The portal for rare diseases and orphan drugs

About 250 patients with cryptic duplications encompassing the MECP2 gene have been reported. The global prevalence of the disorder remains unknown but is estimated to be approximately 1% in males with unexplained X-linked mental retardation.

Clinical presentation is typically in the neonatal period with severe feeding difficulties, hypotonia and global development delay. Whilst affected children may acquire certain development milestones (independent sitting, walking, early speech skills and purposeful hand use) regression is commonly observed. Intellectual disability is moderate to severe in most affected males and speech is most often absent. Behavioral features often include hand stereotypies, bruxism, decreased sensitivity to pain, screaming spells and night laughing. Respiratory infections occur in over three-quarters of males and over one third of females. Seizures develop in over 50% of affected individuals by 9 years of age, and may be daily, weekly or monthly. Non-epileptic seizures have also been described. Progressive spasticity during childhood, predominantly of the lower limbs appears, affects more than 60% of males. Gastrointestinal symptoms may include, constipation, abdominal bloating and infantile gastro-esophageal reflux; gastrointestinal feeding may be required. Scoliosis, divergent strabismus, hypermetropia and facial dysmorphism (large ears, midface hypoplasia, teeth anomalies, open mouth appearance) are frequent. The phenotype and severity in females is highly variable and depends on the level of skewed X-inactivation.

The syndrome is due to Xq28 duplications (< 4 Mb) involving the dosage-sensitive gene MECP2.

Diagnosis is based on clinical features and is confirmed by array-comparative genomic hybridization techniques or gene-targeted duplication analysis.

Differential diagnoses include Xq28 functional disomy due to cytogenetically visible rearrangements, int22h1/int22h2-mediated Xq28 duplication syndrome, Prader-Willi syndrome, Alpha thalassemia X-linked intellectual disability syndrome.

Prenatal diagnosis is possible for families with a proband and is performed by cytogenetic testing including fluorescence in situ hybridization and/or DNA quantification methods.

The pattern of inheritance is X-linked. The recurrence risk is significant if the duplication encompassing the MECP2 gene is inherited from the mother, but very low if the duplication is de novo. There is full disease penetrance in males and variable penetrance in females due the level and type of X-inactivation.

Management is multidisciplinary and symptomatic only, with special attention to prevent malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients.

Malformations do not contribute significantly to the morbidity associated with this syndrome, but early death (before 25 years of age), mostly from respiratory infections, has been reported in 27-39% of patients and may be underestimated. The use of a wheelchair might be necessary in adulthood due to progressive spasticity. Neurological deterioration seems associated with seizures severity.