STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics

Abstract

Background De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. Methods To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1 -associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). Results The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. Conclusions De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families. Electronic supplementary material The online version of this article (10.1186/s11689-019-9278-9) contains supplementary material, which is available to authorized users.

The neurodevelopmental spectrum of synaptic vesicle cycling disorders

“…More positively, we found that strong social motivation and enjoyment of family relationships was a frequent characteristic of individuals with STXBP1 variants, and distinguished this group from other individuals with non-SVC disorders and ID of similar severity (O'Brien et al, 2019). Future studies are required to determine if these features (both problematic and positive) are observed more commonly among individuals with SVC disorders than in other groups with severe ID, visual impairments and movement disorders.…”

“…Missense; Nonsense (Corradi et al, 2014) Docking and priming Gburek-Augustat et al, 2016;Lammertse et al, 2020;O'Brien et al, 2019;Parrini, Marini, & Mei, 2017;Stamberger et al, 2016;Uddin, Woodbury-Smith, & Chan, 2017;Valence et al, 2019) CPLX1 (605,032) COMPLEXIN 1 3 0 AR Nonsense (Redler et al, 2017) RIMS1 (606,629) PROTEIN REGULATING SYNAPTIC MEMBRANE EXOCYTOSIS 1 2 0 AD, de novo Frameshift (Dong et al, 2014;Peter et al, 2019) RIMS3 ( (Salpietro, Lin, & Delle Vedove, 2017;Salpietro et al, 2019;Shen et al, 2017) STX1A ( (Jodice et al, 1997;Epi, 2016;Reinson et al, 2016;Romaniello et al, 2010;Tonelli et al, 2006;…”

Targeted stabilization of Munc18‐1 function via pharmacological chaperones

“…Furthermore, seizure duration, severity, and age of onset are not associated with developmental outcome in patients with Munc18‐1 mutations, meaning that therapies aimed at seizure control do not address the developmental aspects of the disease (Stamberger et al , 2017). Given that the prevalence of Munc18‐1 variants among individuals with unspecified developmental disorders is 0.25–0.5% and the prevalence of intellectual disability in the general population is 1%, the number of individuals diagnosed with Munc18‐1‐associated neurodevelopmental disorders will likely rise substantially (O'Brien et al , 2019). Anti‐epileptic drugs, which are currently the only type of treatment for patients with Munc18‐1 mutations, therefore often fall short in the majority of patients.…”

“…Overall, Munc18-1 encephalopathies are associated with epilepsy, severe to profound intellectual disability, developmental delay, ataxia, tremor, and other neurological symptoms (Saitsu et al, 2008;Milh et al, 2011;Stamberger et al, 2016;Suri et al, 2017). As individuals with neurodevelopmental disorders or intellectual disability without epilepsy are now being screened for Munc18-1 mutations, the number of cases is expected to significantly increase over the coming years (O'Brien et al, 2019). The only treatments that exist for Munc18-1-related syndromes are anti-epileptic drugs, which are unsuccessful in two-thirds of patients and do not lead to long-term improvements (Stamberger et al, 2016;Stamberger et al, 2017;Abramov et al, 2020).…”

Developmental and epileptic encephalopathies: recognition and approaches to care

“…level of functioning, e.g. KCNQ2, STXBP1 [35,36]. The outcome may remain poor even though seizures are controlled.…”