Thompson & Thompson Genetics in Medicine, 8th Edition

Case 40. Rett Syndrome (Mepc2 Mutations, MIM 312750)

X-Linked Dominant


• Loss-of-function mutation

• Variable expressivity

• Sex-dependent phenotype

Major Phenotypic Features

• Age at onset: Neonatal to early childhood

• Acquired microcephaly

• Neurodevelopmental regression

• Repetitive stereotypic hand movements

History and Physical Findings

P.J. had had normal growth and development until 18 months of age. At 24 months, she was referred because of decelerating head growth and progressive loss of language and motor skills. She had lost purposeful hand movements and developed repetitive hand wringing by 30 months. She also had mild microcephaly, truncal ataxia, gait apraxia, and severely impaired expressive and receptive language. No other family members had any neurological diseases. On the basis of these findings, the neurologist suggested that P.J. might have Rett syndrome. The physician explained that Rett syndrome is a result of mutations in the methyl-CpG–binding protein 2 gene (MECP2) in most patients and that testing for such mutations could help confirm the diagnosis. Subsequent testing of P.J.'s DNA identified a heterozygous MECP2 mutation; she carried the transition 763C>T, which causes Arg255Ter. Neither parent carried the mutation.


Disease Etiology and Incidence

Rett syndrome (MIM 312750) is a panethnic X-linked dominant disorder with a female prevalence of 1 in 10,000 to 1 in 15,000. It is caused by loss-of-function mutations of the MECP2 gene. With the advent of array comparative genomic hybridization (array CGH) technology, males with duplications on the X chromosome in the region of MECP2 have been demonstrated; these males typically have severe intellectual disabilities. Males with a mutation in MECP2 and 47,XXY phenotype can also have Rett syndrome with a phenotype similar to females. Two other genes, CDKL5 and FOXG1, can lead to Rett-like phenotypes. CDKL5 is an X-linked serine/threonine kinase that regulates neuronal proliferation and differentiation, and mutations in this gene cause microcephaly, seizures, and severe intellectual disability. Mutations in FOXG1 cause an autosomal dominant disorder with similar features, including brain abnormalities, such as oligogyria, and defects in the corpus callosum.


MECP2 encodes a nuclear protein that binds methylated DNA and recruits histone deacetylases to regions of methylated DNA. The precise function of MeCP2 has not been fully defined, but it is hypothesized to mediate transcriptional silencing and epigenetic regulation of genes in these regions of methylated DNA. Accordingly, dysfunction or loss of MeCP2, as observed in Rett syndrome, would be predicted to cause inappropriate activation of target genes.

The brains of patients with Rett syndrome are small and have cortical and cerebellar atrophy without neuronal loss; Rett syndrome is therefore not a typical neurodegenerative disease. Within much of the cortex and hippocampus, the neurons from Rett patients are smaller and more densely packed than normal and have a simplified dendritic branching pattern. These observations suggest that MeCP2 is important for establishing and maintaining neuronal interactions rather than for neuronal precursor proliferation or neuronal determination.

Phenotype and Natural History

Classic Rett syndrome is a progressive neurodevelopmental disorder occurring almost exclusively in girls (Fig. C-40). After apparently normal development until 6 to 18 months of age, patients enter a short period of developmental slowing and stagnation with decelerating head growth. Subsequently, they rapidly lose speech and acquired motor skills, particularly purposeful hand use. With continued disease progression, they develop stereotypic hand movements, breathing irregularities, ataxia, and seizures. After a brief period of apparent stabilization, usually during the preschool to early school years, the patients deteriorate further to become severely intellectually disabled and develop progressive spasticity, rigidity, and scoliosis. Patients usually live into adulthood, but their life span is short due to an increased incidence of unexplained sudden death.


FIGURE C-40 A 5-year, 3-month-old girl with Rett syndrome demonstrating toe walking. See Sources & Acknowledgments.

Besides Rett syndrome, MECP2 mutations cause a broad spectrum of diseases affecting both boys and girls. Among girls, the range extends from severely affected patients who never learn to speak, turn, sit, or walk, and develop severe epilepsy, to mildly affected patients who speak and have good gross motor function as well as relatively well-preserved hand function. Among boys, the range of phenotypes encompasses intrauterine death, congenital encephalopathy, intellectual disability with various neurological symptoms, and mild intellectual disability only.


Suspected on the basis of clinical features, the diagnosis of Rett syndrome is usually confirmed by DNA testing; however, current testing detects MECP2 mutations in only 80% to 90% of patients with typical Rett syndrome. The clinical diagnostic criteria for typical Rett syndrome include normal prenatal and perinatal periods, normal head circumference at birth, relatively normal development through 6 months of age, deceleration of head growth between 6 and 48 months of age, loss of acquired hand skills and purposeful hand movements by 5 to 30 months of age and subsequent development of stereotyped hand movements, impaired expressive and receptive language, severe psychomotor retardation, and development of gait apraxia and truncal ataxia between 12 and 48 months of age.

Currently there are no curative treatments of Rett syndrome and management focuses on supportive and symptomatic therapy. Current medical therapy includes anticonvulsants for seizures, serotonin uptake inhibitors for agitation, carbidopa or levodopa for rigidity, and melatonin to ameliorate sleep disturbances. Families often have problems with social adjustment and coping and should therefore be provided with the opportunity to interact with similarly affected families through support groups and be referred for professional counseling as needed.

Inheritance Risk

Approximately 99% of Rett syndrome is sporadic; most MECP2 mutations are de novo, although in rare cases they can be inherited from an unaffected or mildly affected mother with skewed X chromosome inactivation. At least 70% of de novo mutations arise in the paternal germline.

If a couple has an affected child but a MECP2, CDKL5, or FOXG1 mutation is not identified in either parent, the risk to future siblings is low, although it is higher than among the general population because of the possibility of undetected germline mosaicism. In contrast, if the mother carries a disease-causing mutation, each daughter and son has a 50% risk for inheriting the mutation. However, the poor genotype-phenotype correlation among patients with MECP2 mutations generally prohibits prediction of whether a female fetus with a MECP2 mutation will develop classic Rett syndrome or another MECP2-associated disease. Similarly, identification of a MECP2 mutation in a male fetus does not predict intrauterine demise, the development of congenital encephalopathy, or another MECP2-associated disease.

Questions for Small Group Discussion

1. MECP2 is on the X chromosome. Discuss how this could affect the phenotypic variability observed among females with MECP2 mutations. Discuss how this might account for the fewer numbers of males with MECP2 mutations and the differences in disease severity observed generally between males and females.

2. Given that MeCP2 is an epigenetic mediator of gene expression, discuss possible molecular mechanisms by which genetic background, environment, and stochastic factors could cause the phenotypic variability observed among males with MECP2 mutations.

3. Rett syndrome is a neurodevelopmental disorder without neurodegeneration. Why might the absence of neurodegeneration make this disease more amenable to treatment than Alzheimer disease or Parkinson disease? Why less amenable? In this context, also discuss possible molecular mechanisms for the neurodevelopmental regression observed with Rett syndrome.

4. What defines a disease, the molecular mutation or the clinical phenotype?


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Neul JL. The relationship of Rett syndrome and MeCP2 disorders to autism. Dialogues Clin Neurosci. 2012;14:253–262.