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Fragile X Syndrome

Fragile X Syndromes

Fragile X syndrome is a genetic condition caused by a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome.


Presentation

Fragile X syndrome in males is usually more severe than in females and males are never asymptomatic. This is because males have only one X chromosome (unlike females that have 2 “X” chromosomes) and therefore any defect on the X chromosome is likely to be displayed. Females tend to have fewer and milder abnormalities than males. This is because they inherit two X chromosomes, one of which is inactivated randomly in each cell.

Common symptoms include:

  • Behavior – Characterized by autism spectrum behaviors such as attention deficit disorder, hyperactivity, expressive delay, tactile defensiveness, repetition of words and phrases, echolalia (parrot like repetition of a word or phrase that has just been spoken by another person), social anxiety and avoidance of eye contact.
  • Cognitive – Males with full mutation have moderate to severe mental impairment. Difficulty comprehending abstract ideas, organization of information, planning ahead and with problem-solving skills. 
  • Health problems – Seizures occur in 10 to 20% of males with Fragile X syndrome. Most are simple or complex partial seizures. The seizures often spontaneously remit during childhood and occur less frequently in women.
  • Appearance/physical characteristics – Some boys have a soft, broad forehead compared to children of their own age. Physical characteristics become more obvious during the teenage years. For example, the characteristic elongated face becomes more obvious during teenage years. During puberty, boys often have macroorchidism, flat feet, hyper flexible joints, mitral valve prolapse. Girls that have fragile X syndrome often experience premature ovarian failure (early menopause). Both boys and girls may develop a tremor which can appear like Parkinson’s disease.
Family History of Mental Retardation
  • You are at greater risk if you have: A family history of fragile X syndrome A family history of mental retardation, developmental delay or autism of unknown cause Infertility problems associated with elevated follicle stimulating hormone (FSH) levels[ucsfhealth.org]
  • history of mental retardation Fetuses of known carrier mothers Patients with cytogenetic fragile X test result that is discordant with their phenotype.[en.wikibooks.org]
  • Behavioral and developmental problems may indicate fragile X syndrome, particularly if there is a family history of mental retardation.[medical-dictionary.thefreedictionary.com]
  • We propose the use of a single Eco RI digestion to test systematically for a fragile X mutation in boys or girls with unexplained mental retardation, late onset of speech, or autistic or hyperactive behavior, even if there is no family history of mental[nejm.org]
Hunting
  • Archibald AD 1, 2, 3 , Smith MJ 1, 2 , Burgess T 1, 2, 3 , Scarff KL 1 , Elliott J 1 , Hunt CE 1 , McDonald Z , Barns-Jenkins C 1, 2 , Holt C 1, 2 , Sandoval K 1, 2 , Siva Kumar V 1, 2 , Ward L 1, 2 , Allen EC 2, 3 , Collis SV 2, 3 , Cowie S 1 , Francis[ncbi.nlm.nih.gov]
  • DNAFTB Animation 10:Thomas Hunt Morgan describes his discoveries using fruit flies. SOURCE: DNALC.DNAFTB[dnalc.org]
Poor Oral Hygiene
  • The experience of caries was correlated with salivary parameters, poor oral hygiene, lower socioeconomic status and an increased count of S. mutans in saliva.[ncbi.nlm.nih.gov]
Dental Caries
  • The aim of this study was to determine the experience of dental caries in individuals with FXS, by examining the saliva profile, oral hygiene, socioeconomic characteristics and use of controlled drugs in these patients.[ncbi.nlm.nih.gov]
Short Arm
  • To the best of our knowledge, this is the first description of an asymptomatic carrier of three different X-linked disorders, involving severe genetic rearrangements on both long and short arms of the X chromosomes.[ncbi.nlm.nih.gov]
Protuberant Ears
  • Typical features include large, protuberant ears, a prominent chin and forehead, a high arched palate, and, in postpubertal males, macroorchidism. The joints may be hyperextensible, and heart disease ( mitral valve prolapse ) may occur.[msdmanuals.com]
  • The classical facial appearance that includes a prominent forehead, a long, narrow face, a prominent jaw, and protuberant ears becomes more evident late in childhood or in early adolescence.[pediatrics.aappublications.org]
Hyperactivity
  • Because many people with Fragile X also have attention disorders, hyperactivity, anxiety, and language-processing problems, a person with Fragile X may have more capabilities than his or her IQ (intelligence quotient) score suggests. Physical.[web.archive.org]
  • The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties[ncbi.nlm.nih.gov]
  • He had lack of speech and severely impaired social skills, hyperactivity, stereotypical hand movements, a special interest towards moving colourful items and a short attention span for other objects around.[ncbi.nlm.nih.gov]
  • Twenty individuals reported previously with rare missense or nonsense mutations or other coding disturbances of the FMR1 gene ranged in age from infancy to 50 years; most were verbal with limited speech, had autism and hyperactivity, and all had intellectual[ncbi.nlm.nih.gov]
Tic Disorder
  • Clinically, 4 patients fulfilled diagnostic criteria for Gilles de la Tourette syndrome (GTS) while 1 patient would have been diagnosed with an adult onset tic disorder.[ncbi.nlm.nih.gov]

Workup

Diagnosis for fragile X syndrome is based on molecular genetic analysis that measures the length of the CGG repeats in the FMR-1 region. This test can be performed from a blood sample and/or (in a fetus), through amniotic fluid testing.

Treatment

The goal of treatment is to minimize the symptoms resulting from fragile X syndrome. Management of children and adolescents with fragile X syndrome is individualized according the degree and type of child’s cognitive and behavioral symptoms, strengths and weaknesses.

Genetic counseling should be offered to families of individuals with fragile X syndrome, since this may be an inherited disorder.

Children and adolescents with fragile X syndrome have special educational and behavioral needs and should be referred to counselors and speech therapists for help with coping and minimizing the associated problems.

Medications may be used to alleviate symptoms such as attention deficit hyperactivity disorder, anxiety, mood instability, depression and/or seizures.

Prognosis

Life span is generally unaffected by the disorder.

Etiology

A mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome causes the clinical features of the fragile X syndrome

Epidemiology

Both genders can be affected; it occurs more commonly in males (1 in 3600 males compared to 1 in 4000-6000 females).

Sex distribution
Age distribution

Pathophysiology

  • Platelets are indeed an attractive model for unraveling pathophysiological mechanisms involved in NDD as well as to search for diagnostic and therapeutic biomarkers.[ncbi.nlm.nih.gov]
  • Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined.[ncbi.nlm.nih.gov]
  • The involvement of leptin and adiponectin in the pathophysiology of FXS was hypothesized. MATERIAL AND METHODS: Twenty-three male patients affected by FXS (full mutation in the FMR1 gene) and 24 controls were included in the study.[ncbi.nlm.nih.gov]
  • Over the past decade, FXS-PSCs have been used to address the fundamental questions regarding the pathophysiology of FXS.[ncbi.nlm.nih.gov]
  • Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). We report on the first trial of acamprosate, a drug with putative mGluR5 antagonism, in three adults with FXS and autism.[ncbi.nlm.nih.gov]

Prevention

There is no guideline for the prevention of fragile X syndrome.

Summary

Fragile X syndrome is the most common inherited cause of intellectual disability. It is a result of expansion of a repetition of a set of genes (the segment CGG) of the fragile X mental retardation 1 (FMR-1) gene, which leads to defective transcription and loss of the FMR-1 gene. 

Patient Information

Fragile X syndrome is a genetic condition that a person is born with. It is a result of a defect of a part of the “X” chromosome. Fragile X syndrome causes learning and behavior problems, as well as abnormal body features. It occurs more commonly in boys than girls. The cause is unknown; it may be inherited or a result of unexpected damage to the X chromosome.

What are the symptoms?

Symptoms that commonly occur in persons with Fragile X include:

  • Larger than normal head
  • Crossed eyes
  • Large ears and “sunken in” eyes
  • Flat feet
  • Testicles that are larger than normal in male teenagers and adults. 
  • Learning and behavior problems such as:
  • Difficulty performing problem solving and tasks that involve organization
  • Difficulty with language and speaking
  • Trouble sitting still, paying attention
  • Feel anxious, worried or sad often
  • Medical problems, such as:
  • Seizures
  • Tremor (shaking of the hands)

How is it diagnosed?

Diagnosis is made through a family history screening during which your doctor will ask if any member of your family has had symptoms seen in patients with fragile X syndrome. Then a blood test will be performed that will determine if a person has problems with their X chromosome.

What is the treatment?

Currently there is no cure for fragile X syndrome. Treatment centers around controlling a person’s symptoms. For example, a children’s teacher can help develop a special learning plan, behavior counselors and speech therapists can work with a child to help improve language and behavior problems, certain medications may be prescribed to help a child pay attention.

References

Article

  1. Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome. Am J Med Genet 1996; 64:196.
  2. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905.
  3. Fisch GS, Simensen R, Tarleton J, Chalifoux M, Holden JJ, Carpenter N, Howard-Peebles PN, Maddalena A. Longitudinal study of cognitive abilities and adaptive behavior levels in fragile X males: a prospective multicenter analysis. Am J Med Genet. 1996;64(2):356.
  4. Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet. 2008;16(6):666.
  5. Philofsky A, Hepburn SL, Hayes A, Hagerman R, Rogers SJ. Linguistic and cognitive functioning and autism symptoms in young children with fragile X syndrome. Am J Ment Retard. 2004;109(3):208.
  6. Musumeci SA, Hagerman RJ, Ferri R, Bosco P, Dalla Bernardina B, Tassinari CA, De Sarro GB, Elia M Epilepsy and EEG findings in males with fragile X syndrome. Epilepsia. 1999;40(8):1092.
  7. Bennetto L, Pennington BF, Porter D, Taylor AK, Hagerman RJ. Profile of cognitive functioning in women with the fragile X mutation. Neuropsychology. 2001;15(2):290.
  8. Hagerman RJ, Jackson C, Amiri K, Silverman AC, O'Connor R, Sobesky W. Girls with fragile X syndrome: physical and neurocognitive status and outcome. Pediatrics. 1992;89(3):395.
  9. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7(8):584.
  10. Whissell PD, Lecker I, Wang DS, Yu J, Orser BA. Altered expression of δGABAA receptors in health and disease. Neuropharmacology. 2014 Aug 13.

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Last updated: 2019-07-11 21:27