Angelman syndrome: Mutations influence features in early childhood

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternal copy of UBE3A. Although the “classic” features of AS are well described, few large-scale studies have delineated the clinical features in AS. We present baseline data from 92 children with a molecular diagnosis of AS between 5 and 60 months old who are enrolled in the National Institutes of Health Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study from January 2006 to March 2008. Seventy-four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations. Participants with UPD/imprinting defects were heavier (P = 0.0002), while those with deletions were lighter, than the general population (P < 0.0001). Twenty out of 92 participants were underweight, all of whom had deletions or UBE3A mutations. Eight out of 92 participants (6/13 (46%) with UPD/imprinting defects and 2/11 (18%) with UBE3A mutations) were obese. Seventy-four out of 92 participants (80%) had absolute or relative microcephaly. No participant was macrocephalic. The most common behavioral findings were mouthing behavior (95%), short attention span (92%), ataxic or broad-based gait (88%), history of sleep difficulties (80%), and fascination with water (75%). Frequent, easily provoked laughter was observed in 60%. Clinical seizures were reported in 65% of participants but all electroencephalograms (EEGs) were abnormal. We conclude that the most characteristic feature of AS is the neurobehavioral phenotype, but specific EEG findings are highly sensitive for AS. Obesity is common among those with UPD/imprinting defects.

Angelman Syndrome

“…1) [7]. While there is variability with each molecular class of AS, in general those with deletion have a more severe phenotype, and those with UPD and imprinting defects a less severe phenotype [2,[8][9][10][11]. The diagnostic algorithm described in Fig.…”

“…Patients with AS with UPD and imprinting defects are predicted to have elevated [9,10,22,23]. One possibility is that the other genes located within 15q11-q13 play significant roles in brain development.…”

“…Treatment is supportive and includes 1) therapies to mitigate gross and fine motor delays; 2) augmentative communication strategies such as the use of communication devices, picture exchange cards, and modified sign language; and 3) intervention for comorbid ASD when present [2][3][4][8][9][10]. The remainder of treatment is limited to managing the problems associated with AS [66].…”

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

“…Angelman syndrome | ARC | EPHEXIN5 | ultrasonic vocalizations | EEG A ngelman syndrome (AS) is a human neurodevelopmental disorder that occurs in the first few years of life and is characterized by severe developmental delay, an absence of purposeful speech, motor discoordination, an abnormal EEG, and unusual behavioral traits, such as easily provoked laughter and hand flapping (1,2). Individuals with AS have mutations in the maternally inherited copy of the UBE3A gene, resulting in a loss of function of the UBE3A protein (also known as E6AP) (3).…”

“…One possible explanation for the disparate findings is that these studies have been conducted using adult mice at a time when the aberrant AS behaviors may have begun to subside. Indeed, seizures are prominent in AS in early childhood (<3 y of age) but begin to vary considerably in frequency and severity as children with AS age (2,23,24). In addition, some core features of human AS that are seen in early childhood, such as abnormal communication,…”