Expanding Phenotype of SYT1-Related Neurodevelopmental Disorder: Case Report and Literature Review

Abstract

Introduction

Synaptotagmin 1 (SYT1), the predominant SYT isoform in the central nervous system, likely acts by promoting vesicle docking, deforming the plasma membrane via Ca²⁺-dependent membrane penetration.

Case Presentation

Here, we describe a 21-year-old woman harboring a novel variant in the SYT1 gene, who presents with a complex phenotype, featuring severe intellectual disability, absent speech, behavioral abnormalities, motor stereotypies, dystonic posturing of her hands, a hyperkinetic movement disorder in her childhood, infantile hypotonia, sialorrhea, mild dysmorphic features, epilepsy, peculiar EEG findings, and severe scoliosis.

Discussion

Based on our case and literature review on the 22 previously described patients, we can confirm a complex neurodevelopmental disorder in which, unlike other synaptopathies, epilepsy is present in a subset of cases (including our patient: 5/23, 22%), although characteristic EEG changes are far more common (10/23, 43.5%). Our patient’s age allows us to provide long-term follow-up data and thus better delineate the SYT1-related clinical phenotype.

Established Facts

• •Pathogenic variants in the SYT1 gene cause a rare, complex neurodevelopmental disorder.
• •Epilepsy is present in a minority of cases.

Novel Insights

• •Childhood hyperkinetic movement disorder can be transient.
• •In our case, EEG abnormalities did not lessen with age.

Introduction

Synaptotagmins are integral membrane proteins of synaptic vesicles, serving as sensors for calcium ions (Ca²⁺) in vesicular trafficking and exocytosis. Ca²⁺ binding to synaptotagmin 1 (SYT1), the predominant SYT isoform in the central nervous system, participates in triggering neurotransmitter release at the synaptic level [Fernández-Chacón et al., 2001]. SYT1 likely acts by promoting vesicle docking [Reist et al., 1998; Liu et al., 2009; Chang et al., 2018], deforming plasma membrane via Ca2+-dependent membrane penetration [Bhalla et al., 2006; Hui et al., 2009; Liu et al., 2014; Evans et al., 2015; Bai et al., 2016], and controlling trans-SNARE complex assembly [Bhalla et al., 2006; Park et al., 2015; Zhou et al., 2015; Bai et al., 2016; Kiessling et al., 2018; Bradberry et al., 2020]. Variants in the SYT1 gene (OMIM *185605), located on chromosome 12q21.2, are associated with a severe neurodevelopmental disorder, known as Baker-Gordon syndrome (OMIM 618218), featuring infantile hypotonia, ophthalmic abnormalities, sleep disturbances, hyperkinetic movements, and global developmental delay with intellectual disability [Melland et al., 2022]. Typical EEG pattern features abnormal background with bursts of synchronous, predominantly posterior high-voltage slow waves, plus isolated epileptiform discharges. Oscillatory bursts vary in duration, cycle frequency, and topography, and the extent and morphology of spike activity are also variable [Baker et al., 2018; Melland et al., 2022].

Case Presentation

A 21-year-old female patient of Italian descent is the daughter of nonconsanguineous parents. She was born by cesarean section at 39 weeks of gestation. Reduced fetal movements had been reported. Birth parameters were as follows: weight 3.650 kg (75th–90th centile), length 48 cm (25th–50th centile), occipito-frontal circumference 34.5 cm (50th centile). Apgar scores were 8 and 9 at 1 and 5 min, respectively. Global developmental delay was evident: head control was reached between 6 and 12 months, trunk control at 2 years, walking without help (for a few steps) at 4 years. Language was limited to babbling without communication purposes. Sphincter control was only partially acquired. She had no regression. She showed severe hypotonia (predominantly axial), poor suck, impaired social interaction with poor eye contact, sialorrhea, and constipation. She also had poor motor coordination since infancy. Motor stereotypies are present, such as swinging of the trunk, hand mouthing, and flickering. Between 7 and 12 years of age, she showed a choreiform hyperkinetic movement disorder, which then subsided. Functional hand use improved with behavioral therapy.

EEG performed within the first year of life reported posterior slow waves. Her latest EEG, at 21 years of age, confirmed previous findings and also revealed alpha-like activity over the central parieto-temporal regions and medium-voltage sharp waves (Fig. 1).

Fig. 1.

Our patient’s EEG at 21 years of age (20 s/pg, 14 µ/mm, 15 Hz, notch 50 Hz).

She experienced atypical absences between 5 and 6 years of age. Due to behavioral disorder and EEG abnormality characteristics, therapy with risperidone and valproic acid was started. At 8 years of age, she experienced seizure recurrence following an attempt to withdraw antiseizure medication. A subsequent EEG showed spike-wave complexes over the temporo-occipital regions, with a tendency to spread, activated by sleep.

She presented with bilateral genu valgum, bilateral calcaneovalgus, and metatarsus adductus on the right side (surgically corrected; Fig. 2a), pectus excavatum, mild microretrognathia, left plagiocephaly, and severe scoliosis, for which she underwent spinal stabilization surgery at 17 years of age. Her hands are held in a dystonic posture (Fig. 2b, c).

Fig. 2.

Surgically corrected bilateral calcaneovalgus and metatarsus adductus on the right side (a); dystonic posturing of her hands (b, c).

Neurometabolic investigations, including sialotransferrin, plasma lactate and pyruvate, plasma and urinary amino acids, urinary organic acids, creatine and its metabolites, uricemia, mitochondrial DNA analysis for neuropathy ataxia retinitis pigmentosa, and myoclonus with epilepsy with ragged red fibers, were negative. Prolactin was normal.

Abdominal ultrasound and echocardiography, nerve conduction studies, electromyography, brainstem auditory evoked potentials, electrocardiogram, and fundoscopy were also normal. Serial brain magnetic resonance imagings at 1, 2, and 9 years of age were normal.

High-resolution karyotype on blood, subtelomeric FISH, array-CGH, and molecular analysis of FMR1 gene were negative. Due to the presence of a hyperkinetic movement disorder, MECP2 and FOXG1 genes (sequencing and MLPA) and methylation test for Angelman syndrome were performed but were also negative. Trio-whole-exome sequencing (WES) revealed the novel variant in the SYT1 gene: NM_005639.2:c.[1101_1103dup];[=], NP_005630.1:p.(Lys367_Ile368insMet);[=]. The WES examination was performed by an external laboratory, and the Sanger sequencing chromatogram is not available. Parental testing indicated its de novo origin. This variant is absent from the reference population database gnomAD v2.1.1. It causes a change in protein length and occurs in a known mutational hot spot (i.e., the calcium-binding domain C2B). It has been reported in the ClinVar database as likely pathogenic in a patient with global developmental delay (accession: SCV002572822.1). For these reasons, it was classified as pathogenic according to the ACMG guidelines [Richards et al., 2015]. WES also revealed the heterozygous variant in the MED13 gene: NM_005121.2:c.2770C>T, p.(Pro924Ser), inherited from her healthy mother and classified as likely benign, and two heterozygous variants of unknown significance: NM_015559.2:c.160C>T, p.(Arg54Cys) in the SETBP1 gene, inherited from her healthy mother, and NM_ 001160133.1:c.61G>T, p.(Gly21Cys) in the KCNQ5 gene, inherited from her healthy father.

Discussion

We report on a 21-year-old young woman with severe global developmental delay, infantile hypotonia, epilepsy, a transient hyperkinetic movement disorder, absent language, orthopedic issues, and hand dystonia who harbors the novel in-frame p.(Lys367_Ile368insMet) variant in the SYT1 gene. Her clinical phenotype is consistent with previous patients’ descriptions [Baker et al., 2018; Bradberry et al., 2020; Melland et al., 2022], except for the transient presence of an atypical choreic hyperkinetic movement disorder.

From our literature review, all patients but 2 (patients #13 and #14) have visual abnormalities, such as strabismus, nystagmus, visual impairment, or hypermetropia (online suppl. Table S1; for all online suppl. material, see www.karger.com/doi/10.1159/000530586). Our patient had both nystagmus and strabismus. Seven patients had orthopedic problems, like scoliosis, joint laxity, and bilateral clubfoot (online suppl. Table S1). The majority of so far described patients, including our case, had a behavioral disorder of variable severity, which in our patient was well controlled on risperidone. This preliminary observation should be evaluated in wider cohorts since there is no previous information on the pharmacological management of behavioral disorder in SYT1-related disorder.

As the literature suggests the possibility of late-onset movement disorder and of declining adaptive and emotional functioning in older patients [Baker et al., 2018], long-term follow-up data (like the ones we provided) are needed in order to distinguish between genuine phenotypic variability and age dependency of symptoms and signs. Hyperkinetic movement disorder or motor stereotypies, especially affecting the hands, with high frequency of mouthing stereotypies, as seen in our patient, are common and seem to persist through adolescence and early adulthood. However, in our case, functional hand use improved with behavioral therapy, thus not suggesting neurological decline or disease progression, at least up to her early twenties.

Most patients with pathogenic SYT1 gene variants show abnormalities in their EEG background activity. In particular, the most frequent finding is slowing of the ongoing activities over the posterior regions. In one previously described patient (#20), hypsarrhythmia was recorded at 5 months of age. Epileptiform discharges were documented in 9 out of 22. In our patient, at 21 years of age, we found slow activities (markedly more evident on the posterior leads), alpha-like activity over the central parietal-temporal regions (never described before), and medium-to-high voltage sharp waves (Fig. 2). Therefore, in our experience, EEG abnormalities do not seem to lessen with age, contrary to previous suggestions, highlighting the need to collect more prospective data.

Our patient experienced atypical absences between 5 and 6 years, which recurred at the age of 8, following valproic acid discontinuation. After reintroducing valproate, there was no recurrence, demonstrating that our patient suffers from drug-responsive epilepsy. Only 4 previously described patients had seizures, including absences (patients #15, 16, 21), tonic-clonic seizures (#16), and spasms (#20) [Baker et al., 2018; Bradberry et al., 2020; Melland et al., 2022]. Interestingly, epilepsy is a universal feature in at least five synaptic vesicle cycling (SVC) disorders and has been reported with variable frequency in most conditions belonging to this group of disorders [John et al., 2021]. Probably, SVC defects variably predispose to abnormalities in background activities (as detectable by EEG) and increased seizure risk. However, current literature suggests the view that epilepsy is neither a prevalent nor prominent feature [Baker et al., 2018]. Additional genotype-phenotype studies are warranted to further explore mechanisms contributing to variable epilepsy risk across the SVC spectrum.

In the first 11 patients with SYT1-related disorder, five missense SYT1 variants were identified, all located in highly conserved residues of the C2B domain, clustering around the Ca²⁺-binding pocket. In detail, Ca2+-binding loops 1 and 3 of the C2B domain seem to be highly sensitive to variation, as pathogenic missense variants cluster here [John et al., 2021; Melland et al., 2022]. Initially described variants were thought to cause loss of function (online suppl. Table S1). They were found to inhibit evoked exocytosis in a dominant-negative and variant-specific fashion [Zhou et al., 2015; Bradberry et al., 2020]. A more recent paper also documented variants located in the C2A domain and additional C2B loci [Baker et al., 2018]. Both domains lie within a region showing significant missense constraint [Baker et al., 2018]. Our variant, although novel, was classified as pathogenic according to the ACMG criteria as it changes protein length in a known hot spot. Furthermore, the c.1100_1102dup, p.Lys367dup (also not reported in gnomAD) has been described [Baker et al., 2018] as likely pathogenic, as the positive charge at Lys367 is considered to impact phospholipid binding [Wang et al., 2003].

Finally, our patient also harbors two inherited heterozygous variants in the SETBP1 and KCNQ5 genes, of unknown clinical significance. To date, only de novo variants in SETBP1 and KCNQ5 genes have been associated with intellectual disability [Lehman et al., 2017; Leonardi et al., 2020]; therefore, they were considered unlikely to significantly contribute to her phenotype.

Conclusion

Describing our patient’s long-term clinical and EEG features contribute to delineate the evolution of a rare disease into early adulthood, highlighting never-described findings, i.e., hands dystonic posturing and alpha-like activity on EEG. Our patient belongs to a minority of cases suffering from epilepsy. We can suggest valproic acid as a potentially useful antiseizure medication in the long term. We also found risperidone as an efficacious option to manage behavioral disorder. Additional descriptions and prospective data collection would be useful to better delineate SYT1-related neurodevelopmental disorder.

Statement of Ethics

The authors declare that this paper complies with internationally accepted standards for research practice and reporting. Written informed consent was obtained from the patient’s parents for the publication of this report and the accompanying images. Ethical approval was not required for this study in accordance with local guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was secured for the completion of this study.

Author Contributions

Carlo Alberto Cesaroni performed the literature review, collected the clinical and EEG data, and wrote the first draft of the manuscript; Carlotta Spagnoli contributed to the writing of the manuscript; Margherita Baga and Susanna Rizzi contributed to collection of clinical data and literature review; Daniele Frattini critically reviewed the manuscript for intellectual content; Stefano Giuseppe Caraffi, Marzia Pollazzon, and Livia Garavelli contributed to the collection and interpretation of the genetic data and critically reviewed the manuscript for intellectual content; and Carlo Fusco supervised clinical and genetic data collection, designed the study, and critically reviewed the manuscript for intellectual content. All authors reviewed and approved the manuscript in its final form.

Funding Statement

No funding was secured for the completion of this study.

Data Availability Statement

The data used for this paper will be made available by the corresponding author upon reasonable request.