Epilepsy in Rett Syndrome: Association Between Phenotype and Genotype, and Implications for Practice

Seizure 20 (2011) 646–649

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Epilepsy in Rett syndrome: Association between phenotype and genotype, and implications for practice

a, b a c d b

Basil Cardoza *, Angus Clarke , Jodie Wilcox , Frances Gibbon , Phil E.M. Smith , Hayley Archer ,

b e

Anna Hryniewiecka-Jaworska , Mike Kerr

Learning Disability Directorate, ABM University Health Board, Treseder Way, Cardiff, Wales, CF5 5WF, UK

Institute of Medical Genetics, University Hospital Wales, Cardiff, CF14 4XW, Wales, UK

Department of Child Health, University Hospital Wales, Cardiff, CF14 4XW, Wales, UK

Department of Neurology, University Hospital Wales, Cardiff, CF14 4XW, Wales, UK

UK School of Medicine, Cardiff University, Cardiff, CF14 4XN, Wales, UK

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: To investigate the association between genotype (methyl-CpG-binding protein 2 (MECP2 gene

Received 27 January 2011

mutation)) and epileptic seizure phenotype in Rett syndrome.

Received in revised form 13 April 2011

Methods: We used the British Isles Rett syndrome survey to identify 137 subjects with one of the nine

Accepted 17 June 2011

most frequent MECP2 gene mutations and invited their parents or carers to participate in a postal

questionnaire and telephone interview. The questionnaire recorded information about epileptic seizure

Keywords:

types, non-epileptic vacant spells and treatments. Two investigators conducted telephone interviews

Rett syndrome

and three epileptologists classiﬁed their epileptic seizures.

Epilepsy

Results: 89 subjects (65%) responded. The epilepsy prevalence was 67%, and 74% had non-epileptic

Epileptic seizure

vacant spells. The epilepsy prevalence within speciﬁc genotypes ranged from 47% (mutation C-terminal

MECP2 (methyl-CpG-binding protein 2)

gene mutation deletion, downstream of the Transcription Repression Domain) to 100% (mutation p.R270X, c.808C>T).

Non-epileptic vacant spells The prevalence of non-epileptic vacant spells within genotypes ranged from 50% (mutation p.R306C,

c.916C>T) to 100% (mutation p.R106W, c.316C>T). The epileptologists differed considerably in their

classiﬁcation of events, particularly of non-epileptic vacant spells.

Conclusions: The large majority of people with Rett syndrome have epilepsy. Most have multiple epileptic

seizure types, although generalised tonic–clonic seizures are the most common. There were no signiﬁcant

clinical differences between genotypes. The clinical differentiation of non-epileptic vacant spells is difﬁcult.

Discordance in epileptic seizure classiﬁcation between clinicians suggests that caution is needed, since the

clinical history alone cannot adequately classify the epileptic seizure type in Rett syndrome.

1. Introduction including complex partial, atypical absence and generalised tonic–

clonic. They usually start between early infancy and late childhood;

Rett syndrome is a neurodevelopmental disorder seen almost although often remitting with progressing age, they remain severe

11,12

exclusively in females, and usually associated with mutation in the and treatment resistant in a minority. After the teenage years,

methyl-CpG-binding protein 2 (MECP2) gene at Xq28. The the epilepsy severity tends to decrease, with lower epileptic seizure

prevalence of the classic syndrome ranges from 1:10 000 to frequency and relatively more partial-onset seizures.

2,3

1:15 000. The phenotype is often severe, with several characteris- Epileptic seizure rates are highest in the 7–12 years age group

tic features including a period of loss of hand and verbal skills, severe and lower in those with p.R294X, p.R255X mutations and C-

psychomotorretardation,stereotyped handmovements,truncaland terminal mutations. Other studies have shown that MECP2

gait dyspraxia: there are also several potential comorbidities mutations most frequently associated with epilepsy were T158M

4,5

including scoliosis, autonomic dysfunction and epilepsy. (74%) and R106W (78%), and less frequently R255X and R306C

6–8 9 14

Epilepsy occurs in between 70% and 90% of individuals with (both 49%). Epileptic seizures frequently appear during the

Rett syndrome. Epileptic seizures are commonly of multiple types, regression stage, with an early onset predicting a more severe

course. The same study showed that brain-derived neurotrophic

factor (BDNF) Val/Met polymorphism was correlated with earlier

* Corresponding author. Tel.: +44 2920564457; fax: +44 2920555047. onset of epileptic seizures, whereas MECP2 type and location did

E-mail address: [email protected] (B. Cardoza). not inﬂuence epilepsy. Early onset of epileptic seizures has also

B. Cardoza et al. / Seizure 20 (2011) 646–649 647

been linked to the combined MECP2 and BDNF genotypes. The BDNF the parents or carers of 137 patients known to the British Isles Rett

Met66 allele may protect against epileptic seizures, whereas Syndrome Survey (BIRSS), each having one of the nine most

missense mutations in the MBD of MECP2 are more frequently frequent mutations in the MECP2 gene (comprising 75% of all

associated with early epileptic seizures. There is no signiﬁcant known Rett-associated mutations). Parents or their carers gave

relationship between the underlying mutation and the likelihood informed consent to the research and to publication of the results.

of either drug-resistant epilepsy or abnormal electroencephalog- We developed a questionnaire to record information about

raphy (EEG). Cases without a detectable MECP2 mutation had a epileptic seizures and autonomic events, and mailed this to

higher risk of epileptic seizure onset up to 4 years of age, but a participants; we sent a single reminder to non-responders. Two

lower risk after 4 years. Epilepsy differs among the various investigators collected further detailed information using semi-

phenotypes and genotypes with respect to age at onset, drug structured telephone interviews across the UK and the Republic of

responsiveness, and epileptic seizure semiology. Infantile Ireland.

spasms, early-onset intractable epilepsy, and a Rett syndrome

like phenotype have also been associated with mutations in the 2.1. Seizure validation

19,20

cyclin-dependent kinase-like 5 (CDKL5) gene in Xp22.13.

Ambulation, hand use and language dysfunction also vary with Three experienced epileptologists analysed the written seizure

the underlying mutation; such abnormalities are fewer in those descriptions obtained from clinical telephone interview. One was

with the R133C mutation, and greater in those with the R168X an adult neurologist working primarily with non-learning disabled

mutation. In contrast, those with carboxy-terminal truncations are patients, with limited experience of Rett syndrome. Another was a

more likely to walk and use words. Individuals with epileptic paediatric neurologist, working with children both with and

seizures had greater overall clinical severity, and greater im- without intellectual disabilities. The third was a psychiatrist in

pairment of ambulation, hand use, and communication. Signiﬁ- intellectual disability, working mostly with people with intellec-

cant differences by mutation are seen for individual phenotypic tual disability and epilepsy. For each case the reviewer was asked

characteristics such as hand use, ambulation, and language, with to classify the seizure type. This led to one of the following

p.R270X and p.R255X being the most severe, and p.R133C and outcomes:

p.R294X being the mildest mutations.

Myoclonic jerks and myoclonic status epilepticus are some- a. Agreement or disagreement that the events were seizures.

times difﬁcult to distinguish clinically from movement disorders b. Agreement or disagreement that the patient had epilepsy.

such as the hand stereotypies, tremor, and dystonia of Rett c. Agreement or disagreement that the events were non-epileptic

23,24

syndrome. Many events presumed to be epileptic seizures vacant spells.

have no EEG correlate during video-EEG monitoring. On the where there was disagreement, the majority view was

other hand, EEG epileptiform activity commonly occurs without accepted.

overt clinical epileptic seizures. The intermittent EEG abnormality

and behavioural changes indicate abnormal ﬂuctuating arousal,

5,6

possibly of midbrain or brainstem origin. 2.2. Analysis

Epileptic seizures have a negative impact on the lives of many

children and their families. This is especially so in patients with Initial analysis was performed using chi square tests, but where

generalized, prolonged, cyanotic and drug-resistant epileptic sei- patient numbers were insufﬁcient to show clinical differences

zures. Non-epileptic‘‘Rettepisodes’’(ornon-epileptic vacant spells) between phenotype, descriptive data were presented.

can be mistaken by observers, parents or professionals for epileptic

seizures and some ‘‘genuine’’ epileptic seizures may not be noticed. 3. Results

These non-epileptic vacant spells) can include motor activity, such as

twitching, jerking, head turning, falling forward, and trembling, as The parents or carers of 89 patients (65%) responded to the

well as staring, laughing, pupil dilatation, breath holding and questionnaire. All were female and aged between 5 and 43 years.

hyperventilation. Breath holding may include expiratory apnoea Sixty of the 89 (67%) received a diagnosis of epilepsy. A total of 199

after hyperventilation, reﬂex expiratory apnoea, inspiratory apnoea, ‘‘episodes’’ were reported as epileptic seizures by the parents or

apnoea or hypoventilation not otherwise speciﬁed. carers of 60 girls. All three epileptologists agreed with the

Abnormal brainstem activity might cause behaviours that could diagnosis of epileptic seizures in 93 of the 199 reported ‘‘episodes’’

be confused with epileptic seizures, such as eye blinking, facial (47%) and in the remainder a majority view was taken, i.e., if 2 out

twitching, vacant spells without EEG epileptiform activity, and of 3 epileptologists agreed that it was an epileptic seizure, then it

28 29

cyanosis. Irregular breathing is also characteristic and Rett was classiﬁed as one. There was also similar agreement that 66 of

syndrome is regarded a cause of congenital dysautonomia. the 89 patients (74%) had non-epileptic vacant spells. There was

Abnormal awake breathing is common and over 70% have either most variation in the differentiation of non-epileptic vacant

hyperventilation or breath holding. Up to thirteen types of spells.

abnormal breathing have been described, sometimes with several The following data uses the consensus seizure classiﬁcation

being displayed sequentially in the same person. Ventilatory and agreed, following discussion between the three epileptologists.

autonomic monitoring has demonstrated reduced resting vagal

tone with episodes of central autonomic instability. 3.1. Seizure type and syndrome

This study aimed to determine the type and frequency of

epileptic seizures and non-epileptic vacant spells in Rett syn- 62% of patients had generalised tonic–clonic seizures, approxi-

drome, and any association of these features with the type of mately a quarter had secondarily generalised tonic–clonic seizures,

MECP2 mutation. and a quarter had complex partial seizures. Symptomatic focal

epilepsy (58%) was more common than symptomatic generalised

2. Methods epilepsy (38%) (Tables 1 and 3).

There was a family history of Rett syndrome in three of the 89

The study was approved by the Multicentre Research Ethics patients, of epilepsy in six of the 89, and of intellectual disability

Committee for Wales, UK. We sent letters inviting participation to (other than Rett syndrome) in a further six. About three-quarters of

648 B. Cardoza et al. / Seizure 20 (2011) 646–649

Table 1

Prevalence of seizure types, epilepsy syndromes and non-epileptic vacant spells listed by MECP2 mutation.

Mutation C terminal p.R133C, p.R106W, p.R168X, p.R255X, p.R270X, p.R294X, p.R306C, p.T158M, deletion, c.397C>T c.316C>T c.502C>T c.763C>T c.808C>T c.880C>T c.916C>T c.473C>T

after TRD (Transcription Repression

Domain)

Number 15 10 3 19 11 8 2 10 11

Number with epilepsy 7 (47%) 6 (60%) 2 (66%) 13 (68%) 7 (64%) 8 (100%) 1 (50%) 8 (80%) 8 (73%)

Non-epileptic vacant spells 11 (73%) 9 (90%) 3 (100%) 14 (74%) 8 (73%) 6 (75%) 2 (100%) 5 (50%) 8 (73%)

Generalised tonic–clonic 4 4 0 12 4 5 0 4 4

Secondarily generalised tonic–clonic 2 1 2 1 1 0 0 5 3

Complex partial seizures without 0 2 1 1 1 3 1 2 5

secondary generalisation

Tonic 1 0 0 0 1 0 0 0 0

Atonic 0 0 0 0 0 0 0 1 0

Absence seizures 0 0 1 0 0 0 0 0 0

Myoclonic 0 0 0 0 0 0 1 0 0

Symptomatic generalised epilepsy 1/7 (14%) 2/6 (33%) 0/2 6/13 (46%) 4/7 (57%) 2/8 (25%) 1/1 (100%) 4/8 (50%) 3/8 (38%)

Symptomatic focal epilepsy 6/7 (86%) 4/6 (67%) 1/2 (50%) 7/13 (54%) 3/7 (43%) 5/8 (63%) 0/1 4/8 (50%) 5/8 (63%)

Diagnosis not possible 0 0 1/2 (50%) 0 0 1/8 (13%) 0 0 0

Table 2

Other clinical features listed by MECP2 mutation.

Mutation C terminal p.R133C, p.R106W, p.R168X, p.R255X, p.R270X, p.R294X, p.R306C, p.T158M, deletion, c.397C>T c.316C>T c.502C>T c.763C>T c.808C>T c.880C>T c.916C>T c.473C>T

after TRD (Transcription Repression

Domain)

Number 15 10 3 19 11 8 2 10 11

Family history of epilepsy in 1 2 0 1 1 0 0 0 1

1st or 2nd degree relatives

Family history of Rett syndrome 0 1 0 2 0 0 0 0 0

in 1st or 2nd degree relatives

Family history of intellectual 1 1 0 1 0 0 0 2 1

disability in 1st or 2nd degree

relatives (excluding Rett

syndrome)

Patients currently or previously 10/15 (67%) 7/10 (70%) 2/3 (66%) 13/19 (68%) 9/11 (82%) 7/8 (88%) 1/2 (50%) 8/10 (80%) 9/11 (82%)

taking antiepileptic medication

(AED)

Patients currently taking AED 8/15 6/10 2/3 12/19 8/11 7/8 1/2 8/10 7/11

Patients taking one AED 7/8 (88%) 5/6 (83%) 2/2 (100%) 7/12 (58%) 4/8 (50%) 3/7 (43%) 1/1 (100%) 2/8 (25%) 4/7 (57%)

Mean age of ﬁrst seizure 4 years, 2 years, 2 years 5 years, 4 years, 4 years, 3 years 8 years 4 years,

11 months 8 months 7 months 5 months 10 months 7 months

Prevalence of carer-reported 13/15 (87%) 8/10 (80%) 3/3 (100%) 12/19 (63%) 10/11(91%) 7/8 (88%) 2/2 (100%) 9/10 (90%) 9/11 (82%)

breath-holding, hyperventilation

or air-swallowing

Association of carer reported 2/7 (29%) 0/5 2/2 (100%) 10/13 (77%) 6/7 (86%) 7/8 (88%) 1/1 (100%) 8/8 (100%) 7/8 (88%)

breath-holding, hyperventilation

or air-swallowing, with epilepsy

Table 3

individuals had previously taken anti-epileptic drugs; two-thirds

Prevalence of seizure types and epilepsy syndromes.

remained on them, including 59% on monotherapy (Table 2).

Number (n = 60) Percentage (%) The age of ﬁrst epileptic seizure ranged from 2 to 8 years, and

Seizure type differed between the classes of mutation (Table 2). The vast

Generalised tonic–clonic 37 62 majority of carers reported that individuals had breath holding,

Secondarily generalised 15 25

hyperventilation or air swallowing. They also felt that there was an

tonic–clonic

association between these and epilepsy (Table 2).

Complex partial 16 27

Tonic 2 3.3

Atonic 1 1.6 3.2. Association between genotype and epileptic seizure classiﬁcation

Absence seizures 1 1.6

Myoclonic 1 1.6

Different mutations of the MECP2 gene showed a prevalence of

Epilepsy type epileptic seizures varying between 47% and 100%, and of non-

Symptomatic generalised 23 38.3 epileptic vacant spells between 50% and 100%; the group numbers

Symptomatic focal 35 58.3

were small and the differences not statistically signiﬁcant (using

Diagnosis not possible 2 3.3

chi-square analysis) (Table 1).

B. Cardoza et al. / Seizure 20 (2011) 646–649 649

4. Discussion and conclusions Conﬂict of interest statement: The authors have no conﬂict of

interest.

We have found a prevalence of epilepsy of 67% among a large

cohort of Rett syndrome patients. Within this population, the

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