Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS)

Tjeertes, Jorrit; Bacino, Carlos A.; Bichell, Terry Jo; Bird, Lynne M.; Bustamante, Mariana; Crean, Rebecca; Jeste, Shafali; Komorowski, Robert W.; Krishnan, Michelle L.; Miller, Meghan T.; Nobbs, David; Ochoa-Lubinoff, Cesar; Parkerson, Kimberly A.; Rotenberg, Alexander; Sadhwani, Anjali; Shen, Mark D.; Squassante, Lisa; Tan, Wen-Hann; Vincenzi, Brenda; Wheeler, Anne C.; Hipp, Joerg F.; Berry-Kravis, Elizabeth

doi:10.1186/s11689-023-09494-w

Table 3 Baseline COA data by genotype and age

From: Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS)

Scales	AS 1–4 years	AS 5–12 years	AS ≥ 18 years	AS deletion	AS nondeletion	TDC 1–4 years	TDC 5–12 years
Bayley-III raw score, n, mean ± SD, range
Cognitive	n = 16	n = 26	n = 12	n = 40	n = 14	N/A	N/A
	35.5 ± 7.4	49.9 ± 11.1	50.9 ± 11.6	41.5 ± 9.6	58.3 ± 10.0	N/A	N/A
	23.0–52.0	29.0–79.0	30.0–66.0	23.0–63.0	41.0–79.0	N/A	N/A
Expressive Communication	n = 15	n = 27	n = 12	n = 39	n = 15	N/A	N/A
	9.0 ± 3.7	11.9 ± 4.3	15.8 ± 5.1	10.9 ± 4.3	14.7 ± 5.5	N/A	N/A
	2.0–17.0	6.0–20.0	7.0–27.0	2.0–20.0	7.0–27.0	N/A	N/A
Receptive Communication	n = 16	n = 25	n = 12	n = 39	n = 14	N/A	N/A
	12.9 ± 4.2	17.4 ± 5.6	19.3 ± 7.0	14.3 ± 4.4	22.6 ± 5.8	N/A	N/A
	7.0–23.0	9.0–28.0	11.0–33.0	7.0–28.0	12.0–33.0	N/A	N/A
Fine Motor	n = 15	n = 26	n = 12	n = 39	n = 14	N/A	N/A
	24.1 ± 3.8	29.6 ± 7.7	35.3 ± 8.0	27.0 ± 6.5	35.9 ± 7.7	N/A	N/A
	18.0–31.0	16.0–43.0	25.0–49.0	16.0–44.0	21.0–49.0	N/A	N/A
Gross Motor	n = 16	n = 27	n = 10	n = 38	n = 15	N/A	N/A
	36.6 ± 10.7	49.3 ± 6.7	48.4 ± 7.6	42.8 ± 10.1	51.5 ± 6.5	N/A	N/A
	15.0–54.0	29.0–66.0	29.0–55.0	15.0–54.0	43.0–66.0	N/A	N/A
Vineland-3 raw score, n, mean ± SD, range
Expressive Communication	n = 16	n = 27	n = 11	n = 40	n = 14	n = 9	n = 11
	11.3 ± 7.2	16.3 ± 8.4	16.0 ± 8.9	12.6 ± 7.1	20.9 ± 8.8	70.6 ± 31.0	96.7 ± 1.4
	4.0–28.0	5.0–40.0	10.0–38.0	4.0–40.0	10.0–38.0	17.0–94.0	95.0–98.0
Receptive Communication	n = 16	n = 27	n = 12	n = 40	n = 15	n = 9	n = 11
	16.7 ± 11.9	29.2 ± 13.5	29.6 ± 15.9	21.0 ± 13.4	38.1 ± 9.5	56.8 ± 17.2	75.6 ± 2.1
	1.0–42.0	9.0–62.0	11.0–55.0	1.0–62.0	25.0–55.0	27.0–72.0	72.0–78.0
Fine Motor	n = 16	n = 27	n = 12	n = 40	n = 15	n = 9	n = 8
	14.0 ± 6.0	24.7 ± 7.0	25.1 ± 8.1	19.0 ± 7.2	28.9 ± 7.3	39.8 ± 11.6	67.0 ± 1.6
	5.0–27.0	14.0–44.0	16.0–38.0	5.0–36.0	18.0–44.0	18.0–51.0	64.0–68.0
Gross Motor	n = 16	n = 27	n = 11	n = 39	n = 15	n = 9	n = 8
	21.6 ± 15.1	48.2 ± 13.3	39.2 ± 15.8	34.4 ± 17.4	49.1 ± 16.3	70.7 ± 17.6	85.1 ± 1.4
	2.0–56.0	17.0–77.0	11.0–58.0	2.0–58.0	25.0–77.0	38.0–83.0	83.0–86.0
Communication Matrix total score, n, mean ± SD, range	n = 13	n = 26	n = 11	n = 38	n = 12	n = 8	n = 11
	38.5 ± 19.9	67.7 ± 26.0	56.6 ± 19.0	48.5 ± 18.3	86.6 ± 25.3	120.6 ± 38.5	145.8 ± 12.8
	5.0–72.0	33.0–135.0	32.0–100.0	5.0–109.0	46.0–135.0	55.0–160.0	126.0–160.0
SNAKE, n, mean ± SD, range
Disturbances going to sleep	n = 13	n = 26	n = 9	n = 36	n = 12	N/A	N/A
	9.0 ± 1.6	11.8 ± 3.5	9.2 ± 2.7	10.2 ± 3.1	11.7 ± 3.2	N/A	N/A
	7.0–12.0	7.0–19.0	6.0–14.0	6.0–18.0	8.0–19.0	N/A	N/A
Disturbances remaining asleep	n = 12	n = 25	n = 9	n = 36	n = 10	N/A	N/A
	15.1 ± 3.3	13.3 ± 3.4	12.8 ± 3.0	13.6 ± 3.1	14.0 ± 4.4	N/A	N/A
	10.0–20.0	5.0–19.0	10.0–18.0	8.0–19.0	5.0–20.0	N/A	N/A
Arousal disorders	n = 13	n = 25	n = 9	n = 35	n = 12	N/A	N/A
	9.5 ± 2.5	9.0 ± 2.7	9.1 ± 3.7	9.3 ± 3.0	8.7 ± 2.1	N/A	N/A
	6.0–14.0	6.0–15.0	6.0–17.0	6.0–17.0	6.0–12.0	N/A	N/A
Daytime sleepiness	n = 12	n = 23	n = 10	n = 32	n = 13	N/A	N/A
	8.6 ± 1.6	5.9 ± 2.1	6.2 ± 3.1	6.6 ± 2.4	6.9 ± 2.7	N/A	N/A
	6.0–11.0	3.0–10.0	3.0–11.0	3.0–11.0	3.0–11.0	N/A	N/A
Daytime behavioral disorders	n = 13	n = 26	n = 9	n = 36	n = 12	N/A	N/A
	9.2 ± 2.3	9.9 ± 3.3	8.3 ± 2.6	9.3 ± 2.8	9.8 ± 3.4	N/A	N/A
	6.0–13.0	4.0–15.0	5.0–12.0	5.0–15.0	4.0–15.0	N/A	N/A
CSDI, n, mean ± SD, range	n = 12	n = 25	n = 10	n = 35	n = 12	N/A	N/A
	5.3 ± 2.4	5.6 ± 2.6	6.0 ± 2.4	5.3 ± 2.5	6.4 ± 2.3	N/A	N/A
	0.0–8.0	2.0–11.0	2.0–9.0	0.0–11.0	2.0–10.0	N/A	N/A
ABC-2-C, n, mean ± SD, range
Irritability	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	4.2 ± 5.5	9.6 ± 8.7	10.0 ± 7.1	7.8 ± 6.8	9.9 ± 10.6	N/A	N/A
	0.0–19.0	1.0–39.0	0.0–23.0	0.0–27.0	0.0–39.0	N/A	N/A
Social withdrawal	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	5.9 ± 5.8	6.4 ± 4.3	4.7 ± 4.8	6.7 ± 4.8	3.7 ± 4.1	N/A	N/A
	0.0–20.0	1.0–16.0	0.0–17.0	0.0–20.0	0.0–16.0	N/A	N/A
Stereotypic behavior	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	4.9 ± 4.7	6.5 ± 5.2	1.9 ± 2.2	5.6 ± 4.7	3.5 ± 5.0	N/A	N/A
	0.0–14.0	0.0–18.0	0.0–6.0	0.0–16.0	0.0–18.0	N/A	N/A
Hyperactivity/ noncompliance	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	9.9 ± 11.6	22.4 ± 11.3	15.7 ± 8.3	18.1 ± 12.2	16.5 ± 11.2	N/A	N/A
	0.0–39.0	5.0–40.0	1.0–25.0	0.0–39.0	1.0–40.0	N/A	N/A
Inappropriate speech	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	0.4 ± 1.4	1.1 ± 2.7	1.6 ± 2.4	0.8 ± 1.8	1.5 ± 3.6	N/A	N/A
	0.0–5.0	0.0–12.0	0.0–6.0	0.0–7.0	0.0–12.0	N/A	N/A
FMS, n (%)
5 m	n = 16	n = 27	n = 12	n = 40	n = 15	n = 9	n = 11
C – Crawling	3 (18.8)	0 (0.0)	1 (8.3)	4 (10.0)	0 (0.0)	0 (0.0)	0 (0.0)
N – Does not apply	2 (12.5)	0 (0.0)	0 (0.0)	2 (5.0)	0 (0.0)	0 (0.0)	0 (0.0)
1 – Wheelchair	2 (12.5)	1 (3.7)	1 (8.3)	4 (10.0)	0 (0.0)	0 (0.0)	0 (0.0)
2 –Walker/frame	3 (18.8)	1 (3.7)	1 (8.3)	4 (10.0)	1 (6.7)	0 (0.0)	0 (0.0)
3 – Crutches	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
4 – Sticks	1 (6.3)	0 (0.0)	0 (0.0)	1 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)
5 – Independent: level surfaces	1 (6.3)	13 (48.1)	3 (25.0)	11 (27.5)	6 (40.0)	0 (0.0)	0 (0.0)
6 – Independent: all surfaces	4 (25.0)	12 (44.4)	6 (50.0)	14 (35.0)	8 (53.3)	9 (100.0)	11 (100.0)
50 m	n = 16	n = 27	n = 12	n = 40	n = 15	n = 9	n = 11
N – Does not apply	4 (25.0)	0 (0.0)	0 (0.0)	4 (10.0)	0 (0.0)	0 (0.0)	0 (0.0)
1 – Wheelchair	4 (25.0)	2 (7.4)	2 (16.7)	8 (20.0)	0 (0.0)	0 (0.0)	0 (0.0)
2 – Walker/frame	2 (12.5)	1 (3.7)	1 (8.3)	2 (5.0)	2 (13.3)	0 (0.0)	0 (0.0)
3 – Crutches	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
4 – Sticks	1 (6.3)	0 (0.0)	0 (0.0)	1 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)
5 – Independent: level surfaces	3 (18.8)	16 (59.3)	4 (33.3)	16 (40.0)	7 (46.7)	0 (0.0)	0 (0.0)
6 – Independent: all surfaces	2 (12.5)	8 (29.6)	5 (41.7)	9 (22.5)	6 (40.0)	9 (100.0)	11 (100.0)
500 m	n = 16	n = 27	n = 12	n = 40	n = 15	n = 9	n = 11
N – Does not apply	5 (31.3)	0 (0.0)	0 (0.0)	4 (10.0)	1 (6.7)	2 (22.2)	0 (0.0)
1 – Wheelchair	5 (31.3)	5 (18.5)	3 (25.0)	10 (25.0)	3 (20.0)	0 (0.0)	0 (0.0)
2 – Walker/frame	3 (18.8)	0 (0.0)	1 (8.3)	3 (7.5)	1 (6.7)	0 (0.0)	0 (0.0)
3 – Crutches	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
4 – Sticks	0 (0.0)	2 (7.4)	0 (0.0)	0 (0.0)	2 (13.3)	0 (0.0)	0 (0.0)
5 – Independent: level surfaces	2 (12.5)	13 (48.1)	4 (33.3)	17 (42.5)	2 (13.3)	0 (0.0)	0 (0.0)
6 – Independent: all surfaces	1 (6.3)	7 (25.9)	4 (33.3)	6 (15.0)	6 (40.0)	7 (77.8)	11 (100.0)
PedsQL™ 4.0 Core, n mean ± SD, range	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	55.9 ± 12.0	53.6 ± 17.1	51.8 ± 17.2	53.1 ± 15.7	55.8 ± 16.5	N/A	N/A
	36.9–72.9	21.4–84.5	25.0–81.0	25.0–84.5	21.4–79.8	N/A	N/A
EQ-5D-Y VAS, n mean ± SD, range	n = 13	n = 24	n = 11	n = 35	n = 13	N/A	N/A
	83.1 ± 9.5	81.9 ± 12.1	89.2 ± 14.7	84.4 ± 12.0	82.5 ± 13.0	N/A	N/A
	70.0–100.0	50.0–98.0	62.0–100.0	55.0–100.0	50.0–100.0	N/A	N/A
CGI-S, n (%)
	n = 16	n = 27	n = 12	n = 40	n = 15	N/A	N/A
1 − Normal, not at all ill	1 (6.3)	2 (7.4)	0 (0.0)	3 (7.5)	0 (0.0)	N/A	N/A
2 − Borderline ill	2 (12.5)	2 (7.4)	1 (8.3)	4 (10.0)	1 (6.7)	N/A	N/A
3 − Mildly ill	5 (31.3)	6 (22.2)	0 (0.0)	4 (10.0)	7 (46.7)	N/A	N/A
4 − Moderately ill	4 (25.0)	10 (37.0)	5 (41.7)	14 (35.0)	5 (33.3)	N/A	N/A
5 − Markedly ill	3 (18.8)	5 (18.5)	5 (41.7)	11 (27.5)	2 (13.3)	N/A	N/A
6 − Severely ill	1 (6.3)	2 (7.4)	1 (8.3)	4 (10.0)	0 (0.0)	N/A	N/A
HOST, n, mean ± SD, range
Sleep disturbances	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	16.0 ± 5.5	15.0 ± 5.0	13.7 ± 7.1	14.7 ± 5.5	15.9 ± 5.8	N/A	N/A
	8.0–24.0	5.0–25.0	5.0–25.0	5.0–25.0	5.0–25.0	N/A	N/A
Impairment of physical/mental functioning	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	12.5 ± 4.3	12.1 ± 5.6	10.7 ± 4.0	11.8 ± 4.7	12.3 ± 5.6	N/A	N/A
	6.0–22.0	5.0–25.0	5.0–16.0	5.0–23.0	5.0–25.0	N/A	N/A
Impairment of social functioning	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	9.5 ± 3.3	11.1 ± 3.5	11.4 ± 3.5	10.7 ± 3.3	11.0 ± 4.0	N/A	N/A
	4.0–15.0	4.0–20.0	7.0–18.0	4.0–18.0	5.0–20.0	N/A	N/A
Impairment of working ability	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	3.5 ± 2.2	4.0 ± 1.8	3.5 ± 1.4	3.8 ± 1.9	3.6 ± 1.6	N/A	N/A
	2.0–8.0	2.0–10.0	2.0–7.0	2.0–10.0	2.0–7.0	N/A	N/A
PSQI, n, mean ± SD, range	n = 12	n = 24	n = 10	n = 35	n = 11	N/A	N/A
	9.3 ± 4.8	7.2 ± 4.1	7.5 ± 3.4	7.7 ± 4.3	8.3 ± 3.9	N/A	N/A
	5.0–17.0	1.0–17.0	3.0–12.0	1.0–17.0	5.0–17.0	N/A	N/A
ESS, n, mean ± SD, range	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	8.2 ± 4.2	8.1 ± 4.2	7.7 ± 4.0	8.0 ± 4.4	8.3 ± 3.0	N/A	N/A
	3.0–16.0	1.0–16.0	2.0–14.0	1.0–16.0	3.0–11.0	N/A	N/A
EQ-5D-5L VAS, n, mean ± SD, range	n = 13	n = 25	n = 11	n = 36	n = 13	N/A	N/A
	82.7 ± 9.3	82.2 ± 9.5	87.6 ± 8.6	84.3 ± 9.6	81.4 ± 8.4	N/A	N/A
	60.0–90.0	60.0–95.0	75.0–100.0	60.0–100.0	70.0–95.0	N/A	N/A
PedsQL™-FIM, n, mean ± SD, range	n = 13	n = 26	n = 11	n = 37	n = 13	N/A	N/A
	56.9 ± 17.8	54.1 ± 20.1	58.6 ± 13.0	56.2 ± 17.1	54.7 ± 20.8	N/A	N/A
	26.4–83.3	10.4–98.6	46.5–94.4	26.4–98.6	10.4–76.4	N/A	N/A

ABC-2-C Aberrant Behavior Checklist Second Edition – Community Version, AS Angelman syndrome, Bayley-III Bayley Scales of Infant and Toddler Development® – Third Edition, CGI-S Clinical Global Impression – Severity, COA clinical outcome assessment, CSDI Composite Sleep Disturbance Index, EQ-5D-5L VAS European Quality of Life 5-Dimensions Questionnaire-Five Levels Visual Analogue Scale, EQ-5D-Y VAS European Quality of Life 5-Dimensions Questionnaire-Youth Visual Analogue Scale, ESS Epworth Sleepiness Scale, FMS Functional Mobility Scale, HOST holistic assessment of sleep and daily troubles in parents of children with severe psychomotor impairment, N/A not accessed, PedsQL™ 4.0 Core Pediatric Quality of Life Inventory™ Generic Core Scales, Version 4.0, PedsQL™-FIM Pediatric Quality of Life Inventory™ Family Impact Module, PSQI Pittsburgh Sleep Quality Index, SD Standard deviation, SNAKE Schlaffragebogen für Kinder mit Neurologischen und Anderen Komplexen Erkrankungen (Sleep Questionnaire for Children with Severe Psychomotor Impairment), TDC Typically developing children, Vineland-3 Vineland Adaptive Behavior Scales® – Third Edition

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