MECP2 – MECP2-related Severe Neonatal-onset Encephalopathy with Microcephaly

Mutations in MECP2 are well-known to cause Rett syndrome in females and a spectrum of related disorders in males, including severe neonatal-onset encephalopathy with microcephaly. A single male patient presenting with microcephaly and profound encephalopathy shortly after birth was found to harbour a de novo hemizygous mutation in exon 1 of MECP2, affecting the MeCP2_e1 isoform (PMID:27090848). This exon 1 variant expands the phenotypic spectrum of MECP2-related disease beyond classic X-linked intellectual disability and Rett syndrome, suggesting that loss-of-function mutations in MECP2 can manifest as neonatal encephalopathy in males. No additional familial cases or co-segregation data were reported, and no functional studies specific to this phenotype have been performed. However, the central role of MeCP2 in neuronal gene regulation supports a pathogenic mechanism of haploinsufficiency in early neural development. Considering the severity and early onset, MECP2 screening should be included in the diagnostic workup of male neonates with unexplained encephalopathy and microcephaly.

Key take-home: A de novo exon 1 MECP2 mutation can cause a severe neonatal encephalopathy phenotype, informing early genetic testing and management.

References

• American journal of medical genetics. Part A • 2016 • A rare MeCP2_e1 mutation first described in a male patient with severe neonatal encephalopathy. PMID:27090848

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