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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.
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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.
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Clinical Presentation
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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 MECP2 mutations.
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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.
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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.
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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.
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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
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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.
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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.
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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.10,11 These
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.