-
Clinical Pharmacokinetics May 2024Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and...
BACKGROUND AND OBJECTIVE
Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.
METHODS
A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen.
RESULTS
A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population.
CONCLUSIONS
The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers.
CLINICAL TRIAL REGISTRATION
NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.
Topics: Humans; Achondroplasia; Child; Adolescent; Models, Biological; Female; Child, Preschool; Male; Body Weight; Infant; Natriuretic Peptide, C-Type; Dose-Response Relationship, Drug
PubMed: 38649657
DOI: 10.1007/s40262-024-01371-6 -
Biomedica : Revista Del Instituto... Mar 2024Introduction. The first neonatal screening program in Colombia – PREGEN – was set up in the medical private sector of Bogotá in 1988. We report the results from...
Introduction. The first neonatal screening program in Colombia – PREGEN – was set up in the medical private sector of Bogotá in 1988. We report the results from recent years that, given the scarcity of similar information in our country, may help estimate the frequency of the evaluated neonatal disorders and which ones should be included in the neonatal screening programs in our country. Objective. To describe the results of PREGEN´s newborn screening program between 2006 and 2019. Materials and methods. We analyzed databases and other informative documents preserved in PREGEN from the 2006-2019 period. Results. One in every 164 newborns screened in our program had an abnormal hemoglobin variant, and one in every 194 carried some hemoglobin S variant. Glucose-6- phosphate dehydrogenase deficiency and congenital hypothyroidism are next as the more common disorders. Conclusions. Abnormal hemoglobin causes the most frequent monogenic disorder in the world. Glucose-6-phosphate dehydrogenase deficiency is the most common enzymopathy affecting nearly 400 million individuals worldwide. Since both disorders are more common in people of African descent and confer some resistance to malaria, we believe that screening for both disorders may be more relevant in the areas with African ancestry in our country.
Topics: Colombia; Neonatal Screening; Humans; Infant, Newborn; Glucosephosphate Dehydrogenase Deficiency; Private Sector; Congenital Hypothyroidism; Anemia, Sickle Cell; Hemoglobinopathies
PubMed: 38648350
DOI: 10.7705/biomedica.6911 -
Horticulture Research Apr 2024A mutant with multiple defects in growth and development has been identified and characterized. The mutant displayed a dwarf phenotype with dark green and shrinking...
A mutant with multiple defects in growth and development has been identified and characterized. The mutant displayed a dwarf phenotype with dark green and shrinking leaves, shortened internodes and petioles, shorter but thicker roots and greater root biomass, and reduced fertility. The causal mutation of the phenotype was found to disrupt gene , the squash orthologue of the brassinosteroid (BR) biosynthesis gene , encoding for 7-dehydrocholesterol reductase. A single nucleotide transition (G > A) causes a splicing defect in intron 6 that leads to a premature stop codon and a truncated CpDWF5 protein. The mutation co-segregated with the dwarf phenotype in a large BCS segregating population. The reduced expression of and brassinolide (BL) content in most mutant organs, and partial rescue of the mutant phenotype by exogenous application of BL, showed that the primary cause of the dwarfism in is a BR deficiency. The results showed that in , is not only a positive growth regulator of different plant organs but also a negative regulator of salt tolerance. During germination and the early stages of seedling development, the dwarf mutant was less affected by salt stress than the wild type, concomitantly with a greater upregulation of genes associated with salt tolerance, including those involved in abscisic acid (ABA) biosynthesis, ABA and Ca signaling, and those coding for cation exchangers and transporters.
PubMed: 38645681
DOI: 10.1093/hr/uhae050 -
BMC Medical Genomics Apr 2024NSUN2-intellectual disability syndrome, also known as intellectual disability type 5 (MRT5), is an autosomal recessive disorder that is characterized by intellectual...
NSUN2-intellectual disability syndrome, also known as intellectual disability type 5 (MRT5), is an autosomal recessive disorder that is characterized by intellectual disability (ID), postnatal growth retardation, dysmorphic facies, microcephaly, short stature, developmental delay, language impairment and other congenital abnormalities. The disease is caused by mutations in the NSUN2 gene, which encodes a tRNA cytosine methyltransferase that has an important role in spindle assembly during mitosis and chromosome segregation. In this study, we recruited a family that had two individuals with ID. Whole exome sequencing was performed to identify a homozygous frameshift variant (c.1171_1175delACCAT(p.Thr391fs*18*)) in NSUN2 (NM_017755.5) in the proband. The varint was confirmed as segregating in his affected brother and his parents by Sanger sequencing. The individuals that we described showed a similar dysmorphology profile to that associated with MRT5. To analyze the correlations between genotypes of NSUN2 and phenotypes of individuals with ID, we examined 17 variants and the associated phenotypes from 32 ID individuals in current and previous studies. We concluded that mutations in NSUN2 cause a wide range of phenotypic defects. Although some clinical manifestations were highly variable, the core phenotypes associated with NSUN2 mutations were dysmorphic facies, microcephaly, short stature, ID, growth restriction, language impairment, hypotonia and delayed puberty. Our study expands the genetic spectrum of NSUN2 mutations and helps to further define the genotype-phenotype correlations in MRT5.
Topics: Male; Humans; Intellectual Disability; Microcephaly; Facies; Mutation; Phenotype; Nervous System Malformations; Dwarfism; Language Development Disorders; China; Pedigree; Methyltransferases
PubMed: 38643142
DOI: 10.1186/s12920-024-01883-x -
DNA Repair Jun 2024Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer's Disease is the most widespread and also most... (Review)
Review
Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer's Disease is the most widespread and also most acknowledged form of dementia today. Together with Parkinson's Disease they account for over 90 % cases of neurodegenerative disorders caused by proteopathies. Far less known are the neurodegenerative pathologies in DNA repair deficiency syndromes. Such diseases like Cockayne - or Werner Syndrome are described as progeroid syndromes - diseases that cause the premature ageing of the affected persons, and there are clear implications of such diseases in neurologic dysfunction and degeneration. In this review, we aim to draw the attention on commonalities between proteopathy-associated neurodegeneration and neurodegeneration caused by DNA repair defects and discuss how mitochondria are implicated in the development of both disorder classes. Furthermore, we highlight how nematodes are a valuable and indispensable model organism to study conserved neurodegenerative processes in a fast-forward manner.
Topics: Humans; Animals; Neurodegenerative Diseases; DNA Repair; Mitochondria; Caenorhabditis elegans; DNA Repair-Deficiency Disorders; Cockayne Syndrome
PubMed: 38640601
DOI: 10.1016/j.dnarep.2024.103679 -
Hormones and Behavior Jun 2024Thyroid hormones are crucial for brain development and their deficiency during fetal and postnatal periods can lead to mood and cognitive disorders. We aimed to examine...
Thyroid hormones are crucial for brain development and their deficiency during fetal and postnatal periods can lead to mood and cognitive disorders. We aimed to examine the consequences of thyroid hormone deficiency on anxiety-related behaviors and protein expression of hippocampal glutamate transporters in congenital hypothyroid male offspring rats. Possible beneficial effects of treadmill exercise have also been examined. Congenital hypothyroidism was induced by adding propylthiouracil (PTU) to drinking water of pregnant Wistar rats from gestational day 6 until the end of the weaning period (postnatal day 28). Next, following 4 weeks of treadmill exercise (5 days per week), anxiety-related behaviors were examined using elevated plus maze (EPM) and light/dark box tests. Thereafter, protein expression of astrocytic (GLAST and GLT-1) and neuronal (EAAC1) glutamate transporters were measured in the hippocampus by immunoblotting. Hypothyroid rats showed decreased anxiety-like behavior, as measured by longer time spent in the open arms of the EPM and in the light area of the light/dark box, compared to control rats. Hypothyroid rats had significantly higher GLAST and GLT-1 and lower EAAC1 protein levels in the hippocampus than did the euthyroid rats. Following exercise, anxiety levels decreased in the euthyroid group while protein expression of EAAC1 increased and returned to normal levels in the hypothyroid group. Our findings indicate that thyroid hormone deficiency was associated with alterations in protein expression of glutamate transporters in the hippocampus. Up-regulation of hippocampal GLAST and GLT-1 could be at least one of the mechanisms associated with the anxiolytic effects of congenital hypothyroidism.
Topics: Animals; Male; Hippocampus; Rats, Wistar; Anxiety; Rats; Female; Congenital Hypothyroidism; Pregnancy; Excitatory Amino Acid Transporter 2; Thyroid Hormones; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 3; Behavior, Animal; Propylthiouracil; Amino Acid Transport System X-AG; Prenatal Exposure Delayed Effects
PubMed: 38636205
DOI: 10.1016/j.yhbeh.2024.105548 -
Virology Journal Apr 2024Viruses have notable effects on agroecosystems, wherein they can adversely affect plant health and cause problems (e.g., increased biosecurity risks and economic...
BACKGROUND
Viruses have notable effects on agroecosystems, wherein they can adversely affect plant health and cause problems (e.g., increased biosecurity risks and economic losses). However, our knowledge of their diversity and interactions with specific host plants in ecosystems remains limited. To enhance our understanding of the roles that viruses play in agroecosystems, comprehensive analyses of the viromes of a wide range of plants are essential. High-throughput sequencing (HTS) techniques are useful for conducting impartial and unbiased investigations of plant viromes, ultimately forming a basis for generating further biological and ecological insights. This study was conducted to thoroughly characterize the viral community dynamics in individual plants.
RESULTS
An HTS-based virome analysis in conjunction with proximity sampling and a tripartite network analysis were performed to investigate the viral diversity in chunkung (Cnidium officinale) plants. We identified 61 distinct chunkung plant-associated viruses (27 DNA and 34 RNA viruses) from 21 known genera and 6 unclassified genera in 14 known viral families. Notably, 12 persistent viruses (7 DNA and 5 RNA viruses) were exclusive to dwarfed chunkung plants. The detection of viruses from the families Partitiviridae, Picobirnaviridae, and Spinareoviridae only in the dwarfed plants suggested that they may contribute to the observed dwarfism. The co-infection of chunkung by multiple viruses is indicative of a dynamic and interactive viral ecosystem with significant sequence variability and evidence of recombination.
CONCLUSIONS
We revealed the viral community involved in chunkung. Our findings suggest that chunkung serves as a significant reservoir for a variety of plant viruses. Moreover, the co-infection rate of individual plants was unexpectedly high. Future research will need to elucidate the mechanisms enabling several dozen viruses to co-exist in chunkung. Nevertheless, the important insights into the chunkung virome generated in this study may be relevant to developing effective plant viral disease management and control strategies.
Topics: Humans; Virome; Ecosystem; Cnidium; RNA, Viral; Coinfection; RNA Viruses; High-Throughput Nucleotide Sequencing; Plant Viruses; Dwarfism; DNA; Phylogeny
PubMed: 38622686
DOI: 10.1186/s12985-024-02361-7 -
Plant Cell Reports Apr 2024The study on the GmDWF1-deficient mutant dwf1 showed that GmDWF1 plays a crucial role in determining soybean plant height and yield by influencing the biosynthesis of...
The study on the GmDWF1-deficient mutant dwf1 showed that GmDWF1 plays a crucial role in determining soybean plant height and yield by influencing the biosynthesis of brassinosteroids. Soybean has not adopted the Green Revolution, such as reduced height for increased planting density, which have proven beneficial for cereal crops. Our research identified the soybean genes GmDWF1a and GmDWF1b, homologous to Arabidopsis AtDWF1, and found that they are widely expressed, especially in leaves, and linked to the cellular transport system, predominantly within the endoplasmic reticulum and intracellular vesicles. These genes are essential for the synthesis of brassinosteroids (BR). Single mutants of GmDWF1a and GmDWF1b, as well as double mutants of both genes generated through CRISPR/Cas9 genome editing, exhibit a dwarf phenotype. The single-gene mutant exhibits moderate dwarfism, while the double mutant shows more pronounced dwarfism. Despite the reduced stature, all types of mutants preserve their node count. Notably, field tests have shown that the single GmDWF1a mutant produced significantly more pods than wild-type plants. Spraying exogenous brassinolide (BL) can compensate for the loss in plant height induced by the decrease in endogenous BRs. Comparing transcriptome analyses of the GmDWF1a mutant and wild-type plants revealed a significant impact on the expression of many genes that influence soybean growth. Identifying the GmDWF1a and GmDWF1b genes could aid in the development of compact, densely planted soybean varieties, potentially boosting productivity.
Topics: Brassinosteroids; Glycine max; CRISPR-Cas Systems; Mutation; Arabidopsis; Gene Editing; Gene Expression Regulation, Plant
PubMed: 38622229
DOI: 10.1007/s00299-024-03204-z -
Molecular Genetics & Genomic Medicine Apr 2024To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature. (Review)
Review
OBJECTIVE
To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature.
METHODS
Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed.
RESULTS
Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001).
CONCLUSION
Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.
Topics: Adult; Child; Humans; Aggrecans; Dwarfism; Genotype; Heterozygote; Homozygote; Human Growth Hormone; Patients; Phenotype
PubMed: 38613222
DOI: 10.1002/mgg3.2439