Development and Adaptive Function in Individuals With SCN2A-Related Disorders.
Developmental impairment is common in individuals with SCN2A-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 SCN2A Natural History Study, who had neurologic/neurodevelopmental disorders due to an SCN2A variant. Individuals with SCN2A intragenic variants were grouped into early-onset (EO) and late-onset (LO) phenotypic groups; those with SCN2A-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%], p < 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 SCN2A-related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.
This was a mixed retrospective cross-sectional study of individuals from an international SCN2A Natural History Study, who had neurologic/neurodevelopmental disorders due to an SCN2A variant. Individuals with SCN2A intragenic variants were grouped into early-onset (EO) and late-onset (LO) phenotypic groups; those with SCN2A-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%], p < 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 SCN2A-related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.
Authors
Goad Goad, Rodda Rodda, Allen Allen, Bamborschke Bamborschke, Overmars Overmars, Kerr Kerr, Bushlin Bushlin, Chopra Chopra, Coorg Coorg, Dabscheck Dabscheck, Freeman Freeman, Mackay Mackay, Devinsky Devinsky, Guerrini Guerrini, Parrini Parrini, Bölsterli Bölsterli, Hughes Hughes, Huh Huh, Kamate Kamate, Kunz Kunz, Melikishvili Melikishvili, Miteff Miteff, Myers Myers, Olson Olson, Poduri Poduri, Pillai Pillai, Riney Riney, Sinclair Sinclair, Calvert Calvert, Reynolds Reynolds, Martinez Martinez, Russo Russo, Sadleir Sadleir, Sanchez-Albisua Sanchez-Albisua, Sartori Sartori, Shea Shea, Smith-Hicks Smith-Hicks, Spooner Spooner, Thomas Thomas, Ardern-Holmes Ardern-Holmes, Webster Webster, Valeriani Valeriani, Veggiotti Veggiotti, Masnada Masnada, Ware Ware, Yoong Yoong, Berecki Berecki, De Dominicis De Dominicis, Specchio Specchio, Trivisano Trivisano, Møller Møller, Wolff Wolff, Fazeli Fazeli, Scheffer Scheffer, Howell Howell
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