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

Introduction

In 1965 Dr. Harry Angelman first described the syndrome that now bears his name (Angelman 1965). However, it was many years before the syndrome's importance was recognized, partly because the syndrome did not involve provisionally unique anomalies or malformations. Additionally, its major clinical attributes, such as seizures and severe mental retardation, were quite nonspecific. Nevertheless, physicians evaluating children with severe speech delay, happy affect, epilepsy and movement disorders were able to recognize increasing numbers of affected children. Now, the incidence of this condition appears to be about 1/12-20,000 (Clayton-Smith and Pembrey 1992; Steffenburg et al. 1996) and AS has emerged as a prototypical genetic syndrome involving seizures and severe developmental delay (Williams et al. 1995b).

The hallmarks of Angelman syndrome (AS) are a jerky, ataxic gait, seizures, and mental retardation and absent speech. In addition, the presence of a flatted occiput (microbrachycephaly), excessive laughter with protruding tongue and skin hypopigmentation usually presents a distinctive clinical picture. Developmental delay is evident by 6 - 12 months of age but forward progression occurs. There is a structurally normal brain although mild cortical atrophy or dysmyelination may be seen on MRI study. The prenatal history and birth parameters are normal and microcephaly is distinctly absent in newborns. Some clinical features may be absent or late to emerge (e.g., seizures, and protruding tongue) so that the syndrome may not be considered or diagnosed until later childhood.

Diagnostic consensus criteria are helpful in understanding the spectrum of abnormalities and in deciding which individuals are candidates for definitive genetic testing (Williams et al. 1995a). A summary of these criteria is listed below:.

Consensus Criteria for Angelman Syndrome

º Consistent (100%)
o Developmental delay, functionally severe
o Speech impairment, none or minimal use of words; receptive and non-verbal communication skills higher than verbal ones
o Movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs
o Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span

º Frequent (more than 80%)
o Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2
o Seizures, onset usually < 3 years of age
o Abnormal EEG, characteristic pattern with large amplitude slow-spike waves

º Associated (20 - 80%)
o Strabismus
o Hypopigmented skin and eyes
o Tongue thrusting; suck/swallowing disorders
o Hyperactive tendon reflexes
o Feeding problems during infancy
o Uplifted, flexed arms during walking
o Prominent mandible
o Increased sensitivity to heat
o Wide mouth, wide-spaced teeth
o Sleep disturbance
o Frequent drooling, protruding tongue
o Attraction to/fascination with water
o Excessive chewing/mouthing behaviors
o Flat back of head

General Clinical Overview

These criteria can be generally grouped into four categories of movement, language, behavior and seizures. Below is discussed in more detail the clinical aspects of each of these areas. In making the clinical diagnosis of AS, there is no single clinical feature that guarantees that the diagnosis is correct. Genetic laboratory testing is however able in most cases to make a definite diagnosis [Jiang, 1999 #69; Mann, 1999 #60 (Williams et al. 1999)].

Angelman syndrome is usually not suspected clinically in the first 6-12 months of age. At that time it may become evident that general developmental delay is present but the AS features are usually not very apparent. Between 1-2 years of age the diagnosis may be considered in those infants who have such findings as pronounced tongue protrusion, unstable, shaky movements or excessive laughter. Often the diagnosis is suspected between age 3-5 years when speech is absent but social understanding seems adequate to allow for speech. This aspect combined now with an unusual, jerky gait or excessive happy affect with tongue protrusion will make one suspicious of the diagnosis. In spite of these presentations, many children are not suspected to have AS until a host of other diagnoses are considered, often with extensive testing that fails to confirm any diagnosis. It is only then that the possibility of AS is considered.

The repertoire of movements seen in AS give it a distinctive manner of walking but this manner may only be evident in the child who is more severely affected. Many AS individuals walk with uplifted arms and the feet are wide apart and the ankles may be turned outward with flattened feet. The pelvis is often tilted forward as the lower part of the back is curved in. The walk may be robotic and jerky. Others can have a lurching forward, running type of gait with out stretched arms. Infants may be hypermotoric with tremulousness and flailing-like movements of the limbs. Athetoid and choreiform movements are not present. Sometimes there are only very mild tremulous or unsteady movements only upon intentional actions but, nevertheless, 100% of AS children do show some type of movement abnormality.
A summary of these movements is listed below:

o Wide-based gait, truncal ataxia
o Stiff, jerky or robot-like gait
o General tremulousness of limbs
o Lurching, forward gait, uplifted arms
o Hyperkinetic limb movements
o Clumsy movements, worse upon intention
o No nystagmus, athetosis, resting tremor, chorea

The behaviors in AS were first noted as involving excessive happiness or paroxysms of laughter, and this was something that impressed Dr. Angelman. We know that excessive happiness may not be the predominant behavior in some children. However, the majority is inclined toward an apparent happy demeanor. The other behavior that stands out is the phenomenon of hyperactive movements, which are best described as hypermotoric. Angelman children are notorious for getting into everything and they have a great deal in interest exploring their environment, handling tiny objects, playing with water, crumpling up paper, etc. They are terrific explorers and I have listed here some of those traits. Excitability can be impressive and this is often is accompanied by hand flapping or hand waving movements. This excitability with hypermotoric actions and excessive happiness, when accompanied by a protruding tongue is very distinctive. The spectrum of behaviors in AS is broad.

o Excessive laughter/happiness
o Easily excitable personality, often with hand-flapping movements
o Hypermotoric/hyperactive behavior
o Absent speech, decreased vocalizations
o Increased mouthing of objects
o Fascination with tiny objects, crinkly paper, water

The third category is the seizure problem. Most children develop seizures usually before three years of age and it is unusual to see seizures in a newborn or in the first months of life. Some will of course develop seizures as older children or teenagers. Initially, we reported that the seizures appeared to improve with advancing age, and I think that this is correct with some qualification. AS children can tolerate many seizures and in general their forward development and general physical health appears to be fairly good. It is not uncommon in later childhood and in young adulthood for the seizures to apparently disappear. But there have been reports lately of a recurrence of seizures in adults, so one needs to be careful in terms of discontinuing anticonvulsants. The seizures can be of many clinical types and no specific type is characteristic (Zori et al. 1992). Again, most brain MRI studies are essentially normal or show non-specific findings. Often these electrical changes can involve multiple brain regions even though no apparent clinical seizure is occurring. A distinctive component of the EEG involves what is called slow, sharp waves where a high, sharp initial stroke occurs followed by a more spread out, higher amplitude wave (Boyd et al. 1988). In younger children the EEG abnormality may involve faster, more frequent activity, and in older children the more characteristic sharp, slow waves can be seen as well as a wave pattern referred to as "triphasic" (Laan et al. 1997). A summary of the seizure problem in AS is listed below.

o Onset usually before age 3 years
o EEG is usually abnormal:
o Runs of rhythmic 2-3/s high voltage activity
o Ill defined slow-spike wave complexes
o Persistent rhythmic 4-6/s activities
o Many types: myoclonic, atypical absence, etc.
o Brain MRI/CT show nonspecific changes
o Seizure severity improves with age

The last major clinical finding category involves language and speech. Of course, one of the hallmarks of AS is absent or severely limited meaningful speech. Many conditions involving developmental delay have absent speech, but what is noteworthy about AS children is that many appear to have enough cognitive understanding and social ability to be able to speak but are not able to do so (Clayton-Smith and Pembrey 1992 ; Penner et al. 1993). It is not clear what the cause for this is, and some have termed it a speech dyspraxia or aphasia. Of course there is vocalization in AS. Oral motor function appears normal and many sounds of course can be made, but clearly spoken, appropriately used words are extremely rare. Angelman children can however become quite adept at understanding words, can point out many body parts, can follow reasonably complex commands in older childhood, yet vocal mimicry is very difficult. Some of the highest functioning children are able to begin to mimic sounds and can become quite good at this, although in my experience, consistent appropriate use of even one or two nouns is very rare. Because of this speech problem, educational treatment places great emphasis on non-verbal communication. Angelman children become very good at a variety of gestures since that becomes an essential way to communicate. ...

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