A 33-Year-Old Woman With Rigidity and Stereotypies

James Robert Brasic, MD, MPH

Disclosures

April 25, 2017

Discussion

Rett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females.[1,2,3] This rare disorder was described in 1966 by Dr Andreas Rett, an Austrian pediatric neurologist. Now considered to be a syndrome of neurodevelopmental arrest, patients experience developmental regression after a period of 6-18 months of normal development.

In the United States, classic Rett syndrome affects 1 in 10,000 to 1 in 15,000 girls by age 12 years.[4] Undiagnosed and misdiagnosed cases make it difficult to determine the exact frequency in various populations.

Patients are phenotypically normal at birth. Growth and development seem normal during the first year of life. Subsequently, a deceleration in head growth occurs (acquired microcephaly). Girls with Rett syndrome lose previously acquired motor and language skills. Impaired control of voluntary movements (gait ataxia) is common, as is apraxia. Nonpurposeful stereotypic hand movements, such as hand-wringing, hand-squeezing, clapping, hand-rubbing, and repetitive hand-to-mouth movement, are distinctive, along with progressive rigidity.[5,6,7,8] A longer example of these types of behaviors that includes more detail is provided in the video below.

Affected females may display autistic mannerisms, feeding and swallowing difficulties, and, as in the patient in this case, a seizure disorder. Females with Rett syndrome generally have profound intellectual disability. Average life expectancy can be as high as the mid-40s. An increased risk for sudden death due to electrophysiologic cardiac irregularities, such as prolonged QT interval and T-wave abnormalities, is noted. Poor seizure control, aspiration pneumonia, and malnutrition are contributing factors to morbidity and mortality.

Most males born with Rett syndrome die in infancy. Those who survive past infancy are severely affected and are described to have a variant condition called "MECP2-related severe neonatal encephalopathy." Rett syndrome is inherited as an X-linked dominant disorder. Cases are sporadic and are typically caused by a de novo mutational event on the X chromosome. This syndrome is caused by mutations in MECP2, a gene located on Xq28, that encodes for methyl-CpG–binding protein 2 (MeCP2).[1,2] Abnormal function of the MECP2 gene hinders normal production of the MeCP2 protein. This protein is critical for neuronal maturation, elaboration of synapses, and pruning of the nervous system in childhood.[9,10,11] In addition, cholinergic neurotransmission is defective in Rett syndrome.[12]

In patients with Rett syndrome, random X-chromosome inactivation (lyonization) affects the clinical severity of the disorder.[13,14,15,16] X-chromosome inactivation is considered skewed when more than 80% of cells reflect a single allele.[17,18,19,20] Hence, a higher percentage of an active abnormal X allele dictates a worse clinical presentation for the patient.

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