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Angelman, syndrome
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(Happy puppet syndrome)
Prevalence: between 1/10,000 and 1/40,000 (6 % of all children with severe mental retardation and epilepsy). Neurogenetic syndrome associating severe mental retardation, a behavior characterized with easy bouts of laugh and hyperactivity, a delay in speech and epilepsy (atypical absences, myoclonus the crises of which start before 3 years of age: the frequency of crises decreases with age). Microcephaly.
Genetic transmission is complex.
Four subtypes are described according to the anomaly that produces the functional absence of the UBEA3 gene:
- 65-75 %: deletion at the level of chromosome 15q11.2-q13, an unstable area during meiosis; it is usually the maternal chromosome which is affected
- 5 to 10 %: uniparental disomy of paternal origin.
- 2-5 %: inprinting defect where the maternal chromosome acts as it was the father chromosome and does not express the gene. Frequency seems to be higher in case of in vitro fertilization
- 10 %: de novo mutations of the UBE3A gene
- other: unknown genetic cause.
The UBE3A gene encodes the protein ligase, E3A ubiquitin, which plays a role in proteolysis of certain proteins by the proteasome (this could interfere with synaptogenesis) and in the synthesis of the β3 subunit of the GABAA postsynaptic receptor: this seems to impair the regulation of GABAA receptors inducing either the absence of the β3 subunit or an excess of the β2 subunit.
- in the neonatal period: difficulty sucking and coordinating the movements of the tongue
- diagnosis generally between 1 and 4 years after the appearance of other signs: severe developmental delay, ataxia (puppet pace), speech problems, progressive microcephaly, onset of seizures (typical: high-voltage slow waves, spike-wave in occipital zone) very sensitive to temperature (increased risk of febrile seizures)
- behavior:frequent bouts of laughing with flapping hands, which may cause significant bradycardia; hyperactivity without aggressivity; decreased duration of the sleep
- dysmorphic craniofacial features: brachycephaly (flat occiput), hypoplasia of the middle part of the face, wide mouth, protrusion of the tongue, excessive salivation, prognathism, wide and caudal larynx
- hypopigmentation of skin and iris
- thoracic scoliosis (40%), constipation, obesity, muscular atrophy
The more severe forms are those associated with a deletion in 15q11.2-q13. The forms resulting from a uniparental disomy are less severe. The forms due to a lack of marking or a mutation in the UBEA3 gene defect are intermediate but obesity is common.
Treatment: sometimes ketogenic diet.
Anesthetic implications:
benzodiazepines are very effective for epileptic seizures. Risk of bradycardia due to vagal tone predominance: anticholinergic premedication could be useful to avoid bradycardia and even asystoly, for example associated with a Valsalva maneuver. Significant risk of bradycardia during the placement of a vagal nerve stimulator. Gastroesophageal reflux disease is common. Risk of difficult intubation. The effect of anesthetic agents acting on the GABAAα receptors are difficult to predict: cases of apparent insensitivity to general anesthetics have been described but the analysis of two series of patients did not found any difference between an intravenous or inhalation anesthesia, although the duration of action of propofol and etomidate seemed to be reduced. Normal response to opiates. Neuromuscular monitoring may be difficult in case of muscular atrophy. Risk of bradycardia with sugammadex.
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- take advice from the neuropediatrician: efficacy of the diet, which treatment in case of seizure, side effects (urinary lithiases ?) - evaluation: RBC, WC, platelets, electrolytes, urea, creatinine, Ca, Mg, albumin and prealbumin (nutrition). SGOT and SGPT levels are often moderately elevated - avoid prolonged fasting: clear unsweetened fluids allowed - avoid sweetened fluids in the premedication - avoid IV administration of carbohydrates containing IV fluids - check glycemia at induction: ideally 50-80 mg/dL |
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anesthesia |
- propofol: OK for induction but avoid TIVA: source of glycerol, risk of PRIS and pancreatitis - fluids: 0.9 % NaCl (risk of worsening metabolic acidosis) or Ringer lactate (but lactate promotes gluconeogenesis) - avoid corticosteroids: dexamethasone? - avoid carbohydrate-containing medications (glucose, mannitol, glycerol) if possible - the transfusion of labile blood products is a hidden intake of carbohydrates - in case of hypoglycemia, correct with low doses of glucose (0.25g/kg) - monitor glycemia, pH, electrolytes, NaHCO3 |
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postoperative |
- resume the ketogenic diet as soon as possible - check ketone bodies (urine): between 40 and 160 mg/dL or at least 2 ++ |
Ketogenic diet: perianesthetic recommendations
References :
- Guerrini R, Carrozzo R, Rinaldi R, Bonanni P.
Angelman syndrome.
Pediatr Drugs 2003; 5 : 647-61.
- Gardner JC, Turner CS, Ririe DG.
Vagal hypertonia and anesthesia in Angelman syndrome.
Pediatr Anesth 2008; 18: 348-9.
- Ramanathan KR, Muthuswamy D, Jenkins BJ.
Anaesthesia for Angelman syndrome.
Anaesthesia 2008; 63: 659-61.
- Witte W, Nobel C, Hilpert J.
Anästhesie beim Angelman-Syndrom.
Der Anaesthetist 2011; 60: 633-40.
- Landsman IS, Mitzel HM, Peters SU, Bichell TJ.
Are children with Angelman syndrome at high risk for anesthetic complications?
Pediatr Anesth 2011; 22 : 263-7.
- Bevinetto CM, Kaye AD.
Perioperative considerations in the patient with Angelman syndrome.
J Clin Anesth 2014 ; 26:75-79
- Makris A, Kalampokini A, Tsagkaris M.
Anesthesia considerations in an adult patient with Angelman syndrome.
J Clin Anesth 2018; 46: 65-6.
- Conover ZR, Talai A, Klockau KS, Ing RJ, Chaterjee D.
Perioperative management of children on ketogenic dietary therapies.
Anesth Analg 2020 ; 131 :1872-82.
- Timko NJ, Marshall JM.
Anesthetic considerations for vagal nerve stimulator implantation in children with Angelman syndrome.
Pediatr Anesth 2023;33:874–5.
Updated: September 2023