1

REVIEW

Rett syndrome: clinical review and genetic update

L S Weaving, C J Ellaway, J Gecz, J Christodoulou
...............................................................................................................................

J Med Genet 2005;42:17. doi: 10.1136/jmg.2004.027730

Rett syndrome (RS) is a severe neurodevelopmental causes RS remains somewhat of an enigma, but
recent advances in our knowledge of its precise
disorder that contributes significantly to severe intellectual roles in neuronal and other cell types have gone a
disability in females worldwide. It is caused by mutations in long way towards clarifying this issue.
MECP2 in the majority of cases, but a proportion of Nevertheless, diagnosis of RS remains a clinical
one, as a small proportion of clinically well
atypical cases may result from mutations in CDKL5, defined RS patients (,510%) do not appear to
particularly the early onset seizure variant. The relationship have MECP2 mutations.
between MECP2 and CDKL5, and whether they cause RS
through the same or different mechanisms is unknown, but CLINICAL OVERVIEW
is worthy of investigation. Mutations in MECP2 appear to RS is characterised by a specific developmental
give a growth disadvantage to both neuronal and profile, with the diagnosis of RS being based on a
consistent constellation of clinical features and
lymphoblast cells, often resulting in skewing of X the use of established diagnostic criteria.7 More
inactivation that may contribute to the large degree of recently, refined diagnostic criteria have been
phenotypic variation. MeCP2 was originally thought to be proposed to clarify previous ambiguities in
interpretation of clinical features8 (table 1, fig
a global transcriptional repressor, but recent evidence 1), and guidelines have been developed to aid
suggests that it may have a role in regulating neuronal researchers in being more consistent in their
activity dependent expression of specific genes such as reporting of clinical features in RS patients.9
The diagnostic criteria for classical RS include
Hairy2a in Xenopus and Bdnf in mouse and rat. a normal prenatal and perinatal period with
........................................................................... normal developmental progress for the first
56 months of life. The birth head circumference
is normal with subsequent deceleration of
head growth, usually leading to microcephaly.

R
ett syndrome (RS) was first described as a
clinical entity in the German literature in Between 3 months and 3 years there is reduction
1966.1 Hagberg and colleagues increased or loss of acquired skills such as purposeful hand
awareness of the disorder in the English medical function, vocalisation, and communication skills.
literature in 1983 with a further description of The hallmark of RS is the intense, sometimes
the condition in 35 girls with strikingly similar continuous, stereotypic hand movements, which
clinical features of progressive autism, loss of develop after the loss of purposeful hand move-
purposeful hand movements, ataxia, and ments. Patterns consist of tortuous hand wring-
acquired microcephaly.2 RS is now recognised ing, hand washing, clapping, patting, or other
as a panethnic disorder, and presents an ever more bizarre hand automatisms, during waking
widening clinical phenotype.3 The estimated hours.5 A jerky truncal and or gait ataxia is
cumulative incidence of RS in Australia is 10 another prominent feature. Supportive diagnos-
per 100 000 females by the age of 12 years4 and it tic criteria include breathing dysfunction, EEG
is considered to be the second most common abnormalities, spasticity, peripheral vasomotor
cause, after Downs syndrome, of severe mental disturbance, scoliosis, and growth retardation. It
retardation in females.5 RS is a severe neuro- has been suggested that the classical RS pheno-
developmental disorder characterised by the type can be described as having a four stage
progressive loss of intellectual functioning, fine clinical evolution, and this has helped in
and gross motor skills and communicative discussing the natural history of the disorder
See end of article for
authors affiliations abilities, deceleration of head growth, and the with parents.10 According to the recently revised
....................... development of stereotypic hand movements, criteria,8 the clinical diagnosis of RS is excluded
occurring after a period of normal development. if there is evidence of a storage disorder,
Correspondence to: retinopathy, cataract, or optic atrophy, an iden-
Professor J Christodoulou, Girls with RS often develop seizures, a disturbed
Western Sydney Genetics breathing pattern with hyperventilation and tifiable metabolic or neurodegenerative disorder,
Program, The Childrens periodic apnoea, scoliosis, growth retardation, an acquired neurological disorder, or evidence of
Hospital at Westmead, perinatal or postnatal brain injury. It must not be
Locked Bag 4001,
and gait apraxia.2
Westmead, 2145, NSW, The association of RS with mutations in the
Australia; johnc@ methyl-CpG binding protein 2 gene (MECP2) was
chw.edu.au recognised in 1999.6 The MeCP2 protein is Abbreviations: BDNF, brain derived neurotrophic factor;
CDKL5, cyclin dependent kinase-like 5; ISSX, infantile
known to bind methylated CpG sequences and
Received 1 October 2004 spasms syndrome, X linked; MECP2, methyl-CpG binding
Revised 1 October 2004 recruit silencing complexes that lead to compac- protein 2; MR, mental retardation; ORF, open reading
Accepted 5 October 2004 tion and silencing of surrounding chromatin. The frame; RS, Rett syndrome; STK9, serine threonine kinase
....................... mechanism(s) by which MeCP2 dysfunction 9; XLRS, X linked retinoschisis

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2 Weaving, Ellaway, Ge cz, et al

Table 1 Revised diagnostic criteria for classical and variant RS. Derived from tables 3 and 4 in the paper by Hagberg et al.8
Necessary criteria Supportive criteria Exclusion criteria

Classical RS Apparently normal prenatal and Breathing disturbances while awake Organomegaly or other evidence of a
perinatal history Bruxism storage disorder
Psychomotor development normal Impaired sleeping pattern from early Retinopathy, cataract, or optic atrophy
during the first 6 months (may be infancy History of perinatal or postnatal
delayed from birth) Abnormal muscle tone accompanied brain damage
Normal head circumference at birth by muscle wasting and dystonia Identifiable inborn error of metabolism
Postnatal deceleration of head Abnormal muscle tone accompanied or neurodegenerative disorder
growth (most individuals) by muscle wasting and dystonia Acquired neurological disorder due to
Loss of purposeful hand skills Peripheral vasomotor disturbances severe infection or head trauma
between 0.52.5 years Progressive scoliosis or kyphosis
Stereotypic hand movements Growth retardation
Evolving social withdrawal, Hypotrophic small and cold feet
communication dysfunction, loss of and/or hands
acquired speech, cognitive impairment
Impaired or deteriorating locomotion

Variant RS At least 3 of the 6 main criteria Breathing irregularities

At least 5 of the 11 supportive criteria Air swallowing or abdominal bloating
Main criteria Bruxism
Absence or reduction of hand skills Abnormal locomotion
Reduction or loss of speech Scoliosis or kyphosis
(including babble)
Hand stereotypies Lower limb amyotrophy
Reduction or loss of Cold, discoloured feet, usually
communication skills hypotrophic
Deceleration of head growth Sleep disturbances, including night
from early childhood time screaming
Regression followed by recovery Inexplicable episodes of laughing or
of interaction screaming
Apparently diminished pain sensitivity
Intense eye contact and/or eye pointing

forgotten that RS may occur coincidently with other Management

disorders,11 12 potentially delaying the diagnosis. Medical management of RS is essentially symptomatic and
With increasing experience it has become clear that supportive. A multidisciplinary team approach is advocated,
females with RS may present with a much broader phenotype aimed at maximising each patients abilities and facilitating
than originally described. A number of variants have been any skills that may be emerging. Management should include
described, which may be more or less severe than the clinical psychosocial support for the families, development of an
picture seen in classical RS.13 Although initially thought to be appropriate education plan, and assessment of available
a disorder exclusively affecting females, males with a Rett- community resources. Parent support groups are crucial in
like phenotype have been reported occasionally, including providing support for families. Pharmacological treatments
those who also have a 47XXY karyotype,14 males who are for RS have included L-carnitine, which may lead to an
mosaic for severe mutations,15 and males who may have improvement in patient wellbeing and quality of life,1719
milder mutations.16 In addition, other non-RS phenotypes magnesium to reduce the episodes of hyperventilation,20 and
have been associated with MECP2 mutations (see below). melatonin to improve sleep dysfunction.21 Evaluation of the
efficacy of these and other potential treatments on the
horizon will require carefully constructed clinical trials, using
Stage I validated instruments for measuring clinical improvements
Developmental stagnation and relevant biochemical markers.
Stage II Decreasing repetitive purposeless hand movements can be
Developmental regression
achieved by the use of various arm restraints, such as soft
Loss of acquired elbow splints, and are occasionally helpful in training specific
hand skills and speech hand skills such as self feeding. These methods are also
Impaired social helpful in decreasing agitation and self injurious behaviour.22
contact
Feeding problems are common in RS.23 Several factors
Hand stereotypies contribute to this, including poor caloric intake secondary to
Stage III swallowing difficulties and immature chewing patterns, and
Seizures energy expenditure imbalances with calories used to sustain
motor activities at the expense of growth. Despite a voracious
Breathing irregularities
appetite, some girls experience poor weight gain. This may be
Stage IV
because the majority of girls are unable to feed themselves,
Late motor deterioration
and very few develop mature chewing patterns. A gastros-
6 1yr 18 2 3 4 5 6 >10 tomy tube may be used as an alternate route to supplement
mths mths nutrition. Gastro-oesophageal reflux may respond to con-
Years servative medical treatment with anti-reflux agents, thick-
ened feeds, and positioning. Budden found that frequent
Figure 1 Staging system for classical Rett syndrome. Derived from small feeds during the day with added carbohydrate foods
Hagberg and Witt-Engerstrom.10 not only maintained growth and weight gain, but had a

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Rett syndrome update 3

definite influence on agitation and irritability in younger

A
girls.23 Alternative
The majority of RS girls lose verbal expressive language, poly A signals
although some retain some speech or single word expres- MECP2B ATG MECP2A ATG MBD TRD
5 kb
A 1.9 kb 10.1 kb
sions. Alternative forms of communication that may be used
1 2 3 4
include communication boards, technical devices, and switch
activated systems. These are used for making choices and
B
facilitate environmental access. Some girls are also able to
communicate through eye pointing, gestures, body language,
and hand pointing.22 These abilities need to be recognised and WW domain
encouraged. B MBD NLS binding region
Seizure control is a common problem in the care of females aa 90174 aa 267283 aa 325C-term
with RS. A major challenge in diagnosis may be differentiat-
ing seizures from the behavioural patterns often associated
NH2 COOH
with RS. Breathing irregularities such as breath holding and
hyperventilation, episodes of motor activity such as twitch-
ing, jerking, or trembling, or a cardiac arrhythmia associated TRD
with a prolonged QT interval are most commonly confused aa 219322
with seizures. Studies using prolonged video EEG polygraphic
monitoring indicate that the occurrence of seizures is Figure 2 (A) Structure of the MECP2 gene and mRNA (adapted from
overestimated. Most episodes identified by parents represent Kriaucionis and Bird,30 and Mnatzakanian et al31). Alternative splicing
for the A (b) isoform is shown above the gene and for the B (a) isoform
non-epileptic behavioural events. On the other hand, some
below the gene. The B isoform has the highest expression in brain, and
actual seizures may be unrecognised by parents or occur mutations specific to this isoform are sufficient to cause RS.31 (B) Structure
during sleep.24 EEG telemetry and parental education may of the B isoform MeCP2 protein sequence. The protein is 486 amino
assist in identifying true seizure events. acids in size. MBD, methyl-CpG binding domain; TRD, transcription
Prolonged heart rate corrected QT values have been repression domain; NLS, nuclear localisation signal.
reported in association with RS.25 26 Prokinetic agents (such
as cisapride), antipsychotics (such as thioridazine), tricyclic
antidepressants (such as imipramine), anti-arrhythmics or Ski/NcoR/HDACII repression complexes to do this.34 In
(such as quinidine, sotolol, amiodarione), anaesthetic agents addition, MeCP2 also has HDAC independent silencing
(such as thiopental, succinylcholine), and antibiotics (such as capabilities.35 The WW domain binding region, from residue
erythromycin, ketoconazole) should therefore be avoided 337 to the C terminus, specifically binds to group II WW
because of the possibility of precipitating electrocardiogram domains of splicing factors including formin binding protein
QT abnormalities and cardiac arrhythmias. II and Huntington yeast protein C (HYPC).36 MeCP2 thus has
Scoliosis is found in approximately 65% of girls with RS. the capability to interpret methylated CpGs differently,
Some girls require bracing, while others require surgical possibly leading to different downstream responses, depend-
intervention.22 27 Increased tone in the Achilles tendon is one ing on the context.
of the earliest manifestations of onset of rigidity, usually Following the first report of MECP2 mutations in RS
followed by toe walking. It is important to maintain patients,6 there was intense mutation screening of cohorts of
ambulation, and so bilateral ankle foot orthoses need to be patients, and attempts to draw phenotypegenotype correla-
used to prevent foot deformities, maintain foot alignment, tions, with conflicting results.3743 Several mutation data-
and keep the heel cords lengthened. Physiotherapy is also bases have also been developed (http://homepages.ed.ac.uk/
required to keep the Achilles tendons stretched.22 skirmis/; http://mecp2.chw.edu.au/).44 There is some agree-
ment that missense mutations are generally milder than
MECP2 MUTATIONS IN RS AND OTHER CLINICAL nonsense mutations, that mutations in the methyl binding
PHENOTYPES domain are often more severe than those in the transcription
The MECP2 gene is located at q28 on the human X repression domain, and that skewing of X inactivation can
chromosome, and has been demonstrated to undergo X modulate the severity of the disorder. In addition, studies of a
inactivation in mice and humans.28 29 It encodes a protein of number of patients with the same mutation have made it
498 (MeCP2B or MeCP2a; encompassing exon 1 but not exon possible to draw firm conclusions as to the severity of speci-
2) or 486 amino acids (MeCP2A or MeCP2b; encompassing fic mutations.43 45 46 However, variation may still be seen
part of exon 2 but not exon 1), depending on the use of between patients with the same mutation and apparently
alternative splice variants,30 31 (figure 2A), with MeCP2B random X inactivation, suggesting that other mechanisms
being the predominant isoform in brain. MeCP2A may may also modulate the clinical severity, with differences in
predominate in other tissues, such as fibroblast and upstream regulators or downstream targets of MeCP2 being
lymphoblast cells.31 There are known MeCP2 orthologues in possible candidates.
rat, mouse, monkey, Xenopus, and zebrafish (http://mecp2. The association of skewing of X inactivation with RS has
chw.edu.au/mecp2/info/MECP2_homologues.shtml), suggest- long been a subject of debate. An increased incidence of
ing that MeCP2 has served important functions throughout skewing has been reported by some authors,41 4749 but not
vertebrate evolution, although these may be different others.5054 Skewing has been investigated in a limited
between widely divergent species. number of regions in a small number of RS brain samples,55
Apart from a nuclear localisation signal, MeCP2 has three and these authors found random inactivation in 10/10
functional domains (figure 2B). The methyl-CpG binding samples that were informative for the assay. However, it
domain, at position 0174, binds exclusively to symmetrically has been demonstrated that both lymphocytes56 and neuronal
methylated CpGs. The transcriptional repression domain, at cells57 expressing mutant MeCP2 are at an in vitro growth
position 219322, is able to recruit co-repressor complexes disadvantage. In addition, two different MeCP2 null mouse
that mediate repression through deacetylation of core models showed uniform distribution of MeCP2 in the brains
histones, with consequent compaction of DNA into hetero- of heterozygous females, but skewed X inactivation favouring
chromatin.32 33 MeCP2 interacts with either the Sin3A/HDACI the wild type allele.5860 Young and Zoghbi57 also identified

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4 Weaving, Ellaway, Ge cz, et al

regional skewing in the brains of mice carrying the common

Resting neuron
308X mutation, and we have demonstrated that there may be
regional variation in human RS brains.61 Furthermore, it has
been demonstrated that skewing in the brains of mutant HDAC
mice correlates with the phenotypic outcome, with the mSin3a
chance of manifestation of certain symptoms decreasing
with increasing expression of the wild type allele.57 These MeCP2
studies, combined with previous studies of X inactivation in
RS patients, strongly suggest that skewing plays a significant Rat BDNF exon II
role in modulating phenotypic severity. Mouse BDNF exon IV
Prior to the identification of the MeCP2B (MeCP2a)
Depolarisation
isoform, mutation detection efforts had focused on PCR
based approaches to screening exons 2, 3, and 4. More
recently, it has been recognised that up to 15% of apparently
MECP2 mutation negative individuals have large deletions
(spanning kilobases) that would be missed by this
Rat BDNF exon III
approach.6265 In addition, the identification of the new
MeCP2 isoform has raised the speculation that some
individuals may have mutations in exon 1,31 although in
our experience this appears to be an uncommon event HDAC
(unpublished observations).66 Using a combination of PCR MeCP2 is phosphorylated and
mSin3a
based screening approaches for the MECP2 coding regions released from BDNF promoter
and one or other method to screen for large deletions, it has MeCP2
been suggested that pathogenic MECP2 defects will be
identified in up to 9095% of RS cases.63 A remaining PO3
challenge is to identify the genetic defect in the remaining
510% of cases, with possible regions of interest including the Figure 3 Proposed model for MeCP2 regulated expression of BDNF. In
MECP2 promoter region, the blocks of highly conserved the resting neurone, MeCP2 binds the BDNF promoter, repressing its
sequence within the very large 39 untranslated region,67 or activity. Following neuronal depolarisation, MeCP2 is phosphorylated,
novel genes (see below).68 69 perhaps by CDKL5, leading to its displacement from the BDNF promoter,
Interestingly, the vast majority of single nucleotide and thus allowing BDNF activation.
changes in the MECP2 gene are the result of CRT transitions
at CpG hotspots.41 70 71 The general restriction of RS to females
and the very low recurrence rate72 appear to be the result of a
large proportion of these mutations arising via spontaneous maturation, particularly in the hippocampus, cortex, and
deamination of 5-methylcytosine to thymine in the heavily cerebellum, the brain regions primarily affected in RS.91 92
methylated male germ cells.7375 These combined expression data suggest that MeCP2 has
A large degree of phenotypic variability is seen in both RS specific functions in neuronal cells of the central nervous
patients and people with MECP2 mutations, ranging from system. Indeed, Aber et al93 demonstrated that MeCP2
classical RS to normal individuals with protective skewing of localises both to the postsynaptic compartments of neuronal
X inactivation. The phenotype associated with MECP2 cells and to the nucleus, suggesting that MeCP2 links the
mutations has broadened even further to include males with regulation of transcription to synaptic activity.
severe neonatal encephalopathy,70 76, males from X linked Two recent papers have identified one possible MeCP2
mental retardation pedigrees,7781 PPM-X syndrome,82 target in this pathway in mammals.94 95 These authors found
Angelman syndrome,83 84 and infantile autism.85 that MeCP2 binds specifically to BDNF (brain derived
neurotrophic factor) promoter III in rat and promoter IV in
FUNCTIONAL CONSEQUENCES OF MECP2 mouse, respectively, thereby repressing BDNF transcription in
MUTATIONS resting neuronal cells. Membrane depolarisation of neuronal
MeCP2 was initially thought to function as a global cells led to calcium dependent phosphorylation and release of
transcriptional repressor, but the specifically neuronal pheno- MeCP2 (fig 3), suggesting that MeCP2 may regulate the
type associated with mutations, and the apparent lack of transcription of activity dependent genes in neuronal cells,94
global gene dysregulation in cell lines from RS patients,86 87 which is important in synapse development and neuronal
and in brains from human RS patients88 and RS mouse plasticity.
models,87 do not support this suggestion. Deletion of the C terminus of MECP2 encompassing the
Recent studies have begun to identify specific MeCP2 WW domain binding region occurs commonly in RS patients,
targets. In Xenopus, MeCP2 inhibits the expression of and is associated with loss of binding to the splicing factors
xHairy2a, which itself is a target of the Notch/Delta signalling FBP11 and HYPC.36 Preliminary evidence from our laboratory
pathway.89 With reduction of MeCP2 activity, xHairy2a suggests that cell lines carrying C terminal deletions may
expression is increased, and this leads to inhibition of shift towards recruiting smaller protein complexes on
primary neurogenesis.89 It will be interesting to study binding unmethylated or partially methylated CpG rich
whether MeCP2 plays a role in other Notch regulated aspects regions (data not shown). As these C terminal deletions do
of neuronal maturation, including dendritic branching, not disrupt the MBD or the TRD, the pathogenesis in these
which is known to be abnormal in the RS brain. cases may be due to loss of the WW domain binding region,
Studies of MeCP2 expression in primate prefrontal cortex and hence, loss of the proteins that normally interact with
demonstrate increases during development, with expression this domain. These findings are yet to be confirmed in brain
expanding from the deeper cortical layers and subplate in and neuronal cells,36 but if they are, it raises the interesting
110 day embryos, to robust expression throughout the possibility that MeCP2 is involved in splicing, or that WW
prefrontal cortex in adult monkeys.90 Moreover, increased binding domains may be found in specific neuronal targets of
MeCP2 expression appears to be associated with neuronal MeCP2.

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Rett syndrome update 5

c.455GT 68 c.525AT 68
Figure 4 Exon structure of the CDKL5
(STK9) gene and its overlap with the
96
c.163 166delGAAA XLRS1 gene. Published mutations
t(X;7) and ISSX97 involving the CDKL5 gene are indicated
t(X;6) and ISSX97 c.2634 2635delCC96
with arrows. Mutations found in
c.183delT96 IVS131GA69
136 kb deletion,
patients with early seizure variant of RS
XLRS and epilepsy98
are underlined. The position of two
ATG translocation breakpoints (associated
with ISSX) and a deletion involving both
1 1a 1b 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
XLRS1 and CDKL5 genes is also
indicated. All known exons of the
Tel. Cen. CDKL5 gene (solid boxes) and some of
the XLRS1 gene (empty boxes) are
6 5 4 3 indicated and numbered.

XLRSI

CDKL5/STK9

CDKL5: A SECOND RS GENE? MECP2 negative RS cases. Whether ARX tested negative cases
The apparent lack of MECP2 mutations in a small proportion with infantile spasms, or autism spectrum disorder cases
of clinically well defined RS cases suggests the existence of at with intellectual disability and early onset seizures, should
least one other RS locus.41 71 Three recent reports,68 69 96 also be considered remains to be investigated.
identified mutations in the gene for cyclin dependent
kinase-like 5 (CDKL5; OMIM #300203; also known as serine CONCLUSIONS
threonine kinase 9 (STK9)) in patients who had been Recent advances in our knowledge of MECP2 splicing, its
diagnosed with atypical RS, supporting the existence of specific targets, and the phenotypes and expression in
genetic heterogeneity in RS. Somewhat similar to the MECP2 mutant mice have greatly contributed to our understanding
involvement in RS, mutations affecting CDKL5 appear to yield of the aetiology of RS. Studies in cell lines and mouse models
clinical outcomes of varying severity. In addition to two have confirmed the contribution that skewing of X inactiva-
female patients with infantile spasms syndrome, X linked
tion can make to phenotypic variability.5658 Identification of
(ISSX) and X;autosome translocations interrupting the
Hairy2a89 and BDNF94 95 as bona fide targets of MeCP2 has
CDKL5 gene who were described by Kalscheuer et al,97 RS
given glimpses of the mechanisms by which MECP2 muta-
patients with early onset seizures (seven cases), one girl with
tions lead to RS, and have enhanced the understanding of the
an autistic disorder and intellectual disability, and a boy with
functions of MeCP2, which no longer appears to be the global
severe, early infantile onset neurological disorder have CDKL5
transcriptional repressor it was once assumed to be.102 Rather,
mutations.68 69 96 Additionally, one male patient with X linked
it may function to regulate the dynamic expression of
retinoschisis (XLRS) and a large deletion involving at least
neuronal genes and the formation of new synaptic connec-
the last coding exon of the CDKL5 gene had seizures, which
tions in response to electrical signalling, thereby explaining
are otherwise not associated with XLRS.98 In this case it is
the specifically neuronal phenotype associated with MECP2
likely that the seizure phenotype was due to deletion of the
mutations. Moreover, some of the phenotypic variability
CDKL5 gene, but other gene contributions cannot be
observed in RS has been confirmed to result from genetic
excluded. In summary, there are currently nine published
heterogeneity. Several reports have identified mutations in
(fig 4) and at least two unpublished RS cases (personal
CDKL5 in specific atypical RS variants associated with early
communication: Dr H Archer, Dr J Evans, Professor A Clarke,
onset seizures. It remains to be determined whether this or
Department of Medical Genetics, University of Wales College
other genes are responsible for a significant proportion of
of Medicine, Cardiff, Wales) with mutations in, or involving
atypical RS cases or other neurological phenotypes.
the CDKL5 gene. From among these, eight cases have been
While much has been learnt about RS since its first des-
diagnosed with the atypical, early seizure variant of RS,
cription over 30 years ago, the pathogenesis of this important
suggesting that this may be the predominant phenotype
and intriguing disorder is still not well understood. To fully
caused by CDKL5 mutations. Although still very tentative,
explain the RS disease phenotype will require the identification
some speculations about the CDKL5 mutation genotype/
of further gene targets for MeCP2 and CDKL5, particularly those
phenotype correlation can be drawn. While protein truncat-
predominantly active in the central nervous system.
ing mutations at the N terminal end97 cause a severe, early
onset phenotype of infantile spasms (phenotype overlapping Such studies would greatly enhance the understanding
with that of ISSX as caused by the Aristaless (ARX) gene of normal brain development and function, and provide
mutations99), truncations more towards the C terminal end opportunities for the development of targeted therapeutic
cause atypical RS in girls, a severe neurological disorder in interventions for RS, possibly in the presymptomatic stage or
boys, or autistic disorder with intellectual disability. Tissue early in the evolution of the disorder.
specific skewing of X inactivation, genetic background, and .....................
as yet unknown environmental factors may contribute to the
Authors affiliations
phenotypic variability, as revealed in at least one case of L S Weaving, Program in Developmental Biology, the Hospital for Sick
discordant monozygous twins.69 Children, Toronto, Canada
CDKL5 is a putative serine/threonine kinase of unknown C J Ellaway, J Christodoulou, Western Sydney Genetics Program, the
function.100 101 The connection between CDKL5 and MeCP2, if Royal Alexandra Hospital for Children, Sydney, and Discipline of
there is one, and the mechanism by which they produce Paediatrics and Child Health, University of Sydney, Australia
overlapping phenotypes, will be important questions for J Gecz, Department of Genetic Medicine, Womens and Childrens
future studies to address. CDKL5 mutations appear to be Hospital, Adelaide, and Department of Paediatrics, The University of
associated with severe, early onset seizures in particular, and Adelaide, Adelaide, Australia
thus CDKL5 gene screening should be considered in atypical, Competing interests: none declared

www.jmedgenet.com
6 Weaving, Ellaway, Ge cz, et al

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