Natural Course of <i>IQSEC2</i>-Related Encephalopathy: An Italian National Structured Survey
Silvia Leoncini,
Lidia Boasiako,
Diego Lopergolo,
Maria Altamura,
Caterina Fazzi,
Roberto Canitano,
Salvatore Grosso,
Ilaria Meloni,
Margherita Baldassarri,
Susanna Croci,
Alessandra Renieri,
Mario Mastrangelo,
Claudio De Felice
Affiliations
Silvia Leoncini
Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
Lidia Boasiako
Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
Diego Lopergolo
Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
Maria Altamura
Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
Caterina Fazzi
Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
Roberto Canitano
Child Neuropsychiatry Unit, Department of Mental Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
Salvatore Grosso
Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
Ilaria Meloni
Medical Genetics, University of Siena, 53100 Siena, Italy
Margherita Baldassarri
Medical Genetics, University of Siena, 53100 Siena, Italy
Susanna Croci
Medical Genetics, University of Siena, 53100 Siena, Italy
Alessandra Renieri
Medical Genetics, University of Siena, 53100 Siena, Italy
Mario Mastrangelo
Maternal Infantile and Urological Sciences Department, Sapienza University of Rome, 00185 Rome, Italy
Claudio De Felice
Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
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.
