Syndrome Foundation Research Articles

The Myhre Syndrome Foundation as a global modern support group: The business of rare.

Advocacy support groups grow into national and international organizations, but they all begin with personal experiences. As the parents to a newly diagnosed two-year-old son with Myhre syndrome, my husband and I were overwhelmed with the journey ahead. Thanks to networking, primarily through social media, we located other families living with Myhre syndrome and were quickly immersed in the challenges and joy of this community. Myhre syndrome, caused by pathogenic missense variants in SMAD4, is a rare connective tissue disease characterized by short stature, hearing loss, neurodevelopmental challenges, and fibroproliferation.This personal essay, written with physician partners, describes the development of a global advocacy group for patients with Myhre syndrome. I have the honor of serving as the founding Executive Director and reflect proudly on the great strides that our marvelous support group has made. We empower the global community impacted by this rare condition by providing meaningful and accessible data, educational opportunities, and connections with others going through similar experiences. Utilizing the expertise of our Board of Directors and my corporate expertise, we discuss how we have been able to elevate our ultra-rare community into a broader, more comprehensive network.

ECG findings are poor predictors for adverse events and cardiac death in Barth syndrome

BackgroundPatients with Barth syndrome (BTHS) can present with cardiomyopathy. BTHS subjects are at risk for cardiac adverse outcomes throughout life, including malignant arrhythmias and death. Electrocardiogram (ECG) parameters have never been assessed as a tool to predict adverse outcomes in individuals with BTHS. ObjectivesThe purpose of this study was to identify any ECG parameters, including QRS fragmentation, presence of arrhythmia, or abnormal intervals, that could predict adverse outcomes and cardiac death among the BTHS population. MethodsWe performed a retrospective case referent study on subjects with BTHS (n = 43) and compared them with our reference group, subjects with idiopathic dilated cardiomyopathy (DCM) from a single institution (n = 53) from 2007 to 2021. BTHS data was obtained from subjects attending the biennial Barth Syndrome Foundation International Scientific, Medical, and Family Conferences (BSFISMFC) from 2002 to 2018. ECG data from the first and last available ECGs prior to an adverse event or cardiac death was analyzed. Then, multivariable regression was performed to determine odd ratios between ECG characteristics and adverse events/cardiac death. ResultsNo ECG variables were statistically significant predictors of adverse events or cardiac death in the BTHS group. Last ECG QRS fragmentation trended to statistically significance (OR 13.3, p = 0.12) in predicting adverse events in the DCM group. ConclusionNo ECG parameters, including QRS fragmentation, presence of arrhythmia, or abnormal interval values, predict adverse events or cardiac death among BTHS patients. QRS fragmentation may be a predictor of adverse events in the DCM population.

A diagnostic dilemma: distinguishing a sulfasalazine induced DRESS hypersensitivity syndrome from a CD30 + lymphoma in a young patient

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe hypersensitivity reaction characterized by cutaneous rash, lymphadenopathy, fever, eosinophilia, leukocytosis, and life-threatening organ dysfunctions. We describe the case of a 26 year old patient admitted to the Emergency Department for DRESS syndrome after sulfasalazine treatment for rheumatoid arthritis in the right knee. Whole body computer tomography showed multiple neck, chest, and abdominal lymphadenopathy with splenomegaly, massive ascites and severe hepatic cytolysis. Serology results for Epstein-Barr Virus (EBV), influenza, measles, rubella, hepatitis A and B were negative. The histologic analysis of skin, lymph node and bone marrow biopsies could not indicate a classical Hodgkin’s Disease or iatrogenic immunodeficiency/EBV-associated lymphoproliferative disorder (LPD), Hodgkin type. The relatively small caliber of the CD30 + immunoreactive blastoid cells in the lymph nodes suggested reactive immunoblasts rather than Hodgkin cells. The morphologic aspects of the lymph node biopsies with predominance of T-cells were compatible with the diagnosis of a sulfasalazine-induced DRESS syndrome as the patient had a high RegiSCAR score for DRESS. [DRESS Syndrome Foundation: Diagnosis and Treatment. (2023)] The patient’s complex clinical course, marked by two hospital admissions, highlights the challenges in diagnosing and managing DRESS. This case underscores the need for individualized care, close patient monitoring, and further research to better understand DRESS’s underlying mechanisms and optimal therapeutic strategies.

Pelvic Floor Dysfunction Among Persons With Marfan and Loeys-Dietz Syndrome.

Connective tissue disorders are proposed in the literature to be predisposing risk factors for pelvic floor disorders. Prior data characterizing the prevalence of and symptom burden related to pelvic floor disorders are limited for individuals with Marfan syndrome and are nonexistent for those with Loeys-Dietz syndrome. The objective of this study was to determine the prevalence and severity of symptoms related to pelvic floor disorders among individuals with Marfan syndrome and Loeys-Dietz syndrome using the Pelvic Floor Distress Inventory-20 (PFDI-20). In this cross-sectional study, a survey including the PFDI-20 was administered to biologically female individuals older than 18 years with a confirmed diagnosis of Marfan syndrome or Loeys-Dietz Syndrome. Respondents were solicited through the websites, email lists, and social media forums of The Marfan Foundation and The Loeys-Dietz syndrome Foundation. A total of 286 respondents were included in the final analysis, 213 with Marfan syndrome and 73 with Loeys-Dietz syndrome. The median PFDI-20 score of the cohort was 43.8. Individuals with Loeys-Dietz syndrome had higher PFDI-20 scores and were more likely to have established risk factors for pelvic floor disorders that correlated with their PFDI-20 scores compared with those with Marfan syndrome. Respondents with Marfan syndrome and Loeys-Dietz syndrome experience a high burden of symptoms related to pelvic floor disorders. Despite the similar pathophysiology and clinical manifestations of these disorders, there were differences in PFDI-20 responses that may suggest that these diseases differ in the ways they affect the pelvic floor.

Cardiovascular and obstetrical outcomes among delivering patients with Marfan or Loeys-Dietz syndrome: a retrospective analysis by hospital delivery setting

BackgroundPregnancy is a high-risk time for patients with Marfan syndrome (MFS) or Loeys-Dietz (LDS) syndrome due to risk for cardiovascular complications including risk of aortic dissection. Little is known about differences in obstetric and cardiac outcomes based on delivery hospital setting (academic/academic-affiliated versus community medical centers). ObjectiveThis study aimed to evaluate obstetric and cardiac outcomes of patients with MFS or LDS based on delivery hospital setting. Study DesignThis is a secondary analysis of a retrospective, observational cohort study of singleton pregnancies among patients with a diagnosis of MFS or LDS from 1990 to 2016. Patients were identified through the Marfan Foundation, Loeys-Dietz Syndrome Foundation, or Cardiovascular Connective Tissue Clinic at Johns Hopkins Hospital. Data were obtained via self-reported obstetric history and verified by review of medical records. Nonparametric analysis was performed via Fisher's Exact Test and Wilcoxon rank-sum tests. Results273 deliveries among patients with MFS or LDS were included in this analysis. More patients who had a known diagnosis prior to delivery for either MFS or LDS delivered at an academic hospital as compared community hospital (78.6% vs. 59.9%, p=0.001). Patients with MFS or LDS who delivered at academic centers were more likely to have an operative vaginal delivery compared to those at community centers (23.7% vs 8.6%, p=0.002). When indications for cesarean delivery were assessed, connective tissue disease was the primary reason for indication for mode of delivery at community centers compared to academic centers (55.6% vs 43.5%, p=0.02). There were higher rates of cesarean for arrest of labor and/or malpresentation at community hospitals compared to academic centers (23.6% vs 5.3%, p=0.01). There were no differences between groups in regards to method of anesthesia for delivery. Among those with a known diagnosis of MFS or LDS prior to delivery, there were increased operative vaginal delivery rates at academic hospitals compared to community hospitals (27.2% vs 15.1%, p=0.03; Table 2). More patients with an aortic root measuring ≥4 cm pre-pregnancy or postpartum delivered at academic centers compared to community centers (33.0% vs. 10.2%, p=0.01), but there were no significant differences in median size of the aortic root during pregnancy or on postpartum assessment between delivery locations. Cardiovascular complications were rare: eight patients who delivered at academic centers and seven patients who delivered at community centers had an aortic dissection either in pregnancy or the postpartum period (p=0.79). ConclusionPatients with MFS/LDS and more severe aortic phenotypes were more likely to deliver at academic hospitals. Those who delivered at academic hospitals had higher rates of operative vaginal delivery. Despite lower frequencies of aortic root diameter >4.0 cm, those delivered at community hospitals had higher rates of cesarean delivery for the indication of MFS/LDS. Optimal delivery management of these patients requires further prospective research.

Koolen-de Vries Syndrome: a journey from diagnosis to treatments.

The Koolen-de Vries Syndrome Foundation was founded in 2013 with the mission to educate, increase awareness, promote research and develop treatments for individuals living with Koolen-de Vries Syndrome (KdVS) and their families. With this aim, the foundation has focused on: developing scientific resources through patient cell and animal models, providing seed funding to basic and clinical researchers, establishing a natural history study of KdVS and increasing patient engagement. Projects have been prioritized across these areas of focus with an emphasis on expanding international research on KdVS, supporting translational research, establishing an international natural history study and conducting studies to assess patient priorities. With the incredible growth amongst our research and patient community in the last decade, our goal is to have our first clinical trial for KdVS in 2026.

International Cohort of Neonatal Timothy Syndrome

Plain Language SummaryTimothy syndrome is a rare, life-threatening condition affecting children. It is a genetic disorder resulting in heart rhythm abnormalities, fusion of digits, and a high risk of sudden death. A diagnosis in early infancy allows appropriate medical therapy to be used to avoid life-threatening rhythm abnormalities and sudden death. This study reports the key findings of the Timothy Syndrome Foundation’s international registry. It highlights the risk of heart rhythm abnormalities from before birth and in childhood. The authors aim to raise awareness of this rare disease among healthcare professionals caring for babies and children to improve early diagnosis and specialist treatment of the condition.

Cognitive reserve in Down syndrome: a new opportunity to understand resilience in Alzheimer’s disease

AbstractBackgroundTraditionally, cognitive reserve (CR) and other related concepts underlying resilience, have been studied in the context of aging and Alzheimer’s disease (AD; Stern et al., 2020). Despite the increasing interest in elucidating how CR measures influence brain and cognitive development through a lifespan perspective (Kremen et al., 2019), its study in developmental diseases such as Down syndrome (DS) remains unexplored. Understanding the role of CR and its neurobiological mechanisms in DS is critical, since this population is genetically determined to develop AD (Fortea et al., 2021). During the last decades, people with DS have experienced an improvement in the number and quality of stimulating activities due to the higher inversions in disability services and community support resources. In this regard, our goal was to test whether this enriched environment would result in a generational effect showing a lower intellectual disability (ID) level and a higher intellectual profile as function of the birth year in DS.MethodWe selected a cross‐sectional subsample from the cohort study of adults with DS recruited at the Alzheimer‐Down Unit from the Catalan Down Syndrome Foundation and Hospital of Sant Pau. We included 528 participants with DS without clinical symptoms of AD born between 1955‐1995 (age: 39.25±9.27 years; 46.02% females). Participants with profound ID (as these individuals perform at floor scores) were excluded for Kaufman Brief Intelligence Test (K‐BIT) analyses (N = 379; age: 39.03±9.10 years; 48.02% females).ResultResults evidenced a generational increase in the proportion of individuals with mild or moderate ID and a decrease in those with profound or severe ID level (Fig1). Similarly, a higher proportion of individuals acquired intellectual milestones (i.e., language, literacy, calculation; Fig2). Furthermore, our analyses revealed an increase in mean K‐BIT scores as function of the birth year (P<.001; Fig3).ConclusionThere have been major changes in CR proxies in individuals with DS. Given the near full penetrance of AD in this population, characterizing the effect of these factors on AD presentation and pathophysiology could signify an important advance in the design of primary prevention plans in this particularly vulnerable population, which could probably be transferred to the general population.

Patient family engagement and partnership: Pilot survey results in assessing behavior, communication, and quality of life in children with Lennox–Gastaut syndrome and other drug-resistant epilepsy

ObjectivesLennox–Gastaut Syndrome (LGS) and other drug-resistant epilepsy (DRE) can impact behavior, communication, and quality of life (QoL). In collaboration with community engagement efforts with the Lennox–Gastaut Syndrome Foundation (LGSF), we aimed to gain an initial snapshot of patient and family perspectives and experiences with evaluation of behavior, communication, and QoL. MethodsA cross-sectional survey was conducted to collect self-reported information from caregivers of children with LGS and other DRE regarding their perspectives and experiences with healthcare providers' evaluation of behavior, communication, and QoL. The survey tool was developed by the study investigators in partnership with the LGS Foundation and had diffused to caregivers online by epilepsy advocacy groups including the Pediatric Epilepsy Surgery Alliance (PESA). Responses were analyzed. Descriptive statistics were calculated. The survey asked for caregiver perspectives and assessed which instruments the caregivers had previously been given for measuring these domains. ResultsResponses from 245 caregivers were included, with 132 (54%) caregivers of an individual with LGS and 113 (46%) caregivers of an individual with non-LGS related DRE. Respondents reported that 66% of their loved ones had undergone epilepsy-related surgery. Over 90% agreed that measuring behavior, communication, and QoL was important, but fewer than half felt that their healthcare providers evaluated these domains well. LGS caregivers largely shared non-LGS caregivers' perspectives; however, they reported more frequently that communication was not evaluated enough. Barriers to measuring these domains included a lack of good surveys (developmentally appropriate and specific to the type of epilepsy) or not receiving any survey instruments for these domains during clinic appointments.Caregivers play a crucial role for individuals with DRE, and their input is essential in identifying challenges and needs. Caregivers believe that measuring behavior, communication, and quality of life is important, and most of them feel that their loved ones are not adequately evaluated during their healthcare encounters. There is a need for appropriately scaled survey instruments to measure areas of importance for patients and caregivers, as well as incorporation of these outcomes in the healthcare discussion.

B-161 Mass Spectrometric Assay for the Early Diagnosis of Barth Syndrome

Abstract Background Barth syndrome (BTHS) is an inborn error of phospholipid metabolism caused by pathogenic variants in the TAFAZZIN gene locus on a chromosome X. TAFAZZIN encodes a phospholipid transacylase enzyme, tafazzin, that promotes cardiolipin (CL) remodeling. Deficiency of tafazzin activity in BTHS results in accumulation of monolysocardiolipin (MLCL) and decreased abundance of mature CL, making an increased ratio of MLCL to CL as a diagnostic marker for BTHS. 52:2-MLCL to 72:8-CL in dried-blood spot (DBS) has been used for provisional identification BTHS using LC-MS/MS. A development of multiplexed method that targets several species of MLCL and CL can enhance the diagnosis of BTHS. Methods A targeted LC-MS/MS with scheduled multiple reaction monitoring (MRM) mode in negative electrospray ionization was developed using a triple quadrupole MS. DBS from patients with BTHS were obtained at Johns Hopkins University and provided by Barth Syndrome Foundation while control DBS were provided by Biochemical Genetics Laboratory at Mayo Clinic. Internal standards and chloroform:methanol (1:1, v/v) were added to DBS (1/8″ diameter) and sonicated. Supernatants were collected and dried under nitrogen gas. Followed by reconstitution in methanol, samples were subjected to LC-MS/MS analysis. Results More than 20 species of MLCL and CL species having various fatty acyl chains were detected and quantified. Remodeled CL species were decreased while MLCL and nascent CL species were found to be increased in known patients of BTHS (n = 8) compared to controls (n = 8). Notably, several ratios of lipids including 52:2-MLCL/72:8-CL and 54:2-MLCL/70:6-CL showed >300-fold elevation in the patients. Conclusion Various species of MLCL and CL that can be used to diagnose BTHS can be measured from an easily accessible specimen such as DBS using this method.

Genetics of kidney disorders in Phelan-McDermid syndrome: evidence from 357 registry participants.

Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by SHANK3 pathogenic variants or chromosomal rearrangements affecting the chromosome 22q13 region. Previous research found that kidney disorders, primarily congenital anomalies of the kidney and urinary tract, are common in people with PMS, yet research into candidate genes has been hampered by small study sizes and lack of attention to these problems. We used a cohort of 357 people from the Phelan-McDermid Syndrome Foundation International Registry to investigate the prevalence of kidney disorders in PMS using a cross-sectional design and to identify 22q13 genes contributing to these disorders. Kidney disorders reported included vesicoureteral reflux (n = 37), hydronephrosis (n = 36), dysplastic kidneys (n = 19), increased kidney size (n = 19), polycystic kidneys (15 cases), and kidney stones (n = 4). Out of 315 subjects with a 22q13 deletion, 101 (32%) had at least one kidney disorder, while only one out of 42 (2%) individuals with a SHANK3 pathogenic variant had a kidney disorder (increased kidney size). We identified two genomic regions that were significantly associated with having a kidney disorder with the peak associations observed near positions approximately 5Mb and 400Kb from the telomere. The candidate genes for kidney disorders include FBLN1, WNT7B, UPK3A, CELSR1, and PLXNB2. This study demonstrates the utility of patient registries for uncovering genetic contributions to rare diseases. Future work should focus on functional studies for these genes to assess their potential pathogenic contribution to the different subsets of kidney disorders.

Evaluating adult care in Dravet syndrome upon transferring from pediatrics in the U.S.: A caregiver-based survey study

Patients with Dravet syndrome (DS) and their caregivers must navigate a complex process upon transitioning from pediatric to adult healthcare settings. Our study examines the state of care transfer of patients with DS in the U.S. A 34-question e-survey evaluating patient demographics, clinical features, and details of the transfer process was sent to caregivers of adults with DS (≥18 years old) residing in the U.S. through the Dravet Syndrome Foundation. Forty-six responses were included in the analysis. Twenty-nine patients (n = 29/46) did not undergo transfer of care – mostly because they were still followed by pediatric neurologists/epileptologists (71%), whereas 17 (n = 17/46) underwent transfer of care. Adult neurology/epilepsy teams providing care never/rarely included a multidisciplinary team (71%), addressed patients’ self-advocacy capabilities (53%), or legal guardianship/end-of-life decision-making (59%). Adult neurology/epilepsy teams were considered very much attentive/available (63%), attentive and accommodating to patients with behavioral/cognitive issues (50%), and knowledgeable about caring for patients with intellectual disability/behavioral issues (63%), collaborating with caregivers (75%), and DS – especially in adults (50%). Most caregivers (62.5%) rated the transfer process as good, very good, or excellent. Patients with DS and their caregivers would benefit from more accessible transition programs, which would be ideally equipped to deliver care tailored to these patients’ needs.

Exploring sex differences in inhibitory synaptic transmission in the kolliker-fuse of rett syndrome mice

Rett Syndrome (RTT) is a rare neurodevelopmental disorder characterized by severe motor impairments including breathing problems. RTT is caused by mutations in the methyl CpG binding protein 2 (MeCP2) gene located on the X chromosome. Accordingly, girls and women account for the majority of RTT patients. The genetic nature of RTT lends itself to study in mice with loss of function mutations in the MeCP2 gene. Importantly, RTT mice display breathing irregularities similar to human patients. Insufficient inhibitory neurotransmission in the brainstem respiratory network is thought to contribute to the breathing problems in RTT. In the pontine Kölliker-Fuse (KF) area of RTT mice, there are fewer GABAergic neurites and injection of a GABA reuptake antagonist alleviates breathing irregularity in vivo. However, no one has examined the physiology of inhibitory synaptic transmission in the KF of RTT mice. In the present work, we tested the hypothesis that inhibitory synaptic transmission was deficient in the respiratory-controlling KF of MeCP2Bird mice. Although girls and women make up the majority of RTT patients, most studies examining synaptic physiology in the brainstem have been performed using male MeCP2-deficient mice. Hemizygous male MeCP2Bird mice lack MeCP2 protein and exhibit rapid onset of severe RTT symptoms which leads to short life spans. Due to partial X-inactivation, MeCP2 expression in heterozygous female MeCP2-deficient mice is mosaic, leading to variable symptom severity and delayed onset, which more closely resembles the human condition. In the present study, we examined inhibitory synaptic transmission in the KF of female heterozygous MeCP2Bird mice compared to male hemizygous MeCP2Bird mice and wild type littermates. Whole-cell voltage-clamp recordings from KF neurons contained in acute brain slices were used to measure inhibitory currents. Most notably, the frequency of spontaneous inhibitory postsynaptic currents is reduced in the KF of male, but not female, MeCP2Bird mice compared to wild type littermates. To better understand this sex difference in inhibitory neurotransmission, we assessed the influence of estrous cycle stage and MeCP2 expression status in the recorded neuron. The outcomes of this research will increase our understanding of synaptic function in respiratory control neurons in female Rett Syndrome mice. This research was supported by the International Rett Syndrome Foundation Basic Research Grant 3608. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nonseizure Outcomes With Cannabidiol (CBD) in Pediatric Versus Adult Patients With Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS): Subgroup Analysis of BECOME, a Caregiver Survey (P14-1.008)

<h3>Objective:</h3> To characterize and quantify nonseizure behavioral and cognitive outcomes in pediatric (&lt;18 years) vs adult (≥18 years) patients from the cross-sectional caregiver survey BECOME (BEhavior, COgnition, and More with Epidiolex^®). <h3>Background:</h3> A substantial proportion of caregivers reported improvements in seizure and nonseizure outcomes in the primary analysis of the survey. <h3>Design/Methods:</h3> US-based caregivers (N=498) of patients with LGS (80%) or DS (20%) who received ≥3 months of CBD treatment (Epidiolex^®, 100 mg/mL oral solution) compared the past month with the period before CBD initiation. The online survey included multiple-choice and rank-order questions; changes were rated using a symmetrical 7-point Likert scale (from worsening to improvement). <h3>Results:</h3> Mean (standard deviation) age of patients: 16 (11) years; median (IQR) CBD dose: 14 mg/kg/d (8–19 mg/kg/d); median concomitant ASMs: 4. A similar proportion of caregivers of pediatric (n=315) and adult (n=183) patients reported any improvement (possible, minor, or definite) in ≥1 question of the following domains: alertness, cognition, and executive function (87% and 81%) and emotional and social function (82% and 80%). A numerically greater proportion of caregivers of pediatric versus adult patients reported any improvement in ≥1 question of the language and communication (verbal patients: 81% versus 63%; nonverbal patients: 85% versus 68%), physical functioning (53% versus 33%), sleep (53% versus 48%), and daily activities (56% versus 44%) domains. Rates of worsening varied by behavior and ranged from 0% to 20% of respondents. In pediatric patients, the most common improvements were in the ability to learn new things (76%) and, in nonverbal patients, looking up or smiling at mention of their name (76%). For adult patients, the most common improvement was in alertness (70%). <h3>Conclusions:</h3> A substantial proportion of caregivers of patients with LGS or DS, regardless of age, reported improvements in outcomes beyond seizure control since initiating CBD treatment. <b>Disclosure:</b> Dr. Dixon-Salazar has received personal compensation for serving as an employee of Lennox-Gastaut Syndrome (LGS) Foundation. Dr. Dixon-Salazar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuelis. Dr. Berg has received personal compensation for serving as an employee of COMBINEDBrain. Dr. Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurocrin. Dr. Berg has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biomarin. The institution of Dr. Berg has received research support from FamilieSCN2A Foundation. Mrs. Meskis has received personal compensation for serving as an employee of Dravet Syndrome Foundation. Ms. Danese has nothing to disclose. Dr. Saurer has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Saurer has stock in Jazz Pharmaceuticals. Dr. Le has received personal compensation for serving as an employee of Greenwich Biosciences. Dr. Le has stock in Greenwich Biosciences. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for stoke therapeutics. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Encoded Therapeutics. Dr. Perry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GW Biosciences. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zogenix. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biomarin. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Taysha. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cycle Pharma. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke Therapeutics. Dr. Perry has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Zogenix. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GW Biosciences.

Seizure Outcomes With Cannabidiol (CBD) in Pediatric Versus Adult Patients With Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS): Subgroup Analysis of BECOME, a Caregiver Survey (P14-1.006)

<h3>Objective:</h3> To characterize and quantify seizure-related outcomes in pediatric (&lt;18 years) versus adult (≥18 years) patients from the cross-sectional caregiver survey BECOME (BEhavior, COgnition, and More with Epidiolex^®). <h3>Background:</h3> A substantial proportion of caregivers reported improvements in seizure and nonseizure outcomes in the primary analysis of the survey. <h3>Design/Methods:</h3> The US-based caregivers (N=498) of patients with LGS (80%) or DS (20%) who received ≥3 months of CBD treatment (Epidiolex^®, 100 mg/mL oral solution) compared the past month with the period before CBD initiation. The online survey included multiple-choice and rank-order questions; changes were rated using a symmetrical 5- and 7-point Likert scale (from worsening to improvement). <h3>Results:</h3> Mean (standard deviation) patient age: 16 (11) years; median (IQR) CBD dose: 14 mg/kg/d (8–19 mg/kg/d); median concomitant ASMs: 4. Most caregivers of pediatric (n=315) and adult (n=183) patients reported any improvement (possible, definite minor, or definite major) in seizure frequency (84% each) and severity (77% and 75%). Worsening in seizure frequency was reported by 7% and 5% of caregivers of pediatric and adult patients, respectively; 10% and 6% reported any worsening in seizure severity. Caregivers of pediatric and adult patients reported any decrease in the frequency of specific seizure type as follows: convulsive (72% each), drop (71% each), nonconvulsive/nondrop (66% and 69%), and night-time seizures (61% and 63%). Similar proportions of caregivers of pediatric and adult patients reported improvements in seizure-free days/week for ≥1 seizure type (65% and 70%) and seizure freedom in the past month (18% and 15%). Many respondents in both groups reported reductions in rescue medication use (57% each), emergency room visits (56% and 51%), hospitalizations (55% and 50%), and occurrence of seizure-related injuries (48% and 49%). <h3>Conclusions:</h3> A substantial proportion of caregivers of patients with LGS or DS, regardless of age, reported improvements in seizure-related outcomes with CBD treatment. <b>Disclosure:</b> Dr. Saurer has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Saurer has stock in Jazz Pharmaceuticals. Dr. Berg has received personal compensation for serving as an employee of COMBINEDBrain. Dr. Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurocrin. Dr. Berg has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biomarin. The institution of Dr. Berg has received research support from FamilieSCN2A Foundation. Dr. Dixon-Salazar has received personal compensation for serving as an employee of Lennox-Gastaut Syndrome (LGS) Foundation. Dr. Dixon-Salazar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuelis. Mrs. Meskis has received personal compensation for serving as an employee of Dravet Syndrome Foundation. Ms. Danese has nothing to disclose. Dr. Le has received personal compensation for serving as an employee of Greenwich Biosciences. Dr. Le has stock in Greenwich Biosciences. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for stoke therapeutics. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Encoded Therapeutics. Dr. Perry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GW Biosciences. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zogenix. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biomarin. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Taysha. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cycle Pharma. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke Therapeutics. Dr. Perry has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Zogenix. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GW Biosciences.

Trofinetide for the treatment of Rett syndrome: an open-label study in girls 2 to 4 years of age (P13-9.005)

Trofinetide for the treatment of Rett syndrome: an open-label study in girls 2 to 4 years of age (P13-9.005)

Treatment with trofinetide shows benefit compared to placebo for the ability to communicate in individuals with Rett syndrome: a secondary analysis of the LAVENDER study (P13-9.006)

Treatment with trofinetide shows benefit compared to placebo for the ability to communicate in individuals with Rett syndrome: a secondary analysis of the LAVENDER study (P13-9.006)

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (S34.007)

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (S34.007)

Clinical Management of Rett Syndrome in the Real World: A Physician Survey (P12-4.002)

Clinical Management of Rett Syndrome in the Real World: A Physician Survey (P12-4.002)

Fragile-X-associated Tremor/Ataxia Syndrome in a Woman with Full Mutation: A Case Report (P5-11.009)

<h3>Objective:</h3> To describe the first case of FXTAS in a full mutation woman without Fragile X syndrome. <h3>Background:</h3> Fragile-X-associated tremor/ataxia syndrome (FXTAS) is caused by expanded trinucleotide (CGG) repeats between 55–199 (premutation) in the <i>Fragile X Mental Retardation 1 (FMR1) gene</i>. Core clinical features of FXTAS include cerebellar ataxia, intention tremor and Parkinsonism. In contrast, a full mutation of CGG repeats&gt;200 repeats with methylation of the gene leads to fragile X syndrome, which is characterized by early intellectual disability, autistic features, and seizures. <i>FMR1</i> premutation carrier women presenting as FXTAS have been reported. This is the first report of a woman with a full mutation presenting with FXTAS. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 65-year-old woman presented with problems with dexterity and shuffling gait. The patient also complained of urinary urgency, constipation, anxiety, depression, and mild cognitive complaints. The patient’s son was diagnosed with fragile X syndrome at 14 months. Neurological exam of the patient showed parkinsonism, action tremor and limb ataxia. MRI brain demonstrated chronic ischemic small vessel disease and mildly reduced brain volume. <i>FMR1 CGG</i> repeat sizes were 20 and &gt;200. The 20 repeat allele was seen on the active X chromosome (representing non-random X-inactivation), while the &gt;200 repeat allele was fully methylated on Southern blot. Testing for Parkinson’s disease-associated genes were negative. <h3>Conclusions:</h3> This is the first report of a woman with a <i>FMR1</i> full mutation presenting with signs and symptoms of FXTAS. Several cases of FXTAS have been reported in <i>FMR1</i> full mutation men with fragile X syndrome due to mosaicism of repeat sizes and the presence of a premutation allele. Full mutation adults with complete methylation have not been reported to have FXTAS. The clinical presentation of this case might be due to size or methylation mosaicism in brain. Alternatively, one could also consider a different disease mimicking FXTAS. <b>Disclosure:</b> Dr. Kazanci has nothing to disclose. The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ovid. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from GW. The institution of Dr. Berry-Kravis has received research support from Anavex. The institution of Dr. Berry-Kravis has received research support from Rett Syndrome Research Trust. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Orphazyme. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Erydel. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson’s Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Biohaven. The institution of Dr. Hall has received research support from Neurocrine. The institution of Dr. Hall has received research support from Uniqure. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as a Study section with NIH.