Differential Diagnosis

While Angelman Syndrome can be misdiagnosed as cerebral palsy or an autistic spectrum disorder, there are several other syndromes that share characteristics with AS and should be considered in making a diagnosis including:

Prader-Willi Syndrome - also results from a deletion on Chromosome 15 that is inherited paternally. As this syndrome presents with severe hypotonia and feeding difficulties, it could be misdiagnosed as Angelman Syndrome and vice-versa. Methylation testing is required to determine if deletions on Chromosome 15 are maternal (Angelman Syndrome) or paternal (Prader-Willi Syndrome) in origin. OMIM 176270

X-linked Mental Retardation Syndrome (XLMR), Christianson Type - This syndrome is caused by mutations in SLC9A6 gene and has been referred to as an "Angelman-like Syndrome." OMIM 300243

Rett Syndrome - A neurodevelopmental disorder that occurs almost exclusively in girls. Characterized by mental retardation, seizures, loss of speech and regression of acquired skills. OMIM 312750

Chromosome 22q13.3 Deletion Syndrome (Phelan-McDermid) - This syndrome is characterized by hypotonia, absent or severely delayed speech and autistic behavior. OMIM 606232

Mowat-Wilson Syndrome - a complex developmental disorder that presents with mental retardation, delayed motor development and epilepsy. OMIM 235730

Monosomy 1p36 Syndrome - deletion of the 1p36 region leads to multiple congenital abnormalities and mental retardation. OMIM 607872

Smith-Magenis Syndrome - deletion of the 17p11.2 regions leads to mental retardation, hypotonia, speech delay and sleeping disorders. OMIM 182290

Chromosome 17q21.31 Microdeletion Syndrome - this deletion leads to mental retardation, hypotonia, and a friendly disposition with characteristic facial anomalies. OMIM 610443

Pitt-Hopkins Syndrome - caused by haploinsufficiency of the TCF4 gene on 18q21. This syndrome can present with behavioral characteristics similar to Angelman Syndrome including lack of speech and happy disposition, but also has distinctive facial and hand features. OMIM 610954 While the OMIM description does not suggest Angelman Syndrome, please see this recent publication where children given a clinical diagnosis of Angelman Syndrome, Prader-Willi Syndrome or Rett Syndrome were found to have Pitt-Hopkins Syndrome PMID 18781613

Chromosome 2q23.1 Microdeletion Syndrome - this syndrome was recently described in PMID 19904302. This syndrome includes microcephaly, seizures and short stature. The report states that individuals originally thought to have Angelman Syndrome, Prader-Willi, or Smith-Magenis have tested positive for this deletion. Deletions studied to date remove the MBD5 gene suggesting the absence of this gene may cause the clinical features of this syndrome see OMIM 611472

For more information on differential diagnosis please see:

GeneReviews on Angelman Syndrome by C.A. Williams and D.J. Discoll

Williams CA, Lossie A, Driscoll D. Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet. 2001; 101: 59-64.

Phelan MC. Deletion 22q13.3 Syndrome Orphanet J. Rare Dis. 2008 ; 3 : 14

Gilfillan GD et al. SL9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman Syndrome Am. J. Hum. Genet. 2008; 82: 1003-10

Jedele KB. The overlapping spectrum of rett and angelman syndromes : a clinical review. Semin. Pediatr. Neurol. 2007; 14: 108-17

Giurgea I, et al. TCF4 deletions in Pitt-Hopkins Syndrome. Hum Mutat. 2008 Nov;29(11):E242-51

Williams SR, Mullegama SV, Rosenfeld JA, Dagli AI, Hatchwell E, Allen WP, Williams CA, Elsea SH. Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Eur J Hum Genet. 2009