Fact-sheet: Fragile X syndrome - Martin Bell Syndrome
Updated on 09/17/2021 at 12:16 PM
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Definition
Fragile X syndrome (FXS) is a rare genetic disease associated with mild to severe intellectual disability, which may be accompanied by behavioral disorders and characteristic physical features.
Its estimated prevalence is approximately 1/2,500 (full mutation prevalence) to 1/4,000 (symptomatic cases) in both sexes.
The clinical picture is variable. In childhood, boys show delayed motor and/or language milestones. In boys and 50% of girls, intellectual impairment is associated with behavioral disorders and/or dysmorphic features. Recurrent otitis and sinusitis and seizures may occur. Intellectual disability ranges from minor learning difficulties with normal IQ to severe impairment affecting immediate and working memory, executive functions, and visuospatial and mathematical abilities. Behavioral disorders may be mild (mood instability) or severe, autism-like (hand flapping, poor eye contact, gaze avoidance, hand biting, tactile defensiveness, and disinhibition). Mood disorders, anxiety, and aggression may occur. In girls, intellectual and behavioral disorders are usually mild, presenting as affective and learning disorders. In both sexes, physical features are subtle: long, narrow face, prominent ears and forehead, finger hyperlaxity, flat feet, and macroorchidism in boys after puberty.
FXS is caused by inhibition of FMR1 gene (Xq27.3) transcription, resulting from expansion of a (CGG)n triplet repeat in its 5' untranslated region and the subsequent methylation. These full mutations arise from unstable, premutated alleles (55 to 200 CGG repeats). Premutations are notably associated with a risk of premature ovarian insufficiency (POI) in women and with fragile X-associated tremor/ataxia syndrome (FXTAS; see this term). Rare cases of intragenic FMR1 point mutations without CGG repeat expansion have been described. The FMR1 gene encodes FMRP, an RNA-binding protein that regulates protein synthesis and other dendritic signaling pathways. Transcriptional silencing of FMR1 is thought to reduce synaptic plasticity and modulation throughout the brain, including the hippocampus.
Since physical features may be subtle or absent, the clinical picture alone does not allow diagnosis; diagnosis therefore relies on molecular screening of any patient presenting with intellectual disability or autism.
Differential diagnoses include other X-linked intellectual disabilities, Sotos syndrome, microdeletion syndromes (e.g., velocardiofacial syndrome), fetal alcohol syndrome (see these terms), and idiopathic autism.
Prenatal diagnosis relies on Southern blot hybridization of chorionic villus or amniocentesis samples.
Transmission is X-linked dominant with incomplete penetrance in girls. Genetic counseling should be offered to families, explaining the mode of mutation transmission.
Management is symptomatic and multidisciplinary. Medications such as stimulants and selective serotonin reuptake inhibitors (SSRIs) (for anxiety, obsessive-compulsive disorders) or atypical antipsychotics (for self-injury, aggression, autism) should be combined with speech therapy, sensory integration occupational therapy, individualized educational programs, and behavioral therapies. Preliminary results of new targeted treatments (mGluR5 antagonists, GABA A and B agonists, and minocycline) are promising and could alter the course and prognosis of the syndrome.
Most boys and about 30% of girls will have significant intellectual disability in adulthood.
A clinical form has been identified in men over 50 years of age carrying the premutation, manifesting as progressive onset of tremor and ataxia. These symptoms are accompanied by progressive cognitive decline.
MRI
T2 hyperintensities of the cerebellar white matter and middle cerebellar peduncles.
Punctate or confluent hyperintensities of the deep hemispheric white matter, periventricular white matter, and corpus callosum.
Pontine, mesencephalic, cerebellar cortex, and cerebral cortex atrophy.