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International Medical Scientific Journal       Issue-3 

10.5281/zenodo.5717607 

87 



Art of Medicine           Volume-1 

International Medical Scientific Journal       Issue-3 

10.5281/zenodo.5717607 

88 

 

Art of Medicine International Medical Scientific journal 

 

Founder and Publisher Pascual Izquierdo-Egea 

Published science may 2021 year. Issued Quarterly. 

Internet address: http://artofmedicineimsj.us 

E-mail: info@artofmedicineimsj.us 

11931 Barlow Pl Philadelphia, PA 19116, USA +1 (929) 266-0862 

 

 
 



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Epileptic encephalopathy and Angelman syndrome 

Gulyamova Durdona Nasriddinovna  

Dotsent at department Pediatric Neurology Center for the development of 

professional qualifications of medical personnel  

 

Abstract: Angelman syndrome (AS) - is a chromosomal syndrome 

characterized by atypical autism with intellectual retardation, epilepsy, a gross 

impairment of speech, motor disorders, ataxia, as well as special the behavior (happy 

demeanor) of patients in combination with frequent laughter or smiling bursts. The 

disease is caused by mutation of the genes on the maternally inherited 15q11.2-13 

locus or gene UBE3A- part of the ubiquitin complex. These genes regulate the 

functional activity of neurons in the hippocampus, olfactory bulb, the primary visual 

cortex, cerebellum.  

Keywords: epilepsy, chromosome, Angelman syndrome, the UBE3A gene, 

tremor-shivering, ataxia. 

 

Introduction. The establishment of a clinical diagnosis and etiology of the 

disease in the examination of patients with mental retardation is the basis of medical 

genetic counseling. The confirmed diagnosis allows to evaluate the course of the 

disease, to determine the possibilities of treatment, the prognosis of the offspring for 

relatives, and, if necessary, the prevention of the disease in the family. One of such 

syndromes, difficult for diagnosis and insufficiently studied in clinical practice, is 

Angelman syndrome (AS). 

Angelman syndrome is a genetic disease characterized by intellectual and 

physical developmental delay, sleep disorders, seizures, sharp movements (especially 

applause), frequent causeless laugh or smile and, as a rule, patients with AS, look 

very happy. 

        AS is named after the British pediatrician, Dr. Harry Angelman, who first 

described the syndrome in 1965. Earlier, another alternative was used to characterize 

the AS, the alternative name is the happy puppet syndrome, but today, officially this 

term is no longer used, because it is considered disparaging. People with AS are 

sometimes called "angels", because of the name of the syndrome, their youth and 

happy appearance. 

     The syndrome occurs with the same frequency in representatives of both sexes. 

The prevalence is 1 to 10-30 thousand newborns, but a significant number of children 

with this disease as a result of the lack of a correct diagnosis are observed as patients 

with epilepsy or suffering from behavioral disorders and delayed speech 

development. 

      Seventy percent of cases occur as a result of a mutation of 15q11.2-13 de novo, 

2% of observations - disomia on the paternal line (loss of the parent locus), 2-3% - 

defect of the imprinting center. Most of the remaining cases are associated with a 

mutation of the ubiquitin UBE3A gene. To establish the form of the disease in 7-9% 

is currently not possible. 



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AS is a classic example of genomic imprinting, as it usually arises from the 

deletion or inactivation of genes on a copy of the 15 chromosome inherited from the 

mother, while the activity of the parent copy (whose sequence may be normal) does 

not affect the functioning of the organism. 

Karyotype 46 XX or XY, 15p-. Usually, the syndrome is caused by a 

spontaneous chromosomal defect when there is no large adjacent region of 3-4 

million base pairs of DNA in the q11-q13 region of the 15th chromosome. 

       The Angelman syndrome arises from the loss of normal maternal copies of genes 

in a specific region of the 15 chromosome. Most often this happens by deletion of the 

segment of this chromosome. Other causes of the onset of the disease may be 

uniparental paternal disomia, translocation or mutation of one gene in this area. 

        This gene (UBE3A), involved in the metabolism of ubiquitin, is present on both 

copies of the chromosomes (on the paternal and on the maternal), but its effect differs 

from the process of methylation (imprinting). Inactivation of the father's copy of the 

gene UBE3A occurs in the brain (in the hippocampus and the cerebellum), whereas 

the maternal allele is almost always remains active. 

The UBE3A gene produces the protein UBE3A (also called E6-AP) and this 

protein is an important component of the pathway for ubiquitin-proteasome 

formation. This pathway is extremely important for all cells, especially neurons of the 

brain. However, it is clear that UBE3A is closely related to the synaptic function of 

neurons. And it was the identification of four E6-AP substrates that allowed us to 

understand somewhat the possible molecular mechanisms underlying the onset of 

Angelman syndrome. 

 The disease is characterized by the absence of abnormalities during the 

perinatal period and pronounced malformations at birth. The main characteristic 

symptoms of Angelman syndrome are manifested at the age of 6-12 months. The 

circumference of the newborn's head does not deviate from the norm. In newborns 

with AS, you can note sluggish sucking and muscle hypotension, which may result in 

regurgitation, gastroesophageal reflux, and children gain weight poorly. At this age, 

patients can detect an obvious delay in development in the absence of a progressive 

loss of acquired skills. 

At half of children by the end of the first year of life the insufficient head growth 

(microcephaly) and hyperreflexia are noted. Strabismus may develop. As the 

development of motor skills becomes noticeable tremor.        

At the age after a year there is a constant smile, fits of laughter. Face 

dysmorphism becomes prominent: a wide mouth, protruding lower jaw, large 

interdental spaces, brachy- and microcephaly, hypopigmentation, blond hair and eyes 

(compared to the family). There are stereotypes (repeated strokes of hands, torsion 

with brushes and frequent clapping), not characteristic of healthy children. In water, 

children with Angelman's syndrome feel more comfortable, increased sensitivity to 

heat and fluid needs (a constant sense of thirst). 

      The results of laboratory tests do not deviate from the norm, examination using 

MRI or CT does not show the presence of structural changes in the brain. Possible 



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moderate cortical atrophy and manifestation of selective damage to the myelin sheath 

(demyelination). 

      At preschool and school age, a child with a AS has a kind of "hard" gait, raised to 

the level of the chest and bent at the elbow joints with hands. Disinhibited, laughable, 

tongue stuck out, salivation increased. There is no speech. 10% of children with AS 

do not go and are usually observed with the diagnosis of "infantile cerebral palsy". 

Sleep disorders (dyssomnia) are very common. Typical difficulties of falling asleep 

and frequent awakening. Characteristic hyperactive behavior, which is more correctly 

called hyperdynamic syndrome. Often there are constipation, obesity. A child with a 

AS is continuously engaged in something: moves from object to object, grabbing, 

licking and discarding toys or other objects. Speech development is grossly violated. 

Rarely developed phrase of two words. The volume of understood speech is usually 

larger than the active vocabulary. Most older children and adults communicate with 

non-verbal means. 

The pubertal in patients with AS does not differ from the norm, the fertility is 

preserved. The main problems: scoliosis and gastroesophageal reflux. Adult patients 

with AS are not capable of self-care, they need constant supervision. Life expectancy 

- as in the general population. 

      Epilepsy is noted in the vast majority of patients with AS (80-90% of cases). 

Epileptic seizures debut at the age of 3 months to 20 years, but more often in young 

children (up to 2 years), often - with febrile seizures. In 50% of cases, epileptic 

seizures continue to be febrile - provoked. In older children, even with a small 

subfebrile condition, there is a greater frequency of seizures; often marked by the 

transition of seizures to serial and the development of epileptic status. Atypical 

absences and epileptic myoclonus are the main types of epileptic seizures in AS, 

which in most cases are detected for the first time during video-electric-phalographic 

(video-EEG) monitoring and are much less frequent complaints of the parents of 

patients. Atypical absences are manifested by a decrease in the level of 

consciousness, motor activity is suspended, there is a general inhibition. Minimal 

atonic (nodding, lowering of the shoulders, torso of the trunk) and myoclonic 

(twitching of limbs and facial musculature) are possible. Salivation may increase 

during seizures. Consciousness often fluctuates. Absences can occur so often that a 

clinical picture of the epileptic status develops (peak-wave stupor), especially this is 

characteristic in the morning, after awakening. Anxiety epileptic status is noted in 

more than half of patients with AS and can last for days, weeks and even months.        

Myoclonic seizures may occur in isolation (usually in the limbs and facial 

muscles) or as a myoclonic component in the structure of atypical absences. Epileptic 

myoclonus in the structure of arbitrary movements is difficult to differentiate from 

tremor. In a dream of myoclonic seizures, as a rule, no. The status of myoclonic 

seizures can develop in isolation or in combination with the status of atypical 

absence. Generalized convulsive seizures and focal epileptic seizures, from the cortex 

of the occipital lobe, are also characteristic. 

        In some patients with the AS phenotype, mutations in the MECP2 genes (Rett's 

syndrome), CDKL5 (X-linked early epileptic encephalopathy) and X-linked mental 



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retardation are revealed. In most cases, the diagnosis is made to the patient at a more 

adult age, about 3-7 years. By this moment, the signs of a defect are, as a rule, 

pronounced. The speed with which the disease progresses will depend on the nature 

of the damage to the 15 chromosomes. For this reason, some patients will be able to 

lead an independent life, while others will not be able to even speak normally. 

Doctors in Europe have drawn attention that children with this disease have much in 

common with patients suffering from autism. They are united by impulsiveness, 

problems in communication, obsessive movements, and also a tendency to use things 

that are not suitable for children of their age.         

          One of the most notable features of the Angelman syndrome is its 

pathognomonic neurophysiological characteristics. For patients with AS, three 

different EEG results are common: very low amplitude rhythms, whose frequency is 

2 -3 Hz, the greatest deviations are observed in the prefrontal zone; symmetrical 

high-amplitude rhythm with a frequency of 4-6 Hz; the presence of close-connected 

acute sharp waves in the occipital areas at a frequency of 3-6 Hz. 

Due to the rarity of such descriptions in the domestic literature, we give a 

description of the clinical case. 

 

Clinical case. 

Girl K. 4 years. Complaints: delay in psycho-speech development, restless sleep, 

cramps, tremor. 

From the anamnesis of life, it is known that the child was born from the first 

pregnancy, which was taking place with mild toxemia. Childbirth on the 38th week, 

immediately screamed. The score for Apgar is 6/7 balls, weight-3450 kg, height 50 

cm. The neonatal period proceeded smoothly. Not a kindred marriage. Heredity for 

neurological diseases is burdened by the father of the girl. After discharge from the 

maternity home, parents noted the increased excitability of the child. From the age of 

two months were observed in the neurologist about anxiety, frequent flinch. From the 

words of the mother until the year the girl developed according to age: crawling, 

sitting alone, playing toys. The first epileptic seizures appeared against the 

background of apparent well-being, from 1 year 2 months in the form of head 

bendings with lifting of the shoulders and dilution of elbows to the sides. Attacks 

with a duration of no more than 5 seconds, without disturbance of consciousness, 

during waking period, 2-4 times a day. The mother began to notice the tremor first in 

the distal parts of the limbs, most of all the torso. We started taking Convulex 50 mg / 

ml at 20 mg / kg per day. As the attacks increased, the child began to experience 

delayed psychomotor development and muscle hypotension. In the further because of 

frequent paroxysms, Convulex was calculated from the calculation at a daily dose of 

40 mg / kg. Paroxysms were absent for 6 months, but there were no positive changes 

in psychomotor development. 

After the acute respiratory viral infection, the paroxysms resumed. Paroxysms 

of atonic character (a drop of a head on a breast, a torso of a trunk), on 10-20 times a 

day were observed. Then the therapy scheme was used - Convulex + Lamictal in the 

maximum tolerated therapeutic doses. Paroxysms partially decreased, insomnia 



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joined and tremor increased, in connection with which hormonal therapy was 

prescribed (prednisone in a daily dose of 1 mg per 1 kg of weight with a gradual 

decrease in a month). The effectiveness of the drugs was partial - the number of 

paroxysms decreased (5-6 times a month). In general, the duration of the relatively 

"quiet" period was about two months. 

On the video EEG monitoring (daytime): background EEG slow-wave activity 

originating from the central-parietal divisions at a frequency of 3 Hz. These 

epileptiform patterns are present in all stages of non-REM with different amplitudes 

from 50 to 150 μV, mainly in the anterolateral parts of the brain on the right. After 

awakening with active wakefulness in the frontal areas slow slow wave complexes 

and rhythmic slow wave activity of the delta range are recorded (Figure 1). 
 

 
Fig.1 

 

Based on the above data, a diagnosis was made: Epileptic encephalopathy. The 

Lennox-Gastaut syndrome. 

Then, against the background of respiratory infectious disease at the age of 2.5 

years, paroxysms resumed and paroxysms joined in the form of tonic torso and limb 

stresses, head and eye movements, nocturnal flinches. After the deterioration of the 

child's condition, another therapy scheme was used - Convulex + Levetiracetam. But 

this combination of the drug worsened the condition, seizures became more frequent, 

generalized clonic convulsions joined the paroxysms. In the future the scheme of 

therapy of Convulex + Topiramate was used. 

At the last hospitalization at the age of 3 years 11 months the state of the child 

on the disease is severe. Paroxysms have become more frequent on the background of 

respiratory infectious disease in the form of tonic seizures of atypical absences with 

atonic component, frequent flinching’s with a frequency of 2-3 times a day. 

In objective status, physical development by age, stigma of dysembryogenesis 

is absent, a head of normal size, a flattened back of the head. Skin, hair and eyes of 

light color. Signs of the pathology of the respiratory and cardiovascular system are 



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absent. Frequent constipation, increased salivation. On the lower extremities in the 

region of the shin there is a spot of blue color, which (according to the mother) 

increases with increasing temperature.  

In neurological status: cranial innervation - movement of eyeballs in full 

volume, nystagmus, there is no strabismus. The face is symmetrical, the function of 

the chewing and facial muscles is not violated. The tongue along the middle line, the 

soft palate with phonation is symmetrically movable, the voice is loud. In the motor 

sphere: muscle tone is hypotonic. Tendon reflexes are called symmetrically. 

Pathological bone, carpal reflexes are not revealed. Severe tremor of the trunk and 

extremities. Expressed motor delay: does not walk alone, stands with support, takes 

objects with hands. Active speech is absent, hardly understands the converted speech. 

The mood is increased, a constant smile on the face, periodically laughs. Frequent 

stereotypes in the hands. 

Video EEG monitoring (full-time): on the background recording, polymorphic 

activity with the predominance of theta waves of the diapason. The slow forms of 

activity are recorded widely, diffusely, often dominate the background, are mainly 

represented by fluctuations in theta of the range of 4-5 Hz with an amplitude of up to 

150 μV, less often in the delta range with an emphasis in the fronto-central and 

parieto-occipital hemispheres. Against this background, on a regular basis, during 

wakefulness and during sleep, slow slow-wave complexes with a frequency of 1.5-3 

Hz and an amplitude of 150 μV are recorded in a generalized manner. Sleep does not 

differentiate in phases and stages. The physiological patterns of sleep are mostly 

mixed in epileptiform activity. (Figure 2 and 3) 

 

 
Fig.2 

 



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Fig.3 

 

MRI of the brain - signs of moderate hypoxic - ischemic encephalopathy, 

delayed myelination (Figure 4). 
 

 
Fig.4 

 

Ultrasound examination of internal organs: reactive changes in the liver, spleen 

and pancreas without pathology. 

       Blood chemistry: Calcium- 1.95mmol/L (N 2.02-2.60); Magnesium- 0.8mmol/L 

(N 0.7-1.0); Iron- 31.4mmol/L (N 8.9-21.0); Ammonia- 197mmol/L (N 9-33); 

Cholesterol- 4.1mmol/L (N 3.7-5.2); Triglycerides- 1.24mmol/L (N 0.1-1.1); Urea- 

6,5mmol/L (N 1,8-6,4); Glucose- 3.35mmol/L (N 2.5-4.7); Lactate- 2.5mmol/L (N 

0.7-2.1). 

The concentration of valproate acid in the blood: 152.5 μG/ML (N 50-100). 



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Immunogram: Imbalance of immunoregulatory T-lymphocytes. Presence of an 

allergic component in the body. Activation of apoptosis of lymphocytes. The 

presence of an inflammatory process on the mucous membranes (LgA increased). 

Tandem mass spectrometry (MS) - pathological abnormalities are not revealed. 

Genetic research: Results of karyotyping - 46, XX. 

Conclusion of the Exome sequencing (WES): on chromosome-15 was detected 

a chromosomal microdeletion, that included a total of 282 exon genes: MKRN3, 

MAGEL2, NDN, PWRN1, NPAP1, SNRPN, SNORD116-1, SNORD114, 

SNORD116-10, SNORD116-22, IPW, SNORD115-1, UBE3A , ATP10A, GABRB3, 

GABRA5, GABRG3, OCA2, HERC2. The deletion is identified as probably 

pathogenic. It should be noted that the UBE3A gene is entered the deletion region 

(OMIM 105830 Angelman syndrome), heterozygous mutations in this gene leads to 

the clinical manifestations of AS. 

Clinical diagnosis: Epileptic encephalopathy. Angelman syndrome.Based on 

laboratory data (elevated blood ammonia level, reactive hepatitis), the anticonvulsant 

therapy regimen was changed. Despite the attacks, the dose of Convulex was reduced 

to 25 mg/kg per day, Lamotrigine was added at a rate of 5 mg/kg per day, Topiramate 

was canceled. Hepatoprotectors were added to the treatment. After a month, the 

condition of the girl improved, the attacks decreased, ammonia in the blood 

normalized to 40.6 mmol/L. Currently, seizures 2-3 times a month, tremor and ataxia 

persists, night sleep restless. 

This clinical case seems interesting with a few poses. The clinical picture of the 

disease itself is of interest - the impossibility of a clear syndromological diagnosis of 

this syndrome and unclassified form of epilepsy. By the type of seizures and 

according to EEG data, we can not attribute this case to classical encephalopathies of 

early childhood. In all cases of early epileptic encephalopathy, we can not explain a 

certain etiology (hypoxic-ischemic encephalopathy, developmental defects of the 

brain), the child needs to carry out a genetic examination, in particular comparative 

genomic hybridization and full genome sequencing. The most important aspect of 

this clinical observation is the mutation of the UBE3A gene, which in some patients 

can be detected with a mutation in the MECP2 genes (Rett syndrome), CDKL5 (X-

linked early epileptic encephalopathy). But it is possible that such cases are much 

more common than they are. The development and accessibility of modern methods 

of genetic research, such as comparative genomic hybridization and full genome 

sequencing, will soon make it possible to clarify the genesis of a number of genetic 

and epileptic syndromes, and possibly help in the development of new ways of 

treating childhood epilepsy. 

 

 



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