Sleep disruptions are common features of Fragile X syndrome – Williams syndrome – Down syndrome

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New research has discovered that Down’s syndrome, Fragile X syndrome and Williams syndrome are all linked to sleep disruption in very young children, and that sleep plays a crucial role in the development of these children’s language skills.

Led by Dr Dean D’Souza of Anglia Ruskin University (ARU) and published in the journal Research in Developmental Disabilities, it is the first cross-syndrome study to examine sleep, and the relationship between sleep and language, in very young children with these neurodevelopmental disorders.

Alongside colleagues from the University of Cambridge; Birkbeck, University of London; The LonDownS Consortium, London; Semmelweis University, Budapest; and the University of Oxford; Dr D’Souza compared the vocabulary size and sleep patterns of 75 infants and toddlers with one of these neurodevelopmental disorders alongside 30 typically developing children of the same age.

The researchers found that sleep was disrupted amongst children with all three neurodevelopmental disorders. On average, typically developing children slept for about 50 minutes longer per night than those with a neurodevelopmental disorder.

They also spent less time awake during the night. Whereas typically developing children spent on average just three minutes awake per night, the children with a neurodevelopmental disorder were awake for around 30 minutes longer.

The study also found that the longer the infants and toddlers with Down’s syndrome and Williams syndrome slept at night, the more words they knew.

For each additional 10 minutes of sleep, these children would understand the meaning of six additional words. The researchers were unable to test this relationship with children with Fragile X syndrome because of the limited sample size.

The children were tested using a list of 416 words that are commonly acquired in early childhood, with the caregiver indicating whether their child can “understand” or “understand and say” the word. Only one of the 75 children with a neurodevelopmental disorder was able to understand, but not say, all 416 words. This child was 47 months old and had Williams syndrome. Nine of the 30 typically developing children (30%) were able to understand, and say, all 416 words.

The researchers found that sleep was disrupted amongst children with all three neurodevelopmental disorders.

Dr D’Souza, Senior Lecturer in Psychology at Anglia Ruskin University (ARU), said: “Children with neurodevelopmental disorders commonly have difficulties with language development. Many different factors are likely to contribute to this, and our study focused on the role of sleep. This is because sleep is important for learning and memory, and individuals with neurodevelopmental disorders often report having problems sleeping.

“Our research demonstrates that sleep is disrupted very early in development across various neurodevelopmental disorders, and the indications are that this is contributing to difficulties with learning language.

“Further research is needed to explore whether early interventions to improve the sleeping patterns of children with Down’s syndrome, Fragile X syndrome and Williams syndrome would be as beneficial for their language skills as interventions later in their development that specifically target language learning.”


Clinical characteristics.

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI).

  • Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement.
  • FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%).
  • FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population.

Diagnosis/testing.

The diagnosis of an FMR1 disorder is established through the use of specialized molecular genetic testing to detect CGG trinucleotide repeat expansion in the 5′ UTR of FMR1 with abnormal gene methylation for most alleles with >200 repeats. Typically, a definite diagnosis of FXS requires the presence of a full-mutation repeat size (>200 CGG repeats) while the diagnosis of FXTAS or FXPOI is associated with a premutation-sized repeat (55-200 CGG repeats). It should be noted that typical multigene panels and comprehensive genomic testing (exome or genome sequencing) are useful only when no CGG repeat expansion is detected but FXS is still suspected.

Management.

Treatment of manifestations:

  • Fragile X syndrome. Supportive and symptom-based therapy for children and adults typically consisting of a dual approach of psychopharmacologic treatment of symptoms as needed in conjunction with therapeutic services, such as behavioral intervention, speech and language therapy, occupational therapy, and individualized educational support; routine treatment of medical problems.
  • FXTAS. Symptomatic and supportive and should be tailored to the individual.
  • FXPOI. Gynecologic or reproductive endocrinologic evaluation can provide appropriate treatment and counseling for reproductive considerations and hormone replacement.

Agents/circumstances to avoid:

  • FXTAS. Typical and atypical antipsychotics with significant anti-dopaminergic effects and metoclopramide, which can exacerbate parkinsonism; anticholinergic agents, which can exacerbate cognitive complaints; excessive alcohol, which can enhance cerebellar dysfunction and postural instability; agents with known cerebellar toxicity or side effects.
  • FXPOI. Tobacco use as this decreases ovarian reserve and the age of onset of FXPOI.

Genetic counseling.

FMR1 disorders are inherited in an X-linked manner:

  • All mothers of individuals with an FMR1 full mutation (expansion >200 CGG trinucleotide repeats and abnormal methylation) are heterozygous for an FMR1 pathogenic variant. Mothers and their female relatives who are heterozygous for a premutation are at increased risk for FXTAS, FXPOI, and fragile X-associated neuropsychiatric disorders (FXAND); those with a full mutation may have findings of fragile X syndrome. All are at increased risk of having offspring with fragile X syndrome, FXTAS, FXPOI, or FXAND.
  • Males with premutations are at increased risk for FXTAS. Males with FXTAS will transmit their FMR1 premutation expansion to all of their daughters, who will be heterozygous for a premutation and at increased risk for FXTAS, FXPOI, and FXAND. Males with FXTAS do not transmit their FMR1 premutation to sons.

Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible once an expanded (or altered) FMR1 allele has been identified in a family member.


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