Angelman syndrome
Incidence
The incidence of AS is unknown, but some authors estimated it to 1/20000 newborns, with a prevalence of 1/12000. AS is caused by loss of function of a gene(s) in the region 15q11-q13, from the maternal chromosome.
Clinical Characteristics
Clinical description: Age at clinical diagnosis is between 3 and 7 years. AS is not usually recognized at birth or in infancy because development problems at this age are non-specific, and the typical outbursts of unprovoked laughter, considered as one of the most striking features of the syndrome, usually appears between 16 months and three years, and seizures later in childhood. The early features are the jerky and uncoordinated movements. The syndrome is suspected in the first year of life on the basis of the EEG pattern and confirmed by genetic studies. During adolescence, puberty may be delayed by 1 to 3 years, but sexual maturation occurs with normal sexual characteristics. Young adults are not known to have significant mental deterioration. Normal life expectancy is possible, although scoliosis with cardiorespiratory complications have been reported in the disease\'s evolution. It is considered an epileptic syndrome. Main signs and symptoms: Craniofacial changes. Microcephaly reflecting a small brain and prognathia resulting from excessive chewing and mouthing. Skull RX reveals impressive occipital flattening. Some AS cases have macrostomia and small wide-spaced teeth. Laughter and happiness. It is not known why laughter is so frequent in AS. This kind of laughter is not related to epilepsy (gelastic seizures) and seems to be an expressive motor event, usually accompanied by grimacing. Persistent social smile is frequent and, later, several types of facial and behavioral expressions with burst of laughter are present in 70% of the patients, giving an apparent happy demeanor as predominant behavior. Gait and movement disorders. Hyperkinetic movement of the trunk and limbs has been noted in early infancy, jitteriness and tremulousness are frequent in the first six months of life. Voluntary movements are often irregular, choreiform-like. Motor milestones are delayed (sitting at 12 months, walking 3-4 years of age). Mild cases can have almost normal ambulation, whereas more severely affected children can be stiff, with robot-like walking. Some children are so ataxic and jerky that walking is not possible until they are older. Ten percent of AS children may fail in achieving ambulation. Mental retardation. Present in 100% of the patients, non-progressive and frequently severe. In milder cases it is manifested by hyperactivity and attention deficit, lack of speech and motor control. Therefore provision of a sheltered living situation will be needed in adult life. Speech and language. Even in the highest functioning children, conversational speech does not develop. In the best cases, use of 10-20 words may occur, but with severe pronunciation difficulties. Seizures and EEG abnormalities. More than 90% of AS are reported to have seizures, most with onset before 3 years, but occurrence in later ages (teenagers) is not exceptional. Seizures can be severe, myoclonic, tonico-clonic generalized, atonic and absences. Febrile convulsions are more frequent in male patients. Epilepsy in AS can be self-limited, patients becoming seizure-free, particularly after puberty. EEG may reveal epileptogenic discharges before clinical evidence of seizures. In 98% of patients, it is usually characterized by three features: - Runs of rhythmic delta activity of high amplitude (more that 300 mv), usually with a frontal emphasis. - Runs of rhythmic theta activity in excess of 100 mv, seen over a wide area. - Runs of rhythmic sharp theta activity of 5-6 Hz over the posterior third of the head, forming complexes with small spikes. These are usually facilitated by eye closure. Sleep disorders. A decreased need for sleep and abnormal sleep/wake cycles are characteristics of AS. Feeding problems and oral-motor behaviors. Feeding problems are frequent but generally not severe, and are expressed by difficulty in sucking and swallowing. In early infancy, hand sucking is frequent, and is later replaced by chewing and oral manipulation. Protruding tongue and drooling are also usually present. Hypopigmentation and ocular albinism. Deletion of the pigment gene (the P gene), located close to the AS gene causes tyrosinase-positive oculocutaneous albinism. Not all AS children with deletions of the P gene have obvious hypopigmentation, but those affected are sun sensitive. Central nervous system abnormalities. Brain is structurally normal in AS children. Occasional abnormalities are reported such as cerebellar hypoplasia, unilateral temporal lobe hypoplasia and vermian cyst. Neuroimaging abnormalities are mild, such as cortical atrophy or thinning of corpus callosum and decreased myelination seen in MRI studies. Histological studies can show decreased dendrites arborization, decreased GABA in the cerebellum and increased glutamate in frontal and occipital lobes.
Precipitants
none
Provocation Tests
none
Diagnostic Procedures
The diagnosis of AS is usually made on the basis of the facial appearance, behaviour and epileptic seizure types of the children. The electroencephalogram (EEG) may also be useful in helping to confirm the condition.The diagnosis of AS is currently a clinical diagnosis that can be confirmed by laboratory testing in about 80% of cases. Patients should have: -Normal prenatal and birth history with normal head circumference. -Absence of birth defects. -Developmental delay, functionally severe. -Delayed but forward progression of development (no loss of skills). -Normal metabolic, hematological and chemical laboratory profiles. -Structurally normal brain using MRI or CT (may have mild cortical atrophy or dysmyelination). the number of tests necessary in the search for genetic AS abnormalities and the order of testing may vary. Chromosome study, including high resolution G-bands confirmed by FISH, DNA polymorphism or methylation analysis, are necessary in all suspected cases to rule out chromosome rearrangements or other chromosome disorders. In AS patients fulfilling the clinical diagnostic criteria and exhibiting a normal methylation pattern, UBE3A sequence analysis is indicated. Molecular genetic testing detects approximately 80% of AS cases. If the child is found to have the abnormality on chromosome 15, then this confirms the diagnosis of AS. The abnormality is not found in every child with AS; it is found in just over two-thirds of children with AS. Prenatal diagnosis is possible when the underlying genetic mechanism is known for the index case.