Epileppsia, 33(6): 107%1082, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy

Angelman Syndrome in Three Siblings: Characteristic Epileptic Seizures and EEG Abnormalities "Tateo Sugimoto, "Akihiro Yasuhara, *tTohru Ohta, "Naoki Nishida, tshinji Saitoh, "i-un-ichi Hamabe, and TNorio Niikawa "Department of Pediatrics, Kansai Medical University Otokoyama Hospital, Kyoto; and Tlhpartment o j Human Genetics, Nagasaki University School c?f' Medicine, Nagasaki, Japan

Summary: Neurologic findings in 3 siblings with Angelman syndrome (AS) with apparently normal karyotype but DNA deletion of 15qll-q12 deriving from their mother are described. Increased auditory brainstem response (ABR) thresholds were noted in all 3. lnterictal EEG findings included periodic 2- to 3-Hz high-voltage slow wave bursts bioccipitally and sporadic slow spike wave complexes mainly bifrontally. EEG findings suggestivc 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), receptor p,-subunit gene. Key Words: Angelman syndrome-Generalized epilepsy-DNA darnnge-Deafness-Brainstern auditory evoked potentials.

Angelman (1965) described 3 patients with sporadic brachycephaly associated with microcephaly , profound mental retardation, easily provoked laughter, and seizures. Subsequently, 140 cases were reported, inciuding some families. We observed 3 siblings with Angelman syndrome (AS) and reported molecular deletions (Hamabe et al., 1991). To our knowledge, this is the only family with AS siblings in whom DNA deletion has been confirmed. Wagstaff et al. (1991) reported that the gene encoding the y-aminobutyric acid (GABA), receptor p,-subunit is mapped to the AS region, with AS patients having a deletion of this gene. Saitoh et al. (1992) reported deletion of the GABA, receptor p3subunit in this family. GABA is the major inhibitory neurotransmitter in mammalian brain, and our family is of great interest when considering the relation between recurrent seizures and DNA deletion in chromosome 15. We report the clinical findings in these 3 siblings with AS and define specific features which represent the characteristic associated epileptic seizures and EEG abnormalities.

CASE REPORTS

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Patient 1 A 6-year-old boy, the first child of nonconsanguineous parents (father aged 32 years, mother aged 21 years), was born at term, weighing 2.896 g and had a head circumference of 31 cm. Developmental retardation, hypotonia, and external strabismus were noted at age 6 months. H e rolled over at 8 months, sat at 15 months, and crawled at 32 months, but cannot walk or speak and is easily excited, with prolonged episodes of laughter. His developmental quotient is 20. Patient 2 A 3-year-old girl, the second child, was born at term weighing 2.980 g and had a head circumference of 31.8 cm. Developmental retardation and hypotonia were noted at age 5 months. She was able to grasp objects at 5 months, rolled over at 9 months, and had paroxysms of laughter at 1 year. She can sit with difficulty and crawl slowly, but cannot walk or speak. Patient 3 A l-year 9-month-old boy, the third child, was born at term weighing 3.1 10 g and had a head circumference of 31.8 cm. He is scarcely able to grasp objects or roll over, and cannot crawl or stand. He

Received October 1991; revision accepted April 1992. Address correspondence and reprint requests to Dr. T. Sugimoto at Department of Pediatrics, Kansai Medical University Otokoyama Hospital, Izumi 19, Otokoyama, Yawata-shi! Kyoto, 614 Japan.

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developed paroxysms of inappropriate laughter at age 6 months. H e has had repeated pneumonia. The craniofacial appearance of the 3 siblings was similar: protruding tongue, microbrachycephaly with occipital flattening, downward-slanting eyes, and mild prognathism. Jerky movements of the upper extremities were also observed. Family chromosome and DNA studies High-resolution chromosome studies of the maternal grandfather and grandmother, father, mother, and the 3 siblings were conducted. All had a normal karyotype. In our previous DNA deletion studies using five DNA markers localized at 15qllq12, we showed deletion of only D15S10 in the maternal grandfather, mother, and 3 siblings (Hamabe et al., 1991). The maternal grandfather and mother were clinically normal. Saitoh et al. (1992) reported the submicroscopic deletion encompassing GABA receptor &-subunit gene in the maternal grandfather, mother, and 3 siblings. Seizures, video-telemetered EEG (V-T-EEG), and magnetic resonance imaging (MRI) Patient I The first seizure episode in patient 1 developed with high fever at age 16 months. Generalized tonicclonic convulsions lasting 2 min were treated with valproate (VPA). Sleep EEG showed severe dysrhythmia without spike discharge. At age 28 months, he had akinetic episodes while playing, with brief (10s) periods of unconsciousness. Sleep

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EEG showed diffuse 2-5-Hz high-voltage slow wave (HVS) bursts with intermixed sporadic single spikes bifrontally . Seizures subsided after VPA was increased to 30 mg/kg/day. At age 38 months, he fell repeatedly, was unable to use his hands, and showed dulling of consciousness and responsiveness. His eyelids drooped, giving the eyes a hooded appearance, and he drooled saliva. V-T-EEG showed severe generalized abnormality with very frequent irregular spike-and-waves (Fig. 1). The episodes and EEG findings were suggestive of minor epileptic status (Brett, 1966). Clonazepam was started, with a marked improvement. Subsequently, the awake V-T-EEG showed theta and delta waves with intermixed paroxysmal spikes bifrontally. During laughter episodes, the E E G showed diffuse 2- to 3-Hz HVS bursts without spike discharge. The V-T-EEG recorded during a falling attack at 45 months (Fig. 2) showed disappearance of the diffuse HVS at the start of the falling attack, with bursts of lower voltage waves suggestive of desynchronization appearing for 6 s (Fig. 2D) after the fall, and the reappearance of a diffuse HVS burst for 5 s. After this - 1 5 s period, which was suggestive of an epileptic generalized seizure, he sat up by himself (Fig. 2E). MRI at age 3 years, 10 months showed poor myelination and a hypoplastic corpus callosum. Patient 2 Sleep EEG at 7 months showed only dysrhythmia. Frequent recurrent head drop developed at age

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A

B C

D

E

FIG. 2. EEG during falling attack in patient 1 at age 45 months. (A) Cessation of body movement and start of falling attack; suggestive of start of an epileptic seizure. (B) Hitting head on bed. (C) Artifact. (D)Akinetic posture in the supine position: suddenly changing bursts of lower voltage waves. ( B E ) Starting the body movement in the supine position: comparatively rhythmic high-voltage slow wave (HVS) burst. (E) Patient sitting up by himself: irregular delta and theta waves intermixed with electromyography.

14 months, at which time the V-T-EEG showed that they did not correspond to HVS bursts or spike discharges (Fig. 3). In the awake state, the EEG showed periodic 1.5- to 2-Hz extreme HVS bursts (5-10 s) mainly over the occipital region (Fig. 3). MRI at 7 months showed poor myelination and a hypoplastic corpus callosum, similar to the findings in patient 1. Patient 3 At age 19 months, patient 3 experienced a first seizure, a generalized tonic attack lasting a few minutes, accompanied by high fever. The awake V-TEEG showed periodic 2- to 4-Hz HVS bursts in all regions without seizure discharges. MRI findings at 7 months were normal.

Evoked potentials Auditory brainstem responses (ABRs), visual evoked potentials (VEPs), and somatosensory evoked potentials (SEPs) were studied with an averaging computer (Signal Processor 7S12, NEC San-ei, Tokyo, Japan). The thresholds of wave V in ABRs were above normal, and the latency of wave I was prolonged in all 3 siblings. VEPs were ob-

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tained from occipital electrodes (Oz - A1 + A2, 01 or 0 2 - A1 + A2); latencies of PI00 were normal in patient 3 but prolonged in patients 1 and 2; SEPs were normal in all 3. DISCUSSION The cause of AS has not been determined, but its occurrence in siblings suggests that some cases represent an autosomal recessive trait (Baraitser et al., 1987; Willems et al., 1987). Williams et al. (1989~) documented 15q12 deletions in 6 of 12 AS patients using a high-resolution chromosome method. We previously reported that DNA deletions in these 3 siblings were maternally derived since the mother and maternal grandfather also had a deletion at this locus (Hamabe et al., 1991). Because autosomal recessive inheritance is less likely in AS, our data support evidence obtained from genomic imprinting showing that 15qlI-ql2 deletions derived from females lead to the AS phenotype (Hamabe et al., 1991). Angelman (1965) reported very frequent attacks resembling infantile spasms. Recurrent seizures

ANGELMAN SYNDROME IN THREE SZBLINGS have been noted in 94 of 105 AS patients (90%). In 70, the epileptic seizures were described: seizures had onset at age 3 years in 13. Seizures were infantile spasms, atypical absence, myoclonic, astatic, and atonic seizures in 54 of 70 patients (77%). Generalized tonic-clonic seizures with or without fever were noted in 33, whereas only 2 patients had partial seizures. Interictal EEGs showed persistent or periodic high-voltage dysrhythmic delta and theta waves with intermixed symmetrical 2-3 Hz spike and waves mainly in the frontal region. These findings resemble those of LennoxGastaut syndrome (LGS) (Gastaut et al., 1966). The generalized seizures of most AS patients have not been recorded on EEG. In patient 1 , the falling attacks (Fig. 2) were suggestive of atonic seizures, a type of attack reported in numerous patients. The ictal EEG findings may be typical of the epileptic seizures in AS patients (Fig. 2A-E). No diffuse slow spike and waves in the interictal EEG or rapid rhythms during sleep were reported in previous case reports or noted in our siblings. Of interest are the EEG findings showing periodic HVS mainly over the occipital regions (Fig. 3). In AS patients, laughing attacks are a characteristic symptom, although the laughing attacks we recorded on V-T-EEG were not epileptic seizures (Fig. 3). The minor epileptic status noted at age 38 months in patient 1 was of special interest because previous EEG findings and symptoms have suggested minor epileptic status (Angelman, 1965; Bower and Jeavons, 1967; Eber et al., 1986; Boyd et al., 1988). The EEG (Fig. 1) and clinical findings of our patient suggest that minor epileptic status may be characteristic of AS patients. Defined by Brett in 1965, this is one form of nonconvulsive generalized status epilepticus (Gastaut, 1983). The underlying condition in patients manifesting this form of minor epileptic status is symptomatic generalized epilepsy, mainly LGS. Because AS patients have severe mental retardation, puppetlike movement, and abnormal EEG findings, distinguishing various attacks from epileptic seizures is difficult. Therefore, it is important to distinguish clinical behavior and epileptic seizures by V-T-EEG. It is important to establish whether an association exists between DNA deletion of chromosome 15 and generalized seizures. Wagstaff et al. (1991) reported deletion of the gene encoding the GABA, receptor @,-subunit in AS patients with interstitial cytogenic deletions and suggested that defects in CABA receptor function in these regions might be

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expected to produce seizures, uncontrolled behavior, and movement disorders. Saitoh et al. (1992) reported in this family the same deletion of the GABA receptor. Jay et al. (1991) reported markedly reduced GABA content in cerebellar cortex in a pathologic and neurochemical study of an AS patient. Thus, AS is a good model of symptomatic generalized epilepsy associated with DNA abnormalities. The ABR threshold in our 3 siblings was definitely increased; Few studies on the hearing of AS patients are available, but a child studied by Angelman (1965) and 2 adults have developed deafness (Williams et al., 1989b). To our knowledge, ABR findings in this condition have not been reported. The mother of our children had DNA deletion but no AS symptoms, and normal ABRs. ABR recording in a larger number of AS patients is required to establish whether ABR abnormalities are a characteristic feature of AS. Acknowledgment: This work was supported by the Mami Mizutani Foundation. We thank Professor Yohnosuke Kobayashi for encouragement.

REFERENCES Angelman H. ‘Puppet’ children. A report on three cases. Dev Med Child Neurol 1965;7:681-8. Baraitser M, Patton M, Lam STS, Brett EM, Wilson J. The Angelman (happy puppet) syndrome: is it autosomal recessive? Clin Genet 1987;31:323-30. Bower BD, Jeavons PM. The ‘happy puppet’ syndrome. Arch Dis Child 1967;42:298-302. Boyd SG, Harden A, Patton MA. The EEG in early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr 1988; 147:508-1 3. Brett EM. Minor epileptic status. J Neurol Sci 1966;3:52-75. Eber SW, Joost S , Gabriel M. Das Angelman-Syndrom. Monatsschr Kinderheilkd 1986;134:1 5 8 4 0 . Gastaut H, Roger J , Soulayrol R, et al. Childhood epileptic encephalopathy with diffuse spike-waves (otherwise known as “petit ma1 variant”) or Lennox syndrome. Epilepsia 1966;7: 139-79. Gastaut H. Classification of status epilepticus. In: DelgadoEscueta AV, Wasterlain C G , Treiman DM, Porter RJ, eds. Status epilepticus. Mechanisms of brain damage and treatment. New York: Raven Press, 1983:15-35. (Advances in neurology; vol 34.) Hamabe J, Kuroki Y, Imaizumi K, et al. DNA deletion and its paternal origin in Angelman syndrome patients. A m J Med Genet 1991 ;41:64-8. Jay V, Becker LE, Chan F-W, Perry TL. Puppet-like syndrome of Angelman: a pathological and neurochemical study. Neurology 1991 ;41:41622. Saitoh S, Kubota T, Ohta T, et al. Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABA receptor @,-subunit gene. Lancet 1992;339:36&7. Epilepsiu, Vol. 33, No.6, 1992

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Wagstaff J, Knoll JHM, Fleming J, et al. Localization of the gene encoding the GABA receptor p3 subunit to the Angelmad Prader-Willi region of human chromosome 15. Am J Hum Genet 1991;49:330-7. Willems PJ, Dijkstra I, Brouwer OF, Smit PA. Recurrence risk in the Angelman (“happy puppet”) syndrome. Am J Med Genet 1987;27:773-80. Williams CA, Gray BA, Hendrickson JE, Stone JW, Cantu ES. Incidence of 15q deletion in the Angelman syndrome: a survey of twelve affected persons. Am J Med Genet 1989a;32: 339-45. Williams CA, Hendrickson JE, Cantu ES, Donlon TA. Angelman syndrome in a daughter with del (15) (qllq13) associated with brachycephaly, hearing loss, enlarged foramen magnum, and ataxia in the mother. Am J Med Genet 1989b; 32:333-8.

RESUME Les auteurs rapportent des constatations neurologiques faites chez 3 enfants d’une m&mefratrie presentant un syndrome d’Angelman (SA), avec caryotype apparemment normal, mais dC1Ction du DNA en 15qll-q12 provenant de leur mbre. Une CICvation du seuil de la reponse auditive du tronc cCrCbral a CtC constatCe chez les 3 enfants. Les EEG intercritiques ont montre des bouffees d’ondes-lentes a 2-3 Hz de haut voltage, bi-occipitdles, et des complexes sporadiques de pointes-ondes lentes, surtout

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bi-frontales. Les elements EEG suggkrant I’existence d’un etat de ma1 non convulsif etait apparents chez le frere ah&,et pourraient representer une caracttristique clinique chez de jeunes malades avec SA. Des crises suggtrant I’existence d’une tpilepsie g6nCralisCe ont t t t constatees chez 90% des patients avec SA. Le SA est considere comme un bon modele d’epilepsie genCraliste symptomatique associee ii une dtlttion chromosomique du gbne de la sous-unit6 R3 du recepteur GABA,.

(P. Genton, Murseille)

ZUSAMMENFASSUNG Die neurologischen Befunde von drei Geschwistern mit Angelman-Syndrom (AS) mit offensichtlich normalem Karyotyp bei DNA-Deletion yon 15qll bis q12 miitterlicherseits weren beschrieben. Alle Kinder zeigten erhohte akustische Hirnstammpotentiale. Im interiktalen EEG fanden sich bioccipital amplitudenhohe Deltawellen und bifrontal sporadische slow-spike-wave Komplexe. Beim Blteren Bruder sprach das EEG fur einen nonkonvulsiven Status epilepticusdieser k6nnte fur das AS charakteristisch sein. In 90% wurde uber Anfalle aus dem Bereich generalisierter Epilepsien berichtet. Das AS kann als Modell fur symptomatische generalisierte Epilepsien betrachtet werden, welches mit der chromosomalen DNA-Deletion einer Untereinheit des Gens fur GABA, R3-Rezeptoren einhergeht. (C. G. Lipinski, Heidelher~lNeckurXemun~