Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1

Abstract

Background and objectives: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control.

Methods: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups.

Results: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset.

Discussion: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders.

Figure 1. Clinical Spectrum and Disease Course of STXBP1-Related Disorders

(A) Frequencies of reported Human Phenotype Ontology terms across the cohort. The absolute frequency of each term is indicated (n=). (B) Age at onset of typical symptoms including epilepsy (n = 49), muscular hypotonia (n = 47), motor and movement disorders (n = 39), spasticity (n = 6), and behavioral disorders (n = 25). (C) Age at onset of epilepsy (median 2 months, IQR 1–7 months, n = 49) and age at last seizure (epilepsy offset) (median 16.5 months, IQR 6.8–35.7 months, n = 20). IQR = interquartile range.

Figure 2. Developmental Milestones in Individuals With STXBP1-Related Disorders

The light blue bars indicate the percentage of patients who reached a given milestone including head control (94%, n = 58/62), sitting (79%, n = 49/62), standing (53%, n = 33/62), unassisted walking (48%, n = 29/61), speaking single words (35%, n = 24/69), and speaking 2-word combinations (13%, n = 8/61). The dark blue boxplots indicate the age when a given individual had reached a particular developmental milestone including head control (n = 22), sitting (n = 37), standing (n = 15), unassisted walking (n = 24), speaking single words (n = 15), and speaking 2-word combinations (n = 5). The age of achievement of motor milestones in our cohort was delayed compared with the ages given by the World Health Organization (sitting without support: mean [SD] = 6 months [1.1]; standing alone: mean [SD] = 11 months [1.9]; walking alone: mean [SD] = 12.1 months [1.8]).

Figure 3. Developmental Outcome of Individuals Across Different Subgroups

Comparison of individuals with no history of epilepsy (in blue), individuals with epilepsy including focal-onset and generalized-onset seizures as well as epileptic spasms (in green), and individuals who had epileptic spasms (in red) regarding their developmental trajectories. (A) Frequency of individuals across subgroups achieving each milestone including head control (n_{no epilepsy} = 17/17, n_epilepsy = 41/45, n_spasms = 11/15), sitting (n_{no epilepsy} = 17/17, n_epilepsy = 32/45, n_spasms = 7/16), standing (n_{no epilepsy} = 13/17, n_epilepsy = 20/45, n_spasms = 4/16), walking (n_{no epilepsy} = 12/17, n_epilepsy = 17/44, n_spasms = 1/16), speaking a single word (n_{no epilepsy} = 8/18, n_epilepsy = 16/51, n_spasms = 3/18), and speaking 2-word combinations (n_{no epilepsy} = 3/16, n_epilepsy = 5/45, n_spasms = 0/18). (B) Age of achievement of milestones across epilepsy subgroups. (C) Distribution of GMFCS score rankings comparing individuals with and without epilepsy. Frequencies are relative within the subgroups; absolute number of individuals who had a certain score value are indicated on each bar. The distribution of GMFCS scores in individuals without epilepsy is shown in blue and the distribution of individuals with epilepsy in green bars. (D) Frequency of speech impairment score rankings comparing individuals with and without epilepsy. Absolute frequencies are indicated on each bar. The distribution of speech impairment scores in individuals without epilepsy is shown in blue and the distribution of individuals with epilepsy in green bars. GMFCS = Gross Motor Function Classification System.

Figure 4. Distribution of Developmental Trajectories Across Different Epilepsy Onset Ranges

Individuals with a history of epilepsy were stratified with regard to seizure onset subgroups: neonatal onset (first months of life), early onset (second month of life until the end of second year of life), and late onset (from beginning of the third year of life). Point size indicates number of observations. (A) Distribution of GMFCS score across subgroups (n_{<1 m} = 8, n_{1 m–2 y} = 12, n_{>2 y} = 4). (B) Distribution of speech impairment score across subgroups (n_{<1 m} = 10, n_{1 m–2 y} = 23, n_{>2 y} = 5). GMFCS = Gross Motor Function Classification System.