anaesthesia for angelman syndrome
TRANSCRIPT
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.
........................................................................................................
Correspondence to: Dr K. R. Ramanathan
E-mail: [email protected]
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
Anaesthesia, 2008, 63, pages 659–661 doi:10.1111/j.1365-2044.2008.05439.x.....................................................................................................................................................................................................................
� 2008 The Authors
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
1 Schneider BB, Maina DM. Angelman syndrome. Journal of
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-
istics of Angelman syndrome. Journal of Neuroscience 1998; 18:
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
plasma gamma amino butyric acid levels in individuals
with either Prader-Willi syndrome or Angelman syn-
drome. Journal of Neuropsychiatry and Clinical Neurosciences
1997; 9: 75–80.
6 Moncla A, Malzac P, Voelckel MA, et al. Phenotype –
genotype correlation in 20 deletion and 20 non-deletion
Angelman syndrome patients. European Journal of Human
Genetics 1999; 7: 131–9.
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
7 Belleli D, Pistis M, Peters JA, et al. General anesthetic action
at transmitter – gated inhibitory amino acid receptors. Trends
in Pharmacological Sciences 1999; 20: 406–502.
8 Weir CJ. The molecular mechanisms of general anaesthesia:
dissecting the GABA-A receptor. Continuing Education in
Anaesthesia, Critical Care and Pain 2006; 6: 49–53.
9 Jurd R, Arras M, Lambert S, et al. General anaesthetic
actions in vivo strongly attenuated by a point mutation in
the GABA-A receptor beta3 subunit. FASEB Journal 2003;
17: 250–2.
10 Reynolds DS, Rosahl TW, Cirone J, et al. Sedation and
anaesthesia mediated by distinct GABA-A receptor isoforms.
Journal of Neuroscience 2003; 23: 8608–17.
11 Homanics GE, DeLorey TM, Firestone LL, et al. Mice
devoid of c-aminobutyrate type A receptor b3-subunit
have epilepsy, cleft palate, and hypersensitive behavior.
Proceedings of the National Academy of Sciences 1997; 94: 4143–
8.
12 Ruggieri M, McShane MA. Parental view of epilepsy in
Angelman syndrome: a questionnaire study. Archives of
Disease in Childhood 1998; 79: 423–6.
13 Rudolph U, Mohler H. Analysis of GABAA receptor
function and dissection of the pharmacology of ben-
zodiazepines and general anesthetics through mouse genet-
ics. Annual Review of Pharmacology and Toxicology 2004; 44:
475–98.
14 Vanagt Y, Pulles-Heintzberger CF, Vernooy K, et al.
Asystole during outbursts of laughing in a child with
Angelman syndrome. Pediatric Cardiology 2005; 26: 866–
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