Children's Specialized Hospital (CSH) is a children's rehabilitation hospital in New Brunswick, New Jersey. It has 140 beds. Founded in 1891, the hospital supports a wide range of research with five core areas of research focus - autism, mobility, cognition, brain injury, and chronic illness. It treats infants, children, teens, and young adults up until the age of 21. Its largest campus is in New Brunswick campus which is a member of the greater Children's Academic Health Campus.
BackgroundMembranoproliferative glomerulonephritis (MPGN) is a rare glomerular disorder characterized by immune complex or complement-mediated injury, often leading to nephrotic syndrome, hypertension, and progressive renal dysfunction. Its management remains challenging, particularly in pediatric patients with coexisting renal pathologies.Case presentationWe report a case of an 11-years-old girl who presented with nephrotic syndrome, severe hypertension, and impaired renal function. Renal biopsy confirmed immune complex-mediated MPGN (IC-MPGN), and genetic testing revealed a homozygous, pathogenic missense PKHD1 variant (NM_138694.3:c.4870C > T; p.(Arg1624Trp), leading to a diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Initial treatment with prednisolone and mycophenolate mofetil failed to halt disease progression, and the patient became dialysis dependent. Pegcetacoplan, a complement C3 inhibitor, was subsequently initiated. After 11 weeks of pegcetacoplan therapy, the patient achieved renal recovery and was successfully weaned from dialysis. Proteinuria decreased from nephrotic to sub-nephrotic levels without significant adverse effects.ConclusionTo our knowledge, this is the first pediatric case of IC-MPGN with genetically confirmed ARPKD successfully treated with pegcetacoplan. The case illustrates that renal recovery occurred following initiation of proximal complement inhibition with pegcetacoplan.
Background and Objectives:Mutations in the GPD1 gene, which encodes glycerol-3-phosphate dehydrogenase 1 (GPD1), are a rare cause of monogenic hypertriglyceridemia (HTG) during childhood. This study is aimed at providing a detailed analysis of the clinical, laboratory, and molecular characteristics of all patients affected by biallelic GPD1 gene variants, including three cases from our center. Methods:A literature search was conducted across the English MEDLINE, PubMed, and Embase databases from 1966 to 2023 for the studies that reported on GPD1 deficiency with confirmed GPD1 gene variants using the search words HTG and GPD1 gene. Results:A total of 39 children (including three from our center) were identified with 15 pathogenic mutations in GPD1 reported in 14 articles from 5 ethnicities (15 Arabs, 14 Caucasians, 4 Chinese, 5 Indian/South Asian, and 1 Turkish): 8 missense variants (one compound heterozygous), 3 nonsense, 3 frameshifts, and 1 splicing. Three of the 15 variants likely originated from a common ancestor, "that is, founder in nature": p.I119fs∗94 (Palestinian Arabs), p.Gly299Arg (Czech population), and p.Thr251Asnfs∗10 (Saudi Arabia). The median age at presentation was 9 months. All patients manifested hepatomegaly, elevated transaminases, and HTG. Nineteen patients underwent liver biopsy; all showed micro- and macrosteatosis, mild to moderate portal fibrosis in 58% (11 out of 19), and cirrhosis in the remaining eight cases (42%). Follow-up data showed that HTG normalized in 28% of patients (11 out of 39) but persisted mildly in the remaining 72% (28 out of 39). Conclusion:Mutations in the GPD1 gene should be considered in children with hepatomegaly, hepatic steatosis, and HTG. This study indicates that GPD1 deficiency may not be a transient or benign condition, as previously considered, due to the persistence of HTG and liver pathology in a significant proportion of cases. Identifying specific GPD1 variants may expedite targeted molecular analysis.
PURPOSE:Gene-disease relationship (GDR) is a key concept in monogenic disease diagnostics. Although functional analysis and disease modeling play important supporting roles, human genetics evidence remains key to supporting or challenging a proposed GDR. Such evidence typically comes from individual publications that address one GDR at a time. We hypothesized that a large cohort composed primarily of Mendelian phenotypes and enriched for consanguinity and founder effect can accelerate evidence generation by enabling high-throughput discovery of homozygous loss-of-function (LOF) variants as well as strong segregation data. METHODS:To test this hypothesis, we analyzed our Lifera Omics Database (LODB) for homozygous high-impact missense variants that are observed in 2 or more unrelated individuals to exploit the power of founder variants, as well as homozygous presumptive LOF variants. The search spanned 2904 genes with tentative GDRs in the literature. RESULTS:The analysis revealed 154 individuals with 119 homozygous LOF variants that support GDRs for 95 genes. Additionally, we identified 13 founder missense variants (33 homozygous individuals) that support GDR for 13 genes. Our data expand the mode of inheritance (MOI) of 19 genes for which the tentative GDRs were based on dominant variants. Phenotypic expansion was encountered in 18 of the supported GDRs, including those in which the full syndromic constellation has not been previously delineated. We also report four novel allelic disorders of reported GDRs. CONCLUSION:This work highlights the potential of diagnostic laboratories to accelerate GDR refinement through data sharing and working closely with referring physicians. It also showcases the added advantage concerning autosomal recessive GDR when the study population is enriched for consanguinity and founder effect.
BACKGROUND:Autism spectrum disorder (ASD) is common in individuals with Down syndrome (DS), with an estimated prevalence of 16%-18%. However, receiving a dual diagnosis of Down syndrome and ASD (DS + ASD) is often delayed. Little evidence exists on the path to ASD diagnosis nor interventions to support individuals with DS + ASD. Barriers to diagnosis and treatment for this unique patient population have yet to be described. This study explores clinicians' practices and perceptions regarding the diagnosis and treatment DS + ASD, and the barriers their patients face in connecting to recommended evaluations and services. METHODS:The study used an anonymous web-based survey developed by a group of physicians, psychologists and researchers who work with individuals with DS, ASD and DS + ASD. The survey queried clinicians from various specialties about their practice patterns regarding assessment of suspected ASD in individuals with DS. The survey inquired about treatment recommendations for DS + ASD and perceived barriers to connecting families with evaluations and services. Data analysis involved descriptive statistics and Mann-Whitney U tests. RESULTS:Most respondents believe diagnosing ASD in individuals with DS significantly impacts management. Challenges were reported in accessing diagnostic evaluations, with heavy reliance on highly specialised DS and ASD clinics. Communication impairment (n = 64, 65%), aggressive behaviours (n = 38, 39%), self-injurious behaviours (n = 33, 34%) and adaptive skills (n = 27, 28%) are priority targets for intervention, and applied behavioural analysis (ABA) (n = 80, 82%), speech therapy through insurance (n = 60, 61%), augmentative and alternative communication evaluation through insurance (n = 59, 60%), and occupational therapy through insurance (n = 57, 58%) are the most frequent referrals following a diagnosis of DS + ASD. All respondents identified multiple barriers to care for individuals with DS + ASD, including waitlists, insurance networks and requirements, lack of experienced providers and high turnover. CONCLUSION:This study highlighted the complexity of caring for individuals with DS + ASD, revealed the heterogeneity of practice patterns among providers, and reported multiple barriers to care for this underserved patient population. Results should prompt work aimed at redressing barriers to care and additional research in the field of effective interventions for individuals with DS + ASD.
ABSTRACT Objective: To examine the associations between medical conditions and early developmental skills in young children with Down syndrome (DS). Method: Data were drawn from the first timepoint of a longitudinal study of children with DS (n = 114; mean age = 20.6 months). Caregivers completed a comprehensive medical history questionnaire, followed by a structured interview and review by a medical doctor to clarify endorsed conditions. Cognitive, expressive, and receptive communication, and fine and gross motor developments were assessed using the Bayley Scales of Infant and Toddler Development, Fourth edition. Associations between medical condition categories and developmental skills across domains were examined using partial correlations adjusting for age. Dominance analyses assessed the unique contributions of significant medical categories. Results: Vision conditions were associated with lower developmental scores across cognitive, communication, and gross motor domains. Seizure/epilepsy was associated with lower cognitive, expressive communication, and motor domain scores. Length of neonatal intensive care unit stay was associated with lower cognitive and communication scores. Additional factors, including premature birth, structural gastrointestinal conditions, dysphagia, eczema, and thyroid disease, were associated with lower scores in specific developmental domains. Dominance analyses revealed overlapping contributions across significant predictors with each developmental domain. Conclusion: Findings highlight the associations between co-occurring medical conditions and developmental heterogeneity among young children with DS. Results underscore the need for further work, including longitudinal research studies, to clarify the role of medical conditions in shaping neurodevelopment in DS.
