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Fragile X Syndrome - FMR1

Clinical Features

The fragile X syndrome is one of the most common monogenic inherited causes for mental retardation. Due to X chromosomal inheritance male individuals are affected more frequently and more severely than females.

  • Infants
    • Sit alone (>10 months)
    • Walk (>20 months)
    • First clear words (>20 months)
    • Muscular hypotonia
    • Head circumference > 50. percentile
    • Otitis media
  • Prepubertal
    • Developmental delay, especially speech
    • Abnormal temperament: tantrums, hyperactivity, autism
    • Intellectual disability: IQ 30-50
    • Abnormal craniofacies: long face, prominent forehead, large ears, prominent jaw
  • Postpubertal
    • Macro-orchidism
    • Abnormal behavior: shyness, gaze aversion
    • Ophthalmologic: strabismus
    • Orthopedic: joint hyperextensibility, pes planus
  • Other features
    • Cardiac: mitral valve prolapse, aortic root dilatation
    • Dermatologic: usually soft and smooth skin

Genetic Information

Fragile X syndrome is an X chromosomal inherited disorder which is caused by expanded CGG repeats in exon 1 of the FMR1-gene (fragile x mental retardation 1) on the long arm of chromosome X (Xq27.3). Regarding the repeat number normal, intermediate/gray zone, premutation and full mutation alleles are distinguished (see table 1).

There is a high risk of expansion of maternal premutation alleles to full mutation upon transmission to offspring. 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.

In full mutation alleles FMR1-promoter is hypermethylated resulting in gene silencing. Generally all males with a full mutation have a fragile X syndrome. Approximately 2/3 of female full mutation carriers are affected, usually presenting with milder clinical symptoms. In rare cases male full mutation carriers present without FMR1-methylation or with methylation mosaicism. They are called „high functioning males“. Normal intellect has been reported in some cases.

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 ZoneAlleles 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

Istable 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

 

Prevalence

Fragile X-syndrome              

  • 1:3300-1:6000 in males

Premutation alleles               

  • 1:200-1:300 in females
  • ca. 1:400 in males

Gray zone alleles                 

  • approx. 1:140 both sexes

 

Diagnostic

 

Indication
  • Psychomotor or mental retardation in both sexes
  • Prenatal diagnostics in women with a permutation
  • Investigation of persons at risk and healthy carriers (female and male) in affected families
Method

PCR analysis for the detection of normal repeats and trinucleotide repeat expansions

Methylation-sensitive genomic Southern-Blot analysis for the detection of premutation and full mutation size alleles and for the analysis of the methylation state of the gene.

Sample Requirement

2 - 4 ml of EDTA blood

Duration

approx. 2 weeks

OMIM

300624 Fragile-X Syndrome

309550 FMR1



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