Download Rett syndrome: clinical correlates of the newly discovered gene

Brain & Development 23 (2001) S202–S205
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Original article
Rett syndrome: clinical correlates of the newly discovered gene q
Alan K. Percy*
Department of Pediatrics, Neurology, and Neurobiology, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35233, USA
Abstract
The recent identification of mutations in the gene, MECP2, in girls with Rett syndrome (RS) firmly establishes the molecular genetic basis
of this X-linked dominant disorder. This discovery, with ramifications far beyond establishing the gene for RS, represents a dramatic
conclusion to an intensive, decade-long search. MECP2 encodes a methyl-CpG-binding protein (MeCP2) involved in transcriptional
silencing of a yet to be defined number and type of genes. The clinical spectrum of resultant disorders extends well beyond RS. Indeed,
the clinical phenotypes for MECP2 mutations range from mild disability in the mother of a girl with RS to rapidly progressive encephalopathy in her brother. Further, the recent identification of MECP2 mutations in boys with phenotypes quite different from RS adds yet another
element to the mix. Within the classic RS group, clinical severity varies remarkably, depending at least in part on the degree of non-random
X-inactivation. Those with clinical patterns in the border zones of RS remain to be examined fully for less severe mutational events. Further,
the pathobiology of RS and the role of transcriptional silencing as a disease-producing mechanism could be a prototype for other disorders of
neurodevelopment. Thus, the identification of mutations in MECP2 creates completely new vistas as to fundamental neurobiologic processes,
to disease mechanisms in the neurodevelopmental disabilities, and to potential new therapeutic strategies for RS and related disorders.
q 2001 Elsevier Science B.V. All rights reserved.
Keywords: Rett syndrome; Phenotypic variation; Transcriptional silencing; MECP2 mutations
1. Rett syndrome and its variant forms
Rett syndrome (RS), with a prevalence of 1:10,000–
20,000, is a numerically significant cause of neurodevelopmental disability in females, exceeding that of phenylketonuria [1–3]. RS typically has its clinical onset between 6–18
months of age following a period of apparently normal
development. The diagnosis of RS requires that certain clinical criteria (Table 1) are met [4]. Variant forms of RS
including formes fruste, preserved speech, and congenital
onset have been recognized for some time and criteria [5]
have been established for these as well (Table 2). Among
the population of girls in Sweden [3], more than 80% have
classic RS (Table 3).
The recent discovery of mutations in the MECP2 gene in
girls fulfilling the established criteria for RS culminates a
decade long search for a genetic explanation of this very
intriguing disorder [6]. This discovery allows the confirmation of clinical diagnoses and the development of genotypephenotype correlations. Further, the border zones of clinical
involvement for girls who do not meet all diagnostic criteria
q
Presented in part at the World Congress on Rett Syndrome 2000, Karuizawa Nagano Japan, July, 2000.
* 1600 7th Avenue South, Suite 516. Tel.: 11-205-939-9588; fax: 11205-939-6184.
E-mail address: [email protected] (A.K. Percy).
for RS can now be examined carefully at the molecular
genetic level. At the present time, the majority of girls fulfilling the criteria for RS have mutations in MECP2 [7–11]. The
remainder either have mutations in as yet unexplored regions
of MECP2 or are explained by alternative genes.
One critical element in advancing our understanding of
the role of MECP2 in neurodevelopmental disabilities is the
establishment of firm criteria that extend over the continuum
of clinical involvement for RS and its variant forms.
Further, these criteria must be carefully applied. This places
the responsibility squarely on the clinician to provide clear
and complete descriptions of the clinical presentations for
all girls in whom mutations in MECP2 are identified.
Furthermore, how far should the net be cast in the evaluation
of girls or boys with unexplained neurodevelopmental
disabilities? As will be discussed below, the phenotypic
spectrum arising from mutations in MECP2 is remarkable.
Are we wise enough to determine which individuals and
under what circumstances mutational analysis should be
requested? The recent data suggest that we are not yet there.
2. Phenotype–genotype correlations
Attempts at providing phenotype-genotype correlations
with respect to RS and mutations in MECP2 have led to
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A.K. Percy / Brain & Development 23 (2001) S202–S205
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Table 1
Rett syndrome. Obligate criteria for diagnosis a
Table 3
Rett syndrome. Phenotypic distribution in Sweden a
Criteria
Onset
Phenotype
Number
Per cent
Normal at birth
Apparently normal early development
Postnatal deceleration of head growth
Loss of purposeful hand skills
Psychomotor regression
Communication dysfunction
Autistic features
Stereotypic movements
Hand washing/wringing
Hand clapping/patting
Hand mouthing
Gait dysfunction
Gait apraxia
Truncal ataxia
Absence of
Organomegaly
Optic atrophy
Retinal changes
Intrauterine growth retardation
–
6–8 months
3 months–4 years
9 months–2 1/2 years
9 months–2 1/2 years
Classical
Formes frustes 9
>
Late regression =
Preserved speech >
;
Congenital
106
15
81.5
11.5
9
7.0
a
a
1–3 years
1–4 years
Adapted from Refs. [3,4].
mixed results [7,9,10]. This may be due in part to the multiplicity of mutations associated with RS and the fact that
different studies are deriving their comparisons from a
different set of mutations. The factor which appears to
have the greatest influence on phenotype is the degree of
non-random X-chromosome inactivation (XCI) [7].
Systematic study of XCI has not been performed. Further,
XCI may vary remarkably between tissues. Thus, correlations based on sampling peripheral tissues such as lymphocytes may be misleading.
One lesson to be learned is that comparisons among girls
with RS must be based on carefully conducted clinical
evaluations using agreed upon clinical criteria and clinical
severity scales. For example, the clinical criteria for RS and
the clinical severity scales differed between the studies of
Table 2
Rett syndrome. Delineation of phenotypic variants a
Inclusion criteria:
1. Female
2. At least 10 years old
3. Meet at least three of six main
criteria
4. Meet at least five of 11
supportive criteria
Eleven supportive criteria:
1. Breathing irregularities
2. Teeth grinding
3. Scoliosis/kyphosis
4. Lower limb amyotrophy
5. Cold, purplish feet
a
Adapted from Hagberg and Witt-Engerström as contained in Ref. [3].
Six main criteria:
1. Loss of finger skills
2. Loss of babble/speech
3. Loss of communication skills
4. Deceleration of head growth
5. Hand stereotypies
6. RS disease profile
6. Bloating
7. Gait apraxia
8. RS EEG pattern
9. RS eye pointing
10. Pain indifference
11. Laughing/screaming spells
Adapted from Hagberg and Skjeldal, Ref. [5].
Amir et al. [7] and Cheadle et al. [9]. As such, direct
comparisons between the two studies is not possible. In
future, it will be important to base phenotype-genotype
correlations on a common clinical severity scale among
girls who fulfill the classic criteria or whose deviation
from these criteria is clearly indicated.
3. MECP2 mutations extending beyond the boundaries
of Rett syndrome
The second major outcome from identification of mutations in MECP2 is the broad spectrum of clinical phenotypes associated with such mutations [8,12–16]. This
finding should, however, not be surprising. Similar results
have been obtained for a number of inherited disorders.
Disease processes associated with mutations in the hexosaminidase A gene (HEXA), which is responsible for TaySachs disease, represent the most striking example. The
phenotypes arising from mutations in HEXA range from
Tay-Sachs disease to the distinct clinical pictures of dystonia, spinocerebellar degeneration, amyotrophic lateral
sclerosis, spinal muscular atrophy, or psychotic depression.
Thus, it is hardly surprising that similar variability in clinical presentation should emerge from mutations in MECP2.
As such, it is necessary to consider how wide to cast the net
over other neurodevelopmental disorders with respect to
mutations in this gene.
If recent experience is a guide, the span will be broad. The
range of disorders associated with MECP2 mutations now
involves both females and males (Table 4). Among females,
mutations have been identified in association with RS and
Table 4
Rett syndrome. Phenotypes associated with MECP2 mutations
Females
Rett syndrome
Formes fruste
Preserved speech variant
Delayed onset variant
Mild learning disability
Normal carriers
Males
Fatal encephalopathy
Rett/Klinefelter syndrome
X-linked mental retardation/progressive spasticity
Somatic mosaicism/neurodevelopmental delay
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A.K. Percy / Brain & Development 23 (2001) S202–S205
Fig. 1. These overlapping circles depict the relationship between Rett syndrome (RS) and mutations in the MECP2 gene. Mutations have been defined in some
but not all girls with RS. Conversely, mutations have been defined in individuals lacking some or all of the features of RS including normal carrier females.
MECP2, designation for the methyl-CpG-binding protein 2 gene; C, female; F, male.
its variants and in normal women as well as those with mild
learning disability. In males, typical RS profiles have been
identified in at least two boys with Klinefelter syndrome
[12,13]. Other males have also been described. These
include (1) severe X-linked mental retardation and progressive spasticity in two boys in one family [16], (2) a Rett-like
phenotype in another boy [14], and (3) progressive encephalopathy in at least two others [17]. In the first family, both
mothers and the two boys share a common mutation in
MECP2 [16]. One mother was normal, but the other had
borderline intelligence. Both boys had non-syndromic
mental retardation and progressive spasticity. The boy
with a Rett-like phenotype lacked stereotypic hand movements and evidence was not presented regarding the
presence or absence of deceleration in the rate of head
growth. His phenotype is explained by somatic mosaicism
for the MECP2 gene, that is, some of his cells express a
mutation in MECP2, the remainder have a normal copy of
this gene [14]. More recent observations of this boy suggest
that he now has hand stereotypies and may well fit the
criteria for classic RS (personal communication, Kathy
Hunter, International Rett Syndrome Association). One of
the boys with progressive encephalopathy shared a common
MECP2 mutation with his mother, who has a mild learning
disability, and his sister and aunt, who have classic RS [8].
This array of phenotypes associated with RS is displayed
in the Fig. 1 as overlapping circles depicting the close relationship between this disorder and individuals with mutations in MECP2. Currently, mutations in this gene have not
been identified in some girls with RS. Conversely, mutations in MECP2 have been described in males and females
who display features either in common with RS or completely disparate. The overlap region includes girls with classic
and variant forms of RS. This pattern is likely to expand as
new associations with MECP2 mutations are defined. As
stated above, it seems unlikely that we are wise enough or
have sufficient information at this time to predict which
neurodevelopmental disabilities are likely to be explained
by such mutations. Certainly, girls fulfilling some or all
criteria for RS should be tested. Mutational analysis should
also be considered carefully in children with non-syndromic
cognitive impairment, autism with progressive features, and
X-linked neurodevelopmental disabilities.
4. Role of MECP2 in developmental neurobiology
The role of MECP2 in transcriptional silencing and of its
subsequent effects on developmental neurobiology is
largely unexplored. The identification of mutations in this
A.K. Percy / Brain & Development 23 (2001) S202–S205
gene in girls with RS has sparked new interest in this area.
From our understanding of the neuropathology of RS,
MECP2 would appear to impact fundamental mechanisms
in synaptic development [18,19]. As proposed by Michael
Johnston at this meeting, the hallmark of cellular dysfunction in RS may be the ‘sick’ synapse. This fits well with the
known involvement of multiple neurotransmitter systems
and abnormalities in dendrite formation and places the
timing of cellular dysfunction in the last third of gestation
or very early infancy. Evidence that proliferation and migration of neurons proceed appropriately during the first 25
weeks of gestation and that deceleration in the rate of
head growth is present already by three months of life
suggests this temporal boundary [20]. The specific neurobiologic events and the downstream genes underlying RS on
the one hand and normal neurodevelopment on the other
remain to be determined. The unfolding panorama of ongoing investigations will certainly provide important new
insights for both.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
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