Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system

Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation.Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed.Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes.Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder

We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients’ records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders

Joint Attention Interventions For Children With Autism Spectrum Disorder: A Systematic Review And Meta-Analysis

Background A core social-communication deficit in children with autism spectrum disorder (ASD) is limited joint attention behaviours-important in the diagnosis of ASD and shown to be a powerful predictor of later language ability. Various interventions have been used to train joint attention skills in children with ASD. However, it is unclear which participant, intervention and interventionist factors yield more positive results. Aims The purpose of this systematic review and meta-analysis was to provide a quantitative assessment of the effectiveness of joint attention interventions aimed at improving joint attention abilities in children with ASD. Methods & Procedures The researchers searched six databases for studies meeting the inclusion criteria at two levels: title/abstract and full-text stages. Two independent coders completed data extraction using a coding manual and form developed specifically for this research study. Meta-analysis procedures were used to determine the overall effects of several comparisons including treatment type, treatment administrator, intervention characteristics and follow-up. Main Contribution Fifteen randomized experimental studies met inclusion criteria. All comparisons resulted in statistically significant effects, though overlapping confidence intervals suggest that none of the comparisons were statistically different from each other. Specifically, treatment administrator, dosage and design (control or comparison, etc.) characteristics of the studies do not appear to produce significantly different effects. Conclusions & Implications The results of this meta-analysis provide strong support for explicit joint attention interventions for young children with ASD; however, it remains unclear which children with ASD respond to which type of intervention

A Randomized Controlled Trial Of An Inference Generation Strategy Intervention For Adults With High-Functioning Autism Spectrum Disorder

Purpose: The present intervention study investigated the efficacy of the ACT & Check Strategy intervention to improve inference generation when reading, metacognitive ability, general reading comprehension, and social inference ability in adults with high-functioning autism spectrum disorder (HF-ASD). Method: Twenty-five adults with HF-ASD were randomly assigned to either a treatment or a control group. Treatment sessions were conducted in 1-hr sessions, twice a week, for a total of 6 weeks. Treatment focused on explicit instruction of components of inference generation, categories of inferences, and increasingly independent strategy use. Results: The treatment group demonstrated significantly superior performance on 1 of 2 measures of inference generation in reading and 1 measure of metacognitive ability compared with the control group. Significant differences between groups were not found on measures of reading comprehension or social inference ability. Conclusion: These findings suggest that the ACT & Check Strategy was effective in improving participants\u27 ability to generate inferences in reading and certain metacognitive abilities, but the skills do not appear to generalize to other social communication contexts, such as social inference generation. This research provides a measure of support for explicitly teaching inference generation to address a reading inference deficit in adults with HF-ASD. © American Speech-Language-Hearing Association

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 Randomized Controlled Trial of an Inference Generation Strategy Intervention for Adults With High-Functioning Autism Spectrum Disorder

Purpose: The present intervention study investigated the efficacy of the ACT & Check Strategy intervention to improve inference generation when reading, metacognitive ability, general reading comprehension, and social inference ability in adults with high-functioning autism spectrum disorder (HF-ASD). Method: Twenty-five adults with HF-ASD were randomly assigned to either a treatment or a control group. Treatment sessions were conducted in 1-hr sessions, twice a week, for a total of 6 weeks. Treatment focused on explicit instruction of components of inference generation, categories of inferences, and increasingly independent strategy use. Results: The treatment group demonstrated significantly superior performance on 1 of 2 measures of inference generation in reading and 1 measure of metacognitive ability compared with the control group. Significant differences between groups were not found on measures of reading comprehension or social inference ability. Conclusion: These findings suggest that the ACT & Check Strategy was effective in improving participants\u27 ability to generate inferences in reading and certain metacognitive abilities, but the skills do not appear to generalize to other social communication contexts, such as social inference generation. This research provides a measure of support for explicitly teaching inference generation to address a reading inference deficit in adults with HF-ASD. © American Speech-Language-Hearing Association