Goad Beatrice Southby, Rodda Jill, Allen Meagan, Bamborschke Daniel, Overmars Isabella, Kerr Rachel J, Bushlin Ittai, Chopra Saurabh, Coorg Rohini, Dabscheck Gabriel, Freeman Jeremy L, Mackay Mark T, Devinsky Orrin, Guerrini Renzo, Parrini Elena, Bölsterli Bigna, Hughes Inna, Huh Linda L, Kamate Mahesh, Kunz Abby B, Melikishvili Gia, Miteff Christina, Myers Kenneth Alexis, Olson Heather E, Poduri Annapurna, Pillai Sekhar, Riney Catherine Kate, Sinclair Adriane, Calvert Sophie, Reynolds Thomas Q, Martinez Ana Roche, Russo Angelo, Sadleir Lynette Grant, Sanchez-Albisua Iciar, Sartori Stefano, Shea Stephanie, Smith-Hicks Constance L, Spooner Claire G, Thomas Rhys H, Ardern-Holmes Simone L, Webster Richard Ian, Valeriani Massimiliano, Veggiotti Pierangelo, Masnada Silvia, Ware Tyson L, Yoong Michael, Berecki Geza, De Dominicis Angela, Specchio Nicola, Trivisano Marina, Møller Rikke Steensbjerre, Wolff Markus, Fazeli Walid, Scheffer Ingrid, Howell Katherine B
Murdoch Children's Research Institute, Melbourne, Australia.
Department of Physiotherapy, University of Melbourne, Australia.
Neurology. 2025 Aug 12;105(3):e213868. doi: 10.1212/WNL.0000000000213868. Epub 2025 Jul 22.
Developmental impairment is common in individuals with -related disorders, although descriptions are limited. We aimed to determine trajectories and outcomes of development and adaptive function.
This was a mixed retrospective cross-sectional study of individuals from an international Natural History Study, who had neurologic/neurodevelopmental disorders due to an variant. Individuals with intragenic variants were grouped into early-onset (EO) and late-onset (LO) phenotypic groups; those with -containing 2q24.3 copy number variants (CNVs) were considered separately. We collected medical and developmental history from parents/caregivers and medical records. Adaptive function and behavior were characterized using functional classification system levels and Vineland Adaptive Behavior Scales-3 (VABS-3) Parent/Caregiver Form. We repeated analyses on individuals with variants known to result in gain-of-function (GOF, typically EO phenotypes) or loss-of-function (LOF, typically LO phenotypes).
A total of 100 individuals (age 0.1-21.9 years, 39% female) were studied. Phenotypic groups were EO (n = 44), LO (n = 48), and 2q24.3 CNV (n = 8). Developmental delay/intellectual disability was present in 91 of 100, and 23 of 80 individuals (29%) older than 2 years had autism spectrum disorder. Of people older than the typical age for skill attainment, 59 of 95 (62%) could sit and 48 of 88 (55%) could walk. In addition, 27 of 86 individuals (31%) spoke more than 1-5 single words, and 24 of 74 (32%) followed two-step commands. Median VABS-3 Adaptive Behavior Composite (ABC) scores were as follows: the EO phenotypic group had a score of 56 (range 21-110), the LO phenotypic group had a score of 45 (range 20-89), and 5 of 6 with a 2q24.3 CNV had an ABC score of <45. The EO phenotypic group had 3 distinct subgroups, consistent with "benign," "intermediate," and "severe" definitions previously published. The LO phenotypic group showed a continuum of severity, without distinct clusters. However, clinically relevant differences in motor function were evident when subgrouped by seizure-onset age; a lower proportion with earlier seizure onset (age <18 months) were independently ambulant than those with later onset or no seizures (5/15 [33%] vs 10/12 [83%] vs 14/15 [93%], < 0.01). Analyses of individuals with confirmed GOF/LOF variants (n = 57) showed similar results to the EO/LO analyses.
The spectrum of developmental impairments and adaptive function in -related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.
发育障碍在患有相关疾病的个体中很常见，尽管相关描述有限。我们旨在确定发育和适应功能的轨迹及结果。
这是一项对来自国际自然史研究的个体进行的混合回顾性横断面研究，这些个体因某变异而患有神经/神经发育障碍。具有基因内变异的个体被分为早发型（EO）和晚发型（LO）表型组；那些含有2q24.3拷贝数变异（CNV）的个体被单独考虑。我们从父母/照顾者及病历中收集医疗和发育史。使用功能分类系统水平和文兰适应行为量表-3（VABS-3）父母/照顾者表格对适应功能和行为进行特征描述。我们对已知会导致功能获得（GOF，通常为EO表型）或功能丧失（LOF，通常为LO表型）变异的个体重复进行分析。
共研究了100名个体（年龄0.1 - 21.9岁，39%为女性）。表型组为EO（n = 44）、LO（n = 48）和2q24.3 CNV（n = 8）。100名个体中有91名存在发育迟缓/智力残疾，80名2岁以上个体中有23名（29%）患有自闭症谱系障碍。在超过技能获得典型年龄的人群中，95名中有59名（62%）能坐，88名中有48名（55%）能走。此外，86名个体中有27名（31%）能说超过1 - 5个单词，74名中有24名（32%）能听从两步指令。VABS-3适应行为综合（ABC）得分中位数如下：EO表型组得分为56（范围21 - 110），LO表型组得分为45（范围20 - 89），6名2q24.3 CNV个体中有5名ABC得分<45。EO表型组有3个不同的亚组，与先前发表的“良性”“中度”和“重度”定义一致。LO表型组显示出严重程度的连续性，无明显聚类。然而，按癫痫发作起始年龄分组时，运动功能存在明显的临床相关差异；癫痫发作起始较早（年龄<18个月）的个体中能独立行走的比例低于发作较晚或无癫痫发作的个体（5/15 [33%] 对10/12 [83%] 对14/15 [93%]，P < 0.01）。对已确认GOF/LOF变异的个体（n = 57）进行的分析显示结果与EO/LO分析相似。
相关疾病中的发育障碍和适应功能谱极其广泛。表型亚组提供了预后信息，并对临床试验设计具有关键指导意义。
