Table 3.

Genes of Interest in the Differential Diagnosis of Angelman Syndrome

GeneDisorderMOICharacteristic FeaturesDistinguishing Features
ADSL Adenylosuccinate lyase deficiency (ADSLD, OMIM 103050)ARPsychomotor disability, autistic features, hypotonia, seizures, motor apraxia, severe speech deficits, excessive laughter, very happy disposition, hyperactivity, short attention span, mouthing of objects, tantrums, & stereotypic movementsIn ADSLD: brain MRI may show cerebral &/or cerebellar atrophy.
ATRX Alpha-thalassemia X-linked ID syndrome (ATR-X) XLMicrocephaly, hypotonia, drooling, GERD, affable behaviorIn ATR-X: genital & skeletal abnormalities
EHMT1 Kleefstra syndrome (KS) ADModerate-to-severe ID w/severe speech delay, childhood hypotoniaIn KS: distinctive facial features (synophrys, everted vermilion of lower lip) & speech ability; mildly affected persons may have >100-word vocab & speak in sentences.
HERC2 HERC2-ID (OMIM 615516)ARDD, ID, hypotonia, delayed independent ambulation (age 2.5-5 yrs), & a broad-based gait w/arms upheld & flexed at the elbow when runningIn HERC2-ID: absence of easily provoked laughter & (in some persons) relatively mild ID
MBD5 MBD5 haploinsufficiency ADDD, ID, severe speech impairment, seizures, sleep disturbances, & abnormal behaviors (e.g. autistic-like behaviors, self-injury, aggression)Tremulous movements or happy, excitable behavior may not be present in MBD5 haploinsufficiency.
MECP2 Rett syndrome XLIn females, partial/complete loss of acquired purposeful hand skills & of acquired spoken language or language skill (e.g., babble); gait abnormalities; stereotypic hand movements (e.g., hand wringing/squeezing, clapping/tapping, mouthing, & washing/rubbing automatisms)In Rett syndrome: a neuroregressive course, lack of purposeful use of hands, & (usually) absence of a distinctive happy demeanor
MECP2 duplication syndrome XLIn males 1, severe-to-profound ID w/limited or absent speech, early-onset hypotonia w/very slow motor development, seizuresIn MECP2 duplication syndrome: progressive spasticity esp of lower limbs, predisposition to infection manifest as recurrent respiratory infections
MTHFR Severe MTHFR deficiency (OMIM 236250)ARReported in a boy w/happy demeanor, ataxic gait, absent speech, & flattened occiput 2Hypotonia & joint laxity may be more severe in MTHFR deficiency.
SLC9A6 Christianson syndrome (CS) XLIn males: DD/ID (usually severe to profound); absent to minimal language development; hyperkinesis; epilepsy (onset age usually <3 yrs); truncal ataxia; postnatal-onset microcephalyIn CS: progressive cerebellar atrophy (generally after 1st decade) & lifelong problems w/poor weight gain & low BMI
TCF4 Pitt-Hopkins syndrome (PTHS) ADDD, ID, behavioral differences (may be described as a happy disposition); most are nonverbal w/receptive often stronger than expressive languageIn PTHS, distinctive facial features 3, unusual breathing patterns
WAC WAC-ID ADDD, ID, hypotonia in infancy ± oral hypotonia, neonatal feeding difficulties, GERD, &/or constipation, behavioral abnormalities, respiratory problems, recurrent infections, asthma &/or abnormal breathing pattern, abnormal visionIn WAC-ID, typically less severe ID, ability to speak words & sentences, lower prevalence of seizures, & absence of microcephaly
ZEB2 Mowat-Wilson syndrome (MWS) ADDD, ID, limited or absent speech w/relative preservation of receptive language skills; most have happy demeanor & wide-based gait.In MWS, distinctive facial features 4 & multiple congenital anomalies
>40 genes Congenital disorders of N-linked glycosylation (CDG-N-linked) AR
(XL)		Rarely, can mimic AS, esp if affected child has unstable gait, speech impairment, & seizuresCDG-N-linked typically presents in infancy & has multisystem clinical manifestations (e.g., failure to thrive, DD, hepatopathy, hypotonia/neurologic abnormalities).

AD = autosomal dominant; AR = autosomal recessive; AS = Angelman syndrome; BMI = body mass index; DD = developmental delay; GERD = gastroesophageal reflux disease; ID = intellectual disability; MOI = mode of inheritance; MTHFR = methylenetetrahydrofolate reductase; XL = X-linked

1.

MECP2 duplication syndrome occurs rarely in females because of skewing of X inactivation against the X chromosome that carries the duplicated fragment. In rare instances, however, females can be as severely affected as males and similar clinical findings can be observed.

2.
3.

Craniofacial features are an important aspect for the diagnosis of PTHS, but may be less obvious in infancy. In many cases, the prominence of the nose and lower face may be the earliest clue to PTHS in an infant with developmental concern.

4.

Widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression

From: Angelman Syndrome

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