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277

Friedreich Ataxia

Klinische Symptomatik

Friedreich ataxia is a slowly progressive ataxia which normally manifests by the age of 25 (between the ages of 10 and 15 on average). It begins with an atactic gait disorder which worsens with loss of visual controls (darkness, Romberg signs). Weak or missing muscle reflexes in the lower extremities and a positive Babinski reflex are observed. Growing dysarthria and muscle weakness develop, followed by muscle atrophy, loss of balance, pallesthesia, eye movement disorders, foot deformities (in most cases pes cavus), and scoliosis. These clinical symptoms are also observed in cases of hereditary motor and sensory neuropathy (HMSN).

Clinical symptoms are progressive degeneration of the spinal ganglion, the spinocerebellar, corticospinal, and posterior funicular tracts as well as the cerebellum. Involvement of the peripheral nervous system presents as a mixed axonal and sensory-motor neuropathy. MRI initially reveals normal findings; later, atrophy of the cerebellum is observed. Functional disorders of the heart (in most cases an initial hypertrophic cardiomyopathy, followed by arrhythmia) may occur, as may Diabetes mellitus (approx. 30 %), optic atrophy (25 %, often asymptomatic), hearing impairment (13 %), and bladder dysfunction.

Approximately 25 % of affected patients show an “atypical” phenotype with retention of muscle reflexes (FRDA with retained reflexes, FARR), an unusually slow progression, or late manifestation: late-onset FRDA (LOFA) by the age of 39, and very late-onset FRDA (VLOFA) after the age of 40.

Genetik

Friedreich ataxia is an autosomal recessively inherited disease. Approximately 95 % of affected patients have a GAA triplet repeat expansion in the first intron of the gene FXN (frataxin) on both parental chromosomes 9q13. The remaining patients carry a triplet expansion on one allele and an additional point mutation on the other allele.

Alleles expanded beyond the normal range can be passed on in an unstable manner, some with greater triplet repeat expansion and some with contraction. Heterozygous carriers of expanded alleles are clinically asymptomatic.

If both parents are carriers of a triplet repeat expansion in the frataxin gene, the risk of having a child with the disease is 25 %. A clinical prediction based on the length of the GAA triplet repeat expansion is not possible.

  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 Central European population
  • In Central Europe, each 85th individual carries one repeat expansion allele
Indikation
  • Clinical features as described above
  • Relatives of patients with Friedreich ataxia
Methodik Next Generation Sequencing (NGS)

Parallele Sequenzierung mehrerer Gene


Material 2-4 ml EDTA-Blut
Dauer
3-6 Wochen

 

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