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. 2024 Nov 25;10(6):e200194.
doi: 10.1212/NXG.0000000000200194. eCollection 2024 Dec.

Adult Phenotype of CHD2-Associated Disorders

Marlene Rong  1 , Quratulain Zulfiqar Ali  1 , Angel Aledo-Serrano  1 , Allan Bayat  1 , Orrin Devinsky  1 , Farah Qaiser  1 , Ilakkiah Chandran  1 , Anum Ali  1 , Alfonso Fasano  1 , Anne S Bassett  1 , Danielle M Andrade  1
Affiliations

Adult Phenotype of CHD2-Associated Disorders

Marlene Rong et al. Neurol Genet. .

Abstract

Background and objectives: Pathogenic CHD2 variants are associated with neurodevelopmental disorders and developmental and epileptic encephalopathy. While pediatric CHD2 phenotypes have been readily explored, adult phenotypes are not well understood. We aimed to investigate the phenotypic spectrum of adult patients with CHD2 variants.

Methods: Patients 18 years or older with likely pathogenic or pathogenic (LP/P) CHD2 variants were included. We used standardized tools to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder, and adaptive behavioral skills of patients.

Results: In this prospective study, 14 unrelated adult patients (age range: 18-45 years, median: 21 years) with LP/P CHD2 variants were described. Eleven novel variants were identified. No genotype-phenotype correlations were identified. 79% of adults still have ongoing seizures. Photosensitivity was present in 64% of adult patients. Autism spectrum disorder was diagnosed in 71% of patients. Only 29% were able to read and understand material at a sixth-grade level or higher. Behavioral issues were reported in 100% of adult patients, and 71% had internalizing features, such as anxiety. Self-injurious behaviors were present in 50%. Only 43% could ambulate independently. Additional characteristics included reflux (36%), constipation (71%), and abnormal pain responsiveness (43%). 1 patient presented with nonepileptic breath-holding spells leading to cyanosis. No patient could perform all basic activities of daily living independently, all the time. Higher seizure severity was associated with worse nonseizure outcomes (p = 0.04).

Discussion: Most adults with CHD2 continue to have seizures, and seizure severity is associated with worse comorbidities such as maladaptive behaviors, gait, gastrointestinal, sleep, and abnormal pain responsiveness. Longevity has not been systematically studied in this group of patients. Here we describe a group of adult patients (up to 45 years of age) and the natural history of this condition. These data may provide prognostic insights for families of pediatric patients and help identify key points to be addressed in future precision trials for patients with CHD2 variants.

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Conflict of interest statement

M. Rong received an unrestricted education grant from Biocodex. Q. Zulfiqar Ali reports no disclosures relevant to the manuscript. A. Aledo‐Serrano received educational, scientific and consulting fees from UCB, Biocodex, Eisai, Angelini, Jazz pharma. A. Bayat reports no disclosures relevant to the manuscript. O. Devinsky receives grant support from NINDS, NIMH, MURI, CDC and NSF. He has equity and/or compensation from the following companies: Ajna Biosciences, Tilray, Receptor Life Sciences, Hitch Biosciences, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, SilverSpike, and California Cannabis Enterprises. He has received consulting fees from Zogenix, Ultragenyx, BridgeBio, GeneMedicine and Marinus. He holds patents for the use of cannabidiol in treating neurologic disorders which are owned by GW Pharmaceuticals for which he waived financial interests. He holds other patents in molecular biology. He is the managing partner of the PhiFund Ventures. F. Qaiser, I. Chandran, A. Ali, A. Fasano, and A.S. Bassett report no disclosures relevant to the manuscript. D.M. Andrade receives grant support from Ontario Brain Institute, McLaughlin Foundation, UHN Foundation, Dravet Syndrome Foundation, SYNGAP1 Research Fund. She also received consulting fees from UCB, Biocodex, Paladin, Jazz, Stoke, and Eisai. Finally, she receives royalties from UpToDate. Go to Neurology.org/NG for full disclosures.

Figures

Figure 1
Figure 1. Study Identification Flow Diagram
Of 231 searches for “CHD2,” 16 full-text articles featuring patients aged 18 years or older were identified.
Figure 2
Figure 2. Walking Abilities of Adults With CHD2
Percentage prevalence of a range of walking abilities is provided (n = 14).
Figure 3
Figure 3. Summary Graphs of Gastrointestinal Clinical Features in Adults With CHD2
Information on (A) constipation, (B) toileting, and (C) reflux are provided (n = 14). No statistically significant differences between variant types or functional domains were found.
Figure 4
Figure 4. Summary Graphs of Other Clinical Features in Adults With CHD2
Information on (A) sleep disturbances, (B) disruptive daytime sleepiness, and (C) pain responsiveness are provided (n = 14). No statistically significant differences between variant types or functional domains were found.
Figure 5
Figure 5. Seizure Severity Scores vs Nonseizure Outcome Severity Score
s (p = 0.04) Increasing seizure severity was associated with increasing severity of nonseizure outcomes reported in Figures 2 and 3.
See this image and copyright information in PMC

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