Rett Syndrome

Epidemiology and Etiology:

· MEPC2 mutations

· Methyl-CPG-binding protein 2 gene

· Encodes a nuclear protein that binds methylated DNA and recruits histone deacetylases to regions of methylated DNA

· Hypothesized to mediate transcrioptional silencing and epigenetic regulation of genes

· Inactivating mutations would therefore result in inappropriate activation of genes

· Hypothesized to be important in maintaining neuronal interactions

· Note that MECP2 mutations causes a broad spectrum of diseases other than Rett, affecting both boys and girls

· Poor genotype-phenotype correlation

· 99% sporadic

· At least 70% arise in paternal germline

· X-linked dominant

· Females almost exclusively (males have more severe phenotype not typical of Rett)

· Variable expressivity and incomplete penetrance

· Onset: neonatal to early childhood

· panethnic

Common sites:

·

Gross features:

· Small brain

· Cortical and cerebellar atrophy

Histologic features:

· Cortex and hippocampus:

· No neuronal loss

· Neurons are smaller and more densely packed

· Simplified dendritic branching pattern

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· MEPC2 mutations (80-90% of typical Rett syndrome patients with current testing)

·

Other features:

· Neurodevelopmental regression

· Normal development up to 6-18 mo.

· Short period of developmental slowing and stagnation with decelerating head growth

· Rapidly lose speech and acquired motor skills (particularly purposeful hand use)

· Repetitive stereotypic hand movements

· Breathing irregularities

· Ataxia

· Seizures

· Pseudostabilization usually during preschool to early school years

· Then deteriorate further to become severely mentally retarded

· Progressive spasticity, rigidity, and scoliosis

· Short life span due to increased unexplained sudden death

References:

· Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine: With STUDENT CONSULT Online Access. 7th ed. Saunders; 2007.