Angelman syndrome

Angelman syndrome results from loss of function of the maternally inherited UBE3A allele at chromosome 15q11-13, a region subject to genomic imprinting. The paternal allele of UBE3A is normally silenced in neurons, so disruption of the maternal copy causes disease. Mechanisms include: (1) maternal deletion (~70% of cases, most common), (2) paternal uniparental disomy (paternal copy duplicated, maternal absent), (3) imprinting defects, or (4) UBE3A gene mutations. This contrasts with Prader-Willi syndrome, which results from loss of the paternally inherited genes in the same chromosomal region (due to paternal deletion, maternal uniparental disomy, or imprinting defects), illustrating genomic imprinting's clinical relevance—same chromosomal region, different parent-of-origin, different phenotype.

Clinical features of Angelman syndrome include severe intellectual disability, absent or minimal speech, ataxic/jerky movements, microcephaly, seizures (often in the first 3 years of life), and a characteristic happy, easily excitable demeanor with inappropriate laughter and hand-flapping—historically termed "happy puppet syndrome." EEG often shows a distinctive pattern with large-amplitude slow-spike waves. Fair skin and hair, strabismus, and feeding difficulties in infancy are also common.

Diagnosis is confirmed via genetic testing (methylation analysis, FISH, or chromosomal microarray) to detect the 15q11-13 deletion or other causative mechanisms. Management is supportive: seizure control with antiepileptics, physical/occupational/speech therapy, and management of sleep disturbances (common due to reduced need for sleep).

Key USMLE point: Compare/contrast with Prader-Willi syndrome (hypotonia, hyperphagia/obesity, hypogonadism, intellectual disability)—both involve chromosome 15q11-13 but differ based on parent-of-origin of the genetic defect, a classic example of genomic imprinting tested on boards.