Friedreich Ataxia - FXN

Klinische Symptomatik

Friedreich ataxia is the most common cause for genetically determined ataxia. The affected individuals show incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus and hammer toe. The triad of hypoactive knee and ankle jerks, signs of progressive cerebellar dysfunction and preadolescent onset indicate the diagnosis.

 

The disorder is usually manifest before the age of 20, the onset may vary between early childhood and advanced age in rare cases. Heart dysfunction (cardiomyopathy or arrhythmias), even heart failures occur. 10% of the patients suffer from diabetes mellitus.

Genetik

Friedreich ataxia is an autosomal recessive condition. In 95% of the affected individuals a homozygous GAA trinculeotide repeat expansion is found in the first intron of the FXN (frataxin) gene on chromosome 9 (9q13). The remainder carries both an expanded trinuleotide repeat on one allele and a point mutation on the second allele. Normal persons carry 6 to 30 GAA trinucleotide repeats, in patients with Friedreich ataxia more than 200 GAA repeats are found.

Expanded alleles can be instably transmitted onto subsequent generations (in part further expansion, in part contraction of the repeat length). Heterozygous carriers of a repeat expansion are completely healthy. If both parents carry a repeat expansion allele in the frataxin gene, each pregnancy has a 25 % probability for a child affected by Friedreich ataxia.

 

	Repeats
Normal allele	5 - 33
Premutation allele, meiotic unstable (non disrupted)	34 - 65
Pathological allele	66 - 1700

Häufigkeit

1: 30 000 to 1: 50 000 in the Middle-European population.
In Middle-Europe each 85th individual carries one repeat expansion allele.

 

Diagnostik