MAEDICA – a Journal of Clinical Medicine 2013; 8(4): 321-327
Mædica - a Journal of Clinical Medicine O RIGINAL
PAPERS
Diagnostic Approach of Angelman Syndrome Denis George DUCAc; Dana CRAIUa; Monica BOERa; Sorina Mihaela CHIRIEACb; Aurora ARGHIRb; Andreea TUTULAN-CUNITAb; Diana BARCAa; Catrinel ILIESCUa; Agripina LUNGEANUb; Sanda MAGUREANUa; Magdalena BUDISTEANUa,b a
“Prof. Dr. Alexandru Obregia” Clinical Hospital of Psychiatry, Bucharest, Romania b “Victor Babes” National Institute of Pathology, Bucharest, Romania c “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
ABSTRACT Background: Angelman syndrome (AS) is a genetic condition, characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behaviour, movement disorder. It is caused by a variety of genetic mechanisms which all interfere with expression of the UBE3A gene on chromosome 15q11-13. Objectives: To present our experience regarding diagnosis of children with Angelman syndrome. Material and methods: 15 children 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. The clinical evaluation focused on the patient history, a general examination, dysmorphological evaluation, a neurological examination, psychological evaluation, and paraclinical tests. Results: All patients from this study presented the characteristic facial features and the characteristic behavior phenotype. Psychomotor development was delayed in all children, most of cases (73%) presenting with sever mental retardation. Epileptic seizures were observed in all patients with microdeletion, the partial seizures being the most frequent type. EEG in all children showed the characteristic pattern for AS. Conclusions: Angelman syndrome is a rare and severe neurodevelopmental disorder, with a complex clinical picture. There are some characteristic facial features, which, in association with hypopigmentation, happy disposition, jerky movements, and ataxia in a child with psychomotor delay should raise the strong suspicion of AS.
Address for correspondence: Magdalena Budisteanu, “Prof. Dr. Alexandru Obregia” Clinical Hospital of Psychiatry, Berceni Avenue, No. 10-12, 4th District, Bucharest, Romania. E-mail: [email protected] Article received on the 9th of September 2013. Article accepted on the 5th of December 2013.
Maedica
A Journal of Clinical Medicine, Volume 8 No.4 2013
321
DIAGNOSTIC APPROACH OF ANGELMAN SYNDROME INTRODUCTION
A
ngelman 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.) Move322
Maedica
A Journal of Clinical Medicine, Volume 8 No.4 2013
ment 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 occipitofrontal circumference (OFC)) by age of 2 years. Microcephaly is more pronounced in those with 15q11.2-q13 deletions; 2.) Seizures, onset usually 10%) 76 (25-50%) 75,5 (75%) 120 (50%) 77(50-75%) 96 (50-75%) 100 (50%) 81 (50%) 97 (75%)
30(>10%) 14 (50%) 17 (10%) 10,3 (90%) 25 (50%) 9(
Mædica - a Journal of Clinical Medicine O RIGINAL
PAPERS
Diagnostic Approach of Angelman Syndrome Denis George DUCAc; Dana CRAIUa; Monica BOERa; Sorina Mihaela CHIRIEACb; Aurora ARGHIRb; Andreea TUTULAN-CUNITAb; Diana BARCAa; Catrinel ILIESCUa; Agripina LUNGEANUb; Sanda MAGUREANUa; Magdalena BUDISTEANUa,b a
“Prof. Dr. Alexandru Obregia” Clinical Hospital of Psychiatry, Bucharest, Romania b “Victor Babes” National Institute of Pathology, Bucharest, Romania c “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
ABSTRACT Background: Angelman syndrome (AS) is a genetic condition, characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behaviour, movement disorder. It is caused by a variety of genetic mechanisms which all interfere with expression of the UBE3A gene on chromosome 15q11-13. Objectives: To present our experience regarding diagnosis of children with Angelman syndrome. Material and methods: 15 children 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. The clinical evaluation focused on the patient history, a general examination, dysmorphological evaluation, a neurological examination, psychological evaluation, and paraclinical tests. Results: All patients from this study presented the characteristic facial features and the characteristic behavior phenotype. Psychomotor development was delayed in all children, most of cases (73%) presenting with sever mental retardation. Epileptic seizures were observed in all patients with microdeletion, the partial seizures being the most frequent type. EEG in all children showed the characteristic pattern for AS. Conclusions: Angelman syndrome is a rare and severe neurodevelopmental disorder, with a complex clinical picture. There are some characteristic facial features, which, in association with hypopigmentation, happy disposition, jerky movements, and ataxia in a child with psychomotor delay should raise the strong suspicion of AS.
Address for correspondence: Magdalena Budisteanu, “Prof. Dr. Alexandru Obregia” Clinical Hospital of Psychiatry, Berceni Avenue, No. 10-12, 4th District, Bucharest, Romania. E-mail: [email protected] Article received on the 9th of September 2013. Article accepted on the 5th of December 2013.
Maedica
A Journal of Clinical Medicine, Volume 8 No.4 2013
321
DIAGNOSTIC APPROACH OF ANGELMAN SYNDROME INTRODUCTION
A
ngelman 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.) Move322
Maedica
A Journal of Clinical Medicine, Volume 8 No.4 2013
ment 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 occipitofrontal circumference (OFC)) by age of 2 years. Microcephaly is more pronounced in those with 15q11.2-q13 deletions; 2.) Seizures, onset usually 10%) 76 (25-50%) 75,5 (75%) 120 (50%) 77(50-75%) 96 (50-75%) 100 (50%) 81 (50%) 97 (75%)
30(>10%) 14 (50%) 17 (10%) 10,3 (90%) 25 (50%) 9(
