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 MECP2 mutations.
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 ...