Cecilia Mellado and Mustafa Sahin
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder and affects mainly females. The prevalence is 1 in 10,000 girls by the age of 12,1 making it one of the most common genetic causes of severe cognitive impairment in girls. RTT is caused by mutations in the MECP2 gene located at Xq28. MECP2 encodes a nuclear protein (MeCP2) that binds methylated DNA. The function of MeCP2 protein has not been fully elucidated; it is thought to mediate transcriptional silencing and epigenetic regulation of genes in regions of methylated DNA through its association with 5-methylcytosine–rich heterochromatin and may play a role in modulation of RNA splicing as well.2 There are different levels of expression depending on the tissue and developmental stage. Mutations in MECP2 can result in a similar constellation of neuropsychiatric abnormalities with either gain or loss of protein function. For example, MECP2 duplications have been reported in males with severe cognitive impairment.
Approximately 99% of Rett syndrome cases are sporadic, resulting from a de novo mutation in most of the affected children or from inheritance of the mutation from 1 parent with germline mosaicism. In rare cases, it can be inherited from an unaffected or mildly affected mother with a favorably skewed X chromosome inactivation.
Clinically, MECP2-related disorders present a spectrum of phenotypes, including classic RTT, variant RTT, and very mild learning disabilities in females. This variability may be related to the pattern of the X-chromosome inactivation, and depending on a favorable X skewing, some patients can be mildly affected or even asymptomatic. Another source of variability may be somatic mosaicism for the MECP2mutations.
In males, MECP2 mutations have a range of effects from syndromic or nonsyndromic cognitive impairment to a severe neonatal encephalopathy.3 Mutations leading to a classic RTT in females cause severe encephalopathy and breathing anomalies in males, and these patients usually die before the age of 1 year. A classic RTT phenotype can be seen in patients with 47,XXY karyotype or somatic mosaicism. Some mutations with no phenotypic effect in females can cause severe cognitive impairment or psychiatric disorders.
Classical RTT symptoms appear in stages (eFig. 575.1 ).4-6 Girls are characterized by an apparent normal prenatal, perinatal, and early infancy period. At 6 to 18 months of age, they start a developmental stagnation period characterized by hypotonia and slow head and general growth. This is followed by regression in language and motor skills; social interaction and cognitive functioning; loss of purposeful hand use, which is replaced with stereotyped hand-wringing or “washing” movements; autistic-like behavior; disturbed sleep; breathing abnormalities; vasomotor changes; limb spasticity and gait ataxia/apraxia. This regression is followed by a pseudostationary stage characterized by amelioration of autistic-like behaviors, weight loss, osteopenia, scoliosis, motor problems, dystonia, rigidity, and foot and hand deformities. About 90% of patients develop seizures. In the late stage, motor deterioration continues, scoliosis is more severe, and finally hypoactivity ends with girls confined to a wheelchair by the adolescent years. Autonomic abnormalities include hypotrophic, cold blue feet, constipation, oropharyngeal anomalies, and cardiac abnormalities, including rhythm anomalies and prolonged QT intervals. In older ages, patients develop parkinsonian features.
Atypical or variant forms of RTT4,5 range from milder forms with a later age of onset to more severe manifestations. These variants include the forme fruste, which is milder, with later progression and hand function, fewer stereotypic movements, and occasional normocephaly. The preserved speech variant is a mild variant. These patients are able to speak few words and are normocephalic, overweight, and kyphotic. More severe variants include the congenital onset variant characterized by significant developmental delay from birth followed by the classical form without evidence of regression; the early seizure onset variant, recognized by seizures before the age of 6 months, followed by a severe RTT-like picture; the Angelman-like variant; the late regression variant characterized by late onset but typical phenotype evolving.
Differential diagnosis includes Angelman syndrome, autism spectrum disorders, and mental retardation syndromes. Mutations in the CDKL5 gene have been identified in patients with RTT-like phenotype and early-onset seizures.7
The diagnosis of RTT is made based on clinical findings and/or on MECP2 molecular testing. A useful clinical tool is the updated RTT clinical criteria consensus (eTable 575.1 ).8 Molecular testing is available clinically; MECP2-sequencing analysis mutations and deletions have been identified in up to 95% of classic RTT cases.9 MRI studies demonstrate reduced cerebral volume, especially of the frontal gray matter, basal ganglia, midbrain, and cerebellum.
Currently, there are no curative treatments for RTT. The management is mainly symptomatic, focused on predicting and treating problems as they develop and trying to improve the skills and quality of life of patients and their families. Regular follow up is recommended through a multidisciplinary approach, paying attention to growth, nutritional intake, dentition, gastrointestinal function, mobility, communication skills, orthopedic and neurologic complications. Medical therapy includes anticonvulsants for seizures individualized to each patient and melatonin to improve the sleep pattern. Serotonin-uptake inhibitors have been used for agitation. Spasticity and scoliosis need to be treated to improve or maintain mobility. Supplemental nutritional support may be required, including placement of a gastrostomy tube prevent malnutrition. Offering genetic testing to both parents is recommended to determine risks in future pregnancy.
Although there is not yet a specific treatment for RTT for humans, some groups, given the fact that neurons are affected but they do not die, have been working to reverse the phenotype in different mouse models. These studies have demonstrated phenotypic reversal when MeCP2 expression is reactivated, even late in development, leading to a reduction of neurologic symptoms and to a prolonged life span.10,11These data are very promising in terms of the possibility of restoring neuronal function in Rett syndrome patients, but many caveats exist since perturbation of MeCP2 levels can be highly deleterious. Therefore, identification of the precise molecular mechanisms by which MeCP2 deficiency leads to neurologic problems is still an important goal.