A Nonverbal 33-Year-Old Woman With Intellectual Impairment

James Robert Brasic, MD, MPH


October 20, 2021


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. Subsequent stages of disease progression occur and are described as rapid developmental regression (onset 1-4 years), pseudostationary or plateau period (onset 2-10 years) and late motor deterioration, during which ambulatory ability decreases or ceases (approximate onset ≥ 10 y). This case illustrates progression to the fourth clinical stage of Rett syndrome, as demonstrated by the patient's marked scoliosis and radiographic evidence of orthopedic interventions.

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 can occur (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 into 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.

In summary, Rett syndrome is diagnosed by obtaining a clear developmental history, clinical exam, and observation of characteristic behaviors, as described in these diagnostic criteria. Rett Syndrome is primarily a clinical diagnosis. Patients diagnosed with Rett syndrome do not all carry MECP2 mutations; conversely, MECP2 mutations have been identified in patients who do not fit the clinical criteria for Rett syndrome. The consistent feature for classic Rett syndrome is a timeline of clear developmental regression, followed by limited recovery or stabilization (plateau period). That is then followed by subsequent motor deterioration. Other key criteria include loss of purposeful hand skills, stereotypic hand movements, loss of spoken language, and gait abnormalities. Deceleration of head growth can occur; however it is not considered diagnostic. Fulfillment of these diagnostic criteria can assist in the clinical diagnosis of Rett syndrome and its variant or atypical forms. Molecular genetic testing can detect mutations in the MECP2 gene and help confirm the suspected diagnosis.


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