II. Epidemiology

  1. Most common inherited Developmental Disability
  2. Full mutation
    1. Prevalence 1:4000 men and up to 1:6000 women
  3. Premutation in FMR1 gene carrier
    1. Prevalence 1:800 men and up to 1:100 women
  4. Diagnosis often not made until age 8
    1. Delayed diagnosis due to subtle features

III. Pathophysiology

  1. Fragile X Mutation (FMR1) Gene is on X Chromosome
  2. Expansion mutation in FMR1 Gene
    1. Occurs with repetitive CCG in FMR1
    2. Unaffected patients have <50 CCG repetitions
    3. Premutation carriers have 50-200 CCG repetitions
    4. Full mutation patients have >200 CCG repetitions

IV. Signs: Subtle Phenotype (milder in women)

  1. Facial features (onset in early childhood)
    1. Large prominent ears
    2. Long face or Macrocephaly
    3. Prominent forehead
  2. Macroorchidism (after Puberty)
  3. Mental Retardation (80% of men, 33-65% of women)
    1. Moderate Mental Retardation (IQ <70)
  4. Developmental Delay
    1. Learning Disability
      1. Abstract reasoning
      2. Sequential processing
      3. Mathematics
    2. Delayed speech
      1. Males start to talk at 20 months
    3. Fine and gross motor coordination problems
      1. Males sit without support at 10 months
      2. Males start to walk at 20 months
  5. Behavior problems
    1. Autistic-like characteristics
    2. Defensiveness
    3. Mood instability
    4. Speech Perseveration
    5. Anxiety
    6. Social problems
    7. Hand flapping
    8. Hand biting
    9. Gaze aversion

V. Associated conditions

  1. Epilepsy
  2. Strabismus
  3. Connective tissue dysplasia
    1. Hyperflexible joints
    2. Mitral Valve Prolapse
    3. Pes Planus
  4. Attention Deficit Hyperactivity Disorder
    1. Affects 80% of fragile X patients

VI. Conditions associated with premutation carriers

  1. Premature Ovarian Failure (20% of women)
  2. Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS)
    1. Affects 30% men aged 50-60 years old

VII. Resources

  1. National Fragile X Foundation
    1. http://www.FragileX.org
  2. Fragile-X Research Foundation
    1. http://fraxa.org
  3. Gene Tests: FRM1-Related Disorders
    1. http://www.geneclinics.org/profiles/fragilex/

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Related Studies

Ontology: Fragile X Syndrome (C0016667)

Definition (MSH) A condition characterized genotypically by mutation of the distal end of the long arm of the X chromosome (at gene loci FRAXA or FRAXE) and phenotypically by cognitive impairment, hyperactivity, SEIZURES, language delay, and enlargement of the ears, head, and testes. INTELLECTUAL DISABILITY occurs in nearly all males and roughly 50% of females with the full mutation of FRAXA. (From Menkes, Textbook of Child Neurology, 5th ed, p226)
Definition (MEDLINEPLUS)

Fragile X syndrome is the most common form of inherited developmental disability. A problem with a specific gene causes the disease. Normally, the gene makes a protein you need for brain development. But the problem causes a person to make little or none of the protein. This causes the symptoms of Fragile X.

People with only a small change in the gene might not show any signs of Fragile X. People with bigger changes can have severe symptoms. These might include

  • Intelligence problems, ranging from learning disabilities to severe intellectual disabilities
  • Social and emotional problems, such as aggression in boys or shyness in girls
  • Speech and language problems, especially in boys

A genetic blood test can diagnose Fragile X. There is no cure. You can treat some symptoms with educational, behavioral, or physical therapy, and with medicines. Getting treatment early can help.

NIH: National Institute of Child Health and Human Development

Definition (NCI) A genetic syndrome caused by mutations in the FMR1 gene which is responsible for the expression of the fragile X mental retardation 1 protein. This protein participates in neural development. This syndrome is manifested with mental, emotional, behavioral, physical, and learning disabilities.
Definition (CSP) X-linked recessive disorder characterized by mental retardation and large head, jaw, ears, and testes; premutation alleles in unaffected carriers give rise to significantly amplified repeats in affected progeny.
Concepts Disease or Syndrome (T047) , Congenital Abnormality (T019)
MSH D005600
ICD9 759.83
ICD10 Q99.2
SnomedCT 390007001, 613003
English Fragile X Syndromes, Syndrome, Fragile X, Syndromes, Fragile X, MARKER X SYNDROME, MARTIN-BELL SYNDROME, X-LINKED MENTAL RETARDATION AND MACROORCHIDISM, FRAGILE X SYNDROME, FRAGILE X MENTAL RETARDATION SYNDROME, fragile X syndrome, fragile X syndrome (diagnosis), Martin Bell Syndrome, Martin-Bell Syndrome, Syndrome, Martin-Bell, Fragile x syndrome, MENTAL RETARDATION, X-LINKED, ASSOCIATED WITH marXq28, Fragile X Syndrome [Disease/Finding], martin-bell syndrome, fragile-x syndrome, martin bell syndrome, autism fragile syndrome x, fragile x syndrome autism, x fragile syndrome, fragile syndrome x, fragile x syndrome, disorder fragile x syndrome, Marker X Syndrome, X Linked Mental Retardation and Macroorchidism, Syndrome, Marker X, X-Linked Mental Retardation and Macroorchidism, Fra(X) Syndrome, Marker X Syndromes, Syndromes, Marker X, Fragile X Mental Retardation Syndrome, Mental Retardation, X-Linked, Associated With Marxq28, Fragile X Syndrome, Fragile X syndrome, Marker X syndrome, Martin-Bell syndrome, FRAXA - Fragile X syndrome, Fragile X syndrome (disorder), fragile X; syndrome, syndrome; fragile X
Italian Sindrome X fragile, Sindrome di Martin-Bell, Ritardo mentale legato all'X e macroorchidismo, Sindrome del cromosoma X fragile
French Syndrome de retard mental du X fragile, Syndrome de l'X fragile, Syndrome de Martin-Bell, Syndrome du chromosome X fragile, Syndrome du chromosome X-fragile
Japanese 脆弱X症候群, ゼイジャクXショウコウグン, X染色体脆弱性症候群, Fragile X症候群, 脆弱X症候群
Swedish Fragil X-syndrom
Czech syndrom fragilního chromozómu X, syndrom fragilního X, Syndrom fragilního X, syndrom fragilního X chromosomu, syndrom křehkého X, syndrom fragilního X-chromozomu, syndrom fragilního X chromozomu, syndrom Martin-Bell, syndrom Martinův-Bellové
Finnish Fragiili X -oireyhtymä
Polish Zespół łamliwego chromosomu X
Hungarian Fragilis X syndroma
Norwegian Fragilt X-syndrom, Martin-Bell-syndrom
Spanish Síndrome de Fragilidad del Cromosoma X, síndrome de Martin - Bell, síndrome del cromosoma X frágil (trastorno), síndrome del cromosoma X frágil, Síndrome del X frágil, Síndrome del Cromosoma X Frágil, Síndrome de Martin-Bell
Portuguese Síndrome de Fragilidade do Cromossomo X, Síndrome do cromossoma X frágil, Síndrome de Martin-Bell, Síndrome do Cromossomo X Frágil
Dutch fragiele-X; syndroom, syndroom; fragiele-X, breekbaar X-syndroom, Fragiele-X-syndroom, Martin-Bell-syndroom, Syndroom, fragiele-X-
German Fragiles-X-Syndrom, Martin-Bell-Syndrom, Syndrom des fragilen X-Chromosoms

Ontology: FMR1 gene (C1414649)

Definition (NCI) This gene may be involved in the regulation of mRNA trafficking.
Concepts Gene or Genome (T028)
LNC LP33555-1
English FMR1 GENE, FMR1, FRAGILE X MENTAL RETARDATION PROTEIN, FMRP, FMR1 Gene, Fragile X Mental Retardation 1 Gene, fragile X mental retardation 1, MGC87458, FRAXA, FMR1 gene