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Electroclinical diagnosis of Angelman syndrome: a study of 7 cases
ELSEVIER
Brain & Development 1995; 17:64-8
Case report
Electroclinical diagnosis of Angelman syndrome: a study of 7 cases Gian Luca Casara a,*, Marilena Vecchi a, Clementina Boniver a, Paola Drigo a, Carlo Baccichetti b Lina Artifoni b, Emilio Franzoni c Valentina Marchiani c a Clinica Pediatrica I, Servizio di Neuroftsiologia, Dipartimento del Bambino, Universit~ di Padova, via Giustiniani 3, 35128 Padova Italy b Servizio di Citogenetica, Padova Italy c Clinica Pediatrica Gozzadini, Bologna Italy
Received 18 January 1994; accepted 6 September 1994
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. Keywords: A n g e l m a n syndrome; H a p p y p u p p e t syndrome; P s y c h o m o t o r retardation; Facial dysmorphism; Infantile
ataxia; Paroxysmal laughter; C h r o m o s o m e 15q-llq13 deletion; E E G
1. I N T R O D U C T I O N Angelman syndrome (AS) was first described in 1965 [1], but it is only in the last 5 years that it has been the frequent subject of reports [1-15] dealing mainly with the identification of clinical [2-4] and instrumental markers [3-7], cytogenetic investigations and, more recently, molecular biology procedures [8-14], all with a view to early diagnosis. One of the most original contributions to the literature concerns the utility of EEG in the early diagnosis of AS [5,6,15]. Boyd et al. [5] examined the EEGs of 19 cases with a confirmed clinical diagnosis of AS and identified the following three patterns that were found separately, in association or in sequence in all the patients: (i) high-amplitude (about
* Corresponding author. Fax: (39) (49) 821 3502. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00104-9
200/~V), generalized 4-6 Hz activity, occupying the majority of the record; (ii) very high-amplitude (200-500 p,V) 2-3 Hz activity in prolonged runs, more prominent anteriorly; these were mixed with spikes and sharp waves, thus forming spike-wave complexes; (iii) spikes and sharp waves mixed with high-amplitude 3-4 Hz activity, seen posteriorly; these were sometimes asymmetrical, typically triggered by eye closure. These EEG features occur very early (in the first 2 years of life) and progressively become less significant, especially in their slow component, sometimes evolving into normal or borderline traces after the age of 10 years; although they are not pathognomonic for AS, they are sufficiently characteristic to suggest or confirm its early diagnosis in an appropriate clinical context. More than 60% of the AS patients have a cytogenetically visible deletion of chromosome 15qll-q13 and 75-80% of the patients have molecular deletions [9-11]. The deletion always involves the maternally inherited chromosome 15. Angelman syndrome (AS) and Prader-Willi syndrome (PWS)
G.L. Casara et al. / Brain & Development 1995; 17:64-8
65
Table 1 Clinical features Case
Sex Age at first observation (mos) Age at last follow-up (yrs:mos) Pre-/perinatal damage Facial dysmorphism Feeding problems (mos) Retarded growth Developmental delay (mos) Absence of speech Tremor/ataxic attitude (mos) Paroxysms of laughter (mos)
1
2
3
4
5
6
7
F 2 10:3 + + + + + + (6) +
M 6 4:6 + + + (6) + + (21) -
M 18 8 + + (20) + + + (36)
F
F
F
M
11 9:8 + + + ( < 12) + + + + + (28)
7 5:5 + ÷ + (7) + + (6) +
8 4:2 + + + (6) + + + + (6) -
17 2:4 + + + + (16) + (7)
mos, months; yrs, years.
have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-q13 region of chromosome 15 as a result of deletion or uniparental disomy [10-12].
2. M A T E R I A L S A N D M E T H O D S This study involved 7 patients (4 females and 3 males) presenting to the Paediatric D e p a r t m e n t s of the University of Padova and Bologna (Italy) in the last 9 years. The age of presentation ranged from 8 to 18 months (two of the patients had previously been in the care of other medical centres); patients' ages on completion of follow-up ranged from 3 to 11 years. All patients were studied by means of repeated E E G both while awake and during spontaneous sleep. M R I a n d / o r C T were used to verify morphological conditions. As for the karyotype, any deletion of the long arm of chr. 15 was
Table 2
investigated using high-resolution banding techniques. Molecular biology procedures were effected in only one case. In all cases, the clinical diagnosis of AS was based on: (i) clinical criteria: facial dysmorphism (brachycephaly with microcephaly a n d / o r wide mouth and bowed teeth a n d / o r thin upper lip a n d / o r prognathism and protruding tongue), developmental delay, absence of speech, ataxia, paroxysms of inappropriate laughter; and (ii) characteristic E E G patterns. The presence of seizures was not considered to be essential to diagnosis. The absence of any chr. 15 deletion was considered to be not sufficient to exclude the diagnosis of AS.
3. R E S U L T S Table 1 shows presence (and age of onset) of the main clinical signs and symptoms in each patient. N o n e of the cases had any family history of AS. The mean age at initial observation was 9.8 months (range 2 - 1 8 months). The clinical conditions were found to be fairly similar in the various
Neurological features (seizures, EEG, neuroradiology) Case 1
Seizures Age of onset (mos) Type of onset Types during follow-up
15 FC Atypical absences, myoclonic fits Effective medication DZP, CZP, ACTH Age of first typical EEG (mos) 15 Slow sharp waves on eye closure Paroxysmal discharges Neuroradiology CT 0 MRI
-
2
3
4
5
6
7
-
18 FC Generalized
19 FC Atypical
21 FC Atypical
17 FC Generalized seizures VPA, CZP
seizures
absences,
absences,
myocionic fits PB, VPA, ESM
15 FC Complex partial seizures PB, CBZ
10 + (asymm)
15 + +
8 + + 0
VPA, NZP
VPA
18 + -
33 + +
myoclonic fits PB, VPA, HC, CBZ 19 + + (asymm)
+**
+*
+*
+**
-
+ *
-
-
+ *
-
FC, febrile convulsions; CZP, clonazepam; ACITI, adrenocorticotropic hormone; VPA, vaiproic acid; NZP, nitrazepam; PB, phenobarbitone; HC, hydrocortisone; CBZ, carbamazepine; ESM, ethosuximide; + *, dilatation of fluid spaces; + * *, a s p e c i f i c c e r e b r a l alterations ( s e e text).
66
G.L. Casara et al. / Brain & Development 1995; 17:64-8
&w&Kt,,
r
.
.
15~C
o
~
~
~ C~5¢. 5
.~m.
O~.O6.66
4ta rnm
~40~
3,~'.
20 0~.~o
DtP P~D. PD
Fig. 1. Case 5. Large-amplitude (200-500/zV) rhythmic activity at 2-3 Hz often prevalent in the anterior regions and persisting over time.
patients, with the earliest symptoms (developmental delay in all patients and retarded growth in three) being the more non-specific. The signs and symptoms most typical of AS (dysmorphism, ataxia, paroxysms of inappropriate laughter,
~lo.d 4~es
absence of speech) became more evident in the course of time (over the age of 2.5 years). Pre- and perinatal pathological data were reported in 3 cases. Case 2 had foetal suffering with respiratory distress at
~.
Q l el ~
~..Rig.
Fig. 2. Case 7. Spikes and sharp waves mixed with 3-4 ~ activity, mainly in the posterior regions, typically triggered by passive eye closure.
G.L. Casara et al. / Brain & Development 1995; 17." 64-8
birth (Apgar Index was 7/1', 9/5'). Case 4 had mild perinatal asphyxia with inhalation of meconium. In Case 6 the mother underwent (4th pregnancy month) an intervention for uterine retroposition and at 35 gestational weeks foetal growth retardation was echographically detected. In 5 / 7 cases signs of an early 'ataxic attitude' (tremors on handling of objects and unstable posture when seated) were also evident when the children were still not walking: these signs were already apparent at 6 months old in 3 / 5 of cases. Simultaneous polygraphic recordings showed neither repeated myoclonias nor ictal EEG patterns. Paroxysms of inappropriate laughter were absent in 2 patients. As for epileptic seizures (Table 2), observed in 6 out of 7 patients, the age of onset fell within a limited range, i.e. between 15 and 21 months. In all 6 patients, epilepsy began with apparently generalized seizures associated with fever beyond 38.5°C. One patient had never suffered from epileptic seizures, but had, however, medical treatment (in a peripheral medical centre) because of the EEG findings. Epilepsy evolved in 1 case in a complex partial form (seizures with loss of consciousness, tonic head and eyes deviation following by vomit), while a generalized form was observed in 5 cases; 3 of them had atypical absences, sometimes of considerable duration, associated with myoclonic fits. The last two patients had generalized tonic seizures. The seizures proved amenable to therapy, however, and none of the patients failed to respond to medication. The most frequent E E G findings (in 6 out of 7 patients) were a very high-amplitude, generalized slow activity (3-4 Hz) (Fig. 1), prevalent in the posterior regions. In 5 out of 7 cases, there were specific abnormalities posteriorly (both spikes and sharp waves, mixed with high-amplitude activity at 3-4 Hz), typically activated by eye closure (Fig. 2), which were asymmetrical in 1 case. Different abnormalities occurred in combination and were multifocal in 5 cases. The first EEG recording was typical for AS in all cases; in 5 patients the characteristic patterns were evident before 19 months (within the first 12 months in 2). The slow, high-voltage activity persisted in 6 out of 7 cases, whereas one patient shifted to a borderline pattern. Six patients underwent MRI (associated with CT in 5 cases) to verify the presence of any brain lesions (Table 2); one patient underwent C'I" only. In 4 cases, CT revealed dilatation of the fluid spaces, associated in 2 patients with alterations to the parenchyma (temporo-polar atrophy in Case 3, hypodensity of the left external capsule in Case 5). MRI confirmed only the dilatation of the fluid spaces, already seen by CT in two cases. All patients underwent genetic testing and karyotype investigations (Table 3). In 4 cases, the cytogenetic analysis Table 3 Karyotypeanalysis Cases Karyotypes 46,XY 46,XY/47,XY+ inv dup (15) 46,XY 46,XX, del. (15) (q11.1q12) 46,XX, dee (15) (qll.lql2) 46,XX 46,XY
67
detected no abnormalities; in 2 cases, it revealed deletion of the 15q11-12; 1 patient was found to have a small extra chromosome derived from chromosome 15 [inv dup (15)]mosaicism. A molecular deletion was found in Case 1, although cytogenetic study was normal.
4. D I S C U S S I O N Some considerations can be drawn from a review of the cases described here and elsewhere in the literature. AS features a peculiar evolution in the clinical and EEG picture. Diagnosis is based on the clinical, EEGic and cytogenetic characteristics. Clinical and EEGic suspicion addresses karyotype analysis. It is important to anticipate possible clinical suspicion as soon as possible for a proper genetic consultation. It has recently been suggested that, in a suspect clinical context, the presence of certain non-specific signs and symptoms may help an early diagnosis of AS [5]. These include feeding problems and retarded growth in the first 6 months, along with an 'ataxic attitude' that becomes a useful diagnostic element during the first 2 years, when the typical puppetlike gait obviously cannot be detected because the child is not yet walking, and other clinical features (facial dysmorphisms, paroxysms of laughter, etc.) are still not apparent [5,14]. With the EEG patterns typical of AS it has become possible to anticipate the mean age of diagnosis of AS, which used to be around 6 years old [5]. The EEG patterns observed in our 7 cases were characteristic of AS within the 19th month of life; they also contributed significantly to the diagnosis when this had yet to be formulated on the basis of clinical data. We suggest that a child less than 1 year old who has cryptogenic developmental delay and a typical EEG pattern is required to undergo cytogenetic tests to check for AS. The neuro-imaging data obtained in our patients were mainly normal, or at least non-specific. The literature provides little information on this aspect [7]. Yamada and Volpe [3] report a case with mild dilatation of the third ventricle, enlarged subarachnoid spaces and focal areas of increased signal intensity (in the T2-weighted images) in the frontal and occipital white matter and at internal capsule level. Van Lierde et al. [4] reported a slight cerebral atrophy, with dilatation of the Sylvian fissure associated with agenesis of the ipsilateral temporal pole. These findings do not seem to support any morphological change lying behind the altered electrical activity detected by the EEG; moreover, the transient nature of the abnormal EEG findings would seem to confirm that they are not due to any lesion but probably are magnified by a particular phase in the child's cerebral development. AS is associated with a genetic defect, but while the diagnosis of AS is confirmed by the finding of a deletion of the long arm of chr. 15, said diagnosis cannot be excluded on failure to find this condition. In fact, analysis of the karyotype with high-resolution banding techniques only detects this microdeletion in 60% of cases of AS [10,11]. In the remainder, molecular biology succeeds in identifying DNA alterations in the 15q11-13 region in 15% of cases. The gene for the GABA receptor subunit/33 has recently been identi-
68
G.L. Casara et al. / Brain & Development 1995; 17:64-8
lied in this region [12,13,15]. Other authors reported a quantitative defect in G A B A in a family with AS [13]. A small percentage of AS patients has paternal uniparental disomy for the whole chromosome 15. In 15% of AS patients it has proved impossible to demonstrate any genetic changes. According to Clayton-Smith [2], this group includes cases at the highest risk of recurrence and cases with a family history of the disease. Although AS is the result of different genetic mechanisms, the outcome in terms of clinical features and E E G findings remains the same. In the 7 cases presented here, no significant differences were found in terms of clinical findings and E E G records between patients with a documented deletion of the 15q11-13 by comparison with those presenting a normal cytogenetic picture or the patient with an extra inverted duplicated chromosome 15 or the patient with microdeletion documented by molecular biology. It seems interesting to note the epileptic behaviour in our series: in all 6 patients with seizures these began with convulsions associated with fever by the age of 21 months [14,15]. The three patients with a documented chr. 15 defect (Cases 1, 4, 5) developed atypical absence seizures associated with myoclonic fits, as in the cases reported by Matsumoto et al. [14]. In conclusion, our study of the 7 patients described here confirms the particular evolution of AS. E E G is particularly useful, whether epileptic seizures have occurred or not, and is one of the most specific parameters for early diagnosis of the syndrome. The combination of certain (non-specific) clinical finding of early onset, together with the E E G features described above, can give rise to a relatively reliable diagnosis of suspect AS. This should lead to high-resolution cytogenetic investigations and, if these should prove negative, then molecular biology must be used to check for any submicroscopic deletions. REFERENCES 1. Angelman H. 'Puppet' children. A report on three cases. Dev Med Child Neurol 1965; 7: 681-8.
2. Clayton-Smith J. Angelman's syndrome. Arch Dis Child 1992; 67: 889-91. 3. Yamada KA, Volpe JJ. Angelman's syndrome in infancy. Dev Med Child Neurol 1990; 32: 1005-10. 4. Van Lierde A, Atza MG, Giardino D, Viani F. Angelman's syndrome in the first year of life. Dev Med Child Neurol 1990; 32: 1011-21. 5. Boyd SG, Harden A, Patton MA. The EEG in the early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr 1988; 147: 508-13. 6. Ganji S, Duncan MC. Angelman's (happy puppet) syndrome: clinical, CT scan and serial electroencephalographic study. Clin Electroencephalogr 1989; 20: 128-40. 7. Dorries A, Spohr HL, Kunze J. Angelman ('happy puppet') syndrome: seven new cases documented by cerebral computed tomography: review of the literature. Eur J Pediatr 1988; 148: 270-3. 8. Beuten J, Mangelschots K, Buntinx I, et al. Molecular study of chromosome 15 in 22 patients with Angelman syndrome. Hum Genet 1993; 90: 489-95. 9. Meijers-Heijboer E J, Sandkuijl LA, Brunner HG, et al. Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. J Med Genet 1992; 29: 853-7. 10. Knoll JHM, Wagstaff J, Lalande M. Cytogenetic and molecular studies in the Prader-Willi and Angelman syndromes: an overview. A m J Med Genet 1993; 46: 2-6. 11. Nicholls RD. Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. A m J Med Genet 1993; 46: 16-25. 12. Wagstaff J, Knoll JHM, Fleming J, et al. Localization of the gene encoding the G A B A receptor /33-subunit to the Angelman/Prader-Willi region of human chromosome 15. A m J Hum Genet 1991; 49: 330-7. 13. Saitoh S, Kubota T, Ohta T, et al. Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABA receptor fl3-subunit gene. Lancet 1992; 339: 366-7. 14. Matsumoto A, Kumagai T, Miura K, et al. Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia 1992; 33: 1083-90. 15. Sugimoto T, Yasuhara A, Ohta T, et al. Angelman syndrome in three siblings: characteristic epileptic seizures and EEG abnormalities. Epilepsia 1992; 33: 1078-82.
Brain & Development 1995; 17:64-8
Case report
Electroclinical diagnosis of Angelman syndrome: a study of 7 cases Gian Luca Casara a,*, Marilena Vecchi a, Clementina Boniver a, Paola Drigo a, Carlo Baccichetti b Lina Artifoni b, Emilio Franzoni c Valentina Marchiani c a Clinica Pediatrica I, Servizio di Neuroftsiologia, Dipartimento del Bambino, Universit~ di Padova, via Giustiniani 3, 35128 Padova Italy b Servizio di Citogenetica, Padova Italy c Clinica Pediatrica Gozzadini, Bologna Italy
Received 18 January 1994; accepted 6 September 1994
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. Keywords: A n g e l m a n syndrome; H a p p y p u p p e t syndrome; P s y c h o m o t o r retardation; Facial dysmorphism; Infantile
ataxia; Paroxysmal laughter; C h r o m o s o m e 15q-llq13 deletion; E E G
1. I N T R O D U C T I O N Angelman syndrome (AS) was first described in 1965 [1], but it is only in the last 5 years that it has been the frequent subject of reports [1-15] dealing mainly with the identification of clinical [2-4] and instrumental markers [3-7], cytogenetic investigations and, more recently, molecular biology procedures [8-14], all with a view to early diagnosis. One of the most original contributions to the literature concerns the utility of EEG in the early diagnosis of AS [5,6,15]. Boyd et al. [5] examined the EEGs of 19 cases with a confirmed clinical diagnosis of AS and identified the following three patterns that were found separately, in association or in sequence in all the patients: (i) high-amplitude (about
* Corresponding author. Fax: (39) (49) 821 3502. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00104-9
200/~V), generalized 4-6 Hz activity, occupying the majority of the record; (ii) very high-amplitude (200-500 p,V) 2-3 Hz activity in prolonged runs, more prominent anteriorly; these were mixed with spikes and sharp waves, thus forming spike-wave complexes; (iii) spikes and sharp waves mixed with high-amplitude 3-4 Hz activity, seen posteriorly; these were sometimes asymmetrical, typically triggered by eye closure. These EEG features occur very early (in the first 2 years of life) and progressively become less significant, especially in their slow component, sometimes evolving into normal or borderline traces after the age of 10 years; although they are not pathognomonic for AS, they are sufficiently characteristic to suggest or confirm its early diagnosis in an appropriate clinical context. More than 60% of the AS patients have a cytogenetically visible deletion of chromosome 15qll-q13 and 75-80% of the patients have molecular deletions [9-11]. The deletion always involves the maternally inherited chromosome 15. Angelman syndrome (AS) and Prader-Willi syndrome (PWS)
G.L. Casara et al. / Brain & Development 1995; 17:64-8
65
Table 1 Clinical features Case
Sex Age at first observation (mos) Age at last follow-up (yrs:mos) Pre-/perinatal damage Facial dysmorphism Feeding problems (mos) Retarded growth Developmental delay (mos) Absence of speech Tremor/ataxic attitude (mos) Paroxysms of laughter (mos)
1
2
3
4
5
6
7
F 2 10:3 + + + + + + (6) +
M 6 4:6 + + + (6) + + (21) -
M 18 8 + + (20) + + + (36)
F
F
F
M
11 9:8 + + + ( < 12) + + + + + (28)
7 5:5 + ÷ + (7) + + (6) +
8 4:2 + + + (6) + + + + (6) -
17 2:4 + + + + (16) + (7)
mos, months; yrs, years.
have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-q13 region of chromosome 15 as a result of deletion or uniparental disomy [10-12].
2. M A T E R I A L S A N D M E T H O D S This study involved 7 patients (4 females and 3 males) presenting to the Paediatric D e p a r t m e n t s of the University of Padova and Bologna (Italy) in the last 9 years. The age of presentation ranged from 8 to 18 months (two of the patients had previously been in the care of other medical centres); patients' ages on completion of follow-up ranged from 3 to 11 years. All patients were studied by means of repeated E E G both while awake and during spontaneous sleep. M R I a n d / o r C T were used to verify morphological conditions. As for the karyotype, any deletion of the long arm of chr. 15 was
Table 2
investigated using high-resolution banding techniques. Molecular biology procedures were effected in only one case. In all cases, the clinical diagnosis of AS was based on: (i) clinical criteria: facial dysmorphism (brachycephaly with microcephaly a n d / o r wide mouth and bowed teeth a n d / o r thin upper lip a n d / o r prognathism and protruding tongue), developmental delay, absence of speech, ataxia, paroxysms of inappropriate laughter; and (ii) characteristic E E G patterns. The presence of seizures was not considered to be essential to diagnosis. The absence of any chr. 15 deletion was considered to be not sufficient to exclude the diagnosis of AS.
3. R E S U L T S Table 1 shows presence (and age of onset) of the main clinical signs and symptoms in each patient. N o n e of the cases had any family history of AS. The mean age at initial observation was 9.8 months (range 2 - 1 8 months). The clinical conditions were found to be fairly similar in the various
Neurological features (seizures, EEG, neuroradiology) Case 1
Seizures Age of onset (mos) Type of onset Types during follow-up
15 FC Atypical absences, myoclonic fits Effective medication DZP, CZP, ACTH Age of first typical EEG (mos) 15 Slow sharp waves on eye closure Paroxysmal discharges Neuroradiology CT 0 MRI
-
2
3
4
5
6
7
-
18 FC Generalized
19 FC Atypical
21 FC Atypical
17 FC Generalized seizures VPA, CZP
seizures
absences,
absences,
myocionic fits PB, VPA, ESM
15 FC Complex partial seizures PB, CBZ
10 + (asymm)
15 + +
8 + + 0
VPA, NZP
VPA
18 + -
33 + +
myoclonic fits PB, VPA, HC, CBZ 19 + + (asymm)
+**
+*
+*
+**
-
+ *
-
-
+ *
-
FC, febrile convulsions; CZP, clonazepam; ACITI, adrenocorticotropic hormone; VPA, vaiproic acid; NZP, nitrazepam; PB, phenobarbitone; HC, hydrocortisone; CBZ, carbamazepine; ESM, ethosuximide; + *, dilatation of fluid spaces; + * *, a s p e c i f i c c e r e b r a l alterations ( s e e text).
66
G.L. Casara et al. / Brain & Development 1995; 17:64-8
&w&Kt,,
r
.
.
15~C
o
~
~
~ C~5¢. 5
.~m.
O~.O6.66
4ta rnm
~40~
3,~'.
20 0~.~o
DtP P~D. PD
Fig. 1. Case 5. Large-amplitude (200-500/zV) rhythmic activity at 2-3 Hz often prevalent in the anterior regions and persisting over time.
patients, with the earliest symptoms (developmental delay in all patients and retarded growth in three) being the more non-specific. The signs and symptoms most typical of AS (dysmorphism, ataxia, paroxysms of inappropriate laughter,
~lo.d 4~es
absence of speech) became more evident in the course of time (over the age of 2.5 years). Pre- and perinatal pathological data were reported in 3 cases. Case 2 had foetal suffering with respiratory distress at
~.
Q l el ~
~..Rig.
Fig. 2. Case 7. Spikes and sharp waves mixed with 3-4 ~ activity, mainly in the posterior regions, typically triggered by passive eye closure.
G.L. Casara et al. / Brain & Development 1995; 17." 64-8
birth (Apgar Index was 7/1', 9/5'). Case 4 had mild perinatal asphyxia with inhalation of meconium. In Case 6 the mother underwent (4th pregnancy month) an intervention for uterine retroposition and at 35 gestational weeks foetal growth retardation was echographically detected. In 5 / 7 cases signs of an early 'ataxic attitude' (tremors on handling of objects and unstable posture when seated) were also evident when the children were still not walking: these signs were already apparent at 6 months old in 3 / 5 of cases. Simultaneous polygraphic recordings showed neither repeated myoclonias nor ictal EEG patterns. Paroxysms of inappropriate laughter were absent in 2 patients. As for epileptic seizures (Table 2), observed in 6 out of 7 patients, the age of onset fell within a limited range, i.e. between 15 and 21 months. In all 6 patients, epilepsy began with apparently generalized seizures associated with fever beyond 38.5°C. One patient had never suffered from epileptic seizures, but had, however, medical treatment (in a peripheral medical centre) because of the EEG findings. Epilepsy evolved in 1 case in a complex partial form (seizures with loss of consciousness, tonic head and eyes deviation following by vomit), while a generalized form was observed in 5 cases; 3 of them had atypical absences, sometimes of considerable duration, associated with myoclonic fits. The last two patients had generalized tonic seizures. The seizures proved amenable to therapy, however, and none of the patients failed to respond to medication. The most frequent E E G findings (in 6 out of 7 patients) were a very high-amplitude, generalized slow activity (3-4 Hz) (Fig. 1), prevalent in the posterior regions. In 5 out of 7 cases, there were specific abnormalities posteriorly (both spikes and sharp waves, mixed with high-amplitude activity at 3-4 Hz), typically activated by eye closure (Fig. 2), which were asymmetrical in 1 case. Different abnormalities occurred in combination and were multifocal in 5 cases. The first EEG recording was typical for AS in all cases; in 5 patients the characteristic patterns were evident before 19 months (within the first 12 months in 2). The slow, high-voltage activity persisted in 6 out of 7 cases, whereas one patient shifted to a borderline pattern. Six patients underwent MRI (associated with CT in 5 cases) to verify the presence of any brain lesions (Table 2); one patient underwent C'I" only. In 4 cases, CT revealed dilatation of the fluid spaces, associated in 2 patients with alterations to the parenchyma (temporo-polar atrophy in Case 3, hypodensity of the left external capsule in Case 5). MRI confirmed only the dilatation of the fluid spaces, already seen by CT in two cases. All patients underwent genetic testing and karyotype investigations (Table 3). In 4 cases, the cytogenetic analysis Table 3 Karyotypeanalysis Cases Karyotypes 46,XY 46,XY/47,XY+ inv dup (15) 46,XY 46,XX, del. (15) (q11.1q12) 46,XX, dee (15) (qll.lql2) 46,XX 46,XY
67
detected no abnormalities; in 2 cases, it revealed deletion of the 15q11-12; 1 patient was found to have a small extra chromosome derived from chromosome 15 [inv dup (15)]mosaicism. A molecular deletion was found in Case 1, although cytogenetic study was normal.
4. D I S C U S S I O N Some considerations can be drawn from a review of the cases described here and elsewhere in the literature. AS features a peculiar evolution in the clinical and EEG picture. Diagnosis is based on the clinical, EEGic and cytogenetic characteristics. Clinical and EEGic suspicion addresses karyotype analysis. It is important to anticipate possible clinical suspicion as soon as possible for a proper genetic consultation. It has recently been suggested that, in a suspect clinical context, the presence of certain non-specific signs and symptoms may help an early diagnosis of AS [5]. These include feeding problems and retarded growth in the first 6 months, along with an 'ataxic attitude' that becomes a useful diagnostic element during the first 2 years, when the typical puppetlike gait obviously cannot be detected because the child is not yet walking, and other clinical features (facial dysmorphisms, paroxysms of laughter, etc.) are still not apparent [5,14]. With the EEG patterns typical of AS it has become possible to anticipate the mean age of diagnosis of AS, which used to be around 6 years old [5]. The EEG patterns observed in our 7 cases were characteristic of AS within the 19th month of life; they also contributed significantly to the diagnosis when this had yet to be formulated on the basis of clinical data. We suggest that a child less than 1 year old who has cryptogenic developmental delay and a typical EEG pattern is required to undergo cytogenetic tests to check for AS. The neuro-imaging data obtained in our patients were mainly normal, or at least non-specific. The literature provides little information on this aspect [7]. Yamada and Volpe [3] report a case with mild dilatation of the third ventricle, enlarged subarachnoid spaces and focal areas of increased signal intensity (in the T2-weighted images) in the frontal and occipital white matter and at internal capsule level. Van Lierde et al. [4] reported a slight cerebral atrophy, with dilatation of the Sylvian fissure associated with agenesis of the ipsilateral temporal pole. These findings do not seem to support any morphological change lying behind the altered electrical activity detected by the EEG; moreover, the transient nature of the abnormal EEG findings would seem to confirm that they are not due to any lesion but probably are magnified by a particular phase in the child's cerebral development. AS is associated with a genetic defect, but while the diagnosis of AS is confirmed by the finding of a deletion of the long arm of chr. 15, said diagnosis cannot be excluded on failure to find this condition. In fact, analysis of the karyotype with high-resolution banding techniques only detects this microdeletion in 60% of cases of AS [10,11]. In the remainder, molecular biology succeeds in identifying DNA alterations in the 15q11-13 region in 15% of cases. The gene for the GABA receptor subunit/33 has recently been identi-
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lied in this region [12,13,15]. Other authors reported a quantitative defect in G A B A in a family with AS [13]. A small percentage of AS patients has paternal uniparental disomy for the whole chromosome 15. In 15% of AS patients it has proved impossible to demonstrate any genetic changes. According to Clayton-Smith [2], this group includes cases at the highest risk of recurrence and cases with a family history of the disease. Although AS is the result of different genetic mechanisms, the outcome in terms of clinical features and E E G findings remains the same. In the 7 cases presented here, no significant differences were found in terms of clinical findings and E E G records between patients with a documented deletion of the 15q11-13 by comparison with those presenting a normal cytogenetic picture or the patient with an extra inverted duplicated chromosome 15 or the patient with microdeletion documented by molecular biology. It seems interesting to note the epileptic behaviour in our series: in all 6 patients with seizures these began with convulsions associated with fever by the age of 21 months [14,15]. The three patients with a documented chr. 15 defect (Cases 1, 4, 5) developed atypical absence seizures associated with myoclonic fits, as in the cases reported by Matsumoto et al. [14]. In conclusion, our study of the 7 patients described here confirms the particular evolution of AS. E E G is particularly useful, whether epileptic seizures have occurred or not, and is one of the most specific parameters for early diagnosis of the syndrome. The combination of certain (non-specific) clinical finding of early onset, together with the E E G features described above, can give rise to a relatively reliable diagnosis of suspect AS. This should lead to high-resolution cytogenetic investigations and, if these should prove negative, then molecular biology must be used to check for any submicroscopic deletions. REFERENCES 1. Angelman H. 'Puppet' children. A report on three cases. Dev Med Child Neurol 1965; 7: 681-8.
2. Clayton-Smith J. Angelman's syndrome. Arch Dis Child 1992; 67: 889-91. 3. Yamada KA, Volpe JJ. Angelman's syndrome in infancy. Dev Med Child Neurol 1990; 32: 1005-10. 4. Van Lierde A, Atza MG, Giardino D, Viani F. Angelman's syndrome in the first year of life. Dev Med Child Neurol 1990; 32: 1011-21. 5. Boyd SG, Harden A, Patton MA. The EEG in the early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr 1988; 147: 508-13. 6. Ganji S, Duncan MC. Angelman's (happy puppet) syndrome: clinical, CT scan and serial electroencephalographic study. Clin Electroencephalogr 1989; 20: 128-40. 7. Dorries A, Spohr HL, Kunze J. Angelman ('happy puppet') syndrome: seven new cases documented by cerebral computed tomography: review of the literature. Eur J Pediatr 1988; 148: 270-3. 8. Beuten J, Mangelschots K, Buntinx I, et al. Molecular study of chromosome 15 in 22 patients with Angelman syndrome. Hum Genet 1993; 90: 489-95. 9. Meijers-Heijboer E J, Sandkuijl LA, Brunner HG, et al. Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. J Med Genet 1992; 29: 853-7. 10. Knoll JHM, Wagstaff J, Lalande M. Cytogenetic and molecular studies in the Prader-Willi and Angelman syndromes: an overview. A m J Med Genet 1993; 46: 2-6. 11. Nicholls RD. Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. A m J Med Genet 1993; 46: 16-25. 12. Wagstaff J, Knoll JHM, Fleming J, et al. Localization of the gene encoding the G A B A receptor /33-subunit to the Angelman/Prader-Willi region of human chromosome 15. A m J Hum Genet 1991; 49: 330-7. 13. Saitoh S, Kubota T, Ohta T, et al. Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABA receptor fl3-subunit gene. Lancet 1992; 339: 366-7. 14. Matsumoto A, Kumagai T, Miura K, et al. Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia 1992; 33: 1083-90. 15. Sugimoto T, Yasuhara A, Ohta T, et al. Angelman syndrome in three siblings: characteristic epileptic seizures and EEG abnormalities. Epilepsia 1992; 33: 1078-82.