia.jpg

https://scientificearthconscientious6.files.wordpress.com/2012/07/new-ge...

 

Differential Diagnosis

  • Ataxia-telengiectasia - autosomal dominant, click HERE for a video of the nystagmus seen in this disorder.
  • Hereditary motor and sensory neuropathy: Roussy-Levy variant
  • Carlevoix-Saguenay - early childhood onset of cerebellar ataxia, pyramidal tract signs, and peripheral neuropathy
  • Infantile onset spinocerebellar ataxia- ataxia, opthalmoplegia, hearing loss

 

Prognosis

  • Life span 30-40 yrs, females live longer
  • Causes of death
  1. Cardiac dysfunction - CHF or arrhythmia
  2. Pneumonia - cannot protect airway

 

Management

  • No specific disease-modifying therapy available
    • Histone deacetylase inhibitors promising area of research
  • Antioxidants - coenzyme Q10, carnitine, idebenone, vitamin E
    • Decrease markers of oxidative injury (urinary 8-hydroxy-2’-deoxyguanosine), but clinical importance of this has not been established
    • In RCT, Idebenone did not improve neurologic function, but has been shown to reduce interventricular septal thickness and LV mass
    • Most commonly used at onset of cardiomyopathy
  • Glucose screening with diabetes mgmt as necessary
  • Cardiology - initial echo and cardiac MRI followed by repeat periodic echo
    • Conventional drugs used to treat CHF and arrythmia
  • Physical therapy

 

 References

  1. Durr A. Cossee M. Agid Y. et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. NEJM 1996 
  2. Maring J.R. Croarkin E. Presentation and progression of Friedreich ataxia and implications for physical therapist examination. Phys Ther 2007
  3. Kearney M., et al. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev 2012
  4. Payne R.M. Wagner G.R. Cardiomyopathy in Friedreich ataxia: clinical findings and research. J Child Neurol 2012
  5. Soragni E. Xu C. Plasterer H.L. Jacques V. Rusche J.R. Gottesfeld J.M. Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia. J Child Neurol 2012