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Genetic counseling: Friedreich Ataxia

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Friedreich Ataxia

ContractingEdit

  • Acknowledge prior contact
  • What do they know about Friedreich Ataxia?
  • Do they have any questions?

EtiologyEdit

  • Slowly progressive ataxia with onset usually during adolescence
  • Autosomal recessive inheritance
  • Majority of cases caused by mutations in X25/FRDA gene
    • Found on chromosome 9q13
    • <1% of patients who meet the clinical diagnostic criteria do not have an identifiable mutation in this gene
    • 96% of patients with FRDA1 are homozygous for a GAA expansion in the X25 gene
      • Normal alleles have 7-38 repeats
      • Premutation alleles have 34-60 repeats
      • Disease-causing alleles 66-1700 triplets
      • GAA repeat length is unstable during germ line transmission:
        • Maternal transmission gives both contractions and expansions
        • Paternal transmission usually contracts repeat size but premutation alleles may expand in size
      • Larger expansion size correlates with earlier onset of disease
  • X25 gene codes for a protein called frataxin
    • Found in inner mitochondrial membrane
    • Putative iron transporter to regulate mitochondrial iron content

Incidence and Carrier FrequencyEdit

  • Population frequency of 2-4 per 100,000
  • Carrier frequency is 1/60-1/100

Clinical FeaturesEdit

  • Obligatory diagnostic criteria:
    • Progressive ataxia of gait and limbs
    • Absent reflexes in legs
    • Dysarthria
    • Decrease in position sense and/or vibration in lower limbs
    • Muscle weakness
    • Motor nerve conduction velocity of >40 m/s with reduced or absent sensory nerve action potential
  • Additional findings:
    • Scoliosis
    • Pes cavus
    • Cardiomyopathy (66%)
      • Usually in later stages of disease but may precede ataxia
      • 2/3 of patients have abnormal EKG
    • Optic nerve atrophy (25%)
    • Sensorineural hearing loss (10%)
    • Diabetes mellitus (10%) or glucose intolerance (20%)

Natural historyEdit

  • Ataxia usually develops in childhood or early teens
  • Rate of progression is variable
    • Mean age of loss of ambulation is 25 years
    • Death usually occurs in 30's
      • Cardiomyopathy
      • Diabetes
      • Pneumonia due to dysphagia
  • 25% of patients have atypical findings
    • Late-onset FRDA (LOFA)
      • Approximately 15% of patients with FRDA
      • Age of onset greater than 25 years of age
      • Usually have repeat size smaller than 500
    • FRDA with retained reflexes (FARR)
      • 12% of patients with FRDA
      • Show brisk tendon reflexes for up to 10 years after disease onset
    • FRDA with slowly progressive disease
      • Disease progression slower in Acadian patients
      • Age on onset and neurological manifestations similar

TestingEdit

  • Molecular genetic testing can be used to identify mutations in X25/FRDA
    • Shortest repeat length causing disease has not yet been determined for sure
    • <1% of patients who satisfy clinical diagnostic criteria have no identifiable mutation
  • Carrier testing
    • Can be offered if two disease-causing mutations are identified in proband
    • Alleles in premutation range may be transmitted unchanged or may expand
  • Prenatal testing
    • Clinically available for couples at 25% risk for having child with FRDA1 if both disease causing mutations are known
    • DNA from amniocentesis at 16-18 weeks or CVS at 10-12 weeks can be analyzed

ManagementEdit

  • No therapy is known to stop, delay, or reverse disease progression
  • Future therapies may include:
    • Drug therapy
    • Gene therapy
    • Other pathophysiology-based treatments
  • Support
    • Psychological support
    • Prostheses, walking aids, and wheelchairs may help patients maintain an active lifestyle
    • Physical therapy
    • Speech therapy
    • Orthopedic intervention for scoliosis and foot deformities
    • Treatment of cardiac disease and diabetes

Differential DiagnosisEdit

  • Demyelinating form of hereditary motor and sensory neuropathy type I (HMSNI or CMT1)
    • Childhood symptoms may be similar
    • Nerve conduction studies or DNA testing can determine definitively
  • Vitamin E deficiency
    • Should be considered in cases that don't show a GAA expansion
    • Fulfill diagnostic criteria for FRDA but often have titubation and hyperkinesia
    • Treated with Vitamin E supplements
  • Other early onset ataxias present with different clinical findings

Psychosocial IssuesEdit

  • Feelings of guilt, anxiety
  • Pregnancy issues: preimplantation genetic diagnosis, prenatal testing, possible pregnancy termination
  • Discussion with other family members about risk, inheritance
  • Disruption of work, school, social life for those affected

ResourcesEdit

  • National Ataxia Foundation
Phone: 763-553-0020
Email: naf@ataxia.org
  • Muscular Dystrophy Association
Phone: 520-529-5300 or 8-572-1717
Email: mda@mdausa.org
Web: www.mdausa.org
  • International Network of Ataxia Friends (INTERNAF)
Web: internaf.org

ResourcesEdit

Geneclinics. "Friedreich Ataxia" Web: www.geneclinics.org Online Mendelian Inheritance in Man. "Friedreich Ataxia" Web: www.ncbi.nlm.nih.gov

NotesEdit

The information in this outline was last updated in 2001.


This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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