Review Article
Perioperative considerations in the patient with Angelman syndrome

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Abstract

Angelman syndrome arises by one of 4 genetic mechanisms. Patients often have craniofacial abnormalities, vagal hypertonia, skeletal muscle atrophy or underdevelopment, a history of seizure disorders, and pharmacodynamic unpredictability. Its pathogenesis, clinical manifestations, diagnosis and treatment options, and perioperative anesthetic considerations are presented.

Introduction

Angelman syndrome is a genetic disorder characterized by severe developmental delay, speech disorder, ataxia, craniofacial abnormalities, and odd behavior accompanied by a happy disposition and occasional bouts of uncontrollable laughter [1], [2]. It was first described in 1965 by pediatrician Harry Angelman as the “happy puppet syndrome,” a name that has since fallen out of favor and been replaced by “Angelman syndrome” [3]. There is no reported male or female predominance, and the reported incidence of the disease varies from one in 10,000 to one in 40,000, with speculation that the disease is underdiagnosed due to its various phenotypes [4]. Furthermore, while it is usually diagnosed around two years of age, there are instances of patients not being diagnosed until their early teens, perhaps because they developed milder clinical manifestations of the disease [5].

While details of the pathogenesis, diagnosis, and risk factors for this rare disease are still being elucidated, there appears to be an association between one of the Angelman syndrome genetic mechanisms and advanced maternal age, and another with babies born via assisted reproductive technologies, including in vitro fertilization and intra-cytoplasmic sperm injection [1]. To effectively manage these patients in the perioperative period, anesthesiologists should be aware of the variability in presentation of this disorder, particularly its phenotypes and pharmacodynamic unpredictability.

Section snippets

Pathogenesis

There are 4 known genetic mechanisms that result in Angelman syndrome, including molecular deletions involving the meiotically unstable 15q11.2-q13 critical region (65% - 75% of cases), paternal uniparental disomy (UPD), imprinting defects (IDs), and mutations in the ubiquitin-protein ligase E3A gene (mUBE3A) [1], [6], [7]. These genetic mechanisms are thought to result in a functional absence of UBE3A, which accounts for approximately 90% of cases, while the other 10% of Angelman syndrome

Clinical manifestations

The 4 genetic mechanisms that result in Angelman syndrome yield some consistent clinical manifestations, yet there are also clinical characteristics unique to each, resulting in phenotypic variability across the Angleman syndrome spectrum [1], [7]. Children with Angelman syndrome typically have normal prenatal and birth histories without major birth defects and with normal head circumference [1]. Neonates and infants may have difficulties with breast or bottle feeding due to uncoordinated

Diagnosis

The wide variety of clinical manifestations of Angelman syndrome suggests that the disease may be underdiagnosed [7]. Individuals with the developmental history and clinical manifestations outlined above should be strongly considered for Angelman syndrome genetic testing [1]. However, a physician may also make a clinical diagnosis of Angelman syndrome based on his or her clinical judgment, regardless of a negative genetic test result [1]. Negative tests occur in approximately 10% to 15% of

Prognosis and treatment

The life expectancy for a person with Angelman syndrome usually does not exceed 15 years [9]. However, there are rare reports of individuals with this disease surviving into adulthood, perhaps due to the variability of presentation of the different phenotypes [9]. For those with a longer lifespan, seizures typically persist with less severity and an improved EEG pattern over time [1], [2], [4]. In addition, adults with Angelman syndrome retain their behavioral uniqueness, but they have a calmer

Anesthetic considerations

Children with Angelman syndrome often require general anesthesia for even the most basic noninvasive procedures (including computed tomographic scan or magnetic resonance imaging) as well as for the common invasive procedures they require, including dental, ear, nose, and throat, and orthopedic surgeries, because they are frequently uncooperative due to their hyperactive behavior [3], [5], [9]. As stated above, patients with Angelman syndrome appear to have a relative deficiency of β3 subunits

Conclusion

Angelman syndrome is a rare disorder that poses a challenge to anesthesiologists. In addition to changes at the receptor level, the various clinical presentations of the disease may complicate the anesthetic plan and require alternative methods. Many of the details concerning Angelman syndrome have yet to be discovered, and it remains a subject of ongoing research. Currently, consideration should be given to the use of general anesthetics and prophylactic medications that reduce exacerbations

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Conflict of interest statement: The authors have no relationships with pharmaceutical companies or products to disclose, nor do they discuss off-label or investigative products in this lesson.

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