Diagnostic Approach of Angelman Syndrome (2024)

ABSTRACT

INTRODUCTION

Angelman syndrome (AS) is a severe neurodevelopmental condition. Developmental deficits, mental retardation, epilepsy, severe speech impairment with small or without the use of words, hyperactivity and microcephaly are distinctive for the syndrome. Coordination disturbance and movement disorders (ataxia) are a reason for main functional deficits. Babies with the disease have a regular appearance at birth, but at one to two months, feeding problems can be noticed and developmental delay becomes apparent between six and twelve months of life, whereas seizures typically start before three years of age. Patients with AS are recognizable by their content attitude with frequent smiling and laughter and hand- flapping movements (1,2). Different studies estimate the prevalence between 1/10.000 – in Denmark – and as rare as 1/40.000 – in Australia (3,4). 60-80% of persons with AS etiologically have a deletion in the proximal part of the long arm of the maternal chromosome 15 in the gene locus 15q11.2- 15q13. Six per cent have imprinting mutations, five per cent show a mutation in the ubiquitin- protein ligase E3A (UBE3A) gene and one per cent of patients either have unipaternal disomies (UPD) or chromosomal structural anomalies (translocations) (5). Deletions or UPDs show a low reoccurrence risk whereas imprinting defects and translocations have an increased incidence of reoccurrence (6). In the other 20 per cent of patients, no abnormal genetic patterns can be found (5). In these cases the clinical criterions diagnose the syndrome but the molecular genetic studies do not show abnormalities (7).

The consensus criteria for the diagnosis of AS are a summary of the developmental and physical findings according to their frequencies in the syndrome. Not all of the characteristics have to be present for the diagnosis (8). The most consistent clinical feature is the behavioral one and a wide index of clinical suspicion for the behavioral phenotype should be made (9). The three categories of the consensus criteria comprise consistent features in 100 per cent of patients, frequent features in over 80 per cent of patients and associated features in 20 to 80 per cent of patients (9).

Consistent (100%) features are: 1.) Developmental delay, functionally severe; 2.) Movement or balance disorder, usually ataxia of gait and/ or tremulous movement of limbs. Movement disorder can be mild. May not appear as frank ataxia but can be forward lurching, unsteadiness, clumsiness, or quick, jerky movements; 3.) Behavioral uniqueness: any combination of frequent laughter/ smiling. Apparent happy demeanor; easily excitable personality, often with uplifted hand-flapping or waving movements; hypermotoric behavior; 4.) Speech impairment, none or minimal use of words; receptive and non-verbal communication skills higher than verbal ones.

Frequent features (>80%) are: 1.) Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (≤2 standard deviations (SD) of normal occipito- frontal circumference (OFC)) by age of 2 years. Microcephaly is more pronounced in those with 15q11.2-q13 deletions; 2.) Seizures, onset usually <3 yrs. of age. Seizure severity usually decreases with age but the seizure disorder lasts throughout adulthood; 3.) Abnormal EEG, with a characteristic pattern. The EEG abnormalities can occur in the first 2 years of life and can precede clinical features, and are often not correlated to clinical seizure events.

Associated features (20-80%) are: flat occiput, occipital groove, protruding tongue, tongue thrusting, suck/swallowing disorders, feeding problems and/or truncal hypotonia during infancy, prognathia, wide mouth, wide-spaced teeth, frequent drooling, excessive chewing/mouthing behaviors, strabismus, hypopigmented skin, light hair and eye color (compared to family), seen only in deletion cases, hyperactive lower extremity deep tendon reflexes, uplifted, flexed arm position especially during ambulation, wide-based gait with pronated or valgus-positioned ankles, increased sensitivity to heat, abnormal sleep wake cycles and diminished need for sleep, attraction to/fascination with water, fascination with crinkly items such as certain papers and plastics, abnormal food related behaviors, obesity (in the older child), scoliosis, constipation (10). ❑

AIM

To present our experience regarding the clinical diagnosis of children with AS, in the Department of Pediatric Neurology of "Prof. Dr. Alexandru Obregia" Clinical Hospital.

MATERIAL AND METHODS

Between 2008 and 2013, 15 children (5 male and 10 female) were clinically and genetically diagnosed with AS in the Department of Pediatric Neurology of the "Prof. Dr. Alex. Obregia" Clinical Hospital. In all cases, diagnosis of AS was made by the clinical criteria for AS established by Williams and colleagues (10). The clinical evaluation of the children included: patient history, general, dysmorphological and neurological examination, and psychological evaluation (developmental quotient score, DQ, and behavioral phenotype). This evaluation was completed with paraclinical investigations: biological test, EEG and neuroimagistic studies (computed tomography, CT; Magnetic resonance imaging, MRI). The anamnesis included family history, personal history, with a special attention to pregnancy and birth aspects, psychom*otor development, as well as disease and seizure history. Seizure history focused on seizure onset, type and treatment. Genetic tests, including FISH with specific probes for AS region and methylation PCR, were performed by the Medical Genetic Laboratory of 'Victor Babes" National Institute of Pathology. ❑

RESULTS

DISCUSSIONS

AS is a rare genetic condition with a prevalence of 1/15.000 – 1/20.000, which explains the small number of patients included in this study.

Even though not much is known about the preconceptional and conceptional period of patients with AS, some studies associate in vitro fertilization, especially intracytoplasmic sperm injection or a hormonal regimen with imprinting disorders, such as AS. There is no higher risk for preterm births than in the general population.

AS is a severe neurodevelopmental disorder, with a complex clinical picture. Yet, in an infant or small child with psychom*otor delay, the characteristic facial features (deep set eyes; pointed chin; wide, smiling mouth) associated with blonde hair/blue eyes (especially in those with microdeletion), happy disposition, jerky movements, and ataxia should raise a strong suspicion of AS. Due to the above-described characteristic phenotype, the clinical diagnosis could be made with relative ease, even in younger children (aged 6 months-3 years), contrary to the more general opinion of a difficult diagnosis. All patients from this study presented the characteristic facial features and the characteristic behavior phenotype.

Motor development was delayed in all children, especially in that regard the ability to walk. A retarded mental development was noted in all cases, most of cases (73%) presenting with sever mental retardation. This observation is consistent with other studies that also found the majority of patients with severe mental delay. The severity of the delay increases proportionally with age, explaining the current mild phenotype of case 14.

53% of the children investigated by CT/MRI presented some abnormal aspects, including ventricular enlargement, leukomalacia, cerebral atrophy, an abnormal white-gray matter difference, diffuse cerebral lesions and plagiocephaly. Some of these findings were reported, also, by other authors and considered as nonspecific (11).

In agreement with the literature, epileptic seizures were observed in all patients with microdeletion, starting from infancy/early childhood. The seizure type distribution of our cohort was not similar to the predominant myoclonic seizures reported in the literature. Thus, the most frequent seizures were partial seizures, followed in frequency by atonic seizures and atypical absences; no patient had convulsive status epilepticus. One child presented infantile spasms (case 9). Regardless the individual natural course of the seizures, EEG in all children showed the characteristic pattern for AS, namely a slow background activity, mixed with spikes, even before epilepsy onset.

In our study, each consistent feature of AS, implementing developmental delay, speech impairment, a movement disorder or behavioral abnormalities were present in all patients. Also, the frequent features of AS found in over 80% of cases: an abnormal EEG was present in all cases; microcephaly was present in 13 patients, and 11 cases presented seizures. The associated features were demonstrated to be present in 43% of the children. All these features, together, allowed us to establish a clinical diagnosis of AS. ❑

CONCLUSIONS

Angelman syndrome is a rare and severe neurodevelopmental disorder, with a complex clinical picture. There are some characteristic facial features (deep set eyes; pointed chin; wide, smiling mouth), which, in association with hypopigmentation, happy disposition, jerky movements, and ataxia in an infant or small child with psychom*otor delay, should raise the strong suspicion of AS. Epileptic seizures are very common in children with AS – microdeletion type; in our cohort the most common seizure types were partial seizures, atonic seizures, and atypical absences. EEG in children with AS has a very characteristic pattern (slow background activity, mixed with spikes) and is a very useful instrument in the diagnosis of AS.

ACKNOWLEDGEMENTS

This work was supported by the following grants: CNCSIS project no. 1203, PN project no 09330203 and PN II project no. 42-130.

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References