MECP2 duplication syndrome
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A 4-year-old boy has severe intellectual disability, infantile hypotonia that has evolved into progressive spasticity, no expressive language, and a history of multiple hospitalizations for recurrent pneumonia. His mother and maternal aunt are healthy. Chromosomal microarray shows a duplication at Xq28 spanning MECP2.
XLR-like inheritance of an Xq28 duplication encompassing MECP2 (and often IRAK1, L1CAM, and other neighboring genes depending on duplication size).
- Almost exclusively affects males. Carrier females are typically asymptomatic due to highly skewed X-inactivation preferentially silencing the duplicated allele.
- Carrier mothers account for most cases (inherited duplication); a minority are de novo. Recurrence risk for sons of a carrier mother is 50%; daughters are obligate carriers but usually unaffected.
- A subset of carrier women report anxiety, depression, and mild psychiatric features; counsel accordingly.
- Mechanism: MECP2 dosage sensitivity. MECP2 loss-of-function in girls causes Rett syndrome; duplication / overexpression in boys causes MECP2 duplication syndrome. The same gene, opposite mechanisms: a classic dosage-sensitive locus.
- Severe intellectual disability, absent or minimal speech
- Infantile hypotonia → progressive spasticity (especially lower limbs)
- Recurrent severe respiratory infections: leading cause of mortality (~50% by age 25); thought to reflect intrinsic immune dysfunction plus aspiration
- Seizures in ~50% (often refractory; later-onset)
- Autistic features, stereotypies
- GI dysmotility, constipation
- Mild dysmorphic features: brachycephaly, midface hypoplasia, large ears (subtle, not pathognomonic)
- Genitourinary anomalies in some
- Chromosomal microarray (CMA) is the test; detects the Xq28 duplication. Karyotype usually misses it (too small).
- Increasingly identified prenatally on CMA performed for other indications; counsel carefully given variable size and uncertainty about minimal critical region.
- Confirm parental origin (maternal carrier vs de novo) for recurrence-risk counseling.
- Multidisciplinary developmental, neurology, pulmonology care
- Aggressive respiratory management: pneumonia surveillance, vaccination, prompt antibiotics; consider IVIG in selected cases of recurrent severe infections
- Seizure management
- Feeding/GI support
- Family planning: maternal carrier testing, prenatal diagnosis options, discuss preimplantation genetic testing
Same locus, opposite mechanisms, opposite sex predominance: MECP2 loss-of-function causes Rett (girls); MECP2 duplication / overexpression causes MECP2 duplication syndrome (boys).