SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

Patient-derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice.

The solute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a γ-aminobutyric acid transporter expressed on astrocytes and inhibitory neurons. Mutations in SLC6A1 are associated with epilepsy and developmental disorders, including motor and social impairments, but variant-specific animal models are needed to elucidate mechanisms. Here, we report electrocorticographic (ECoG) recordings and clinical data from a patient with a variant in SLC6A1 that encodes GAT-1 with a serine-to-leucine substitution at amino acid 295 (S295L), who was diagnosed with childhood absence epilepsy. Next, we show that mice bearing the S295L mutation (GAT-1S295L/+ ) have spike-and-wave discharges with motor arrest consistent with absence-type seizures, similar to GAT-1+/- mice. GAT-1S295L/+ and GAT-1+/- mice follow the same pattern of pharmacosensitivity, being bidirectionally modulated by ethosuximide (200 mg/kg ip) and the GAT-1 antagonist NO-711 (10 mg/kg ip). By contrast, GAT-1-/- mice were insensitive to both ethosuximide and NO-711 at the doses tested. In conclusion, ECoG findings in GAT-1S295L/+ mice phenocopy GAT-1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations.

A case of Bainbridge-Ropers syndrome with breath holding spells and intractable epilepsy: challenges in diagnosis and management.

BACKGROUND: Bainbridge-Ropers syndrome is caused by monoallelic ASXL3 variants on chromosome 18. Clinical features include dysmorphic facies, developmental delay, intellectual disability, autistic traits, hypotonia, failure to thrive, seizures and hyperventilation. Breath-holding spells with choreathetoid movements have been previously described. CASE PRESENTATION: We describe an 11-year old boy who has daily intractable seizures reported since birth, developmental delay, autistic features and feeding difficulties. He was eventually found to have de novo, heterozygous pathogenic variant (c.1612G > T, p.E538*) in the ASXL3 gene. He has frequent episodes of breath-holding accompanied by dystonic posturing with right leg extension and head turning without ictal EEG correlate. The breath-holding spells have been refractory to several medication trials including iron supplementation, acetazolamide, and desipramine. CONCLUSIONS: This case represents a more severe phenotype of Bainbridge-Ropers Syndrome than previously described with refractory breath-holding spells with dystonia, intractable epilepsy, and progressive cerebral/cerebellar atrophy. Breath-holding spells cause significant morbidity, are poorly understood, and have very limited treatment options.

Current Clinical Applications of In Vivo Gene Therapy with AAVs.

Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency [ADA-SCID] in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy [SMA]; Duchenne muscular dystrophy [DMD]; X-linked myotubular myopathy [XLMTM]; and diseases of the central nervous system, including Alzheimer's disease, Parkinson's disease, Canavan disease, aromatic l-amino acid decarboxylase [AADC] deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration [AMD], choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.

Gene Transfer Therapy for Neurodevelopmental Disorders.

Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders that disrupt normal brain development. Though some NDDs are caused by acquired insults (i.e., toxic or infectious encephalopathy) or may be cryptogenic, many NDDs are caused by variants in a single gene or groups of genes that disrupt neuronal development or function. In this review, we will focus on those NDDs with a genetic etiology. The exact mechanism, timing, and progression of the molecular pathology are seldom well known; however, the abnormalities in development typically manifest in similar patterns such as delays or regression in motor function, social skills, and language or cognitive abilities. Severity of impairment can vary widely. At present, only symptomatic treatments are available to manage seizures and behavioral problems commonly seen in NDDs. In recent years, there has been a rapid expansion of research into gene therapy using adeno-associated viruses (AAVs). Using AAVs as vectors to replace the non- or dysfunctional gene in vivo is a relatively simple model which has created an unprecedented opportunity for the future of NDD treatment. Advances in this field are of paramount importance as NDDs lead to a massive lifelong burden of disease on the affected individuals and families. In this article, we review the unique advantages and challenges of AAV gene therapies. We then look at potential applications of gene therapy for 3 of the more common NDDs (Rett syndrome, fragile X syndrome, and Angelman syndrome), as well as 2 less common NDDs (SLC13A5 deficiency disorder and SLC6A1-related disorder). We will review the available natural history of each disease and current state of preclinical studies including a discussion on the application of AAV gene therapies for each disease.

Pitt-Hopkins Syndrome: A Unique Case Study.

OBJECTIVES: Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Most cases are characterized by severe intellectual disability, absent speech, motor delays, and autism spectrum disorder. Many have abnormal brain imaging, dysmorphic facial features, and medical comorbidities: myopia, constipation, epilepsy, and apneic spells. The present case study expands existing understanding of this disorder by presenting a unique phenotype with higher cognitive abilities and fewer medical comorbidities. METHODS: The present case study reports on a 13-year-old, Caucasian male with a recent diagnosis of PTHS following genetic testing (i.e., whole exome sequencing). He was referred for a neuropsychological evaluation to document his neurocognitive functioning to assist with intervention planning. RESULTS: Evaluation of intellectual, attention/executive, memory, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning revealed global impairment across all areas of functioning. However, he demonstrated abilities beyond what has been detailed in the literature, including use of full sentences, capacity to learn and solve novel problems, basic academic functioning, and independent ambulation. CONCLUSIONS: Children with PTHS may demonstrate a spectrum of abilities beyond what has been documented in the literature thus far. Failure to recognize this spectrum can result in late identification of an accurate diagnosis. (JINS, 2018, 24, 995-1002).

Beyond the Diagnosis: Evaluation of Quality-of-Life Measures and Family Functioning in SLC6A1-Related Neurodevelopmental Disorder.

BACKGROUND: SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is a rare genetic disorder linked to autism spectrum disorder, epilepsy, and developmental delay. In preparation for future clinical trials, understanding how the disorder impacts patients and their families is critically important. Quality-of-life (QoL) measures capture the overall disease experience of patients. This study presents QOL findings from our SLC6A1-NDD clinical trial readiness study and the Simons Searchlight SLC6A1-NDD registry. METHODS: We compiled QoL data from participants with SLC6A1-NDD enrolled in our clinical trial readiness study (n = 20) and the Simons Searchlight registry (n = 32). We assessed the distribution of scores on the Quality-of-Life Inventory-Disability (QI Disability), Quality of Life of Childhood Epilepsy (QOLCE-55), and Pediatric Quality of Life Inventory Family Impact Module (PedsQL-FIM) administered to caregivers. RESULTS: In our cohort of 52 participants, the mean QI Disability total score was 73 ± 12.3, the QOLCE-55 mean total score was 49 ± 17.1, and the mean total PedsQL score was 51 ± 17.6. Longitudinal QoL scores for a subset of participants (n = 7) demonstrated a reduction in the Family Relationship domain of PedsQL-FIM (Δ-10.0, P = 0.035). Bootstrap resampling of total scores displays nonoverlapping 95% confidence intervals for the 10th, 50th, and 90th percentiles on all three measures. CONCLUSIONS: This is the first study to investigate QoL measures for SLC6A1-NDD. Findings suggest that scores within the 10th percentile's confidence interval could be clinically significant, referring to QI-Disability scores of <61, QOLCE-55 scores of <46, and PedsQL-FIM scores of <42. Future validation studies are needed.

Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder.

BACKGROUND: SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients. METHODS: Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices. RESULTS: A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model. CONCLUSIONS: Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted.

Electroencephalographic (EEG) Biomarkers in Genetic Neurodevelopmental Disorders.

Collectively, neurodevelopmental disorders are highly prevalent, but more than a third of neurodevelopmental disorders have an identifiable genetic etiology, each of which is individually rare. The genes associated with neurodevelopmental disorders are often involved in early brain development, neuronal signaling, or synaptic plasticity. Novel treatments for many genetic neurodevelopmental disorders are being developed, but disease-relevant clinical outcome assessments and biomarkers are limited. Electroencephalography (EEG) is a promising noninvasive potential biomarker of brain function. It has been used extensively in epileptic disorders, but its application in neurodevelopmental disorders needs further investigation. In this review, we explore the use of EEG in 3 of the most prevalent genetic neurodevelopmental disorders-Angelman syndrome, Rett syndrome, and fragile X syndrome. Quantitative analyses of EEGs, such as power spectral analysis or measures of connectivity, can quantify EEG signatures seen on qualitative review and potentially correlate with phenotypes. In both Angelman syndrome and Rett syndrome, increased delta power on spectral analysis has correlated with clinical markers of disease severity including developmental disability and seizure burden, whereas spectral power analysis on EEG in fragile X syndrome tends to demonstrate abnormalities in gamma power. Further studies are needed to establish reliable relationships between quantitative EEG biomarkers and clinical phenotypes in rare genetic neurodevelopmental disorders.

Patterns of developmental regression and associated clinical characteristics in SLC6A1-related disorder.

Introduction: SLC6A1-related disorder is a genetic neurodevelopmental disorder that is caused by loss of function variants in the SLC6A1 gene. Solute Carrier Family 6 Member 1 (SLC6A1) gene encodes for gamma-aminobutyric acid (GABA) transporter type 1 (GAT1), which is responsible for reuptake of GABA from the synaptic cleft. Tight regulation of GABA levels plays an important role in brain development by balancing inhibitory and excitatory neuronal signaling. Consequently, individuals with SLC6A1-related disorder can have manifestations such as developmental delay, epilepsy, autism spectrum disorder, and a subset have developmental regression. Methods: In this study, we identified patterns of developmental regression among a cohort of 24 patients with SLC6A1-related disorder and assessed for clinical characteristics associated with regression. We reviewed medical records of patients with SLC6A1-related disorder and divided subjects into two groups: 1) regression group and 2) control group. We described the patterns of developmental regression including whether there was a trigger prior to the regression, multiple episodes of regression, and whether or not skills were recovered. We assessed the relationship of clinical characteristics among the regression and control groups including demographic factors, seizures, developmental milestone acquisition, gastrointestinal problems, sleep problems, autism spectrum disorder, and behavioral problems. Results: Individuals with developmental regression had a loss of skills that were previously mastered in developmental domains including speech and language, motor, social, and adaptive skills. The mean age at regression was 2.7 years and most subjects had regression of language or motor skills triggered by seizures, infection, or spontaneously. Although there was no significant difference in clinical characteristics between the two groups, there was a higher prevalence of autism and severe language impairment in the regression group. Discussion: Future studies of a larger cohort of patients are required to make definitive conclusions. Developmental regression is often a sign of severe neurodevelopmental disability in genetic syndromes, but it is poorly understood in SLC6A1-related disorder. Understanding the patterns of developmental regression and the associated clinical characteristics in this rare disorder will be important to medical management, prognostication, and could impact the design of future clinical trials.

The genetics of autism spectrum disorder in an East African familial cohort.

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry. We investigate the genetics of ASD in an East African cohort (129 individuals) from a population with higher prevalence (5%). Whole-genome sequencing identified 2.13 million private variants in the cohort and potentially pathogenic variants in known ASD genes (including CACNA1C, CHD7, FMR1, and TCF7L2). Admixture analysis demonstrated that the cohort comprises two ancestral populations, African and Eurasian. Admixture mapping discovered 10 regions that confer ASD risk on the African haplotypes, containing several known ASD genes. The increased ASD prevalence in this population suggests decreased heterogeneity in the underlying genetic etiology, enabling risk allele identification. Our approach emphasizes the power of African genetic variation and admixture analysis to inform the architecture of complex disorders.

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders.

Introduction: Phenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants. Methods: We collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers. Results: Main clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype-phenotype associations were identified. Discussion: Our study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling.

Corrigendum: Intrafamilial variability in SLC6A1-related neurodevelopmental disorders.

[This corrects the article DOI: 10.3389/fnins.2023.1219262.].

A Case Report of Topiramate for Severe Breath Holding Spells in a Teenage Boy with Pitt-Hopkins Syndrome.

Pitt-Hopkins syndrome is a rare genetic neurodevelopmental disorder characterized by intellectual disability, delayed motor development, and absent speech. Patients often show symptoms of respiratory dysrhythmia, including episodes of hyperpnea followed by apnea with cyanosis. These spells occur while awake and do not have ictal correlate on electroencephalogram (EEG). The episodes can become quite frequent and can be challenging to treat. We present a case of a teenage patient with Pitt-Hopkins syndrome who had very frequent apneic spells that responded well to treatment with topiramate after limited response to acetazolamide.

Abnormal Genetic Testing in Males With Concomitant Neurodevelopmental Disabilities and Genital Malformation.

BACKGROUND: Neurodevelopmental disorders (NDDs) affect 1:6 children in the United States and are often linked to genetic disorders. Because many genes are enriched in brain and testicular tissue, genital malformations identified early may be a predictor of genetic disorders in children with NDDs. However, few studies have evaluated the specific effects of genital malformations. This study assesses the association between genital malformations and abnormal genetic testing among male patients with NDD. METHODS: A retrospective chart review was performed of 447 male patients seen at Children's Health Dallas (2009 to 2019) with concomitant genital malformations and NDDs. We assessed the strength of factors associated with obtaining a genetic test and having abnormal results. RESULTS: We identified 447 patients with concomitant genital malformations and NDD. Fifty-six percent (251 of 447) received genetic testing, of which 68.5% (172 of 251) had abnormal results. Patients with mixed genitourinary malformations, global developmental delay (GDD), intellectual delay, or autism spectrum disorder were more likely to have a genetic test. Patients with bilateral testicular involvement, GDD, severe language delay, wheelchair dependence, or abnormal magnetic resonance imaging findings were more likely to have abnormal results. CONCLUSION: The diagnostic yield of 68.5% in our cohort of male patients with genital malformations was higher than previous reports of 5% to 35% in NDD populations. More severe phenotypic features may be associated with increased yield. Identification of genital malformations during infancy may guide clinical surveillance, and copresentations with NDDs may support genetic testing.

Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications.

BACKGROUND: SLC6A1-related disorder is a recently identified, rare, genetic neurodevelopmental disorder that is associated with loss-of-function variants in SLC6A1. This gene encodes GABA transporter type I that is responsible for re-uptake of GABA from the synapse into the pre-synaptic terminal or circulating neuroglia. Based upon retrospective review of published cases and available research databases including Epi25 collective and SLC6A1 Connect patient database, the phenotypic spectrum is broad and includes developmental delay, epilepsy, and autism or autistic traits. SLC6A1 is one of the genes included in the Simons Searchlight registry, which includes standardized data collection across genetically identified neurodevelopmental conditions. METHODS: In this study, we compare parent-report measures of phenotypic features in the Simons Searchlight registry to previously published, provider-reported cases to assess if parent-report measures are consistent with what has been reported in the literature. RESULTS: There were 116 participants in the provider-reported dataset compared to 43 individuals in the caregiver-reported dataset. Carriers in Searchlight had 83 unique pathogenic or likely pathogenic variants in SLC6A1, which were predominantly missense or nonsense variants. There was no significant difference between groups for the prevalence of developmental delay, ASD, or ADHD. Caregivers more often reported hypotonia, while epilepsy was slightly more frequently reported by providers. CONCLUSIONS: We propose that standardized parent-report data collection methods are consistent with provider reports on many core features of SLC6A1-related disorder. The availability of patient registries and standardized natural history studies may fill an important need in clinical trial readiness programs, with larger sample sizes than smaller published case series.

Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies.

Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy-particularly of childhood onset-experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions.

SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy.

Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter. Patients typically experience seizure onset within the first week of life and have developmental delay and intellectual disability. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and non-epileptic features of SLC13A5 deficiency disorder. Gene therapy may offer hope to these patients and better clinical outcomes than current available treatments. Here, we discuss SLC13A5 genetics, natural history, available treatments, potential outcomes and assessments, and considerations for translational medical research for an AAV9-based gene replacement therapy.

A cross-sectional natural history study of aspartylglucosaminuria.

Aspartylglucosaminuria (AGU) is a rare lysosomal storage disorder that causes stagnation of development in adolescence and neurodegeneration in early adulthood. Precision therapies, including gene transfer therapy, are in development with a goal of taking advantage of the slow clinical course. Understanding of disease natural history and identification of disease-relevant biomarkers are important steps in clinical trial readiness. We describe the clinical features of a diverse population of patients with AGU, including potential imaging and electrophysiological biomarkers. This is a single-center, cross-sectional study of the clinical, neuropsychological, electrophysiological, and imaging characteristics of AGU. A comprehensive assessment of eight participants (5 Non-Finnish) revealed a mean non-verbal IQ (NVIQ) of 70.25 ± 10.33 which decreased with age (rs = -0.85, p = 0.008). All participants demonstrated deficits in communication and gross/fine motor dysfunction. Auditory and visual evoked potentials demonstrated abnormalities in one or both modalities in 7 of 8 subjects, suggesting sensory pathway dysfunction. Brain imaging demonstrated T2 FLAIR hypointensity in the pulvinar nuclei and cerebral atrophy, as previously shown in the Finnish AGU population. Magnetic resonance spectroscopy (MRS) showed a 5.1 ppm peak corresponding to the toxic substrate (GlcNAc-Asn), which accumulates in AGU. Our results showed there was no significant difference between Finnish and Non-Finnish patients, and performance on standardized cognitive and motor testing was similar to prior studies. Age-related changes on functional assessments and disease-relevant abnormalities on surrogate biomarkers, such as MRS, could be used as outcome measures in a clinical trial.

A draft conceptual model of SLC6A1 neurodevelopmental disorder.

Introduction: SLC6A1 Neurodevelopmental Disorder (SLC6A1-NDD), first described in 2015, is a rare syndrome caused by a mutation in the SLC6A1 gene which encodes for the GABA Transporter 1 (GAT-1) protein. Epilepsy is one of the most common symptoms in patients and is often the primary treatment target, though the severity of epilepsy is variable. The impact of seizures and other symptoms of SLC6A1-NDD on patients and caregivers is wide-ranging and has not been described in a formal disease concept study. Methods: A literature search was performed using the simple search term, "SLC6A1." Papers published before 2015, and those which did not describe the human neurodevelopmental disorder were removed from analysis. Open-ended interviews on lived experiences were conducted with two patient advocate key opinion leaders. An analysis of de-identified conversations between families of people with SLC6A1-NDD on social media was performed to quantify topics of concern. Results: Published literature described symptoms in all of the following domains: neurological, visual, motor, cognitive, communication, behavior, gastrointestinal, sleep, musculo-skeletal, and emotional in addition to epilepsy. Key opinion leaders noted two unpublished features: altered hand use in infants, and developmental regression with onset of epilepsy. Analysis of social media interactions confirmed that the core symptoms of epilepsy and autistic traits were prominent concerns, but also demonstrated that other symptoms have a large impact on family life. Discussion: For rare diseases, analysis of published literature is important, but may not be as comprehensive as that which can be gleaned from spontaneous interactions between families and through qualitative interviews. This report reflects our current understanding of the lived experience of SLC6A1-NDD. The discrepancy between the domains of disease reported in the literature and those discussed in patient conversations suggests that a formal qualitative interview-based disease concept study of SLC6A1-NDD is warranted.