Fragiles X associated Tremor Ataxia syndrome, FXTAS - FMR1

Klinische Symptomatik

4.2% of men with cerebellar ataxia have a Fragile X associated Tremor Ataxia Syndrome (FXTAS), a progressive cerebellar ataxia with intentions tremor in adulthood (Brussino et al., 2005). Women are less often affected.

 

Criteria for diagnosis:

Primary symptoms:

• Premutation in the FMR1 gene

• Heightened signal intensities in white matter (cerebellar peduncle or brain stem)

• Intention tremor, ataxia


Secondary symptoms:


• Heightened signal intensities in white matter

• Generalised cerebral atrophy

• Parkinson's Disease

• Problems with short-term memory

 

Diagnosis is assured when all primary and secondary symptoms are present.
Diagnosis is probable when a primary neuroradiologic and a secondary symptom are present.
Possible additional symptoms include dementia, peripheral neuropathy, proximal myasthenia in the lower extremities, or participation of the autonomic nervous system. Microscopically, eosinophilic inclusion bodies are found in nerve and glial cells.

17% of male premutation carriers fall ill between 50 and 59 years of age, 38% between 60 and 69 years of age, 47% between 70 and 79 years of age, and 75% after age 79.

Proof of mutation clarifies the cause of FXTAS and provides indications regarding the probability with which other family members could be affected by FMR1 associated diseases.These are:

• Fragile X Syndrome (FraX)

• Fragile X associated Tremor Ataxia Syndrome (FXTAS)
• 
Premature Ovarian Failure (POF)

• Psychological problems, especially compulsive disorders and psychoses.

Genetik

FXTAS is inherited via the X chromosome and is caused by expanded CGG repeats in exon 1 of the FMR1 gene (fragile x mental retardation 1) located on the long arm of the X chromosome (Xq27.3). Depending on the number of repeats, a differentiation is made between normal, gray zone/intermediate, premutation and full mutation alleles (see table 1).

There is a high risk of expansion of maternal premutation alleles to full mutation upon transmission to offspring. Female premutation carriers have a 50% risk of transmitting an abnormal (premutation or full mutation) allele in each pregnancy. Risk for expansion of a maternal premutation to full mutation depends on repeat number (see also Fragile X Syndrome).

Premutations cause an increased risk for FMR1-associated disorders such as premature ovarian failure (POF) and/or Fragile X Related Tremor/Ataxia Syndrome (FXTAS). An increase in transcription is detectable from upper normal repeats onwards to the premutation region. Probably increased FMR1-mRNA has a toxic effect.

In males premutations and full mutations are transmitted as premutations to offspring. The premutation is inherited by all their daughters and none of their sons.

 

	CGG-Repeats	male	female
Normal Alleles	5 - 40	stable in individual and stable upon transmission
Intermediate or Gray Zone Alleles	41 - 55	stable in individual and unstable upon transmission, however no expansion to full mutation in one generation
Premutation Alleles	56 - 200	stable in individual and unstable upon transmission: daughters are obligate carriers of a premutation; increased risk of FXTAS	stable in individual and unstable upon transmission, risk for full mutation in offspring depending on the repeat number; risk for expansion to full mutation when transmitted to offspring: 55-69: 3-5% 70-79: 31% 80-89: 58% 90-99: 80% 100-200: 94-100%; increased risk of POF and FXTAS
Full Mutation Alleles	> 200	Fragile X Syndrome, unstable in individual (mosaicism) and unstable upon transmission: daughters are obligate carriers of a premutation	approx. 60% of cases clinical manifestation of fragile X syndrome; unstable in individual (mosaicism) and unstable upon transmission: max. 50% risk of having children with a full mutation

 

Häufigkeit

Premutation alleles:

1:200 to 1:300 in females

approx. 1:400 in males

 

Diagnostik