Original Paper Received: October 29, 2014 Accepted: October 29, 2014 Published online: November 29, 2014
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
Angelman Syndrome: A Case Series Assessing Neurological Issues in Adulthood Marie Giroud a Benoît Daubail c Norbert Khayat b Mondher Chouchane d Eric Berger a Emelyne Muzard a Elisabeth Medeiros de Bustos a Christel Thauvin-Robinet e Laurence Faivre e Alice Masurel e Véronique Darmency-Stamboul d Frédéric Huet d, e Yannick Béjot c Maurice Giroud c Thierry Moulin a
Departments of a Neurology and b Electrophysiology, University Hospital of Besançon, Besançon, c Department of Neurology, University Hospital of Dijon and EA4184 of the University of Burgundy, d Department of Paediatrics, University Hospital of Dijon, and e Federation Translad, The Genetic Centre and EA4271 of The University of Burgundy, Dijon, France
Abstract Background: This study aimed to evaluate the clinical symptoms of Angelman syndrome (AS) in adults and to identify the neurological pathways affected in this disease. AS is a neurogenetic disorder resulting due to the deletion or inactivation of the ubiquitin-protein-ligase E3A gene on maternal chromosome 15. Summary: A retrospective analysis of data from six adults patients with clinical, electroencephalographic and genetic confirmation of AS was performed. Movement disorders of the hands and mouth, laughing spells, severe expressive speech disorders, a happy nature, hyposomnia and anxiety are the major neurological characteristics of AS in adulthood. Cerebellar ataxia, muscle hypotonia and tremor, though constant in childhood, tend to be attenuated in adulthood. Epilepsy, one of the most frequent symptoms in childhood and in adulthood, is characterised
© 2014 S. Karger AG, Basel 0014–3022/14/0732–0119$39.50/0 E-Mail [email protected] www.karger.com/ene
by specific electroencephalographic patterns. Key Messages: These clinical characteristics are important to improve the clinical awareness and genetic diagnosis of AS. Clinicians must be better informed concerning the adult phenotype as it is not well described in the literature. We stress the importance of AS as one of the main causes of intractable epilepsy. The authors suggest frontal and cerebellar dysfunction. Further functional cerebral imaging studies are necessary. © 2014 S. Karger AG, Basel
Introduction
Angelman Syndrome (AS) is a neurogenetic disease resulting due to the deletion or inactivation of the ubiquitin-protein ligase E3A gene (UBE3A) on chromosome 15 [1–3]. UBE3A plays a major role in the cellular ubiquitin-proteasome pathway, which has a major influence in synaptic development and neuronal plasticity [4, 6]. Four genetic mechanisms are responsible for the AS phenotype [3, 4]: (1) the microdeletion of the maternal Prof. Maurice Giroud Neurology Service – CHU 14 Rue Gaffarel, FR–2100 Dijon (France) E-Mail maurice.giroud @ chu-dijon.fr
Downloaded by: Selçuk Universitesi 193.255.248.150 - 2/2/2015 6:49:29 PM
Key Words Epilepsy · Movement disorders · Ataxia · Laughing seizures · Genetics
Methods Data from AS patients who were treated by the Genetics, Neurological and Electroencephalographic departments of the University Hospital of Dijon and Besançon (France), were screened. Only patients with an AS diagnosis that was confirmed by molecular analyses [7] with one of the four classical mechanisms [4, 8], were included. Clinical 16 channel EEG studies were recorded for at least 30 minutes in both awake and sleeping patients. We recorded the following data: birth conditions, mental and neurological development, physical description, neurological, cognitive and psychiatric disorders, types of epileptic seizures, and sleep dysfunction.
Results
Six patients older than 18 years of age were recruited (3 cases with maternal deletion, 2 cases with paternal disomy and 1 case with a UBE3A mutation). In all cases, the birth weight was normal. The clinical features included axial hypotonia, flat occiput bone (4/6), 120
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
swallowing troubles (4/6), and congenital stridor (3/6) (table 1). The initial evolution in all cases was characterised by facial dysmorphism including a large mouth (6/6), prognathism (5/6) and microcephaly (2/6). Later, widely spaced teeth (5/6) and scoliosis (6/6) were observed. Psychomotor and neurological development was marked by hypotonia associated with a walking delay acquired at a mean age of approximately 24 months and intellectual deficiency with no expressive language but better receptive language in all cases. The neurological symptoms were characterised by cerebellar ataxia in childhood (6/6), immediately after independent walking had been acquired. Uplifted arms (5/6) were associated with increased deep tendons reflexes and central swallowing disorders. For the 4 of the 6 patients who experienced epileptic seizures, most of the seizures appeared after 1 year of age except for two patients who experienced West syndrome at 6 months (cases 2 and 3), as documented by EEG. There were multiple seizures (e.g., tonic, atonic and tonic-clonic seizures, myoclonus and absences), that were initially resistant to antiepileptic drugs. EEGs were characterised by posterior delta waves, with or without eyeclosure-related spikes in childhood. These spikes shifted towards anterior regions in adulthood. Behavioural troubles were characterised by obsessivecompulsive behaviour (5/6), particularly for water (1/5) and food (4/5), which led to obesity. Abnormal arm movements (hand flapping) were observed mainly during periods of anxiety or great happiness (5/6). Smiling, a happy nature and laughing seizures were the main identifiable features observed during the outpatient consultations in childhood and in adulthood (6/6). In two cases, the parents also reported laughing seizures during sleep. In contrast, noise intolerance was an unusual symptom (1/6). Other primary features included strabismus (2/6) and hypopigmented skin in two cases. Puberty was normal in all cases. Brain MRI performed in two cases (between 2 and 4 years of age) revealed a thin corpus callosum associated with frontal atrophy and hypomyelination. The course in adulthood is interesting because some neurological manifestations were more pronounced. In all six patients (table 1), the remaining symptoms included dysmorphism (with a typical large mouth and widely spaced teeth) (figure 1) and severe intellectual deficiency (with typical speech disturbances associated with the lack of expressive language and relatively good receptive language). The behavioural troubles were stable and Giroud et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 2/2/2015 6:49:29 PM
15q11.2–13.1 allele, the most common molecular subtype (68%), (occurring de novo in most of the cases), explains the low recurrence rate [4]; (2) mutations in the UBE3A gene, the second most common genotype (12%), have a high recurrence rate (up to 50%) in contrast to the deletion group; (3) the paternal uniparental disomy (3–8%), which is secondary to the inheritance of two paternal copies of chromosome 15, has a low recurrence rate (200 μvolts) theta waves (44%) and slow posterior activity (44%) [19]. Posterior sharp waves easily triggered by passive eye closure correlate with clinically severe epileptic seizures [19, 20] and can be mixed with epileptic discharges [17, 21]. Spikes tend to move from the posterior to the anterior regions of the brain over time [21], as observed in the six cases presented here. Finally, these EEG patterns are observed across all genotypes [19]. They may precede the diagnosis [17, 19] but are not absolutely specific [3, 7, 22]. Neuro-imaging studies may be normal but show global atrophy and abnormal myelination in the frontal lobes, as well as a thin corpus callosum [23, 24], in approximately 60% of the cases [25]. This MRI finding is now an important feature in the evaluation and
124
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
We observed that the AS symptoms change with age, reflecting the maturational pattern of the brain, as previously observed in AS adults [3, 28]. It is important for clinicians to understand the clinical and EEG features of adult AS. Moreover, our study is interesting in that it provides a greater understanding of the AS neurological manifestations and may inspire the development of new approaches in therapeutic research.
Acknowledgments The authors thank Philip Bastable for his language assistance.
Contributors M.G. and B.D. collected the clinical files and drafted the original manuscript, N.K., M.C., C.T.-R., L.F., A.M. and V.D.-S. contributed to the patient diagnoses and follow-ups, and E.B., E.M., E.M. de B., F.H., Y.B., M.G. and T.M. contributed to the study design and manuscript revision.
Funding This study received no financial support.
Competing Interests None reported.
Provenance and Peer Review This study was not commissioned but was peer reviewed externally.
References
1 Kishino T, Lalande M, Wagstaff J: UBE3A/ E6-AP mutations cause Angelman syndrome. Nat Genet 1997;15:70–73. 2 Albrecht U, Sutcliffe JS, Cattanach BM, et al: Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet 1997; 17: 75–78. 3 Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA: Neurologic manifestations of Angelman syndrome. Pediatr Neurol 2013; 48: 271–279. 4 Dagli A, Buiting K, Williams CA: Molecular and clinical aspects of Angelman syndrome. Mol Syndromol 2011;2:100–112.
Giroud et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 2/2/2015 6:49:29 PM
understanding of AS and may explain the language and motor difficulties observed in patients [23, 25]. The second specificity concerns the hypothesis of the pathophysiology of AS and the localisation of the cerebral dysfunction. Movement and muscle tone disorders may be induced by a disorder of the first motor neuron manifesting as spasticity in adulthood, with late hypertonia of legs [6], walking with up-lifted arms in childhood, increased deep tendon reflexes and central swallowing disorders. There may also be a cerebellar syndrome marked by ataxia with broad-based, asymmetric movement of the limbs and tremor, which is more present in childhood. Early hypotonia observed mainly during infancy [6] may indicate the cerebellar disturbance, which may overshadow the pyramidal syndrome in this period, explaining the great prevalence of scoliosis and a flat occipital bone. A frontal syndrome may be suggested by the presence of certain symptoms including hyperactive behaviour, restlessness, distractibility [11], stereotypical obsessive compulsive stereotyped activities (hand flapping), and self-mutilation or aggressive behaviour. Epileptiform discharges tend to shift towards the frontal region [21] as observed in all cases, and reflect the functional neurochemical or maturational disorder of the frontal area: from a pathophysiological point of view as suggested by MRI [23–26], the mechanism could consist of delayed myelination, associated with a thin corpus callosum [23, 26]. A previous study [27] using diffusion tensor imaging has demonstrated that in addition to delayed myelination, there was decreased axonal density and aberrant axonal organisation mainly in the temporal pathways, which partly explained the language, cognitive and social functioning disorders [26, 27]. Frequent and inappropriate laughter, a common symptom in all AS patients, could be the consequence of a pyramidal syndrome, the so-called spasmodic laughter of the pseudo-bulbar syndrome. The second explanation could be of an epileptic origin, so-called gelastic seizures. Gelastic seizures are characteristic of hypothalamic hamartomas. However, we found no references to hypothalamic hamartomas in any published AS study. We did not record any epileptic discharges on the EEG during laughter: although we observed 2 cases of laughter during the night, it is clearly not epileptic. The limitations of our study are its retrospective nature, the very small number of patients, the absence of a detailed description of the seizures and the lack of long polygraphic EEGs. Broad conclusions cannot be drawn from 6 subjects.
Angelman Syndrome in Adulthood
13 Galvan-Manso M, Campistol J, Conill J, Sanmarti FX: Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome. Epileptic Disord 2005;7:19–25. 14 Thibert RL, Conant KD, Braun EK, et al: Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia 2009;50:2369–2376. 15 Valente KD, Koiffmann CP, Fridman C, et al: Epilepsy in patients with Angelman syndrome caused by deletion of the chromosome 15q11–13. Arch Neurol 2006;63:122–128. 16 Buoni S, Grosso S, Pucci L, Fois A: Diagnosis of Angelman syndrome: clinical and EEG criteria. Brain Dev 1999;21:296–302. 17 Uemura N, Matsumoto A, Nakamura M, et al: Evolution of seizures and electroencephalographical findings in 23 cases of deletion type Angelman syndrome. Brain Dev 2005; 27: 383–388. 18 Espay AJ, Andrade DM, Wennberg RA, Lang AE: Atypical absences and recurrent absence status in an adult with Angelman syndrome due to the UBE3A mutation. Epileptic Disord 2005;7:227–230. 19 Vendrame M, Loddenkemper T, Zarowski M, Gregas M, Shuhaiber H, Sarco DP, Morales A, Nespeca M, Sharpe C, Haas K, Barnes G, Glaze D, Kothare SV: Analysis of EEG patterns and genotypes in patients with Angelman syndrome. Epilepsy Behav 2012;23:261– 265.
20 Valente KD, Andrade JQ, Grossmann RM, et al: Angelman syndrome: difficulties in EEG pattern recognition and possible misinterpretations. Epilepsia 2003;44:1051–1063. 21 Yum MS, Lee EH, Kim JH, Ko TS, Yoo HW: Implications of slow waves and shifting epileptiform discharges in Angelman syndrome. Brain Dev 2013;35:245–251. 22 Laan LA, Vein AA: A Rett patient with a typical Angelman EEG. Epilepsia 2002;43:1590– 1592. 23 Harting I, Seitz A, Rating D, Sartor K, Zschocke J, Janssen B, Ebinger F, Wolf NI: Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2009; 13: 271– 276. 24 Peters SU, Kaufmann WE, Bacino CA, et al: Alterations in white matter pathways in Angelman syndrome. Dev Med Child Neurol 2010;53:361–367. 25 Castro-Gago M, Gómez-Lado C, Eirís-Puňal J, et al: Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2010;14:292. 26 Wilson BJ, Sundaram SK, Huq AH, et al: Abnormal language pathway in children with Angelman syndrome. Pediatr Neurol 2011; 44:350–356. 27 Tiwari VN, Jeong JW, Wilson BJ, Behen ME, Chugani HT, Sundaram SK: Relationship between aberrant brain connectivity and clinical features in Angelman syndrome: a new method using tract based spatial statistics of DTI color-coded orientation maps. Neuroimage 2012;59:349–355. 28 Smith JC: Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med Child Neurol 2001;43:476–480.
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
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5 Brun Gasca C, Obiols JE, Bonillo A, Artigas J, Lorente I, Gabau E, Guitart M, Turk J: Adaptive behaviour in Angelman syndrome: its profile and relationship to age. J Intellect Disabil Res 2010;54:1024–1029. 6 Tan WH, Bacino CA, Skinner SA, et al: Angelman syndrome: mutations influence features in early childhood. Am J Med Genet A 2011; 155A:81–90. 7 Online Medenlian Inheritance in Man. Baltimore, MD, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. http://omim.org/ (accessed July 1, 2012). 8 Tzagkaraki E, Sofocleous C, Fryssira-Kanioura H, Dinopoulos A, Goulielmos G, Mavrou A, Kitsiou-Tzeli S, Kanavakis E: Screening of UBE3A gene in patients referred for Angelman syndrome. Eur J Paediatr Neurol 2013; 17:366–373. 9 Williams CA, Beaudet AL, Clayton-Smith J, et al: Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 2006;140:413–418. 10 Beckung E, Steffenburg S, Kyllerman M: Motor impairments, neurological signs, and developmental level in individuals with Angelman syndrome. Dev Med Child Neurol 2004; 46:239–243. 11 Williams CA: The behavioral phenotype of the Angelman syndrome. Am J Med Genet C Semin Med Genet 2010;154C:432–437. 12 Varela MC, Kok F, Otto PA, Koiffmann CP: Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet 2004;12:987–992.
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
Angelman Syndrome: A Case Series Assessing Neurological Issues in Adulthood Marie Giroud a Benoît Daubail c Norbert Khayat b Mondher Chouchane d Eric Berger a Emelyne Muzard a Elisabeth Medeiros de Bustos a Christel Thauvin-Robinet e Laurence Faivre e Alice Masurel e Véronique Darmency-Stamboul d Frédéric Huet d, e Yannick Béjot c Maurice Giroud c Thierry Moulin a
Departments of a Neurology and b Electrophysiology, University Hospital of Besançon, Besançon, c Department of Neurology, University Hospital of Dijon and EA4184 of the University of Burgundy, d Department of Paediatrics, University Hospital of Dijon, and e Federation Translad, The Genetic Centre and EA4271 of The University of Burgundy, Dijon, France
Abstract Background: This study aimed to evaluate the clinical symptoms of Angelman syndrome (AS) in adults and to identify the neurological pathways affected in this disease. AS is a neurogenetic disorder resulting due to the deletion or inactivation of the ubiquitin-protein-ligase E3A gene on maternal chromosome 15. Summary: A retrospective analysis of data from six adults patients with clinical, electroencephalographic and genetic confirmation of AS was performed. Movement disorders of the hands and mouth, laughing spells, severe expressive speech disorders, a happy nature, hyposomnia and anxiety are the major neurological characteristics of AS in adulthood. Cerebellar ataxia, muscle hypotonia and tremor, though constant in childhood, tend to be attenuated in adulthood. Epilepsy, one of the most frequent symptoms in childhood and in adulthood, is characterised
© 2014 S. Karger AG, Basel 0014–3022/14/0732–0119$39.50/0 E-Mail [email protected] www.karger.com/ene
by specific electroencephalographic patterns. Key Messages: These clinical characteristics are important to improve the clinical awareness and genetic diagnosis of AS. Clinicians must be better informed concerning the adult phenotype as it is not well described in the literature. We stress the importance of AS as one of the main causes of intractable epilepsy. The authors suggest frontal and cerebellar dysfunction. Further functional cerebral imaging studies are necessary. © 2014 S. Karger AG, Basel
Introduction
Angelman Syndrome (AS) is a neurogenetic disease resulting due to the deletion or inactivation of the ubiquitin-protein ligase E3A gene (UBE3A) on chromosome 15 [1–3]. UBE3A plays a major role in the cellular ubiquitin-proteasome pathway, which has a major influence in synaptic development and neuronal plasticity [4, 6]. Four genetic mechanisms are responsible for the AS phenotype [3, 4]: (1) the microdeletion of the maternal Prof. Maurice Giroud Neurology Service – CHU 14 Rue Gaffarel, FR–2100 Dijon (France) E-Mail maurice.giroud @ chu-dijon.fr
Downloaded by: Selçuk Universitesi 193.255.248.150 - 2/2/2015 6:49:29 PM
Key Words Epilepsy · Movement disorders · Ataxia · Laughing seizures · Genetics
Methods Data from AS patients who were treated by the Genetics, Neurological and Electroencephalographic departments of the University Hospital of Dijon and Besançon (France), were screened. Only patients with an AS diagnosis that was confirmed by molecular analyses [7] with one of the four classical mechanisms [4, 8], were included. Clinical 16 channel EEG studies were recorded for at least 30 minutes in both awake and sleeping patients. We recorded the following data: birth conditions, mental and neurological development, physical description, neurological, cognitive and psychiatric disorders, types of epileptic seizures, and sleep dysfunction.
Results
Six patients older than 18 years of age were recruited (3 cases with maternal deletion, 2 cases with paternal disomy and 1 case with a UBE3A mutation). In all cases, the birth weight was normal. The clinical features included axial hypotonia, flat occiput bone (4/6), 120
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
swallowing troubles (4/6), and congenital stridor (3/6) (table 1). The initial evolution in all cases was characterised by facial dysmorphism including a large mouth (6/6), prognathism (5/6) and microcephaly (2/6). Later, widely spaced teeth (5/6) and scoliosis (6/6) were observed. Psychomotor and neurological development was marked by hypotonia associated with a walking delay acquired at a mean age of approximately 24 months and intellectual deficiency with no expressive language but better receptive language in all cases. The neurological symptoms were characterised by cerebellar ataxia in childhood (6/6), immediately after independent walking had been acquired. Uplifted arms (5/6) were associated with increased deep tendons reflexes and central swallowing disorders. For the 4 of the 6 patients who experienced epileptic seizures, most of the seizures appeared after 1 year of age except for two patients who experienced West syndrome at 6 months (cases 2 and 3), as documented by EEG. There were multiple seizures (e.g., tonic, atonic and tonic-clonic seizures, myoclonus and absences), that were initially resistant to antiepileptic drugs. EEGs were characterised by posterior delta waves, with or without eyeclosure-related spikes in childhood. These spikes shifted towards anterior regions in adulthood. Behavioural troubles were characterised by obsessivecompulsive behaviour (5/6), particularly for water (1/5) and food (4/5), which led to obesity. Abnormal arm movements (hand flapping) were observed mainly during periods of anxiety or great happiness (5/6). Smiling, a happy nature and laughing seizures were the main identifiable features observed during the outpatient consultations in childhood and in adulthood (6/6). In two cases, the parents also reported laughing seizures during sleep. In contrast, noise intolerance was an unusual symptom (1/6). Other primary features included strabismus (2/6) and hypopigmented skin in two cases. Puberty was normal in all cases. Brain MRI performed in two cases (between 2 and 4 years of age) revealed a thin corpus callosum associated with frontal atrophy and hypomyelination. The course in adulthood is interesting because some neurological manifestations were more pronounced. In all six patients (table 1), the remaining symptoms included dysmorphism (with a typical large mouth and widely spaced teeth) (figure 1) and severe intellectual deficiency (with typical speech disturbances associated with the lack of expressive language and relatively good receptive language). The behavioural troubles were stable and Giroud et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 2/2/2015 6:49:29 PM
15q11.2–13.1 allele, the most common molecular subtype (68%), (occurring de novo in most of the cases), explains the low recurrence rate [4]; (2) mutations in the UBE3A gene, the second most common genotype (12%), have a high recurrence rate (up to 50%) in contrast to the deletion group; (3) the paternal uniparental disomy (3–8%), which is secondary to the inheritance of two paternal copies of chromosome 15, has a low recurrence rate (200 μvolts) theta waves (44%) and slow posterior activity (44%) [19]. Posterior sharp waves easily triggered by passive eye closure correlate with clinically severe epileptic seizures [19, 20] and can be mixed with epileptic discharges [17, 21]. Spikes tend to move from the posterior to the anterior regions of the brain over time [21], as observed in the six cases presented here. Finally, these EEG patterns are observed across all genotypes [19]. They may precede the diagnosis [17, 19] but are not absolutely specific [3, 7, 22]. Neuro-imaging studies may be normal but show global atrophy and abnormal myelination in the frontal lobes, as well as a thin corpus callosum [23, 24], in approximately 60% of the cases [25]. This MRI finding is now an important feature in the evaluation and
124
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
We observed that the AS symptoms change with age, reflecting the maturational pattern of the brain, as previously observed in AS adults [3, 28]. It is important for clinicians to understand the clinical and EEG features of adult AS. Moreover, our study is interesting in that it provides a greater understanding of the AS neurological manifestations and may inspire the development of new approaches in therapeutic research.
Acknowledgments The authors thank Philip Bastable for his language assistance.
Contributors M.G. and B.D. collected the clinical files and drafted the original manuscript, N.K., M.C., C.T.-R., L.F., A.M. and V.D.-S. contributed to the patient diagnoses and follow-ups, and E.B., E.M., E.M. de B., F.H., Y.B., M.G. and T.M. contributed to the study design and manuscript revision.
Funding This study received no financial support.
Competing Interests None reported.
Provenance and Peer Review This study was not commissioned but was peer reviewed externally.
References
1 Kishino T, Lalande M, Wagstaff J: UBE3A/ E6-AP mutations cause Angelman syndrome. Nat Genet 1997;15:70–73. 2 Albrecht U, Sutcliffe JS, Cattanach BM, et al: Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet 1997; 17: 75–78. 3 Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA: Neurologic manifestations of Angelman syndrome. Pediatr Neurol 2013; 48: 271–279. 4 Dagli A, Buiting K, Williams CA: Molecular and clinical aspects of Angelman syndrome. Mol Syndromol 2011;2:100–112.
Giroud et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 2/2/2015 6:49:29 PM
understanding of AS and may explain the language and motor difficulties observed in patients [23, 25]. The second specificity concerns the hypothesis of the pathophysiology of AS and the localisation of the cerebral dysfunction. Movement and muscle tone disorders may be induced by a disorder of the first motor neuron manifesting as spasticity in adulthood, with late hypertonia of legs [6], walking with up-lifted arms in childhood, increased deep tendon reflexes and central swallowing disorders. There may also be a cerebellar syndrome marked by ataxia with broad-based, asymmetric movement of the limbs and tremor, which is more present in childhood. Early hypotonia observed mainly during infancy [6] may indicate the cerebellar disturbance, which may overshadow the pyramidal syndrome in this period, explaining the great prevalence of scoliosis and a flat occipital bone. A frontal syndrome may be suggested by the presence of certain symptoms including hyperactive behaviour, restlessness, distractibility [11], stereotypical obsessive compulsive stereotyped activities (hand flapping), and self-mutilation or aggressive behaviour. Epileptiform discharges tend to shift towards the frontal region [21] as observed in all cases, and reflect the functional neurochemical or maturational disorder of the frontal area: from a pathophysiological point of view as suggested by MRI [23–26], the mechanism could consist of delayed myelination, associated with a thin corpus callosum [23, 26]. A previous study [27] using diffusion tensor imaging has demonstrated that in addition to delayed myelination, there was decreased axonal density and aberrant axonal organisation mainly in the temporal pathways, which partly explained the language, cognitive and social functioning disorders [26, 27]. Frequent and inappropriate laughter, a common symptom in all AS patients, could be the consequence of a pyramidal syndrome, the so-called spasmodic laughter of the pseudo-bulbar syndrome. The second explanation could be of an epileptic origin, so-called gelastic seizures. Gelastic seizures are characteristic of hypothalamic hamartomas. However, we found no references to hypothalamic hamartomas in any published AS study. We did not record any epileptic discharges on the EEG during laughter: although we observed 2 cases of laughter during the night, it is clearly not epileptic. The limitations of our study are its retrospective nature, the very small number of patients, the absence of a detailed description of the seizures and the lack of long polygraphic EEGs. Broad conclusions cannot be drawn from 6 subjects.
Angelman Syndrome in Adulthood
13 Galvan-Manso M, Campistol J, Conill J, Sanmarti FX: Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome. Epileptic Disord 2005;7:19–25. 14 Thibert RL, Conant KD, Braun EK, et al: Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia 2009;50:2369–2376. 15 Valente KD, Koiffmann CP, Fridman C, et al: Epilepsy in patients with Angelman syndrome caused by deletion of the chromosome 15q11–13. Arch Neurol 2006;63:122–128. 16 Buoni S, Grosso S, Pucci L, Fois A: Diagnosis of Angelman syndrome: clinical and EEG criteria. Brain Dev 1999;21:296–302. 17 Uemura N, Matsumoto A, Nakamura M, et al: Evolution of seizures and electroencephalographical findings in 23 cases of deletion type Angelman syndrome. Brain Dev 2005; 27: 383–388. 18 Espay AJ, Andrade DM, Wennberg RA, Lang AE: Atypical absences and recurrent absence status in an adult with Angelman syndrome due to the UBE3A mutation. Epileptic Disord 2005;7:227–230. 19 Vendrame M, Loddenkemper T, Zarowski M, Gregas M, Shuhaiber H, Sarco DP, Morales A, Nespeca M, Sharpe C, Haas K, Barnes G, Glaze D, Kothare SV: Analysis of EEG patterns and genotypes in patients with Angelman syndrome. Epilepsy Behav 2012;23:261– 265.
20 Valente KD, Andrade JQ, Grossmann RM, et al: Angelman syndrome: difficulties in EEG pattern recognition and possible misinterpretations. Epilepsia 2003;44:1051–1063. 21 Yum MS, Lee EH, Kim JH, Ko TS, Yoo HW: Implications of slow waves and shifting epileptiform discharges in Angelman syndrome. Brain Dev 2013;35:245–251. 22 Laan LA, Vein AA: A Rett patient with a typical Angelman EEG. Epilepsia 2002;43:1590– 1592. 23 Harting I, Seitz A, Rating D, Sartor K, Zschocke J, Janssen B, Ebinger F, Wolf NI: Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2009; 13: 271– 276. 24 Peters SU, Kaufmann WE, Bacino CA, et al: Alterations in white matter pathways in Angelman syndrome. Dev Med Child Neurol 2010;53:361–367. 25 Castro-Gago M, Gómez-Lado C, Eirís-Puňal J, et al: Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2010;14:292. 26 Wilson BJ, Sundaram SK, Huq AH, et al: Abnormal language pathway in children with Angelman syndrome. Pediatr Neurol 2011; 44:350–356. 27 Tiwari VN, Jeong JW, Wilson BJ, Behen ME, Chugani HT, Sundaram SK: Relationship between aberrant brain connectivity and clinical features in Angelman syndrome: a new method using tract based spatial statistics of DTI color-coded orientation maps. Neuroimage 2012;59:349–355. 28 Smith JC: Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med Child Neurol 2001;43:476–480.
Eur Neurol 2015;73:119–125 DOI: 10.1159/000369454
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