Neuropathological and neurochemical studies supporting the concept of Rett syndrome (RS) as a neurodevelopmental disorder are reviewed from the Kennedy Krieger Institute and Johns Hopkins Hospital, Baltimore, MD. Prevalence in females is 1:10,000 to 1:22,000. Incomplete, forme fruste, cases are common. Twin data support a genetic basis but its nature is undetermined and no biological marker has been defined. Reduction in velocity of head growth begins at 2 to 4 months of age. Brain weight and size are reduced by 12 to 34% compared to age-matched controls in autopsy studies, but without evidence for progressive decrease in brain weight with age. Immunological studies suggest that certain pyramidal neurons are preferentially affected. Low levels of dopamine receptors and transporters are associated with decreased dopamine levels in the neocortex and basal ganglia. Choline acetyltransferase is reduced in the neocortex, hippocampus, putamen, and thalamus. Abnormal neurotransmitter systems can account for the clinical manifestations of RS. The early rapid evolution of symptoms followed by a static course suggest a neurodevelopmental disorder. [1]

COMMENT. Rett syndrome as a specific disease still eludes definition. Its static course after age five years is at variance with most genetic neurodegenerative disorders, and an abnormality in neurodevelopment appears more likely. My colleague Dr John Wilson at Great Ormond Street Hospital, London, suggests that the age-specific decelerating head growth in RS may be an apoptotic phenomenon.(In: Progress in Pediatric Neurology III, PNB Publ, 1997;p567).

A prevalence rate for RS of 2.17 per 10,000 girls is reported in a Norwegian study [2]. This higher than usual rate was associated with clustering in certain restricted geographical areas, a finding important in identifying a possible genetic basis for RS.

Four cases of RS with a single family tree and prevalence rate of 2.1 per 10,000 are reported from Northern Tuscany, Italy [3]. This study supports a genetic basis for RS.