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Research Article: Natural Course of IQSEC2-Related Encephalopathy: An Italian National Structured Survey

Date Published: 2023-08-24

Abstract:
Pathogenic loss-of-function variants in the IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause intellectual disability with Rett syndrome (RTT)-like features. The aim of this study was to obtain systematic information on the natural history and extra-central nervous system (CNS) manifestations for the Italian IQSEC2 population (>90%) by using structured family interviews and semi-quantitative questionnaires. IQSEC2 encephalopathy prevalence estimate was 7.0 to 7.9 × 10?7. Criteria for typical RTT were met in 42.1% of the cases, although psychomotor regression was occasionally evidenced. Genetic diagnosis was occasionally achieved in infancy despite a clinical onset before the first 24 months of life. High severity in both the CNS and extra-CNS manifestations for the IQSEC2 patients was documented and related to a consistently adverse quality of life. Neurodevelopmental delay was diagnosed before the onset of epilepsy by 1.8 to 2.4 years. An earlier age at menarche in IQSEC2 female patients was reported. Sleep disturbance was highly prevalent (60 to 77.8%), with mandatory co-sleeping behavior (50% of the female patients) being related to de novo variant origin, younger age, taller height with underweight, better social interaction, and lower life quality impact for the family and friends area. In conclusion, the IQSEC2 encephalopathy is a rare and likely underdiagnosed developmental encephalopathy leading to an adverse life quality impact.

Introduction:
Pathogenic variants on chromosome X represent an important cause of neurodevelopmental disorders (NDDs) [1]. Clinical features of X-linked NDDs are influenced by gender [2,3]. In female patients, clinical phenotype is more variable due to X chromosome inactivation (XCI) status [2,3] and the rate of genes escaping XCI (15–20%) [4], such as IQ motif and SEC7 domain containing protein 2 (IQSEC2) [5]. Variants in the IQSEC2 gene are associated with a rare form of intellectual disability (ID) and epilepsy (OMIM #…

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