Angelman syndrome in three biological siblings: Focusing on the neuropsychiatric domain.

Angelman syndrome (AS) is a neurogenetic disorder that usually presents with delayed motor milestones, ataxic gait, mental retardation, language disorder, seizures, sleep disturbances, characteristic facial features, and happy demeanor. The genetic abnormality of AS has been located on chromosome 15q11-q13. The AS gene(s) is exclusively expressed from the maternal chromosome. Loss of the maternally contributed AS region can occur by deletion, paternal uniparental disomy, imprinting defects, mutation of the ubiquitin-protein ligase (UBE3A) gene, and by yet unidentified mechanisms. Deletion of maternal chromosome accounts for most of the cases of AS with imprinting accounting for 2%-5% of cases. In imprinting inheritance, offsprings of carrier mothers are theoretically at 50% risk of having AS. Familial occurrence of AS has been reported. Here, we highlighted the rare incident of AS in three biological siblings and their neuropsychiatric manifestations as well as different psychosocial aspects.

Introduction

Angelman syndrome (AS) was first described in 1965 by Dr. Harry Angelman, a British pediatrician. He reported three children with a similar pattern of mental retardation (MR), seizures, ataxia, easily provoked laughter, absent speech, and dysmorphic facial features whom he called “puppet children.”[1] In 1995, Williams et al.,[2] established the clinical criteria for the diagnosis. The prevalence of AS is estimated to be around 1:10 000-1:20 000.[3] AS is a clinical diagnosis that can be confirmed by either genetic studies in about 80%-85% of the cases.

Case Reports

Case 1

A 7-year-old female presented with complaints of delayed milestones and seizures. She is the 2nd order in the family, born of nonconsanguinity with normal birth and delayed milestone. She attained neck holding at the age of 2 years, sitting with support at the age of 3 years, standing without support at the age of 4 years, walking without support at the age of 5 years. She has only palmer grasp now, feeds herself without spilling, and spells only bisyllables and is not toilet trained. There was no regression of attained milestones. When she started walking independently, she walked with wide-based ataxic gait. She was always smiley with a history of inappropriate laughter and happy demeanor. She did not have history of limb incoordination or any extrapyramidal symptoms. Her intelligence quotient was found to be 24 on Seguin Form Board test, suggestive of severe MR.

Case 2

An 8-year-old girl, the elder sister of the above, also had similar history of delayed milestones (social, motor, language and cognition), wide-based ataxic gait, since she learned walking with support. Always she used to remain happy and cheerful with frequent excessive, inappropriate laughter. There was no history of seizure, vision impairment, hearing loss, motor incoordination, and any extrapyramidal symptoms. Her social quotient (SQ) was found to be 15 on Vineland Social Maturity Scale, suggestive of profound MR.

Case 3

A 5-year-old girl, younger sister of the above two also had complaints of difficulty in speech, poor comprehension, and communication ability, compromised ability to do the activities of daily living with history of global delayed developmental milestones and ataxic gait. There was no evidence of vision impairment, hearing, motor function, or history of seizure. She had microcephaly with an open mouth and protruded tongue. Her SQ was found to be 19 on Vineland Social Maturity Scale, suggestive of profound MR.

Neuropsychiatric Assessment

All the three children were assessed on Kidde's schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version, and they did not qualify for any syndromal psychiatric illnesses.

Investigations

The routine blood investigations including copper studies (serum copper, ceruloplasmin, and 24 hour urine copper) and serum alpha fetoprotein, serum homocysteine were within normal range. The magnetic resonance imaging (3Tesla MRI) of brain was normal in all three siblings. Electroencephalogram (EEG) of case 1 had revealed high-amplitude (200-300 μV), generalized 2-4 Hz spike-wave complexes with slow background rhythm of delta range [Figures 1–2]. EEG of case 2 showed slow background with intermittent high amplitude generalized sharp and slow wave without history of seizures [Figure 3]. The EEG of case 3 was normal. Karyotyping of all the three children revealed 46×× pattern. Genetic analysis of case 2, using amplification of deoxyribonucleic acid sequences of SNRPN gene did not reveal any abnormality suggestive of mutation, deletion, or uniparental diasomy (UPD). Genetic tests for other siblings could not be performed due to low economic profile of patients. Ubiquitin-protein ligase (UBE3A) gene could not be done due to unavailability and financial constraints.

Figure 1

High-amplitude (200-300 μV), generalized 2-4 Hz spike and slow wave complexes with slow background rhythm of delta range characteristics of Angelman syndrome

Figure 2

Angelman syndrome with happy puppet children

Figure 3

EEG showing slow background with intermittent high amplitude generalized sharp and slow wave without history of seizures.

Discussion

Angelman syndrome usually becomes apparent at 1-4 years of age with the average age at diagnosis being 6 years.[456] The most consistent clinical manifestations (100%) are developmental delay, speech impairment with better receptive, and nonverbal communication skills, gait ataxia, behavioral abnormalities including inappropriate laughter and apparent happy demeanor, hypermotoric behavior, and short attention span. Microcephaly, seizures, and abnormal characteristics EEG are frequent manifestations (80%) of AS. EEG abnormalities are more prominent in the first 2 years of life and become progressively less significant after 10 years of age. In childhood, the EEG showed high voltage 4-6 Hz activity and in adulthood it showed rhythmic triphasic 2-3 Hz activity of high amplitude (200-500 mV), mixed with spikes or sharp waves with a maximum over the frontal regions. It is characteristic in AS and can occur before a clinical diagnosis is considered in about 45% of these children.[78] Other associated features are (20%-80%) flat occiput or occipital groove, protruding tongue, swallowing disorders, feeding difficulty during infancy, prognathia, wide mouth, widely spaced teeth, frequent drooling, strabismus, hypopigmented skin, light hair and eye color, hyperactive lower limb deep tendon reflexes, increased sensitivity to heat, sleep disturbance, and attraction to water.[7] Paroxysms of easily provoked, prolonged laughter may start as early as the age of 10 weeks and become more evident in the first 6-12 months of life. Age at onset varies from 1 month to 5 years (mean: 2-3 years).

Diagnosis

Angelman syndrome is caused by one of the following mechanisms. (1) Deletion of the AS/PWS region on the maternally inherited chromosome 15 (68%). (2) Paternal UPD in which the father contributes both copies of chromosome 15 (7%). (3) An imprinting defect (3%). (4) A mutation in UBE3A (11%). (5) Unidentified mechanism(s).[910] As accepted internationally, the diagnosis of AS is established on the basis of clinical features.[9] As per recent genetic research, nearly 90% of individuals with AS lack UBE3A gene in their chromosome 15q.[910] Up to 20% of patients with AS may not have detectable cytogenetic pathologies, on the currently available molecular-genetic technologies, so normal genetic reports do not exclude the diagnosis of AS.[11]

Differential diagnosis

The differential diagnosis is often broad and nonspecific. The following entities may be encountered as the differential diagnosis of AS.[12]

Mowat-Wilson syndrome: It is caused by mutation or deletion of ZEB2 gene. The clinical presentations are seizures, happy demeanor, prominent mandible and ear lobes, decreased speech output, microcephaly, constipation, Hirschsprung's disease, congenital heart defects, or agenesis of the corpus callosum.

Christianson syndrome may mimic AS. It is an X-linked disorder and usually presents with apparently happy affect, decreased intellectual performances, ataxia, microcephaly, and seizure. The EEG pattern differs between AS and Christianson syndrome. AS typically shows a generalized high amplitude, slow spike, and wave complexes of frequency 2-4 Hz, while those with Christianson syndrome have a more rapid (10-14 Hz) background frequency. It is caused by mutations in SLC9A6 gene.

Adenylosuccinate lyase deficiency may mimic AS. It results in accumulation of succinylpurines. The common clinical features are psychomotor regression, hypotonia, seizures, severe speech deficits, excessive laughter, a very happy affect, attention deficit, hyperactive behavior, autistic features, and stereotyped movements.

Methylenetetrahydrofolatereductase deficiency: It is associated with low methionine and an elevated homocysteine blood level was reported in a boy with happy demeanor, ataxic gait, absent speech, and flattened occiput.

Rett syndrome: It is caused by mutation of MECP2. Usually seen in female infants and associated with seizures, microcephaly, and speech impairment without having distinctive happy affect. Unlike Rett syndrome, AS do not have regression of milestones.

Others: Sometimes cerebral palsy, Lennox-Gastaut syndrome, pervasive developmental disorder, static encephalopathy, and chromosomal disorder like deletion of 15q12 (Prader-Willi syndrome) may mimic AS.

Management

There is no specific therapy for AS. Epileptic seizures are treated with antiepileptic drugs like valproic acid and clonazepam with good seizure control. Physiotherapy, occupational therapy, and speech therapy may be required to keep them mobile. Pharmacological treatment like anticholinergic medications (scopolamine patch, glycopyrolate) may be required for excessive drooling. Behavior therapy, one-on-one personal interaction may be required in the school or home to deal with the hyperactivity behavior and developmental training.[8]

In our cases, there was absence of classical genetic imprinting, mutation, deletion, or uniparental diasomy as revealed from genetic analysis; however, we could not analyze for the gene UBE3A due to unavailability and financial constraints. The diagnosis was made on the basis of consensus clinical criteria by Willam et al., characteristic EEG findings and exclusion of other AS mimic. This is a unique case series, as AS is manifested in all the three biological siblings (sisters) in the same family. The morbidity due to profound to severe MR with significant disability due to impairment of locomotion had affected the family economy and increased the caregiver burden. In underdeveloped and developing countries, where poverty, unemployment are the major threats to the existence of common man, Severe to profound intellectual disability in all biological siblings carries a lot of significance. Rehabilitative measures, adequate control of behavioral problems, appropriate treatment of seizure, and speech therapy can increase the quality of life of the individuals with AS and decrease caregiver burden and stress.