RESEARCH ARTICLE
Angelman Syndrome in Adulthood Anna M. Larson Julianna E. Shinnick Elias A. Shaaya Elizabeth A. Thiele and Ronald L. Thibert* Pediatric Epilepsy Program, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts Manuscript Received: 26 March 2014; Manuscript Accepted: 15 October 2014
Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype–phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16–50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men. Sixty-eight percent were able to walk independently, and 13% were able to speak 5 or more words. Self-injurious behavior was exhibited in 52% of individuals. The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood. While late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety. Ó 2014 Wiley Periodicals, Inc.
Key words: Angelman syndrome; adults; seizures; behavior; selfinjury
INTRODUCTION Angelman syndrome (AS) is a neurogenetic disorder clinically characterized by features of epilepsy, poor sleep, ataxia, frequent smiling/ sociability, and scoliosis. Individuals typically have severe cognitive impairment and limited expressive speech. Eighty to 90% of individuals with AS develop seizures, which may include multiple semiologies [Thibert et al., 2009]. Children may have gross motor delays, sitting at an average age of 20.5 months and walking at 3.7 years, and 10% of individuals with AS do not develop the ability to walk independently [Williams et al., 2010]. Although many children with AS have significant receptive language skills, the majority of individuals gain very few words [Jolleff and Ryan, 1993; Williams 2005].
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Larson AM,Shinnick JE, Shaaya EA, Thiele EA, Thibert RL. 2014. Angelman syndrome in adulthood. Am J Med Genet Part A. 9999:1–14.
AS has an estimated incidence of approximately 1 in 12,000– 20,000 live births, but life expectancy by epidemiologic measures remains unknown [Williams et al., 2010]. The molecular etiology of AS is a loss of function of the maternally inherited UBE3A gene, which codes for E6AP-3A ubiquitin protein ligase [Knoll et al., 1989; Albrecht et al., 1997; Kishino et al., 1997]. There are four molecular subtypes of AS, and deletion of the 15q11.2–13.1 region (Del) is the most common. Mutation of the maternal UBE3A gene, paternal uniparental disomy (UPD), and imprinting defects also cause an AS phenotype [Knoll et al., 1989; Malcom et al., 1991; Buiting et al., 1995; Kishino et al., 1997 Matsuura et al., 1997]. The first individuals to undergo genetic testing for AS in early childhood during the late 1980s are now young adults. Over the past three decades, there has been significant progress in diagnostics and care for adults with AS. Drs. Jill Clayton-Smith and Charles Williams were the pioneers of this field and among the first to characterize the adult phenotype and to study the impact of age [Williams and Frias, 1982; Clayton-Smith, 1993]. In 1984, Bjerre et al. contributed a case report of a 75-year-old patient with a clinical diagnosis of AS from Sweden who was described to be in generally good health [Bjerre et al., 1984]. The case, which features the oldest patient reported in the literature, played a pivotal role in AS research, as it provided some evidence that the disease was not a degenerative process [Bjerre et al., 1984; Sandanam et al., 1997]. Today, research on aging in the setting of AS continues to advance, and quality of life for the majority of individuals with AS has been found to be maintained into adulthood [Bjerre et al., 1984; ClaytonGrant sponsor: The Harvard Clinical and Translational Science Center; Grant number: UL1 RR 025758; Grant sponsor: Harvard University. Correspondence to: Ronald L. Thibert, DO, MsPH, Pediatric Epilepsy Program, Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36864
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. Demographics of Angelman Syndrome Study Cohort Mean age(y) 16–20 21–25 26–30 31–40 41–50 Sex Female Male Interviewee Mother Father Both Other Genotype Maternal deletion UBE3A mutation UPD Mosaic Clinical Unknown Home environment Parents’ home Group home Residential center Other
Full cohort (n ¼ 109) 24.3y (sd: 7.24) 38% 27% 21% 11% 4%
Known genotype (n ¼ 93) 24.3y (sd: 7.46) 38% 28% 19% 11% 4%
P-valuea 0.895b 1.000 0.552 0.322 0.689 1.000
50% 50%
51% 49%
0.788
89% 6% 2% 3%
89% 5% 2% 3%
0.689 0.273 1.000 1.000
68% 8% 9% Single case 10% 5%
80% 10% 11%
75% 17% 6% 3%
74% 16% 7% 3%
0.756 0.731 0.588 1.000
y, years; UPD, uniparental disomy. a Two-sided Fisher’s Exact Test.bIndependent Samples T-Test/Levene’s Test for Equality (Sig. 0.510).
Smith and Laan, 2003]. In this study, investigators aimed to further characterize the natural history and current clinical manifestations of AS in adulthood.
MATERIALS AND METHODS This institutional review board-approved study conducted at the Massachusetts General Hospital investigated AS in adulthood with subject data collected by a series of phone interviews with primary caregivers. Subject recruitment information was sent by e-mail to close to 1,120 addresses from the Angelman Syndrome Foundation (ASF) database. Study information was also posted to the “Current Research” page on the ASF website. Subject inclusion criteria were as follows: diagnosis of AS by a physician, 16 years of age or older, interviewee self-identification as one of the subject’s primary caregivers. Subjects were from 34 states in the United States, Puerto Rico, and two Canadian provinces. All interviews were completed over a period of four months in 2011. The impact of age, sex, and genotype on specific outcomes in neurology, internal medicine, orthopedics, and psychiatry were investigated. The interview consisted of a set of standardized questions developed by the investigators. In addition, there were several designated points in the
interview during which participants were asked to describe additional pertinent medical history not specifically covered in the standardized questions. The investigators were contacted by three families with a son or daughter with AS who had previously died. These caregivers completed the standardized interview, and their responses were included in the full data set. In one case, the subject had died prior to an AS diagnosis; however, his sibling, who had a similar phenotype, was subsequently diagnosed with AS, identified by a mutation in UBE3A. Both siblings were therefore included and reported as having the same associated genotype. One subject had a diagnosis of mosaicism (unknown to investigators if the individual’s genotype was an imprinting defect or a chromosomal type). Because she was a genotypic outlier, her case data were not included in the full cohort analyses. The interview included a modified Early Childhood Epilepsy Severity Scale (E-Chess) [Humphrey et al., 2008]. The score was modified from the rubric initially described by Humphrey et al. in two ways: (a) “time period over which seizure occurred” was eliminated, given that the full cohort would receive the same score (“more than 6 months”); (b) “response to treatment” was reduced to 1 of 2 possible responses, “complete cessation” or “partial/no improvement” [Humphrey et al., 2008]. Caregivers
63% (103) 45% (103) 68% (103) 7.53(SD:7.035, n ¼ 100) 52% (100) 25% (100) 12% (100) 6% (100) 5% (62) 0% (33) 20% (15)
1.782 1.107 0.847 1.192 0.472 0.875 4.519* 6.190 2.370 – 0.500
0.673 1.033 1.809 0.588 0.490 0.264
0.055 0.817
4.65(SD:2.754, n ¼ 103) 26% (103) (103) (103) (103) (103) (103) (103)
1.021 2.266
29% (103) 16% (103)
39% 17% 17% 13% 9% 9%
0.937 0.844 1.154 0.676 0.497
(103) (103) (103) (103) (103)
12% 48% 41% 45% 12%
Female odds ratio 0.437
IS, infinite solution (%, n); AED, anti-epileptic drugs; Tx, treatment; y, years. Age sub-groups compared with the 16–20y cohort. Genotype sub-groups compared with the Del cohort. a Cohort of individuals with history of seizures who have not had an event in 1 year or more. b Includes three individuals who were not being treated with an AED. c Reported to have two or more types of seizure, i.e., events that look different to caregiver. d Events occurring at least monthly. e Regression coefficient listed for each covariate. * Statistically significant odds ratio (a ¼ 0.05). ** statistically significant regression coefficient (a ¼ 0.05).
History of seizures Current seizures Seizure free/off AEDsa Seizure free/AED Txa Active seizuresb Current AED 2 2 semiologiesc Frequency Monthlyd Daily Seizure severity Modified E-chess scoree Score >6 Current medications Valproate Clonazepam Lamotrigine Levetiracetam Ethosuximide Topiramate Lifetime seizure severity AEDs >2 lifetime AEDs >3 lifetime Seizure onset 31 y
Full cohort % (n) 94% (109)
2.020 2.455 1.555 1.772 0.863 0.568 0.922 2.827 – – –
1.614 1.232 2.080 3.948 0.198 0.258
0.807 1.464
3.051 2.110
0.786 0.525 2.345 2.241 1.418
21–25y odds ratio IS (100%, 29)
1.188 2.008 2.076 0.111 0.667 1.071 2.956 IS(0%, 18) – – –
2.234 0.431 0.622 0.955 0.279 0.653
1.577 1.754 2.777 4.041 1.827 0.154 0.602 IS(0%, 15) – – –
1.493 0.277 0.855 9.329* 0.383 0.477
1.688** 2.28
7.802* 6.883*
4.558* 10.328* 1.706** 3.032
2.470 0.202* 6.701* 1.556 1.832
31–50y odds ratio 0.775
1.197 0.238* 4.102* 1.445 2.966
26–30y odds ratio 0.335
TABLE II. Epilepsy Parameters for Individuals With Angelman Syndrome, Late-Adolescence Through Adulthood
0.283 0.140 0.206* 2.536 2.000 0.964 IS(0%, 9) 2.062 IS(0%, 5) – IS(0%, 2)
0.424 IS(0%,9) 0.567 0.775 1.675 3.943
0.139 0.857
1.214 0.567
1.584 0.945 1.853 0.625 IS (0%, 9)
UBE3A odds ratio IS (100%, 9)
0.942 0.671 1.235 1.339 1.000 0.482 0.766 2.357 7.167 – IS(0%, 1)
0.890 0.500 0.648 IS(0%, 8) 1.914 1.533
0.569 1.000
0.810 IS(0%, 8)
0.792 1.970 0.494 0.750 0.886
UPD odds ratio 0.111*
LARSON ET AL. 3
1.310 0.997 0.949 2.449 1.727 2.139 1.150 3.985 1.373 2.224 1.193 0.997 0.837 1.282 0.175 3.762 0.948 1.741 0.487 0.648 1.995 0.302 0.650
72% (109) 22% (109) 25% (109) 65% (85) 45% (85) (85) (85) (84) (109) (85) (109)
66% 20% 11% 17% 24% 37% 56% (108) 35% (108) 40% (108) 7.4(sd:1.67, n ¼ 61) 18% (61) 59% (61) 77% (108) 6% (108) 18% (108) 68% (108) 7% (108) 24% (108)
Female odds ratio
4.315* 3.304*
4.424* 3.214*
1.344 6.852 0.346
1.740 1.478 0.363
1.426 6.292 0.333
0.799 1.853 1.019
0.439 2.073 0.871
3.125*
3.704*
0.985** 0.261 4.526*
0.587 0.969 3.026 4.080* 2.721 1.999
0.827 3.263
3.479 1.228 0.942
26–30y odds ratio
0.907 0.426 0.522 1.468 1.170 3.311*
0.539 2.035
0.977 3.070 0.345
21–25y odds ratio
IS, infinite solution (%, n); Tx, treatment; hr, hours. Age sub-groups compared with the 16–20y cohort. Genotype sub-groups compared with the Del cohort. a Sleep medications included: trazadone, clonidine, clonazepam, seroquel, tranxene, eszopiclone, zolpidem, mirtazepine, temazepam, ramelteon, and doxylamine. b Awake for a period of an hour or more overnight. c Awake caregiver overnight, audio/video monitoring, or posey bed. d Regression coefficient listed for each covariate. * Statistically significant odds ratio (a ¼ 0.05). ** statistically significant regression coefficient (a ¼ 0.05).
Sleep Sleep problems Melatonin Tx Other sleep medicationa Sleep latency Trouble falling asleep TV on to fall asleep Night waking Difficulty staying asleep Awake overnight weeklyb Never sleeps through the nightb Co-sleeping TV on all night long Close nighttime monitoringc Daytime sleepiness Naps routinely Often falls asleep Riding in the car Watching TV or movies Sleep quantity Hours of sleep per nightd 5 hr 8 hr Lifetime sleep severity Compared to infancy Improved Worse Unchanged Compared to childhood Improved Worse Unchanged
Full Cohort % (n)
0.748 IS (0%, 15) 1.470
0.406 IS (0%, 15) 3.339
1.470 2.619 0.273
2.833 1.803
2.778
3.036 0.848 3.420 2.131 1.821 1.858
1.042 2.146
1.553 1.945 0.497
31–50y odds ratio
TABLE III. Sleep Parameters for Individuals With Angelman Syndrome, Late-Adolescence Through Adulthood
0.903 1.971 0.841
0.964 2.500 0.612
0.850 4.714 0.905
1.477 0.375
0.545
5.469 0.484 IS (0%, 9) IS (0%, 8) 1.680 0.694
0.357 1.111
1.296 1.812 1.447
UBE3A odds ratio
4.333 1.725 IS (0%, 9)
2.893 IS (0%, 10) 0.476
0.207 1.886 1.206
0.923 0.656
0.545
2.344 2.031 1.000 1.173 0.400 0.347
1.071 0.370
1.481 0.906 1.241
UPD odds ratio
4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(105) (109) (109) (51) (31) (109) (40) (109) (109) (80)
50% 49% 47% 61% 48% 37% 83% 85% 43% 40% 13.2(sd:2.18, n ¼ 52) 17% 52 27% (52) 31% (54) 62% (37) 13% (54)
(84) (16) (85) (85) (43) (43) (85) (85)
40% 56% 38% 51% 49% 53% 64% 48% 0.318 0.924 1.848 0.764 0.505 0.110 IS(100%, 8) 0.527 0.917 0.731
3.152* 1.761 1.291 0.743 0.740 1.447 0.436 1.333 0.825 0.715 0.689 1.308 0.623 2.000 2.333 IS(0%, 15)
1.524 0.926 1.254 2.239 2.239 0.928 1.589 0.628
21–25y odds ratio
0.648 0.631 0.916 0.569 2.675 3.836 1.191 0.737
Female odds ratio
HEENT, Head eyes ears nose and throat; IS, infinite solution (%, n); OCP, oral contraceptive. Age sub-groups compared with the 16–20y cohort. Genotype sub-groups compared with the Del cohort. a Abnormal results included swallow delay and silent aspiration. b Unrelated to eating. c Drinks 6hr or necessitating trip to emergency room. f 10 years or more than 2 years earlier than maternal menarche. g 15 years or more than 2 years later than maternal menarche. h Depot medroxyprogesterone acetate. i Individuals not on OCP/ Depo-provera. j Significant pain and/or increased irritability. k Regression coefficient listed for each covariate. * Statistically significant odds ratio (a–¼ 0.05). ** Statistically significant regression coefficient (a ¼ 0.05).
Heent History of severe choking Abnormal swallow studya History of severe pneumonia Episodic gaggingb Progresses to vomiting Triggered by a strong smell Dental care non-sedated Seasonal allergies Gastrointestinal/nutrition Decreased satiety Poor hydrationc Gastroesophageal refluxd History of medication Improvement with treatment Cyclic vomiting Episode >6hrse Constipation Medication for constipation Typically
Angelman Syndrome in Adulthood Anna M. Larson Julianna E. Shinnick Elias A. Shaaya Elizabeth A. Thiele and Ronald L. Thibert* Pediatric Epilepsy Program, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts Manuscript Received: 26 March 2014; Manuscript Accepted: 15 October 2014
Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype–phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16–50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men. Sixty-eight percent were able to walk independently, and 13% were able to speak 5 or more words. Self-injurious behavior was exhibited in 52% of individuals. The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood. While late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety. Ó 2014 Wiley Periodicals, Inc.
Key words: Angelman syndrome; adults; seizures; behavior; selfinjury
INTRODUCTION Angelman syndrome (AS) is a neurogenetic disorder clinically characterized by features of epilepsy, poor sleep, ataxia, frequent smiling/ sociability, and scoliosis. Individuals typically have severe cognitive impairment and limited expressive speech. Eighty to 90% of individuals with AS develop seizures, which may include multiple semiologies [Thibert et al., 2009]. Children may have gross motor delays, sitting at an average age of 20.5 months and walking at 3.7 years, and 10% of individuals with AS do not develop the ability to walk independently [Williams et al., 2010]. Although many children with AS have significant receptive language skills, the majority of individuals gain very few words [Jolleff and Ryan, 1993; Williams 2005].
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Larson AM,Shinnick JE, Shaaya EA, Thiele EA, Thibert RL. 2014. Angelman syndrome in adulthood. Am J Med Genet Part A. 9999:1–14.
AS has an estimated incidence of approximately 1 in 12,000– 20,000 live births, but life expectancy by epidemiologic measures remains unknown [Williams et al., 2010]. The molecular etiology of AS is a loss of function of the maternally inherited UBE3A gene, which codes for E6AP-3A ubiquitin protein ligase [Knoll et al., 1989; Albrecht et al., 1997; Kishino et al., 1997]. There are four molecular subtypes of AS, and deletion of the 15q11.2–13.1 region (Del) is the most common. Mutation of the maternal UBE3A gene, paternal uniparental disomy (UPD), and imprinting defects also cause an AS phenotype [Knoll et al., 1989; Malcom et al., 1991; Buiting et al., 1995; Kishino et al., 1997 Matsuura et al., 1997]. The first individuals to undergo genetic testing for AS in early childhood during the late 1980s are now young adults. Over the past three decades, there has been significant progress in diagnostics and care for adults with AS. Drs. Jill Clayton-Smith and Charles Williams were the pioneers of this field and among the first to characterize the adult phenotype and to study the impact of age [Williams and Frias, 1982; Clayton-Smith, 1993]. In 1984, Bjerre et al. contributed a case report of a 75-year-old patient with a clinical diagnosis of AS from Sweden who was described to be in generally good health [Bjerre et al., 1984]. The case, which features the oldest patient reported in the literature, played a pivotal role in AS research, as it provided some evidence that the disease was not a degenerative process [Bjerre et al., 1984; Sandanam et al., 1997]. Today, research on aging in the setting of AS continues to advance, and quality of life for the majority of individuals with AS has been found to be maintained into adulthood [Bjerre et al., 1984; ClaytonGrant sponsor: The Harvard Clinical and Translational Science Center; Grant number: UL1 RR 025758; Grant sponsor: Harvard University. Correspondence to: Ronald L. Thibert, DO, MsPH, Pediatric Epilepsy Program, Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36864
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TABLE I. Demographics of Angelman Syndrome Study Cohort Mean age(y) 16–20 21–25 26–30 31–40 41–50 Sex Female Male Interviewee Mother Father Both Other Genotype Maternal deletion UBE3A mutation UPD Mosaic Clinical Unknown Home environment Parents’ home Group home Residential center Other
Full cohort (n ¼ 109) 24.3y (sd: 7.24) 38% 27% 21% 11% 4%
Known genotype (n ¼ 93) 24.3y (sd: 7.46) 38% 28% 19% 11% 4%
P-valuea 0.895b 1.000 0.552 0.322 0.689 1.000
50% 50%
51% 49%
0.788
89% 6% 2% 3%
89% 5% 2% 3%
0.689 0.273 1.000 1.000
68% 8% 9% Single case 10% 5%
80% 10% 11%
75% 17% 6% 3%
74% 16% 7% 3%
0.756 0.731 0.588 1.000
y, years; UPD, uniparental disomy. a Two-sided Fisher’s Exact Test.bIndependent Samples T-Test/Levene’s Test for Equality (Sig. 0.510).
Smith and Laan, 2003]. In this study, investigators aimed to further characterize the natural history and current clinical manifestations of AS in adulthood.
MATERIALS AND METHODS This institutional review board-approved study conducted at the Massachusetts General Hospital investigated AS in adulthood with subject data collected by a series of phone interviews with primary caregivers. Subject recruitment information was sent by e-mail to close to 1,120 addresses from the Angelman Syndrome Foundation (ASF) database. Study information was also posted to the “Current Research” page on the ASF website. Subject inclusion criteria were as follows: diagnosis of AS by a physician, 16 years of age or older, interviewee self-identification as one of the subject’s primary caregivers. Subjects were from 34 states in the United States, Puerto Rico, and two Canadian provinces. All interviews were completed over a period of four months in 2011. The impact of age, sex, and genotype on specific outcomes in neurology, internal medicine, orthopedics, and psychiatry were investigated. The interview consisted of a set of standardized questions developed by the investigators. In addition, there were several designated points in the
interview during which participants were asked to describe additional pertinent medical history not specifically covered in the standardized questions. The investigators were contacted by three families with a son or daughter with AS who had previously died. These caregivers completed the standardized interview, and their responses were included in the full data set. In one case, the subject had died prior to an AS diagnosis; however, his sibling, who had a similar phenotype, was subsequently diagnosed with AS, identified by a mutation in UBE3A. Both siblings were therefore included and reported as having the same associated genotype. One subject had a diagnosis of mosaicism (unknown to investigators if the individual’s genotype was an imprinting defect or a chromosomal type). Because she was a genotypic outlier, her case data were not included in the full cohort analyses. The interview included a modified Early Childhood Epilepsy Severity Scale (E-Chess) [Humphrey et al., 2008]. The score was modified from the rubric initially described by Humphrey et al. in two ways: (a) “time period over which seizure occurred” was eliminated, given that the full cohort would receive the same score (“more than 6 months”); (b) “response to treatment” was reduced to 1 of 2 possible responses, “complete cessation” or “partial/no improvement” [Humphrey et al., 2008]. Caregivers
63% (103) 45% (103) 68% (103) 7.53(SD:7.035, n ¼ 100) 52% (100) 25% (100) 12% (100) 6% (100) 5% (62) 0% (33) 20% (15)
1.782 1.107 0.847 1.192 0.472 0.875 4.519* 6.190 2.370 – 0.500
0.673 1.033 1.809 0.588 0.490 0.264
0.055 0.817
4.65(SD:2.754, n ¼ 103) 26% (103) (103) (103) (103) (103) (103) (103)
1.021 2.266
29% (103) 16% (103)
39% 17% 17% 13% 9% 9%
0.937 0.844 1.154 0.676 0.497
(103) (103) (103) (103) (103)
12% 48% 41% 45% 12%
Female odds ratio 0.437
IS, infinite solution (%, n); AED, anti-epileptic drugs; Tx, treatment; y, years. Age sub-groups compared with the 16–20y cohort. Genotype sub-groups compared with the Del cohort. a Cohort of individuals with history of seizures who have not had an event in 1 year or more. b Includes three individuals who were not being treated with an AED. c Reported to have two or more types of seizure, i.e., events that look different to caregiver. d Events occurring at least monthly. e Regression coefficient listed for each covariate. * Statistically significant odds ratio (a ¼ 0.05). ** statistically significant regression coefficient (a ¼ 0.05).
History of seizures Current seizures Seizure free/off AEDsa Seizure free/AED Txa Active seizuresb Current AED 2 2 semiologiesc Frequency Monthlyd Daily Seizure severity Modified E-chess scoree Score >6 Current medications Valproate Clonazepam Lamotrigine Levetiracetam Ethosuximide Topiramate Lifetime seizure severity AEDs >2 lifetime AEDs >3 lifetime Seizure onset 31 y
Full cohort % (n) 94% (109)
2.020 2.455 1.555 1.772 0.863 0.568 0.922 2.827 – – –
1.614 1.232 2.080 3.948 0.198 0.258
0.807 1.464
3.051 2.110
0.786 0.525 2.345 2.241 1.418
21–25y odds ratio IS (100%, 29)
1.188 2.008 2.076 0.111 0.667 1.071 2.956 IS(0%, 18) – – –
2.234 0.431 0.622 0.955 0.279 0.653
1.577 1.754 2.777 4.041 1.827 0.154 0.602 IS(0%, 15) – – –
1.493 0.277 0.855 9.329* 0.383 0.477
1.688** 2.28
7.802* 6.883*
4.558* 10.328* 1.706** 3.032
2.470 0.202* 6.701* 1.556 1.832
31–50y odds ratio 0.775
1.197 0.238* 4.102* 1.445 2.966
26–30y odds ratio 0.335
TABLE II. Epilepsy Parameters for Individuals With Angelman Syndrome, Late-Adolescence Through Adulthood
0.283 0.140 0.206* 2.536 2.000 0.964 IS(0%, 9) 2.062 IS(0%, 5) – IS(0%, 2)
0.424 IS(0%,9) 0.567 0.775 1.675 3.943
0.139 0.857
1.214 0.567
1.584 0.945 1.853 0.625 IS (0%, 9)
UBE3A odds ratio IS (100%, 9)
0.942 0.671 1.235 1.339 1.000 0.482 0.766 2.357 7.167 – IS(0%, 1)
0.890 0.500 0.648 IS(0%, 8) 1.914 1.533
0.569 1.000
0.810 IS(0%, 8)
0.792 1.970 0.494 0.750 0.886
UPD odds ratio 0.111*
LARSON ET AL. 3
1.310 0.997 0.949 2.449 1.727 2.139 1.150 3.985 1.373 2.224 1.193 0.997 0.837 1.282 0.175 3.762 0.948 1.741 0.487 0.648 1.995 0.302 0.650
72% (109) 22% (109) 25% (109) 65% (85) 45% (85) (85) (85) (84) (109) (85) (109)
66% 20% 11% 17% 24% 37% 56% (108) 35% (108) 40% (108) 7.4(sd:1.67, n ¼ 61) 18% (61) 59% (61) 77% (108) 6% (108) 18% (108) 68% (108) 7% (108) 24% (108)
Female odds ratio
4.315* 3.304*
4.424* 3.214*
1.344 6.852 0.346
1.740 1.478 0.363
1.426 6.292 0.333
0.799 1.853 1.019
0.439 2.073 0.871
3.125*
3.704*
0.985** 0.261 4.526*
0.587 0.969 3.026 4.080* 2.721 1.999
0.827 3.263
3.479 1.228 0.942
26–30y odds ratio
0.907 0.426 0.522 1.468 1.170 3.311*
0.539 2.035
0.977 3.070 0.345
21–25y odds ratio
IS, infinite solution (%, n); Tx, treatment; hr, hours. Age sub-groups compared with the 16–20y cohort. Genotype sub-groups compared with the Del cohort. a Sleep medications included: trazadone, clonidine, clonazepam, seroquel, tranxene, eszopiclone, zolpidem, mirtazepine, temazepam, ramelteon, and doxylamine. b Awake for a period of an hour or more overnight. c Awake caregiver overnight, audio/video monitoring, or posey bed. d Regression coefficient listed for each covariate. * Statistically significant odds ratio (a ¼ 0.05). ** statistically significant regression coefficient (a ¼ 0.05).
Sleep Sleep problems Melatonin Tx Other sleep medicationa Sleep latency Trouble falling asleep TV on to fall asleep Night waking Difficulty staying asleep Awake overnight weeklyb Never sleeps through the nightb Co-sleeping TV on all night long Close nighttime monitoringc Daytime sleepiness Naps routinely Often falls asleep Riding in the car Watching TV or movies Sleep quantity Hours of sleep per nightd 5 hr 8 hr Lifetime sleep severity Compared to infancy Improved Worse Unchanged Compared to childhood Improved Worse Unchanged
Full Cohort % (n)
0.748 IS (0%, 15) 1.470
0.406 IS (0%, 15) 3.339
1.470 2.619 0.273
2.833 1.803
2.778
3.036 0.848 3.420 2.131 1.821 1.858
1.042 2.146
1.553 1.945 0.497
31–50y odds ratio
TABLE III. Sleep Parameters for Individuals With Angelman Syndrome, Late-Adolescence Through Adulthood
0.903 1.971 0.841
0.964 2.500 0.612
0.850 4.714 0.905
1.477 0.375
0.545
5.469 0.484 IS (0%, 9) IS (0%, 8) 1.680 0.694
0.357 1.111
1.296 1.812 1.447
UBE3A odds ratio
4.333 1.725 IS (0%, 9)
2.893 IS (0%, 10) 0.476
0.207 1.886 1.206
0.923 0.656
0.545
2.344 2.031 1.000 1.173 0.400 0.347
1.071 0.370
1.481 0.906 1.241
UPD odds ratio
4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(105) (109) (109) (51) (31) (109) (40) (109) (109) (80)
50% 49% 47% 61% 48% 37% 83% 85% 43% 40% 13.2(sd:2.18, n ¼ 52) 17% 52 27% (52) 31% (54) 62% (37) 13% (54)
(84) (16) (85) (85) (43) (43) (85) (85)
40% 56% 38% 51% 49% 53% 64% 48% 0.318 0.924 1.848 0.764 0.505 0.110 IS(100%, 8) 0.527 0.917 0.731
3.152* 1.761 1.291 0.743 0.740 1.447 0.436 1.333 0.825 0.715 0.689 1.308 0.623 2.000 2.333 IS(0%, 15)
1.524 0.926 1.254 2.239 2.239 0.928 1.589 0.628
21–25y odds ratio
0.648 0.631 0.916 0.569 2.675 3.836 1.191 0.737
Female odds ratio
HEENT, Head eyes ears nose and throat; IS, infinite solution (%, n); OCP, oral contraceptive. Age sub-groups compared with the 16–20y cohort. Genotype sub-groups compared with the Del cohort. a Abnormal results included swallow delay and silent aspiration. b Unrelated to eating. c Drinks 6hr or necessitating trip to emergency room. f 10 years or more than 2 years earlier than maternal menarche. g 15 years or more than 2 years later than maternal menarche. h Depot medroxyprogesterone acetate. i Individuals not on OCP/ Depo-provera. j Significant pain and/or increased irritability. k Regression coefficient listed for each covariate. * Statistically significant odds ratio (a–¼ 0.05). ** Statistically significant regression coefficient (a ¼ 0.05).
Heent History of severe choking Abnormal swallow studya History of severe pneumonia Episodic gaggingb Progresses to vomiting Triggered by a strong smell Dental care non-sedated Seasonal allergies Gastrointestinal/nutrition Decreased satiety Poor hydrationc Gastroesophageal refluxd History of medication Improvement with treatment Cyclic vomiting Episode >6hrse Constipation Medication for constipation Typically
