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Key Features

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Essentials of Diagnosis
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  • Clinical expression differs in male and female offspring depending on which parent is transmitting the gene

  • The premutation can change into the full mutation only when passed through a female

  • The most common inherited cause of intellectual disability

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General Considerations
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  • Present in approximately 1 in 1000 males

  • The responsible gene is FMR1, which has unstable CGG repeats at the 5′ end

  • Normal individuals have up to 50 CGG repeats

  • Individuals with 51–200 CGG repeats have a premutation and may manifest symptoms

  • Affected individuals with Fragile X syndrome (full mutation) have more than 200 CGG repeats and also have hypermethylation of both the CGG expansion and an adjacent CpG island

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Clinical Findings

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  • Intellectual disabilities

  • Oblong facies with large ears

  • Large testicles after puberty

  • Other physical signs include hyperextensible joints and mitral valve prolapse

  • Many affected individuals are hyperactive and exhibit behaviors along the autism spectrum

  • Females with a full mutation may exhibit a phenotype ranging from normal IQ to intellectual disability and may show behaviors along the autism spectrum

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Diagnosis

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  • DNA analysis is a reliable test for prenatal and postnatal diagnosis and facilitates genetic counseling

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Treatment

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Nonpharmacologic
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  • Speech and language therapy

    • Can decrease oral hypersensitivity

    • Improve articulation

    • Enhance verbal output and comprehension

    • Stimulate abstract reasoning skills

  • Augmentative communication techniques may be helpfulbecause approximately 10% of boys will be nonverbal at age 5 years

  • Occupational therapy can be helpful in

    • Providing techniques for calming hyperarousal to stimuli

    • Improving the child's fine and gross motor coordination and motor planning

  • If the behavioral problems are severe, it can be helpful to involve a behavioral psychologist who emphasizes

    • Positive reinforcement

    • Time-outs

    • Consistency in routine

    • Use of auditory and visual modalities, such as a picture schedule, to help with transitions and new situations

  • Genetic counseling is an important component of management

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Pharmacologic
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  • Clonidine or guanfacine may be helpful in low doses to treat hyperarousal, tantrums, or severe hyperactivity

  • Methylphenidate or dextroamphetamine

    • Usually beneficial by age 5 years and occasionally earlier

    • Relatively low doses are used because irritability is often a problem with higher doses

  • Selective serotonin reuptake inhibitor (SSRI), such as fluoxetine

    • Often helpful foranxiety

    • May also decrease aggression or moodiness, although in approximately 25% of cases, an increase in agitation or activation may occur

  • Clonidine, guanfacine, and an SSRI may decrease aggression, which may become a significant problem; atypical antipsychotic may be needed; counseling can be helpful in these cases

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Outcome

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Prognosis
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  • Male carriers are at risk for fragile X tremor ataxia syndrome (FXTAS), a neurodegenerative disorder, as they age

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When to Refer
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  • Families in whom fragile X syndrome is diagnosed ...

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