CASE REPORT

Anaesthesia for Angelman syndrome

K. R. Ramanathan,1 D. Muthuswamy2 and B. J. Jenkins3

1 Senior House Officer, 2 Consultant, 3 Senior Lecturer and Honorary Consultant, Department of Anaesthetics, Prince

Charles Hospital, Merthyr Tydfil, UK

Summary

We describe the administration of anaesthesia to a patient with Angelman syndrome, which

is characterised by an abnormality of chromosome 15, where a subunit of the GABA receptor

is coded. This has far-reaching anaesthetic implications as many drugs used in anaesthesia are

thought to act via GABA receptors. Our patient had an uneventful peri-operative period and was

discharged home on the second postoperative day.

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Correspondence to: Dr K. R. Ramanathan

E-mail: krramanathan@yahoo.com

Accepted: 19 December 2007

Angelman syndrome was first described by Harry Ang-

elman in 1965 [1]. The syndrome is characterised by

mental retardation, delayed speech, protruding tongue,

craniofacial abnormalities (including microcephaly, deep-

set eyes, and a high arched palate), ataxia, frequent

drooling, paroxysmal laughter and seizures. In most cases

the syndrome is caused by an abnormality of the maternal

chromosome 15q11–13. This segment of the chromo-

some accounts for the coding of a subunit of the gamma

amino butyric acid (GABA) A receptor, which is the

current focus of attention as a receptor that is associated,

at least in part, with the action of many drugs used during

anaesthesia [2]. There is only one report in the literature

regarding the anaesthetic problems associated with this

syndrome [3], although there are descriptions on The

Angelman Syndrome Forum of the surgical management

of these patients [4].

Case report

A 5-year-old boy with Angelman syndrome with exces-

sive drooling was scheduled for reconstruction of the

submandibular duct. He had microcephaly, developmen-

tal delay (most marked in his speech and language

modality), learning difficulties and a broad gait. He had

poor oral motor control and had difficulty controlling his

saliva, blowing ⁄ sucking and with mouth closure. He was

hyperactive, with incomprehensible speech and would

move from one activity to another without engaging

in constructive play. He had a high arched palate, but

clinical examination otherwise was uneventful and his

blood results were within normal limits. Inhalational

anaesthesia was induced with oxygen, nitrous oxide and

sevoflurane (8%) and an intravenous infusion of dextrose

and saline started. Onset of anaesthesia was rapid (within

three to four breaths). He was given glycopyrrolate

(4 lg.kg)1) and tracheal intubation was facilitated with

atracurium (0.3 mg.kg)1). A 4.5-mm uncuffed tracheal

tube was placed in the trachea without difficulty, and

anaesthesia was maintained with oxygen, nitrous oxide

and sevoflurane (1.5%). He was also received alfentanil

(15 lg.kg)1), morphine (0.1 mg.kg)1) and paracetamol

(20 mg.kg)1, PR) prior to surgery. He remained cardio-

vascularly stable throughout the procedure, which lasted

for approximately 2 h. At the end of the procedure,

the nitrous oxide and sevoflurane were stopped and

the patient maintained on oxygen alone; spontaneous

respiration restarted within 2–3 min. Neostigmine

(40 lg.kg)1) and glycopyrrolate (4 lg.kg)1) were given

to ensure complete reversal of the atracurium. The

postoperative period was uneventful and the patient was

discharged home on the second postoperative day.

Discussion

The genetics of Angelman syndrome is complex. The

incidence is believed to be as high as one in 10 000

births [2]. About 70% have a de novo deletion of DNA

in the maternal chromosome 15q11–q13 (class I). A

deletion of a similar portion of the paternal chromosome

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Journal compilation � 2008 The Association of Anaesthetists of Great Britain and Ireland 659

leads to Prader–Willi syndrome in 60% of subjects.

Prader–Willi is a different clinical condition that is

characterised by infantile hypotonia, obesity in early

childhood, mental deficiency and hypogonadism.

Another 5–10% of Angelman syndrome patients (class

II) result from uniparental paternal disomy (where both

chromosome 15q11–13 alleles are of paternal origin) and

‘imprinting’ mutations (class III). Prader–Willi and

Angelman syndromes are the first examples of genetic

imprinting in humans, that is, differential expression of

the genetic material from the mother versus the father

[2, 5]. The remaining 20% of cases have no detectable

molecular abnormality (class IV). It has been suggested

that these types may have a mutation of the UBE3A

gene which causes a milder phenotype of the syndrome

with less electro-encephalographic abnormalities and

few, if any, seizures [6].

One consequence of the mutation or deletion is on the

expression of the RB3 gene, which is important in the

genetic coding for the b3 subunit of the GABA A

receptor [2]. A wide range of drugs that act on the CNS

(including anxiolytics, sedative hypnotics, general anaes-

thetics and anticonvulsants) are thought to have actions at

GABA receptors. The specific interaction of the intra-

venous general anaesthetics at the receptor level is a

matter of ongoing research; existing studies suggest that

they have selective affinity for certain subtypes of the bsubunit [7, 8]. The effects of inhalational general anaes-

thetics may be manifest through the a subunit of

the GABA-A receptor which may not be affected in

Angelman syndrome [8].

Angelman syndrome may be unrecognised at birth or

during infancy. It is most commonly diagnosed after the

age of 2 years, when the characteristic behaviours and

features become most evident [3]. Studies in genetically

engineered mice harbouring a single amino acid mutation

in the b3 subunit show that they are insensitive to certain

effects of propofol and etomidate [9]. The duration of

hypnosis was greatly reduced, and immobilisation com-

pletely absent. Mutations in the b2 subunit revealed

resistance to the sedative effects of intravenous anaesthet-

ics such as etomidate [10]. Homanics et al. reported

a significant reduction in benzodiazepene binding in

a genetically engineered mouse model of the human

Angelman syndrome [11]. Logically, these principles

should apply to patients with Angelman syndrome

subjected to anaesthesia, although there are few articles

that have highlighted the problems specific to this clinical

entity [3]. These patients may be less susceptible to

hypnotic and sedative effects of intravenous general

anaesthetics, though similar susceptibility to inhalational

agents may not be so easy to explain. The response to

anaesthetic drugs may be difficult to predict [3], adding a

layer of complexity to the anaesthetic and peri-operative

management of such patients.

Patients with Angelman syndrome may present for a

variety of conditions including corrective surgery for

skeletal deformities, strabismus or corrective surgery for

drooling. These patients are frequently un-cooperative

because of their hyperactive behaviour, and many are on

anticonvulsants [3, 12]. It would seem prudent to

continue anticonvulsants during the peri-operative peri-

od, as there have been reports of epilepsy following fever,

illness and tiredness [12]. Whether this warrants prophy-

lactic anticonvulsants in all Angelman syndrome patients

presenting for surgery is unclear.

In our patient, we decided on inhalational anaesthesia

and there was a rapid onset and offset of anaesthesia,

unlike the only other report of anaesthesia when the

authors noted a prolonged recovery time [3]. The

differences could be explained, in part, by the avoidance

of intravenous agents in our patient. The effect of

benzodiazepines may be significantly limited, as seen with

genetically engineered mice [13], though opioids may not

have a significant interaction with the GABA system.

Angelman syndrome patients may have a predominant

vagal tone of central origin, which may cause peri-

operative changes in heart rate [3]. The phenomenon has

been noted more commonly during the bouts of laughter

and the reasons postulated include changes in intra-

thoracic pressures and Valsalva-like manoeuvres [14].

Because of muscular atrophy neuromuscular blocking

agents should be titrated with use of neuromuscular

monitoring [3].

References

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the American Optometric Association 1993; 64: 502–6.

2 DeLorey TM, Handworth A, Anagnostaras SG, et al. Mice

lacking the b3 subunit of the GABA-A receptor have the

epilepsy phenotype and many of the behavioural character-

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8505–14.

3 Bujok G, Knapik P. Angelman syndrome as a rare anaes-

thetic problem. Pediatric Anesthesia 2004; 14: 281–3.

4 Sparks M. General Health Issues-tonsils. http://www.angel-

manforum.org (accessed 11 May 2007)

5 Ebert MH, Schmidt DE, Thomson MG. Elevated

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with either Prader-Willi syndrome or Angelman syn-

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6 Moncla A, Malzac P, Voelckel MA, et al. Phenotype –

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K. R. Ramanathan et al. Æ Anaesthesia for Angelman syndrome Anaesthesia, 2008, 63, pages 659–661......................................................................................................................................................................................................................

� 2008 The Authors

660 Journal compilation � 2008 The Association of Anaesthetists of Great Britain and Ireland

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8.

Anaesthesia, 2008, 63, pages 659–661 K. R. Ramanathan et al. Æ Anaesthesia for Angelman syndrome......................................................................................................................................................................................................................

� 2008 The Authors

Journal compilation � 2008 The Association of Anaesthetists of Great Britain and Ireland 661