CLINICAL FEATURES AND CLINICAL DIAGNOSIS
OF ANGELMAN SYNDROME
Charles Williams, R. C. Philips Unit, Division of Genetics University of Florida, Gainesville, USA

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A general summary of the language problems in AS is listed below.

o Babies and infants typically quiet
o Correct single work usage is rare
o Some vocal mimicry (high functioning AS)
o Gesture, some signing possible
o Receptive skills may be impressive
o Understanding complex verbal requests
o Knowledge of many body parts, colors, etc.
o Understanding of social interactions

Genetic Aspects

Now that a broad picture of the clinical aspects of AS has been reviewed it is helpful to review briefly the different genetic types and their clinical features. The figure below illustrates the genetic region on chromosome 15 and the horizontal jagged lines show the general break areas for the large common deletion and it is labeled as mechanism number one. Also pictured are the mechanisms that involve inheritance of two of the father's number 15 chromosomes and that is listed as number two. You also see number three indicating mutations in a controlling imprinting region, and number four a mechanism involving mutations within the Angelman gene that is labeled UBE3A.

Figure 1.

Genetic map of human chromosome 15q11-13, that extends over 4 megabases. The jagged lines indicate the common large deletion breakpoint locations. Vertical lines represent other critical regions in which either gene deletions or mutations cause AS. The imprinting control region (IC) is depicted as bipartite, illustrating that IC deletion more proximal to SNRPN (small ribo-nucleo-protein-N) cause AS. Dotted horizontal arrows and the associated circled numbers indicate the mechanisms that lead to AS: 1 = large deletions. Deletion of the entire q11-13 region leads to either AS or PWS depending on the parental chromosome of origin (maternal deletion for AS and paternal for PWS); 2 = paternal uniparental disomy; 3 = imprinting center abnormalities; 4 = UBE3A mutations. Other abbreviations refer to genes located within the critical deletion area: P = P gene (tyrosine transporter); HERC2 = Human End Repeat 2 gene; GABRB3, A5, G3 = gama aminobutyric acid receptor genes; NDN = Necdin; ZNF127 = Zinc finger protein 127 gene.

One hallmark of children who have the large deletion is relative skin hypopigmentation. This problem could be due to the loss of a gene termed the P gene that is named after a corresponding gene in the mouse that is associated with the "pink-eyed" mutation, indicating an albino appearance. It is believed that children with AS who have the large deletion are missing half of the P gene product and that may contribute to the problem of relative skin hypopigmentation (Lee et al. 1994). It also may cause hypopigmented hair, light iris color and a so-called albinoid retina. When pigment is diminished in retinal cells there is also a problem in proper crossover of the optic nerves and an unequal amount of crossing over can cause imbalance in visual tracking resulting in strabismus (King et al. 1993). Children, who have the large deletion as their mechanism, have decreased pigment as well as increased risk for strabismus. This problem similarly occurs in the allied condition known as Prader-Willi syndrome, which can also be caused by these large chromosome deletions. So the appearance of fair skin and ocular depigmentation really was the first clinical finding associated with the various genetic mechanisms. It should be emphasized that, although there have been several papers recently looking at differences among these classes, the similar features of all the groups seem to me to be much more impressive than are the differences. But there are some differences. For example, seizures and small head size are rare findings in individuals with uniparental disomy (Bottani et al. 1994; Fridman et al. 2000).

Adult Clinical Features

We now know enough about the developmental course of AS to characterize adults that have this disorder. Much of this knowledge comes from the work by Jill Clayton-Smith who was able to follow older children and young adults in their community setting (Clayton-Smith 1993). In general, their developmental course is relatively good. The physical health of adults remains fairly good, but there are some problems than can occur. Listed below are the major ones and weight gain appears to be an issue in most older children and adults, although it doesn't approach the severity seen in the allied disorder of the Prader-Willi syndrome.

o Obesity
o Decreased mobility, non-ambulation
o Scoliosis, kyphosis
o Continued seizures
o Keratoconus due to eye-rubbing
o Inadequate access to health care
o Some shortening of life span

There may be problems with progressive scoliosis and seizures may remain difficult to control. A unique finding of keratoconus has recently been noted which may be due to persistent eye rubbing (Sandanam et al. 1997). There are now a large number of adults with AS and our experience has been that it is not uncommon to know of AS individuals who are 50 or 60 years of age. So if there is a shortening of life span it does not appear to be severe.

Differential Diagnosis

Infants with AS commonly present with either nonspecific psychomotor delay and/or seizures and the differential diagnosis is often broad and nonspecific, encompassing such entities as cerebral palsy, pervasive developmental disorder and static encephalopathy. EEG abnormalities may resemble that associated with the Lennox-Gastaut syndrome, a descriptive neurologic condition associated with severe seizures and mental retardation (Markand 1977). The presence of hypotonia and seizures may raise the possibility of an inborn error of metabolism or a defect in oxidative phosphorylation such as a mitochondrial encephalomyopathy. Subsequent testing for these abnormalities is normal including urine organic acids, serum amino acids, plasma acylcarnitine profiles, and mitochondrial enzyme and DNA mutation screens. Some AS infants may be suspected of having a myopathic disorder although the typical presence of brisk deep tendon reflexes suggests that the lower motor neuron and muscle cell unit are normal. Subsequent muscle biopsy with routine histology and electron microscopy studies, and EMG, are normal or show mildly abnormal, nonspecific findings.

Seizures and severe speech impairment in AS infants can resemble that seen in the Rett syndrome(Clarke 1996), but AS children do not lose purposeful use of their hands. The distinction between these two syndromes is usually resolved by age 3-4 years when AS children are moving forward developmentally but those with Rett syndrome are clearly at a developmental plateau or have apparent regression. It is unusual for AS infants to have a dysmorphic facial appearance or to have any congenital anomalies, so chromosomal syndromes are usually not suspected. Infants with AS who do have some degree of apparent facial dysmorphia usually are only manifesting unique parental traits, accentuated by the child's microcephaly and behavioral abnormalities. Rarely, syndromes such as Williams or Coffin-Lowry may be initially considered but are quickly ruled out by a complete history and physical examination. Occasionally, an infant will be misdiagnosed as having Prader-Willi syndrome but actually has AS, due to the 15q11-13 deletion involving the maternal and not the paternal derived chromosome (DNA methylation testing will distinguish between the two) (Williams et al. 1999).

Older children with nonspecific cerebral palsy are often referred for AS evaluation because they exhibit gait ataxia, happy affect and abnormal speech. However, most occurrences of cerebral palsy do not manifest the extent of tremulousness, jerkiness and the ballismic-like limb movements seen in AS. Some minimal degree of expressive speech is usually present in those with cerebral palsy; speech remains extremely disrupted in AS (only minimal sounds) even in the face of relatively good attention and socialization
.
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