Bibliographie

1. S. G. BOYD, S. GALIFFA and W. REARDON, No evidence for a common EEG pattern between 4p- and Angelman syndromes ;
2. J. BRAECKEVELDT, L. DIVANO, P. MOETWIL and G. VANDERMOT, Somatosensory evoked potentials and serial electroencephalograms in Angelman syndrome : case study ;
3. L. A. E. M. LAAN, W. O. RENIER and Oebele F. BROUWER, EEG findings in Angelman syndrome.

Angelman's syndrome is a rare genetic disorder characterized by developmental delay, craniofacial abnormalities, ataxia, paroxysmal laughter, and seizures. The diagnosis is suspected in infants who have the characteristic clinical features and electroencephalographic (EEG) abnormalities and is confirmed by the genetic identification of a maternally derived 15q11-13 deletion. We report on 3 patients with genetically confirmed Angelman's syndrome who had the characteristic clinical and EEG features. The EEGs demonstrated high-amplitude 2- to 3-Hz delta activity, with intermittent spike-and-slow-wave discharges maximal in the occipital region in 2 patients and generalized sharp-and-slow-wave discharges, occipital spikes, and electrographic status epilepticus during slow-wave sleep in the other patient. The findings of generalized high-amplitude delta slowing and occipital spike-and-wave discharges, facilitated by eye closure, in children with developmental delay and seizures suggest the diagnosis of Angelman's syndrome and should lead to genetic testing.

The diagnosis of Angelman syndrome has seldom been made in infancy because the typical craniofacial dysmorphism and the typical outbursts of unprovoked laughter are not fully developed before the second and third year of life. Other features such as mental retardation or absence of language, though invariably present, are less obvious in the first year of life. We describe three children in whom consecutive electroencephalographic (EEG) studies show very large amplitude slow activity at 2-3/s, often rhythmic, usually occurring in prolonged runs and often more prominent posteriorly, sometimes with spikes or sharp-wave activity, and invariably associated with a diffuse rhythmic activity at 4-6/ s of 200 microvolts. The changes were present as early as six months of life. They preceded development of seizure and occurred much earlier than the craniofacial dysmorphology. It is concluded that methodical use of EEG in the elucidation of children with developmental disorder and knowledge of the characteristic EEG picture may help to identify patients with Angelman syndrome at an early age and before the clinical features become obvious.

PURPOSE: To evaluate the evolution of epileptic seizures and EEG features in a large group of patients with Angelman syndrome (AS).
METHODS: Thirty-six patients with AS with a proven chromosome 15q11-13 deletion were retrospectively analyzed with regard to their epilepsy and EEG findings by examination of patient files and EEGs. AIJ EEGs were reviewed by one of the authors. A logistic regression model, with a follow-up from 1 to 39 years (mean, 15 years), was used for statistical analysis.
RESULTS: Epileptic seizures had occurred in 30 (83%) patients. In 43% of them, the initial symptoms of epilepsy were febrile convulsions in infancy. In childhood, epilepsy could start with almost any type of seizure. Atypical absences and myoclonic seizures prevailed in adulthood. Epileptic seizures were present in 92% of the adult patients. The most typical EEG findings were rhythmic triphasic delta waves of high amplitude with a maximum over the frontal regions, identified in 99 (66%) of 150 EEGs, and continuously or intermittently, in 30 (83%) of 36 patients with AS. In 47% it was present even before a clinical diagnosis of AS was considered. High-amplitude rhythmic 4-6/s slow activity, seen in 44 (29%) of 150 EEGs, was not present after the age of 12 years.
CONCLUSIONS: In contrast to previous reports suggesting a decreasing frequency of epileptic seizures with age, we found that 92% of the adult patients with AS continued to have epileptic seizures. The most typical EEG finding in AS, in both children and adults, was the presence of frontal triphasic delta waves. In mentally retarded patients, this EEG pattern should point the physician in the direction of AS.

Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11-13. This region encompasses three GABAA receptor subunit genes (beta3, alpha5, and gamma3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a >3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompanied by rhythmic 5- to 10-Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 +/- 13 msec and had a frequency of 11 +/- 2.4 Hz. Burst-locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 +/- 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast-bursting cortical myoclonus is a prominent feature of AS.

We report an electroclinical and cytogenetic study of 4 patients with Wolf-Hirschhorn syndrome (WHS). In all cases, we observed a stereotyped EEG and clinical picture characterized by generalized or unilateral myoclonic seizures followed later by brief atypical absences. Electrographically, these were accompanied by a sequence of centroparietal or parietotemporal sharp waves; high-voltage wave with a superimposed spike becoming unusual spike-wave complexes, often elicited by eye closure; burst of diffuse spikes and waves; and frequent jerks. This electroclinical pattern is very similar to the one described in Angelman syndrome (AS) in which a defect in GABAA receptor function has been suggested. Moreover, the genes encoding the GABAA receptor subunit have been mapped to the p12-p13 bands of chromosome 4. Even though the deletion in these cases does not encompass the 4p12-p13 region, we suggest that the electroclinical picture common to WHS and AS might represent a characteristic type of epilepsy linked to a common genetic abnormality.

We studied the seizure and polygraphic patterns of 18 patients with Angelman's syndrome. All patients showed movement problems. Eleven patients were also reported to have long-lasting periods of jerky movements. The polygraphic recording showed a myoclonic status epilepticus in nine of them. Seven patients had partial seizures with eye deviation and vomiting, similar to those of childhood occipital epilepsies. These seizures and electroencephalographic patterns suggest that Angelman's syndrome occurs in most of the patients as a nonprogressive, age-dependent myoclonic encephalopathy with a prominent occipital involvement. These findings indicate that, whereas ataxia is a constant symptom in Angelman's syndrome, the occurrence of a transient myoclonic status epilepticus may account for the recurrence of different abnormal movements, namely the jerky ones.

The authors describe 7 new cases of Angelman syndrome (AS: 3 males and 4 females) diagnosed on the basis of clinical features (dysmorphic facial features, severe mental retardation with absent speech, peculiar jerky movements, ataxic gait and paroxysms of inappropriate laughter) and neurophysiological findings. Failure to detect deletion of the long arm of chromosome 15 or the absence of epileptic seizure were not considered sufficient to exclude a diagnosis of AS. Feeding problems, developmental delay and early signs of ataxia, especially tremor on handling objects and unstable posture when seated, proved effective as clinical markers for early diagnosis of AS. The EEG patterns characteristic of AS were found within the first 2 years of life (under 18 months in the majority of cases). The authors conclude that AS should be included in differential diagnosis in a child aged under 12 months having cryptogenic psychomotor retardation with prevalent language compromise. Repeat EEG recordings are needed to check for the typical trace, and cytogenetic investigations are mandatory.

Electroencephalography plays a very important role in the diagnosis and course monitoring of epilepsy. The EEG is also able to give decisive clues in diseases other than epilepsy. It is important to know these specific EEG patterns which may assume a key role in the diagnosis of rare neuropediatric diseases. Familiarity with such specific patterns will allow to select only specific investigations for diagnostic confirmation. We report six guiding EEG patterns and the associated disorders:
1. Re-build up phenomena for Moyamoya syndrome.
2. High amplitude alpha-beta activity for lissencephaly type I.
3. Positive spikes during low frequency photostimulation for late infantile neuronal ceroid lipofuscinosis.
4. Periodic high amplitude discharges for subacute sclerosing panencephalitis (SSPE).
5. Burst suppression pattern in non-asphyctic mature newborns for Ohtahara syndrome, non ketotic hyperglycinemia or molybden cofactor deficiency.
6. High amplitude 3-4 HZ activity with small spikes for Angelman syndrome.

We report eight sporadic cases of typical Angelman syndrome (AS) associated with chromosome 15q12 deletion. Age at first visit was 3-35 months (average 18 months), and follow-up period was 4-20 years (average 14.1 years). The characteristic features of epilepsy in AS are (a) seizure onset in early childhood (8 of 8); (b) evolution of seizure type with age (8 of 8); (c) EEG abnormality changes from high-voltage slow bursts (HVS) in infancy to diffuse spike and waves in middle childhood (4 of 5); (d) atypical absence seizures (8 of 8), often occurring as atypical absence status (4 of 8); and (e) diminution of seizure discharges and clinical seizures after puberty (7 of 7). We believe that AS may frequently exist in the intractable epilepsies of childhood with severe mental retardation. We stress the importance of AS as one of the main etiologic background diseases of the intractable epilepsies with infantile onset such as West syndrome, Lennox-Gastaut syndrome, and others.

Neurologic findings in 3 siblings with Angelman syndrome (AS) with apparently normal karyotype but DNA deletion of 15q11-q12 deriving from their mother are described. Increased auditory brainstem response (ABR) thresholds were noted in all 3. Interictal EEG findings included periodic 2- to 3-Hz high-voltage slow wave bursts bioccipitally and sporadic slow spike wave complexes mainly bifrontally. EEG findings suggestive of minor epileptic status were apparent in the elder brother and may be a characteristic feature in young AS patients. Seizures suggestive of generalized epilepsy have been reported in 90% of AS patients. AS is considered a good model of symptomatic generalized epilepsy associated with chromosomal DNA deletion of the (GABA)A receptor beta 3-subunit gene.

EEG studies have been carried out on 52 girls with Rett syndrome, the majority of records being taken between two and 7 years of age. Discharges were a common feature, occurring in 43 patients, and did not appear to be related to the onset of seizures. The discharges, consisting of sharp waves or spikes, were characteristically most prominent around the middle third of the head, often occurring asymmetrically and could be infrequent or almost continuous. They were usually enhanced by light sleep and were seen only during sleep in 15 EEGs taken in 13 patients, most of whom were under four years of age. These EEG features when present may help confirm the diagnosis of Rett syndrome in the appropriate clinical setting and in particular are quite distinct from the usual EEG patterns seen in Angelman (Happy Puppet) syndrome.

Of four patients having Angelman's syndrome admitted to a state mental facility who were clinically and electroencephalographically evaluated, 2 patients had CT scan studies of the brain. The most impressive and striking features that help in the diagnosis are the mental and physical retardation, nondevelopment of speech despite adequate visual and auditory function, various types of seizures, and episodic uncontrollable laughter. The CT scans of the brain did not offer any clue as to the pathogenesis. The EEGs appeared to fall into two groups: in one an arrest of electrical maturation occurred between ages 1 and 3 and in the other a slow but progressive maturation was evident.

An EEG study has been carried out on 19 children (including siblings in 3 families) with clinical features of Angelman syndrome. The age at time of the first EEG ranged from 11 months to 11 years with the majority under 5 years. Six children had no history of seizures at the time of the first EEG. One or more of the following EEG abnormalities were seen in all patients: 1. Persistent rhythmic 4-6/s activities reaching more than 200 microV not associated with drowsiness. 2. Prolonged runs of rhythmic 2-3/s activity (200-500 microV) often more prominent anteriorly, sometimes associated with discharges (ill-defined spike/wave complexes). 3. Spikes mixed with 3-4/s components usually more than 200 microV mainly posteriorly and facilitated by, or only seen with, eye closure. Two and sometimes three of these EEG features could be present in the same record particularly at a young age. The appearance of discharges mixed with slow components on eye closure was the commonest finding seen at some stage in 17 patients (aged from 11 months to over 12 years). The EEG features of Angelman syndrome appear to be sufficiently characteristic to help identify patients at an early age before the clinical features become obvious and at a time when genetic counselling may be particularly important.

Two cases of happy puppet or Angelman syndrome are presented. They have the typical clinical features and represent the first Swedish cases. One of the patients is a man of 75 years of age, which shows that this form of severe mental retardation is well compatible with long life. Extended EEG monitoring may identify the typical EEG abnormality when this is difficult to demonstrate in routine EEG records. The typical laughter has no specific correlate in the EEG and thus is probably not an epileptic manifestation. Regional cerebral blood flow studies were normal in the young patient (11 years of age) but in the older patient showed a reduced cerebral circulation, compatible with organic dementia.