Fragile X Syndrome

Key Features

Essentials of Diagnosis

• 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

General Considerations

• 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

Clinical Findings

• 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

Diagnosis

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

Treatment

Nonpharmacologic

• Speech and language therapy

  • Can decrease oral hypersensitivity

  • Improve articulation

  • Enhance verbal output and comprehension

  • Stimulate abstract reasoning skills

• Augmentative communication techniques may be helpful because 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

Pharmacologic

• 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 for anxiety

  • 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

Outcome

Prognosis

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

When to Refer

• Families in whom fragile X syndrome ...