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FXN gene mutation

Friedreich ataxia (FRDA) is an inherited neurological disorder causing progressive damage to the nervous system. FRDA is the most common form of hereditary ataxia, affecting about 1 person in 50, 000 in the United States. An estimated 1 in 90 individuals of European ancestry carries an abnormal FXN gene. FRDA is an autosomal recessive disease and males and females are equally affected.

FRDA is typically silent for several years after birth until a pattern of symptoms begin to appear. Signs and symptoms usually appear between the ages of 5 and 15, but may occur as early as 18 months or as late as 30 years of age. Cerebellum, spinal cord, and peripheral nerves are affected. The first indication is usually difficulty walking. Other signs and symptoms that may develop later include:

  • Progressive loss of movement and coordination
  • Heart disease, including arrhythmia, heart enlargement and heart failure
  • Muscle weakness
  • Skeletal deformities (scoliosis)
  • Vision and/or hearing impairment
  • Diabetes

Currently, there is no effective cure or treatment for FDRA. However, many of the symptoms and accompanying complications can be treated to help patients maintain optimal functioning as long as possible.

FRDA is caused by mutations in the FXN (frataxin) gene located on the long arm of chromosome 9 that encodes for the mitochondrial protein frataxin. In the normal version of the gene, a GAA sequence of DNA in intron 1 is repeated between 7 and 22 times. In the defective FXN gene, the GAA sequence repeats 600 to 1,200 times. FRDA is the only known recessive genetic disorder caused by this abnormal GAA expansion. Approximately 98% of individuals with FRDA have a homozygous expansion of the GAA trinucleotide repeat in intron 1 of the FXN gene. The remaining 2% of FRDA patients have the trinucleotide expansion on 1 allele and a point mutation or deletion of the second allele.

The GAA trinucleotide repeat expansion results in a deficiency of frataxin. Frataxin is important for the incorporation of iron inside mitochondria. A deficiency of frataxin affects iron metabolism, antioxidant protection, and overall energy production.

Historically, laboratory diagnosis of FRDA has relied on genetic testing to detect GAA trinucleotide repeat expansions within intron 1 or other FXN gene mutations. Genetic testing provides a conclusive diagnosis and can be used to determine carrier status.

More recently, Mayo Medical Laboratories developed an immunoassay for quantitation of frataxin that is more cost effective than genetic testing. It can be used for both diagnosis and treatment monitoring. Patients with FRDA have decreased levels of frataxin protein. Reference range is 19 ng/mL or greater for pediatric patients and 21 ng/mL or greater for adult patients.

Specimen requirement for genetic testing is 3 to 5 mL of blood collected in an EDTA lavender top tube. Specimen requirement for measurement of frataxin is 2 mL of blood collected in an EDTA lavender top tube.

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