ABSTRACT
Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be recapitulated in Drosophila melanogaster with depletion of the PMSD11 ortholog Rpn6, which compromised reversal learning. Our investigations in subject samples further revealed that PSMD11 loss of function resulted in impaired 26S proteasome assembly and the acquisition of a persistent type I interferon (IFN) gene signature, mediated by the integrated stress response (ISR) protein kinase R (PKR). In summary, these data identify PSMD11 as an additional member of the growing family of genes associated with neurodevelopmental proteasomopathies and provide insights into proteasomal biology in human health.
Subject(s)
Drosophila melanogaster , Intellectual Disability , Neurodevelopmental Disorders , Obesity , Proteasome Endopeptidase Complex , Adolescent , Animals , Child , Child, Preschool , Female , Humans , Male , Drosophila melanogaster/genetics , Intellectual Disability/genetics , Interferons/metabolism , Interferons/genetics , Loss of Function Mutation , Neurodevelopmental Disorders/genetics , Obesity/genetics , Phenotype , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolismABSTRACT
The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.
Subject(s)
Chloride Channels/genetics , Disease Models, Animal , Ion Channels/physiology , Mutation , Neurodevelopmental Disorders/pathology , Phenotype , Adolescent , Animals , Child , Child, Preschool , Female , Homozygote , Humans , Infant , Infant, Newborn , Male , Mice , Mice, Knockout , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/metabolismABSTRACT
Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU). Thirty-four patients were analyzed of which 21 and 29 patients had received triheptanoin and/or medium chain triglycerides (MCT), respectively. 36% experienced MCEs while receiving triheptanoin versus 54% on MCT. Total mean annualized MCE rates on triheptanoin and MCT were 0.1 and 0.7, respectively. Annualized disease-related inpatient and ER events were lower on triheptanoin (0.2, 0.3, respectively) than MCT (1.2, 1.0, respectively). Patients were managed more in an outpatient setting on triheptanoin (8.9 annualized outpatient visits) vs MCT (7.9). Overall, this shows that those with LC-FAOD in the Odyssey program experienced fewer MCEs and less HRU in inpatient and ER settings during triheptanoin-treated periods compared with the MCT-treated periods. The MCE rate was lower after initiation of triheptanoin, consistent with clinical trials.
Subject(s)
Fatty Acids , Lipid Metabolism, Inborn Errors , Triglycerides , Humans , Male , Female , United States , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/drug therapy , Fatty Acids/metabolism , Adolescent , Oxidation-Reduction , Child , Adult , Child, Preschool , Rhabdomyolysis/genetics , Rhabdomyolysis/drug therapy , Hypoglycemia , Cardiomyopathies/drug therapy , Cardiomyopathies/genetics , Infant , Young Adult , Health Resources , Middle AgedABSTRACT
Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress. This case highlights the importance of a robust neurometabolic differential diagnosis for prenatally diagnosed structural anomalies and the use of prenatal molecular testing to facilitate rapid, genetically tailored intervention.
ABSTRACT
BACKGROUND: Identifying a precise genetic diagnosis can improve outcomes for individuals with rare disease, though the resources required to do so may impede access and exacerbate healthcare disparities leading to inequitable care. Our objective was therefore to determine the effect of multiple sociodemographic factors on the yield of the diagnostic evaluation for genetics outpatients. METHODS: This is a retrospective cohort study from 2017 to 2019 of outpatient genetics referrals at a pediatric academic tertiary care center. Exposures included: primary language, insurance type, and neighborhood resources (via the Childhood Opportunity Index, COI). The primary outcome was identification of a genetic diagnosis within 2 years of the initial clinic visit. RESULTS: COI quintile was not significantly associated with the odds of diagnosis but was significantly associated with clinic attendance, with lower neighborhood resources leading to incomplete referrals. Limited English proficiency was associated with a higher odds of diagnosis, though at an older age. Public insurance was associated with increased access to genetic testing. CONCLUSIONS: Lower neighborhood resources are negatively associated with clinic attendance. Our findings further suggest delays in care and a referral bias for more severe phenotypes among families with limited English proficiency. Improved access to clinical genetics is needed to improve diagnostic equity. IMPACT: The resources required to identify a genetic diagnosis may impede access and exacerbate healthcare disparities leading to inequitable care. In an analysis of pediatric outpatient genetics referrals, we observed a significant association between neighborhood resources and clinic attendance but not diagnostic yield for those attending, and a higher diagnostic yield for families with limited English proficiency, suggesting referral bias for more severe phenotypes. Thus, the primary barrier to finding a genetic diagnosis was initiation of care, not the ensuing diagnostic odyssey. Further research efforts should be directed at increasing access to clinical genetics evaluations for children with rare disease.
Subject(s)
Limited English Proficiency , Rare Diseases , Humans , Rare Diseases/diagnosis , Rare Diseases/genetics , Retrospective Studies , Referral and Consultation , Healthcare DisparitiesABSTRACT
The NFE2L1 transcription factor (also known as Nrf1 for nuclear factor erythroid 2-related factor-1) is a broadly expressed basic leucine zipper protein that performs a critical role in the cellular stress response pathway. Here, we identified a heterozygous nonsense mutation located in the last exon of the gene that terminates translation prematurely, resulting in the production of a truncated peptide devoid of the carboxyl-terminal region containing the DNA-binding and leucine-zipper dimerization interface of the protein. Variant derivatives were well expressed in vitro, and they inhibited the transactivation function of wild-type proteins in luciferase reporter assays. Our studies suggest that this dominant-negative effect of truncated variants is through the formation of inactive heterodimers with wild-type proteins preventing the expression of its target genes. These findings suggest the potential role of diminished NFE2L1 function as an explanation for the developmental delay, hypotonia, hypospadias, bifid scrotum, and failure to thrive observed in the patient.
Subject(s)
Failure to Thrive , Muscle Hypotonia , Gene Expression Regulation , Genitalia , Humans , Male , NF-E2-Related Factor 1/genetics , NF-E2-Related Factor 1/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND: Children with inborn errors of metabolism (IEM) are at risk for metabolic crises triggered by acute illnesses. Crises are identified through laboratory evaluations. OBJECTIVES: Our objective was to determine national adherence to minimum laboratory evaluations for patients with IEM in emergency departments (EDs), as well as factors associated with laboratory evaluation adherence. METHODS: Using the Pediatric Health Information System, we identified visits to 48 EDs from 2012 to 2017 by children with IEM. We analyzed visits for catabolic conditions (dehydration, gastroenteritis, or vomiting) and determined variation in minimum laboratory evaluation adherence. Multivariable models were created to determine predictors of adherence. RESULTS: Among the visits by children with disorders of the urea cycle, organic acid metabolism, and fatty acid oxidation, 1457 (76.3%) of 1909 adhered to the minimum laboratory evaluation. Median ED-level adherence was 78.2% (interquartile range, 67.4-92.5). Factors associated with adherence were disorder [fatty acid oxidation vs urea cycle disorder; adjusted odds ratio (aOR), 9.35; 95% confidence interval (CI), 4.07-21.47], annual ED volume of patients with IEM (quartile 4 vs 1; aOR, 3.58; 95% CI, 1.51-8.49), and presence of a biochemical genetics fellowship (aOR, 0.29; 95% CI, 0.14-0.62). CONCLUSIONS: Patients with IEM frequently did not receive minimum laboratory evaluations for catabolic conditions. Measures to improve laboratory use in children with IEM should be undertaken.
Subject(s)
Metabolism, Inborn Errors , Urea Cycle Disorders, Inborn , Child , Emergency Service, Hospital , Humans , Laboratories , Metabolism, Inborn Errors/diagnosis , Odds RatioABSTRACT
3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.
Subject(s)
Abnormalities, Multiple/diagnosis , Amino Acid Metabolism, Inborn Errors/diagnosis , Mutation , Thiolester Hydrolases/deficiency , Abnormalities, Multiple/genetics , Adult , Amino Acid Metabolism, Inborn Errors/genetics , Female , Humans , Infant, Newborn , Phenotype , Thiolester Hydrolases/genetics , Young AdultABSTRACT
Maple syrup urine disease (MSUD) is an inborn error of metabolism that causes elevated leucine in the setting of acute illnesses. We describe an 8-year-old boy with MSUD who developed acute pancreatitis and subsequent leucinosis. This case highlights the complexities of fluid management in patients with MSUD.
Subject(s)
Maple Syrup Urine Disease/complications , Maple Syrup Urine Disease/therapy , Pancreatitis/etiology , Pancreatitis/therapy , Child , Humans , Male , Maple Syrup Urine Disease/diagnosis , Pancreatitis/diagnosisABSTRACT
We describe 2 children with cobalamin G disease, a disorder of vitamin B12 metabolism with normal serum B12 levels. They presented with megaloblastic anemia progressing rapidly to severe thrombotic microangiopathy. In infants presenting with acute thrombotic microangiopathy, cobalamin disorders should be considered early as diagnosis and targeted treatment can be lifesaving.
Subject(s)
Anemia, Megaloblastic/diagnosis , Anemia, Megaloblastic/drug therapy , Disease Progression , Hydroxocobalamin/therapeutic use , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/etiology , Anemia, Megaloblastic/blood , Anemia, Megaloblastic/complications , Blood Chemical Analysis , Blood Transfusion/methods , Child, Preschool , Early Diagnosis , Failure to Thrive , Hematologic Tests , Humans , Infant , Injections, Intramuscular , Male , Prognosis , Risk Assessment , Severity of Illness Index , Treatment Outcome , Vitamin B 12 Deficiency/blood , Vitamin B 12 Deficiency/diagnosisABSTRACT
Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
Subject(s)
Cell Division , Induced Pluripotent Stem Cells , Neural Stem Cells , Neural Stem Cells/metabolism , Neural Stem Cells/cytology , Humans , Animals , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/cytology , Mice , Neurogenesis/genetics , Male , Female , Membrane Proteins/metabolism , Membrane Proteins/genetics , Guanine Nucleotide Exchange Factors/metabolism , Guanine Nucleotide Exchange Factors/genetics , Disease Models, Animal , Cell PolarityABSTRACT
Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
ABSTRACT
BACKGROUND: Evaluations of suspected non-accidental trauma (NAT) often include consultation with genetic and metabolic teams to assess patients for rare genetic conditions that can mimic or exacerbate child abuse. Diagnoses that may be questioned during court proceedings include osteogenesis imperfecta (OI) and glutaric aciduria type 1 (GA1). Currently there are no official society guidelines for the genetic or metabolic workup of suspected NAT. OBJECTIVE: To standardize consult recommendations for suspected NAT through collaboration between the Genetics and Genomics Division and the Child Protection Team (CPT). PARTICIPANTS AND SETTINGS: Children evaluated for suspected NAT at a single pediatric referral center. METHODS: A year of inpatient consult requests for suspected NAT to the genetics division were reviewed. The most common indications for consult were fractures and subdural hematoma. Consult recommendations for similar indications varied between providers. A standard operating procedure (SOP) with specific recommendations for suspected NAT consults for fractures, intracranial hemorrhage, and other indications was created based on expert reviews and other relevant literature. A questionnaire assessing division practice patterns for these consults was distributed both pre (n = 17) and post-introduction of the SOP (n = 11). RESULTS: Adherence to the SOP and impact on suspected NAT consult recommendations were assessed at 18 months after SOP introduction. Consult recommendations were in line with the SOP for 7/11 consults pre-intervention and 6/7 consults post-intervention. Providers were more likely to report feeling extremely or very confident they were using evidence-based medicine for NAT consults post-intervention.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Brain Diseases, Metabolic , Child Abuse , Osteogenesis Imperfecta , Amino Acid Metabolism, Inborn Errors/diagnosis , Brain Diseases, Metabolic/diagnosis , Child , Child Abuse/diagnosis , Diagnosis, Differential , Glutaryl-CoA Dehydrogenase/deficiency , Guidelines as Topic , Humans , Osteogenesis Imperfecta/diagnosis , Referral and ConsultationABSTRACT
Pegvaliase, an injectable form of phenylalanine ammonia lyase, is an enzyme substitution therapy for adults with phenylketonuria (PKU). Experience with pegvaliase during lactation is scarce. Limited evidence suggests that pegvaliase does not pass into breast milk. The case presented here describes the pregnancy and lactation experience of a woman with PKU who was treated with pegvaliase prior to pregnancy, discontinued pegvaliase and was treated with a phenylalanine-restricted diet in preparation for and during pregnancy, and then reinstituted pegvaliase two weeks after giving birth and throughout lactation. No pegvaliase activity was detected in pumped breast milk samples prior to reinstituting pegvaliase, and at doses of 80, 110 and 140 mg/week during lactation. The phenylalanine content of breast milk samples collected during pegvaliase therapy were not significantly different than controls, and the infant has grown and developed normally, indicating that pegvaliase therapy during lactation is safe.
ABSTRACT
SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.
Subject(s)
Genes, Dominant , Genetic Predisposition to Disease , Genetic Variation , Neurodevelopmental Disorders/genetics , Spectrin/genetics , Animals , Genetic Association Studies/methods , Heterozygote , Humans , Mice , Neurodevelopmental Disorders/diagnosis , Phenotype , Spectrin/metabolismABSTRACT
The focus of dietary therapy for long chain fatty acid oxidation disorders (LC-FAODs) is to minimize fatty acid oxidation by avoiding fasting and providing sufficient calories. Dietary therapy involves restriction of long-chain triglycerides (LCT), and provision of medium-chain triglycerides as an alternate energy source. It is well established that the use of breast milk through the first year of a newborn's life has significant health benefits. While very few medical contraindications to breastfeeding exist, feeding an infant with a severe carnitine acylcarnitine translocase (CACT) deficiency typically requires cessation of breastfeeding as approximately 50% of the calories in human milk come from LCT. In this case report, we present the innovative and successful use of skimmed breast milk incorporated into the dietary management of an infant with severe CACT deficiency. Given the poor prognosis for individuals with severe CACT deficiency on standard dietary therapy, the use of skimmed breast milk represents an important measure to try to improve short-term and long-term outcomes. Given the many proven benefits of breast milk, this case illustrates that skimmed breast milk can be combined with appropriate fat sources to provide complete nutrition for children with severe CACT deficiency. After over 12 months on this regimen, this patient has experienced normal growth and development and has had no acute decompensations.
ABSTRACT
We present Boston Children's Hospital's clinic model for pegvaliase therapy in adults with phenylketonuria (PKU) and clinical outcomes in 46 patients over the first 1.5 years of commercial therapy. Approximately 70% (18/26) of patients starting pegvaliase achieved blood phenylalanine (Phe) <360 µmol/L, with an average of a 68 ± 24% decrease in blood Phe from baseline. All patients experienced at least minor side effects, but in most, management of the side effects allowed for treatment to continue.
ABSTRACT
Fabry disease is an X-linked lysosomal storage disorder which often presents with renal, cardiac, gastrointestinal, and nervous system abnormalities. Available enzyme replacement therapies have demonstrated efficacy at significantly reducing elevated biomarkers associated with increased disease activity, while improving the clinical symptoms associated with Fabry disease. In two cases with classical Fabry disease, we demonstrate that the initiation of enzyme replacement therapy prior to the onset of overt clinical disease is well tolerated and effectively reduces elevated biomarkers, mitigating unnecessary organ damage that may occur prior to the onset of clinical manifestations of disease. This proactive approach should be considered as a best-practice management strategy which has the potential to significantly improve health outcomes in patients with classical Fabry patients, particularly in the context of newborn screening for Fabry disease.
ABSTRACT
BACKGROUND: Joubert syndrome (JS) is a rare, autosomal recessively inherited genetic disorder characterized morphologically by unique developmental malformations of the cerebellum and brainstem (the molar tooth sign), and clinically by impaired motor functions and intellectual disability. Patients with JS often face multiple cognitive challenges, but the neuropsychological profile of this condition has not been well characterized. METHODS: We performed comprehensive neurological and neuropsychological evaluations in three adult brothers with JS, ages 32, 27, and 25 years. RESULTS: They all exhibited impaired motor control, global developmental delay most evident in executive function, affect regulation, and social skill set, and similar patterns of neuropsychiatric symptoms. CONCLUSIONS: These findings provide new insights into the intellectual and neurobehavioral phenotype of JS, which we regard as a developmental form of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). These observations have direct clinical relevance for the diagnosis and care of patients with JS, and they help further the understanding of the multiple manifestations of atypical cerebrocerebellar development.