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Clinical Rounds
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Deciphering the Complexities of Rett Syndrome
R
ett syndrome is a neurodevelop- ratory irregularities, such as hyperventimental disorder that is seen most lation, breath-holding, or aerophagia.
EEG spikes in the central parietal reoften in girls, with an incidence of
1 in 10,000-22,000 live female births. The gions are visible early, with or without
prevalence among males is not known, seizures.
After the first decade of life, there is
because the severity of infantile encephalopathy, early death, or lack of clas- considerable clinical stabilization with
sic symptoms—even in the few older amelioration of seizures and respiratory irboys that survive—preclude precise iden- regularities.
However, there is also progressive rigidtification, except when there is familial
ity of limbs and scoliosis.
occurrence.
Life expectancy varies, with
In 1999, researchers idenearly death more common
tified the genetic cause for
in males.
Rett syndrome: mutations in
Death from sudden unexthe MECP2 or methyl cytoplained causes can occur in
sine binding protein 2 gene,
females in the first two
which is located at chromodecades of life through
some Xq28.
adulthood.
MECP2 is thought to be
The course of Rett synnecessary to stabilize and
drome varies considerably
maintain the mature neufrom child to child. The imronal state.
BY SAKKUBAI
pact on families, however,
To date, more than 200
N A I D U, M . D
is universally devastating,
different MECP2 mutations
as they experience their
have
been
identified.
MECP2 mutations also have been seen in child’s developmental delay, neurologic
some cases of childhood schizophrenia, abnormalities, and the uncertainty of
how the disorder will fully manifest in
classic autism, and learning disabilities.
Nevertheless, most cases of Rett syn- their child.
Some anxiety can be alleviated if the pedrome are random, with fewer than 1%
of recorded cases being identified as in- diatrician dispels parents’ fears that Rett
syndrome is a neurodegenerative disease.
herited.
Children with Rett syndrome show abThe X-linked disorder was first recognized in 1966 by the late Viennese physi- normal neuronal morphology, but not incian Dr. Andreas Rett, who observed two creased neuronal death. They do not progirls in his waiting room with the same gressively deteriorate, as with Tay-Sachs
disease; rather, their course stabilizes with
stereotypic hand-washing motion.
Today, a sequence of clinical features— age.
Parents also can be spared some anxiety
including decelerating head growth and
the loss of hand use, speech, and com- caused by the use of the previous four-part
munication—is recognized, starting in staging system, which conveys a sense of
the second half of the first year of life and progressive clinical deterioration to them.
following a period of apparently normal Presently, the broad phenotype of Rett is
more widely recognized, and is confirmed
development.
Subsequent features include poor eye by mutation analysis.
Parents also should understand that
contact, which may be mistaken for
autism; stereotypic behaviors, such as Rett syndrome is not an autism spechand-wringing or hair-pulling; and respi- trum disorder, as has been suggested;
many affected children can maintain eye
contact and communication skills.
Perhaps the most important consideration for the pediatrician is to conduct regular head-circumference measurements,
and to retain a high index of suspicion if
they encounter a young infant, particularly
a female, who is more hypotonic than usual and whose velocity of head growth is
not in keeping with his or her age.
Without careful monitoring, a head circumference at the 40th percentile at 4
months could be mistaken as normal, despite the child’s slipping from the 50th percentile at birth and 2 months.
Children with MECP2 mutations do
not have changes in the white matter on
MRI; this characteristic may be useful to
distinguish Rett from other neurologic
diseases.
It is not known why some cases are
more severe than others, but scientists are
studying genotype-phenotype relationships in Rett syndrome. Scientists have
demonstrated that the mutations
p.R133C and p.R294X have a less severe
phenotype, whereas the p.R270X mutation is associated with higher severity
(Neurology 2008;70:868-75).
Significant differences by mutation have
been seen for individual phenotypic characteristics such as ambulation, hand use,
and language (Neurology 2008;70:131321). Further improvements in the identification of correlates between specific mutations and clinical or biochemical markers
will allow physicians to better counsel
parents on their children’s clinical profiles.
There is no cure for Rett syndrome.
Treatment is focused on the management
of symptoms using a multidisciplinary approach. Medications can control seizures
and improve behaviors; hydrotherapy and
occupational and speech therapy are essential to maintain neuronal activity. Efforts are being made to modify the clinical course of the disorder.
An ongoing study at the Kennedy
Krieger Institute in girls (aged 2-15 years)
with Rett syndrome is evaluating varied
doses of the common drug dextromethorphan, which is known to block
N-methyl-D-aspartate (NMDA)/glutamate
receptors.
This trial is based on previous research,
confirming that girls with Rett syndrome
have abnormally high levels of amino
acid glutamate receptors in the gray matter of the prefrontal cortex, as well as increased levels of glutamate in their spinal
fluid.
Moreover, a recent landmark study has
given hope that the neurologic deficits associated with Rett syndrome could someday be reversed.
The study, co-led by Adrian Bird, Ph.D.,
who first identified the MECP2 gene,
showed that activation of MECP2 expression led to a robust reversal of advanced
neurologic symptoms in a genetic mouse
model of Rett syndrome (Science
2007;315:1143-7).
For more information, helpful resources
include the International Rett Syndrome
Foundation (www.rettsyndrome.org), the
Kennedy Krieger Institute (www.kennedy
krieger.org), and the Baylor College of
Medicine Blue Bird Circle Rett Center
(www.bcm.edu/pediatrics/index.cfm?
Realm=99991118).
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DR. NAIDU is a pediatric neurologist and
director of the neurogenetics unit and the
Rett Syndrome Research Project at the
Kennedy Krieger Institute, Baltimore.
An international leader in the fields of
research, treatment and education for
disorders and injuries of brain and spinal
cord, Kennedy Krieger Institute provides a
wide range of services to over 13,000
children each year with developmental
concerns mild to severe. For more
information, visit www.kennedykrieger.org.
Thyroid Dysfunction Is Linked to Pediatric Headache
BY DIANA MAHONEY
Ne w England Bureau
B O S T O N — Thyroid disease might play a role in the etiology of pediatric headache.
The findings of a new study conducted at the Cleveland Clinic revealed statistically significant associations between hyper- and hypothyroidism and headaches, which,
if confirmed, could have an impact on the diagnosis and
management of pediatric headache, according to investigators.
Although thyroid dysfunction has been linked to
headache in adults, the presence of such a link has been
unexplored in the pediatric population, medical student
Angela Stanga said in a poster presentation at the annual meeting of the American Headache Society.
In an effort to assess the incidence of headache in children with endocrine dysfunction, Ms. Stanga, along
with Dr. Douglas Rogers, head of the Cleveland Clinic’s pediatric endocrinology section, and Dr. A. David
Rothner, director of the clinic’s pediatric/adolescent
headache program, conducted a retrospective study of
Specifically, 36.2% of hyperthyroid patients and 18.5%
children and adolescents being treated for hypo- or hyperthyroidism in the hospital’s pediatric endocrinology of hypothyroid patients experienced headache, she observed.
department.
Correlations between hypothyroidism and new daily
The investigators reviewed the charts of 275 patients
aged between 5 and 18 years who were seen in the en- persistent headache as well as between hypothyroidism
docrinology clinic between Jan. 1, 2006, and Dec. 31, and chronic migraine were also observed.
Given these findings, a
2006, and collected data reprospective study is warrantgarding age, sex, thyroid dysCorrelations between hypothyroidism
ed to further quantify the ocfunction, headache presence,
and new daily persistent headache as
currence of headache and its
and etiology.
particular characteristics in
Patients with congenital
well as between hypothyroidism and
this population, Ms. Stanga
hypothyroidism and those
chronic migraine were observed.
commented.
with incomplete records were
The medical student added
excluded from the analysis.
Of the 275 patients, 249 met the study criteria and were that “an attempt should also be made to determine
whether headache frequency changes in response to the
included in the analytical sample, Ms. Stanga noted.
Both hyperthroidism and hypothyroidism were asso- treatment of thyroid disease.”
If further studies confirm the significant association
ciated with headache in the study population to a statistically significant degree, said Ms. Stanga, a third-year between thyroid dysfunction and headache, the inclusion
medical student at Southern Illinois University, Spring- of thyroid work-up might be considered part of a stanfield, and a Weller Scholar at the Cleveland Clinic under dard evaluation for headache in this patient population,
according to Ms. Stanga.
Dr. Rothner.
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