MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities. A MECP2 mutation in a male is presumed to most often be lethal; phenotypes in rare surviving males are primarily severe neonatal encephalopathy and manic-depressive psychosis, pyramidal signs, Parkinsonian, and macro-orchidism (PPM-X syndrome). Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Atypical Rett syndrome is observed increasingly as MECP2 mutations are identified in individuals previously diagnosed with: clinically suspected but molecularly unconfirmed Angelman syndrome; intellectual disability with spasticity or tremor; mild learning disability; or (rarely) autism. Severe neonatal encephalopathy resulting in death before age two years is the most common phenotype observed in affected males.
The diagnosis of all MECP2-related disorders relies on molecular genetic testing. Sequence analysis and deletion testing for exonic, multiexonic, and whole-gene deletions are available on a clinical basis. The diagnosis of classic Rett syndrome rests on clinical diagnostic criteria.
MECP2-related disorders are inherited in an X-linked manner. More than 99% are simplex cases (i.e., a single occurrence in a family), resulting from a de novo mutation, or possibly from inheritance of the disease-causing mutation from a parent who has germline mosaicism. Rarely, a MECP2 mutation may be inherited from a carrier mother in whom favorable skewing of X-chromosome inactivation results in minimal to no clinical findings. When the mother is a known carrier, the risk to her offspring of inheriting the MECP2 mutation is 50%. Prenatal testing is possible in pregnancies at increased risk if the MECP2 mutation has been identified in the family. Because of the possibility of germline mosaicism, it is appropriate to offer prenatal diagnosis to couples who have had a child with a MECP2-related disorder regardless of whether the disease-causing mutation has been detected in a parent.