6 Angelman Syndrome

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6 Angelman Syndrome

Angelman Syndrome 591

AS, Happy puppet

Severe motor and intellectual retardation, unpro- voked laughter, ataxia, hypotonia, seizures, absent speech, characteristic facies

Frequency: 1 in 20,000 births.

Genetics

Lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion (75% of the cases) or from uniparental disomy (5%); 2% have DNA methylation pattern consistent with mutation of the imprinting center; several cases are due to mu- tation of the UBE3A gene (OMIM 105830).

Clinical Features

• Severe mental retardation

• Microbrachycephaly, ﬂat occiput

• Peculiar facies, deep set eyes, large mandible and mouth, open mouthed expression, tongue thrust- ing, wide spaced teeth, relative prognathism

• Hypopigmentation

• Motor retardation

• Absent speech

• Paroxysmal laughter

• Hypotonia, hyperreﬂexia, hyperkinesis

• Arm ﬂapping with ﬂexed elbow

• Ataxia

• Seizures, unusual EEG

• Mild cortical atrophy on CT or MRI Differential Diagnosis

• Ataxia and mental retardation with cerebral palsy

• Epilepsy, gelastic

Radiographic Features Skull

• Microbrachycephaly

• Vertical inclination of the skull base

• Prognathism

Bibliography

Chan CTJ, Clayton-Smith J, Cheng XJ, Buxton J, Webb T, Pem- brey ME, Malcolm S. Molecular mechanisms in Angelman syndrome: a survey of 93 patients. J Med Genet 1993; 30:

895–902

Clayton-Smith J. Clinical research on Angelman syndrome in the United Kingdom: observations on 82 affected individu- als. Am J Med Genet 1993; 46: 12–5

Clayton-Smith J, Pembrey ME. Angelman syndrome. J Med Genet 1992; 29: 412–5

Connerton-Moyer KJ, Nicholls RD, Schwartz S, Driscoll DJ, Hendrickson JE, Williams CA, Pauli RM. Unexpected famil- ial recurrence in Angelman syndrome. Am J Med Genet 1997; 70: 253–60

Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS, Christian SL, Kubota T, Halley DJ, Meijers-Heijboer H, Langlois S, Graham JM Jr, Beuten J, Willems PJ, Ledbetter DH, Beaudet AL. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet 1999; 8:

129–35

Fryburg JS, Breg WR, Lindgren V. Diagnosis of Angelman syndrome in infants. Am J Med Genet 1991; 38: 58-64 Jiang Y, Lev-Lehman E, Bressler J, Tsai TF, Beaudet AL. Genetics

of Angelman syndrome. Am J Hum Genet 1999; 65: 1–6 Moncla A, Malzac P,Voelckel MA, Auquier P, Girardot L, Mattei

MG, Philip N, Mattei JF, Lalande M, Livet MO. Phenotype- genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur J Hum Genet 1999; 7:

131–9

Saithoh S, Harada N, Jinno Y, Hashimoto K, Imaizumi K, Kuro- ki Y, Fukushima Y, Sugimoto T, Renedo M, Wagstaff J, Lalande M, Mutirangura A, Kuwano A, Ledbdetter DH, Niikawa N. Molecular and clinical study of 61 Angelman syndrome patients. Am J Med Genet 1994; 52: 158–63

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Angelman Syndrome 592

Fig. 6.2. Patient 2, age 6 years. Note protruding tongue, laugh- ing face, and light hair

Fig. 6.1 a, b.

Patient 1 a at 20 months and b at 26 months. Note some of the sub- tle ﬁndings in Angelman syndrome, including wide mouth with thin upper lip, pointed chin, prominent jaw, and constant smil- ing and drooling (Reprinted, with permission, from Fryburg et al.

1991)

a b