Gene Symbol: FXN
Chromosomal Locus: 9q21.11
TURNAROUND TIME: 10 days
Several polymerase chain reactions (PCR) that bracket the FXN GAA repeat region and sizing by fluorescent capillary electrophoresis and agarose gel electrophoresis for larger expansions.
- Collect: Prefer two 5ml whole blood EDTA (lavender top) tube.
- Min. Collection: 0.7 ml whole blood EDTA.
- Transport: blood EDTA at Room Temp shipped regular next day air (No Saturday delivery; store specimen refrigerated and ship Monday).
- Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
- Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.
- Prenatal testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask. Maternal blood sample is required for maternal cell contamination studies.
Counseling and informed consent are recommended for genetic testing. A consent form
is available as a resource but not required.
Incidence: About 1 in 25,000 – 50,000. Carrier incidence is 1 in 60.
Inheritance: Autosomal recessive. Variable age of onset but complete penetrance.
Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with mean onset between age ten and 15 years and usually before age 25 years. FRDA is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis,bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy; up to 30% have diabetes mellitus; and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes.
Arrhythmias and congestive heart failure frequently occur in the later stages of the disease and are the most common cause of mortality. The size of the GGA repeat regions dictate the age of onset and the speed of the progression of symptoms rather than the actual spectrum of symptoms.
Molecular Genetic Mechanism: The most common mutation is an expansion of a GAA triplet repeat within intron 1 of the FXN gene. Therefore, the clinical affect is correlated with the smallest allele expansion. In a small number of cases (less than 2%) one of the allele defects is a point mutation, which this assay will not detect.
Normal and clinically unaffected individuals have between 5-33 GAA triplet repeats. Mutable alleles are associated with 34-65 repeats; however the penetrance of expression is variable within this region. Expansions of 66-1000 GAA repeats the disease will be full penetrant; however the age of onset and severity vary dramatically within that range. The expanded repeat range is highly mutable; as a result transmission to the next generation may result in an increase or decrease of the GAA trinucleotide repeat size.
- Normal alleles: 5 to 33 GAA repeats
- Mutable Normal Alleles : 34 to 65 GAA repeats
- ‘Borderline” Abnormal Alleles : 44 to 66 uninterrupted GAA repeats
- “Classical” Abnormal Alleles: 66 - 1700 GAA repeats
Clinical Sensitivity: 98%
Test Limitations: This test examines the GAA repeat regions, exclusively. However, no other mechanism has been described for FRDA and the test is considered diagnostic.
INDICATIONS FOR USE:
- Individuals with a family history of FRDA who want to determine their true risk.
- Families considering future medical and disability insurance needs.
- Individuals at risk who wish prenatal diagnosis.
- To determine whether individuals with an ataxia and lower limb weakness may have FRDA.
- To differentiate individuals with FRDA from other ataxias.