Fragile X Syndrome

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Introduction

Fragile X Syndrome (FXS) is an X-linked disorder primarily characterized by mild to moderate mental retardation, cognitive and behavioral issues, and a characteristic appearance. It is the most common inherited cause of both mental retardation and autism.

 

Genetics

FXS is caused by an unstable trinucleotide repeat (CGG) at the FMR1 (familial mental retardation) gene locus on the long arm of the X chromosome. This trinucleotide repeat leads to hypermethylation of a CpG island which silences the FMR1 gene. Depending on the amount of methylation, the fragile X mental retardation protein (FMRP) is decreased or absent. In normal individuals, FMRP negatively regulates protein synthesis and is involved in neural synapse maturation.

Normal unaffected individuals have between 5 to 50 CGG triplet repeats in the FMR1 promoter region. Patients with the full mutation have >200 CGG trinucleotide repeats and Fragile X Syndrome. However a third group with 50-200 repeats have a premutation, which can result in premature ovarian failure or Fragile X associated Tremor/Ataxia (intention tremor, cerebellar ataxia, autonomic dysfunction, parkonsonism).

The full mutation has a frequency of 1 in 3,600 in males and 1 in 6,000 in females. The premutation has a frequency of 1 in 250-800 in males and 1 in 100-260 in females.

Men pass on the gene to all of their daughters, but there is no expansion of the repeat in transmission. Women have a 50% chance of passing the gene on to each of their children which can result in an expansion of the repeat. The risk of a premutation expanding to a full mutation in transmission increases linearly with maternal repeat size.

There is a wide phenotypic range from mild to very severe mental retardation; generally, males are more severely affected than females. These phenotypic variations can result from mosaicism for the size of the repeat, the degree of methylation of the gene, and/or lyonization in females. The number of affected family members usually increases with successive generations.

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Depiction of the FRM1 gene and impact of the trinucleotide repeat on gene methylation.  Image from http://www.fragilex.org/wp-content/uploads/2012/01/FMR1-Gene-Categories.png

 

Clinical Features

Fragile X Syndrome should be tested for in any child presenting with developmental delay, hypotonia or autism.

Neurocognitive abnormalities

  1. Mental retardation: Affected males: IQs average 30-50; females have IQs in the 70s
  2. Developmental delay in childhood
  3. Autism or Autism-like features: perseverative speech, repetitive chewing, hand flapping, poor eye contact, shyness and intolerance of change
  4. Attention deficit-hyperactivity disorder: associated with poor attention and increased activity
  5. Speech and language problems, particularly mathematics abilities, visuospatial abilities, attention and executive function, and visual-motor coordination
  6. Decline in cognitive level and adaptive behavior skills after early childhood: prepubertal boys generally have higher IQs than adolescents and adults.
  7. Seizures

Anatomic abnormalities:

  1. Characteristic facies: Long and narrow face, prominent forehead and chin, large ears
  2. Macrocephaly: associated with underlying structural abnormalities in the brain
  3. Macro-orchidism: volume >25mL after puberty with normal testicular function
  4. Mitral Valve Prolapse
  5. Joint abnormalities: finger laxity, scoliosis, congenital hip dysplasia
  6. Patent Eustacian Tube: chronic otitis media
  7. Obesity: subgroup with "Prader-Willi phenotype" of FXS

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Characteristic phenotype of Fragile X Syndrome.  Image from http://upload.wikimedia.org/wikipedia/commons/b/b3/Fragile_x_syndrom.png

 

Diagnosis

Initially, Fragile X syndrome was diagnosed by karyotyping cells in a folate-deficient medium to look for the fragile site on the X chromosome (thus leading to the disease's name). The current gold standard for diagnosis is either PCR or Southern blot analysis.

There have been pilot studies for inclusion of Fragile X syndrome in newborn screening, however it is not currently included. There is also a commercial test available for screening women prior to pregnancy. It can also be detected by amniocentesis or chorionic villus sampling.

Following diagnosis, genetic counseling should be initiated and family members should be offered testing.

 

Treatment

Currently, treatment is symptomatic. Individuals diagnosed with FXS should be provided with special educational services to meet their specific cognitive disabilities, PT/OT and consultation with a speech/language pathologist. Seizures should be controlled with carbamazepine or valproic acid. FXS patients may also require referral to a child psychiatrist for treatment of ADHD, either with methylphenidate or clonidine and guanfacine. SSRIs can be used to treat anxiety, risperidone can be used for agression and low dose aripiprazole for behavioral problems.

As more has been learned about the biochemical pathways FRMP is involved in, new therapeutic targets have been identified. Pilot studies and small RCTs have shown promising results in mGluR5 (metabotrophic glutamate receptor 5) antagonists, Lithium (involved in mGluR5 signaling) and GABA agonists, but more trials are needed.

Additionally, women with a child or a family history of Fragile X should be evaluated for carrier status and may undergo pre-implantation or prenatal genetic testing.

 

References

  1. Phalen, James A. Fragile X Syndrome. Pediatrics in Reivew. 26: 181-182. 2005.
  2. Hersh, Joseph H. et al. Health Supervision for Children with Fragile X Syndrome. Pediatrics. 127: 984-1005. 2011.
  3. Hagerman, Randi J. et al. Advances n the Treatment of Fragile X Syndrome. 123: 378-385. 2009.
  4. Wenstrom, K. D. Fragile X and Other Trinucleotide Repeat Diseases. Obstetrics and Gynecology Clinics of North America. 29: 1367-1376. 2002.

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