Abstract
Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein (SCAMP5) associated with epilepsy and neurodevelopmental delay. Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed. Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp). Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected.
Highlights
Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane molecules implicated in regulating vesicular transport (Law et al, 2012)
Clinical features of affected individuals with SCAMP5 variants G180W were summarized in Tables 1, 2
Among the four patients derived from four unrelated families, three patients were born after a normal pregnancy and uneventful delivery
Summary
Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane molecules implicated in regulating vesicular transport (Law et al, 2012). There have been cases of patients with a chromosomal microdeletion of 15q leading to a series of neurological diseases (Sharp et al, 2007; Klopocki et al, 2008; Castermans et al, 2010; Ahram et al, 2017; Huynh et al, 2018). No disease-associated human SCAMP5 point mutations were reported until 2020, when Hubert et al reported two unrelated patients with an identical heterozygous SCAMP5 variant SCAMP5 variant knock-in mice showed typical early-onset epilepsy similar to that of humans (Zhang et al, 2020). The genetic pattern and specific phenotype of SCAMP5 in human disease are unknown to date due to the limited numbers of reported cases
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