Rett syndrome “We’ll keep the genes on for you”

Beginning as a clinical observation in two girls attending the Vienna pediatric neurology clinic of Dr. Andreas Rett,1 the disorder that now bears his name is a frequent (1 in 10,000 to 22,000 female births) worldwide cause of mental retardation and autism in girls. First recognized as a distinct nosologic entity by Hagberg et al. in 1983,2 relatively restrictive international criteria were established for Rett syndrome (RS) in 1988 and have since been modified only slightly.3,4⇓ With the delineation of diagnostic criteria, but without a defined etiology, it readily became apparent that RS was more heterogeneous in its phenotype, and investigators even proposed its presence in males. Most cases of RS are sporadic, but familial occurrence suggested an X-linked dominant inheritance with possible male lethality. More recently, genetic mapping studies in familial cases identified an Xq28 locus5,6⇓ that subsequently was shown to contain mutations in the MECP2 gene, which encodes the transcriptional silencing methyl-CpG binding protein-2.7,8⇓ Armed with a diagnostic marker, investigators are currently redefining the clinical disorder and seeking to understand the pathomechanisms of RS.

Historically, classic RS, as clinically defined, is characterized by its occurrence in young girls who have had a normal prenatal and perinatal history, appropriate head circumference, and apparently normal psychomotor development through the first 6 to 12 months of life.9 The course is then one of developmental arrest or regression, with deterioration of communicative skills, social withdrawal, and loss of fine finger function. The child with RS continues to deteriorate over the next few years resulting in a loss of language, poor motor function (truncal and gait apraxia/ataxia), a “hand-washing” stereotypy, and a deceleration of head growth. Affected children then stabilize with a severe psychomotor dysfunction, although some make small recoveries in contact and communication …