Where there is no genetic counselor: An online decision-aid supports the majority of parents' diagnostic genomic testing choices for their children.

PURPOSE: We evaluated DECIDE, an online pre-test decision-support tool for diagnostic genomic testing, in non-genetics specialty clinics where there are no genetic counselors (GCs). METHODS: Families of children offered genomic testing were eligible to participate. Fifty-six parents/guardians completed DECIDE at home, at their convenience. DECIDE includes an integrated knowledge quiz and decisional conflict screen. Six months later, parents were offered follow-up questionnaires and interviews about their experiences. RESULTS: Forty parents (71%) had sufficient knowledge and no decisional conflict surrounding their testing decision but six of this group had residual questions. These six, plus 16 with decisional conflict or insufficient knowledge, saw a genetic counselor. At follow-up, little-to-no decisional regret and few negative emotions were identified in any parents. Most chose testing and described their decision as easy, yet stressful, and described many motivations for sequencing. Parents appreciated the simple comprehensive information DECIDE provided and the ability to view it in a low stress environment. CONCLUSION: DECIDE provides adequate decision-support to enable most parents to make value-consistent choices about genetic testing for their child. Parents reported that DECIDE helped to clarify motivations for pursuing (or declining) testing. DECIDE is a timely, well tested, and accessible tool in clinical settings without GCs.

Morquio B disease: a case report.

Mucopolysaccharidosis IV type B, or Morquio B disease (MBD), is an autosomal recessive disorder caused by a genetic mutation in GLB1 gene encoding for ß-galactosidase on chromosome 3p22.33. ß-galactosidase deficiency can result in two different conditions, GM1 gangliosidosis and MBD, of which MBD has a milder phenotype and presents later in life with keratan sulfate accumulation in the retina and cartilage. In this case report, we present a patient diagnosed with MBD at the age of 5 after initially presenting with Morquio dysostosis multiplex and characteristic radiographic findings. Genetic testing confirmed that the patient has ß-galactosidase deficiency due to mutation W273l/N484K on GLB1 gene. The patient exhibited elevated mucopolysaccharide levels in urine at 18 mg/mmol and demonstrated an abnormal band pattern of urine oligosaccharides on electrophoresis. The activity of ß-galactosidase in his white blood cells was reduced to 12.3 nmol/h/mg protein. At the time of diagnosis, the patient did not present with gait and ambulation issues, but his ability to walk progressively deteriorated in his adolescence as a result of instability and pain in the ankle, knee, and hip joints, accompanied by a global decrease in muscle strength. This case report is the first in the literature to provide an in-depth exploration of the orthopedic treatment and follow-up received by a young adolescent with MBD to provide symptom relief and improve walking ability.

Generation of a human induced pluripotent stem cell line from a patient with hypomyelinating leukodystrophy 22 (HLD22).

Hypomyelinating Leukodystrophy 22 (HLD22) is caused by a stoploss mutation in CLDN11. To study the molecular mechanisms underlying HLD22, human induced pluripotent stem cells (hiPSCs) were generated from patient fibroblasts carrying the stop-loss mutation in CLDN11.

Use of dexamethasone in acute rhabdomyolysis in LPIN1 deficiency.

Introduction: LPIN1 deficiency is an autosomal recessive form of early childhood recurrent severe rhabdomyolysis. Although not completely lucid yet, LPIN1 has been shown to modulate endosomal-related pro-inflammatory responses via peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α). Treatment with anti-inflammatory agents such as dexamethasone has been proposed to improve the outcome. Case: We report a male toddler with recurrent episodes of complicated rhabdomyolysis, requiring prolonged intensive care unit admissions. Whole exome sequencing revealed a common homozygous 1.7 kb intragenic deletion in LPIN1. Despite optimal metabolic cares, the patient presented with an extremely high CK level where he benefited from intravenous dexamethasone (0.6 mg/Kg/day) for a period of 6 days. Results: Dexamethasone administration shortened the course of active rhabdomyolysis, intensive care admission and rehabilitation. It also prevented rhabdomyolysis-related complications such as kidney injury and compartment syndrome. Conclusion: Our patient showed a favorable response to parenteral dexamethasone, in addition to hyperhydration with IV fluids, sufficient calorie intake, and restricted dietary fat. The improvement with corticosteroids suggests an uncontrolled inflammatory response as the pathophysiology of LPIN1 deficiency.

Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test.

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined. Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13C-glucose breath test (13C-GBT). Design: A case of GSD Ib (18y; female) underwent 13C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review. Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point. Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of 13C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib.

Iron deficiency and common neurodevelopmental disorders-A scoping review.

BACKGROUND: A wealth of human and experimental studies document a causal and aggravating role of iron deficiency in neurodevelopmental disorders. While pre-, peri-, and early postnatal iron deficiency sets the stage for the risk of developing neurodevelopmental disorders, iron deficiency acquired at later ages aggravates pre-existing neurodevelopmental disorders. Yet, the association of iron deficiency and neurodevelopmental disorders in childhood and adolescence has not yet been explored comprehensively. In this scoping review, we investigate 1) the association of iron deficiency in children and adolescents with the most frequent neurodevelopmental disorders, ADHD, ASD, and FASD, and 2) whether iron supplementation improves outcomes in these disorders. METHOD: Scoping review of studies published between 1994 and 2021 using "iron deficiency / iron deficiency anemia" AND "ADHD" OR "autism" OR "FASD" in four biomedical databases. The main inclusion criterion was that articles needed to have quantitative determination of iron status at any postnatal age with primary iron markers such as serum ferritin being reported in association with ADHD, ASD, or FASD. RESULTS: For ADHD, 22/30 studies and 4/4 systematic reviews showed an association of ADHD occurrence or severity with iron deficiency; 6/6 treatment studies including 2 randomized controlled trials demonstrated positive effects of iron supplementation. For ASD, 3/6 studies showed an association with iron deficiency, while 3/6 and 1/1 systematic literature review did not; 4 studies showed a variety of prevalence rates of iron deficiency in ASD populations; 1 randomized controlled trial found no positive effect of iron supplementation on behavioural symptoms of ASD. For FASD, 2/2 studies showed an association of iron deficiency with growth retardation in infants and children with prenatal alcohol exposure. CONCLUSION: Evidence in favor of screening for iron deficiency and using iron supplementation for pediatric neurodevelopmental disorders comes primarily from ADHD studies and needs to be further investigated for ASD and FASD. Further analysis of study methodologies employed and populations investigated is needed to compare studies against each other and further substantiate the evidence created.

Disruptive Behaviors and Intellectual Disability: Creating a New Script.

Background: Terms currently used to describe the so-called challenging and disruptive behaviors (CBDs) of children with intellectual disabilities (ID) have different connotations depending on guiding contextual frameworks, such as academic and cultural settings in which they are used. A non-judgmental approach, which does not attempt to establish existing categorical diagnoses, but which describes in a neutral way, is missing in the literature. Therefore, we tried to describe CDBs in youth with ID in an explorative study. Methods: Interviews with families investigated the CDBs of five youth with Down syndrome. At home, families tracked youth's sleep/wake behaviors and physical activity. Youth were observed in a summer school classroom. The collected information and suggested explanatory models for observed CDBs were reviewed with the families. Results: We grouped CDBs as challenging, if they were considered to be reactive or triggered, or unspecified, if no such explanatory model was available. A third category was created for light-hearted CDBs: goofy, acknowledging the right to laugh together with peers. We found some relationships between sleep, physical activity, and CDBs and developed an explorative approach, supporting a child-centered perspective on CDBs. Conclusion: The controversial discussions on terminology and management of CDBs in the literature demonstrate the need for a non-judgmental approach. Such an explorative approach, allowing non-professionals to not label, has been missing. The fact that, up to now, the light-hearted behaviors of an individual with ID have not been integrated in commonly-used behavioral checklists as their natural right, proves our concept and indicates that a paradigm change from judgment-based to exploratory-driven approaches is needed.

Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study.

Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals' primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.

Development of minimally invasive 13C-glucose breath test to examine different exogenous carbohydrate sources in patients with glycogen storage disease type Ia.

Background: Glycogen storage disease type Ia (GSD Ia) is an autosomal recessive disorder caused by deficiency of glucose-6-phosphatase (G6Pase), resulting in fasting hypoglycemia. Dietary treatment with provision of uncooked cornstarch (UCCS) or a novel modified cornstarch (Glycosade®) is available to treat hypoglycemia, yet choice of carbohydrate to achieve a desirable glycemic control is debated.13C-glucose breath test (13C-GBT) can be used to examine glucose metabolism from different carbohydrate sources via 13CO2 in breath. Objectives: Our objectives were: 1) establishing the use of a minimally invasive 13C-GBT to examine in vivo glucose metabolism in healthy adults, and 2) using 13C-GBT to measure utilization of the standard UCCS vs. Glycosade® in GSD Ia and healthy controls. Design: Experiment 1- Ten healthy adults (6F: 4 M, 22-33y) underwent 13C-GBT protocol twice as a proof-of-principle, once with oral isotope dose (glucose 75 g + [U-13C6] d-glucose 75 mg) and once without isotope (only glucose 75 g) to test sensitivity of natural 13C-enrichment. Breath samples were collected at baseline and every 20 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Experiment 2- Three GSD Ia (12y, 13y, and 28y) and six healthy controls (2F: 4 M, 10-32y) underwent 13C-GBT protocol twice: with UCCS or Glycosade® (based on their current prescribed dose 42-100 g) after ~4 h fast based on our GSD Ia patients with fasting tolerance. Results: Findings 1- Maximum 13C-enrichments occurred at 200 min without and with [U-13C6] d-glucose in all healthy adults, suggesting natural enrichment is sensitive for the 13C-GBT. Findings 2- Glycosade® utilization was lower than UCCS utilization in 12y and 13y GSD Ia, but was similar in the 28y GSD Ia. Conclusions: 13C-GBT is a novel minimally invasive functional test to examine glucose metabolism in GSD Ia, and test new products like Glycosade®, which has the potential to improve nutritional management and individualized carbohydrate supply in GSD.

Sleep as an outcome measure in ADHD randomized controlled trials: A scoping review.

Sleep disturbances are highly prevalent among children with ADHD. Yet, diagnostic and treatment regimens are primarily focused on daytime symptomatology. The goals of this scoping review are to 1) identify interventional ADHD RCTs that have used sleep as an outcome measure, 2) describe and assess the validity of tools utilized to measure sleep-specific outcomes. 40/71 RCTs used sleep as a primary outcome. Actigraphy (n = 18) and sleep log/diary (n = 16) were the most common tools to measure sleep, followed by Children's Sleep Habits Questionnaire (n = 13), and polysomnography (n = 10). Sleep was a secondary outcome in 31 RCTs. Polysomnography and actigraphy used a heterogeneous spectrum of sleep-related variables and technical algorithms, respectively. 19/23 sleep questionnaires were validated covering a spectrum of sleep-related domains. Despite the intrinsic nature of sleep disturbances in ADHD, the number of RCTs measuring sleep-specific outcomes is limited and tools to measure outcomes are not standardized. Given the potential adverse effects of ADHD medications on sleep, sleep should be included as a core outcome measure in future clinical trials.

Families' healthcare experiences for children with inherited metabolic diseases: protocol for a mixed methods cohort study.

INTRODUCTION: Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada. METHODS AND ANALYSIS: A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5-7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display. ETHICS AND DISSEMINATION: The study protocol and procedures were approved by the Children's Hospital of Eastern Ontario's Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences.

Family Experiences with Care for Children with Inherited Metabolic Diseases in Canada: A Cross-Sectional Survey.

BACKGROUND AND OBJECTIVE: Children with inherited metabolic diseases often require complex and highly specialized care. Patient and family-centered care can improve health outcomes that are important to families. This study aimed to examine experiences of family caregivers (parents/guardians) of children diagnosed with inherited metabolic diseases with healthcare to inform strategies to improve those experiences. METHODS: A cross-sectional mailed survey was conducted of family caregivers recruited from an ongoing cohort study. Participants rated their healthcare experiences during their child's visits to five types of healthcare settings common for inherited metabolic diseases: the metabolic clinic, the emergency department, hospital inpatient units, the blood laboratory, and the pharmacy. Participants provided narrative descriptions of any memorable negative or positive experiences. RESULTS: There were 248 respondents (response rate 49%). Caregivers were generally very or somewhat satisfied with the care provided at each care setting. Appropriate treatment, provider knowledge, provider communication, and care coordination were deemed essential aspects of satisfaction with care by the majority of participants across many settings. Memorable negative experiences were reported by 8-22% of participants, varying by setting. Among participants who reported memorable negative experiences, contributing factors included providers' demeanor, lack of communication, lack of involvement of the family, and disregard of an emergency protocol letter provided by the family. CONCLUSIONS: While caregivers' satisfaction with care for children with inherited metabolic diseases was high, we identified gaps in family-centered care and factors contributing to negative experiences that are important to consider in the future development of strategies to improve pediatric care for inherited metabolic diseases.

Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases characterized by chronic, progressive multi-system manifestations with varying degrees of severity. Disease-modifying therapies exist to treat some types of MPS; however, they are not curative, underscoring the need to identify and evaluate co-interventions that optimize functioning, participation in preferred activities, and quality of life. A Canadian pediatric MPS registry is under development and may serve as a platform to launch randomized controlled trials to evaluate such interventions. To promote the standardized collection of patient/family-reported and clinical outcomes considered important to patients/families, health care providers (HCPs), and policymakers, the choice of outcomes to include in the registry will be informed by a core outcome set (COS). We aim to establish a patient-oriented COS for pediatric MPS using a multi-stakeholder approach. METHODS: In step 1 of the six-step process to develop the COS, we will identify relevant outcomes through a rapid literature review and candidate outcomes survey. A two-phase screening approach will be implemented to identify eligible publications, followed by extraction of outcomes and other pre-specified data elements. Simultaneously, we will conduct a candidate outcomes survey with children with MPS and their families to identify outcomes most important to them. In step 2, HCPs experienced in treating patients with MPS will be invited to review the list of outcomes generated in step 1 and identify additional clinically relevant outcomes. We will then ask patients/families, HCPs, and policymakers to rate the outcomes in a set of Delphi Surveys (step 3), and to participate in a subsequent consensus meeting to finalize the COS (step 4). Step 5 involves establishing a set of outcome measurement instruments for the COS. Finally, we will disseminate the COS to knowledge users (step 6). DISCUSSION: The proposed COS will inform the choice of outcomes to include in the MPS registry and, more broadly, promote the standardized collection of patient-oriented outcomes for pediatric MPS research. By involving patients/families from the earliest stage of the research, we will ensure that the COS will be relevant to those who will ultimately benefit from the research. TRIAL REGISTRATION: PROSPERO CRD42021267531 , COMET.

Patient and family engagement in the development of core outcome sets for two rare chronic diseases in children.

BACKGROUND: Core outcome sets (COS) are lists of consensus-determined outcomes to be measured and reported in all clinical research studies within a disease area. While including patients and families in COS development to improve their relevance and applicability to patient values is key, there is limited literature documenting practical barriers and facilitators to successful patient engagement in COS development. In this paper, as researchers and patient partners, we provide a resource for COS developers to meaningfully and effectively engage patients and families. MAIN BODY: To establish a consensus-based COS for children with two inherited metabolic diseases (medium-chain acyl-CoA dehydrogenase deficiency and phenylketonuria), we conducted an evidence review, Delphi survey, and workshop. Two adult patient partner co-investigators co-developed the study protocol, co-designed strategies to address challenges with incorporating patient perspectives, and led all patient engagement activities, including communication with a group of family advisors. Seven adult family advisors received training about COS development and subsequently contributed to Delphi survey development, outcome definitions, the consensus workshop, and selection of outcome measurement instruments. Patient partner co-investigators and family advisors were essential to the successful design, conduct, and completion of the two COS. Patient partner co-investigators supported the understanding, inclusion and engagement of family advisors, and helped develop accessible tools to determine patient-oriented outcome measurement instruments. Patient partner co-investigators and family advisors collaborated with the study team to co-develop surveys, modify technical language, and recruit participants to the study. Together, we addressed challenges to patient engagement in COS development such as unfamiliarity with study methods, comprehensibility of materials and ongoing engagement, and power imbalances between team members. CONCLUSION: Our approach to patient and family engagement in COS development for two rare conditions for children was feasible and considered valuable by all study team members, including patients and family members, in improving the relevance of the deliverable to patients. This approach to patient engagement in developing COS can be applied to other paediatric disease contexts, allowing patient and family perspectives to influence the direction of future studies to develop COS.

Core outcome sets (COS) are lists of outcomes agreed upon by a group of people to be measured and reported in studies about certain diseases and populations. Core outcomes are meant to represent what is useful to study from the perspectives of health care providers, researchers and patients. For researchers who seek to include patients in the development of a COS, there is little guidance about how to do this well. We recently developed COS for two rare diseases in children, medium-chain acyl-CoA dehydrogenase deficiency and phenylketonuria. We did this by reviewing available information from published research, surveying health care providers, researchers, and patients, and eventually coming to agreement during a workshop. We included two adult patient partner co-researchers who helped design the COS study and co-developed the patient engagement strategy. These partners formed relationships with seven adult family advisors, who helped ensure that materials were accessible, participated in outcome selection, and helped select tools to measure core outcomes. Strategies we used to engage patient partners included a) training about both the scientific research process and how to help other researchers in the future, and b) frequent communication about study progress and how family advisor feedback was used. Also, we made sure that the impacts of power imbalances between health care providers, researchers and patients were low. Our approach to patient engagement in COS development for two rare conditions in children proved to be both feasible and considered valuable by all study team members, including patient partners and family advisors. To include patient perspectives and values, future COS developers may take a similar approach.

Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria.

BACKGROUND: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies. METHODS: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1-3: not important, 4-6: important but not critical, 7-9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome. RESULTS: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations. CONCLUSIONS: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.

Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects.

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range.

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome.

PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.

Iron deficiency and sleep - A scoping review.

Iron deficiency (ID) is associated with sleep disorders, but standardized assessment of iron status in the diagnostic work-up and iron supplementation as treatment have not been considered in clinical practice. We investigated associations of ID with type and severity of sleep disorders and whether iron supplementation improves sleep-related symptoms. In 2017, we conducted a scoping review for the period 1972-2016 using the terms "iron deficiency anemia" and "sleep" on biomedical database search engines, and in 2019, we updated our review with an ad-hoc search. Among the 93 articles meeting our inclusion criteria, 74/93 studies investigated restless legs syndrome (RLS), 8/93 periodic limb movements in sleep (PLMs), 3/93 sleep disordered breathing (SDB), 6/93 general sleep disturbances (GSD), and 2/93 attention-deficit/ hyperactivity disorder related sleep disorders (ADHD-SDs). A statistically supported positive association with ID was found in 22/42 RLS, 3/8 PLMs, 1/2 SDB, 3/4 GSD, and 1/2 ADHD-SDs association studies. The ad-hoc literature search revealed eight additional association studies with a statistically supported positive association in 2/5 RLS, 1/1 SDB, 1/1 ADHD-SDs, and 1/1 restless sleep disorder (RSD) studies. Iron supplementation was beneficial in 29/30 RLS (including five randomized controlled trials [RCTs]), 1/1 SDB, and 2/2 GSD treatment studies. Iron supplementation was also beneficial in 2/2 RLS (including two RCTs), 1/1 GSD (RCT), and 1/1 RSD studies identified in the ad-hoc search. In pediatric populations, 1/1 RLS, 1/1 SDB, 2/5 PLMs, 2/3 GSD and 1/2 ADHD-SDs studies found positive associations, and 6/6 RLS and 2/2 GSD studies demonstrated a benefit with iron supplementation. In conclusion, iron investigation and supplementation should be considered in patients presenting with sleep disorders. To investigate the role of ID in sleep in the future, a harmonization of study designs, including outcome measures and standardized iron and inflammation status is necessary.