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The Journal of Allergy and Clinical... Mar 2020We describe the first case of MAN2B2 deficiency in a patient with immune dysregulation, developmental delay, and stroke. Altered mannosylation profile was restored in...
We describe the first case of MAN2B2 deficiency in a patient with immune dysregulation, developmental delay, and stroke. Altered mannosylation profile was restored in patient cells upon transduction of wild-type MAN2B2.
Topics: Child; Female; Glycosylation; Humans; Immunologic Deficiency Syndromes; Mannosidase Deficiency Diseases; alpha-Mannosidase
PubMed: 31775018
DOI: 10.1016/j.jaci.2019.11.016 -
JIMD Reports Nov 2019Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene . Patients have distinct...
Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene . Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha-mannosidosis (ages 8-59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha-mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.
PubMed: 31741826
DOI: 10.1002/jmd2.12073 -
Italian Journal of Pediatrics Sep 2019Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to...
BACKGROUND
Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors.
CASE REPORT
we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 μg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred.
CONCLUSION
intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.
Topics: Administration, Intranasal; Anesthetics, Dissociative; Child, Preschool; Dexmedetomidine; Humans; Hypnotics and Sedatives; Infusions, Intravenous; Ketamine; Magnetic Resonance Imaging; Male; Spinal Puncture; alpha-Mannosidosis
PubMed: 31481093
DOI: 10.1186/s13052-019-0711-1 -
Frontiers in Immunology 2019Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated...
Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated by three genome-wide association studies. However, genes from such suggestive loci may also provide crucial information to unravel genetic mechanisms that determine sepsis heterogeneity. Therefore, in this study, we made use of integrative approaches to prioritize genes and pathways affected by sepsis associated genetic variants. By integrating expression quantitative trait loci (eQTL) results from the largest whole-blood eQTL database, cytokine QTLs from pathogen-stimulated peripheral blood mononuclear cells (PBMCs), publicly available blood transcriptome data from pneumoniae-derived sepsis patients, and transcriptome data from pathogen-stimulated PBMCs, we identified 55 potential genes affected by 39 independent loci. By performing pathway enrichment analysis at these loci we found enrichment of genes for adherences-junction pathway. Finally, we investigated the functional role of the only one GWAS significant SNP rs4957796 on sepsis survival in altering transcription factor binding affinity in monocytes and endothelial cells. We also found that transient deficiency of and affect endothelial response to stimulation, indicating that both and could be the causal genes at this locus. Taken together, our study suggests that in addition to immune pathways, genetic variants may also affect non-immune related pathways.
Topics: Cells, Cultured; Endothelial Cells; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Leukocytes, Mononuclear; Polymorphism, Single Nucleotide; Protein-Tyrosine Kinases; Quantitative Trait Loci; Sepsis; Signal Transduction; THP-1 Cells; Transcriptome; alpha-Mannosidase
PubMed: 31475010
DOI: 10.3389/fimmu.2019.01949 -
Molecular Genetics and Metabolism 2019Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle....
Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle. Here we report the clinicopathological, metabolic, and molecular genetic features of canine beta-mannosidase (MANBA, EC 3.2.1.25) deficiency. A 1-year-old male mix-breed dog from St. Kitts was presented with progressive stumbling, weakness, and regurgitation. Vacuolated lymphocytes were observed on the blood film. Postmortem findings included marked enlargement of nerves, megaesophagus, and internal hydrocephalus. Vacuolated macrophages, neurons, and secretory epithelial cells suggested an oligosaccharide storage disease. Plasma concentration of the β-mannosidosis specific oligosaccharide was approximately 75 fold that of controls. The plasma beta-mannosidase activity was severely reduced to ~5% of controls; five other lysosomal acid hydrolase activities were increased or within their normal reference interval. Genomic sequencing of this dog's MANBA gene identified a homozygous exonic five bp tandem duplication in the penultimate exon of the MANBA gene (c.2377_2381dupTATCA) which results in a reading frame shift, altering the subsequent amino acid sequence and creating a premature stop codon. The truncated beta-mannosidase enzyme is expected to be dysfunctional. This enzyme deficiency causes the accumulation of un-degraded oligosaccharides in cells, which affect the myelination of the peripheral and central nervous systems. This insertion was not encountered in 121 and 80-screened samples from dogs on St. Kitts (all were homozygous for wild-type) and Philadelphia region (wild-type), respectively. In conclusion, canine β-mannosidosis has similar clinicopathological features with some human patients, but milder signs than in ruminants and more severe than in knockout mice. Hence, dogs with β-mannosidosis could become a valuable disease model for the human disease.
Topics: Animals; Codon, Nonsense; DNA Mutational Analysis; Dog Diseases; Dogs; Exons; Male; Mutation; beta-Mannosidase; beta-Mannosidosis
PubMed: 31439511
DOI: 10.1016/j.ymgme.2019.08.002 -
Molecular Genetics and Metabolism Jul 2019Multiplex tandem mass spectrometry (MS/MS)-based enzyme activity assays for newborn screening (NBS) and diagnosis of lysosomal storage diseases (LSDs) in newborns, using...
Multiplex tandem mass spectrometry (MS/MS)-based enzyme activity assays for newborn screening (NBS) and diagnosis of lysosomal storage diseases (LSDs) in newborns, using dried blood spots (DBS) on newborn screening cards, have garnered much attention due to its sensitivity, high precision, and the capability to screen for an unprecedented number of diseases in a single assay. Herein we report the development of MS/MS-based enzyme assays for the diagnosis of α-mannosidosis and fucosidosis. These new protocols are able to distinguish untreated patients from random newborns, carriers and a post-bone marrow transplant patient. We have successfully multiplexed the α-mannosidosis assay with a multiplex MS/MS assay for the screening and diagnosis of other LSDs, namely Fabry, Pompe, MPS I, Gaucher, Niemann-Pick-A/B, and Krabbe diseases. Additionally, we also multiplexed the fucosidosis NBS assay with a 5-plex assay that tests for MPS-II, MPS-IIIB, MPS-IVA, MPS-VI and MPS-VII.
Topics: Enzyme Assays; Fucosidosis; Humans; Infant, Newborn; Lysosomal Storage Diseases; Neonatal Screening; Tandem Mass Spectrometry; alpha-Mannosidosis
PubMed: 31235216
DOI: 10.1016/j.ymgme.2019.05.016 -
Molecular Genetics and Metabolism... Sep 2019Alpha-mannosidosis is an ultra-rare lysosomal storage disorder resulting from the deficient activity of lysosomal alpha-mannosidase. Alpha-mannosidosis presents as a...
INTRODUCTION
Alpha-mannosidosis is an ultra-rare lysosomal storage disorder resulting from the deficient activity of lysosomal alpha-mannosidase. Alpha-mannosidosis presents as a highly heterogenous condition with large variations in symptom severity and disease progression rates. Quantitative and qualitative data for alpha-mannosidosis patients and their caregivers provide important insights into their daily experiences.
METHODS
A survey of nine alpha-mannosidosis patients was carried out in the UK between August 2017 and January 2018. Patient demographics, health-related quality of life (HRQoL), and qualitative data from patients and carers relating to clinical characteristics and impact of the disease and treatment were analysed.
RESULTS
At the time of survey completion, patient age ranged from 7 to 37 years. Five patients were described as 'walking unassisted', one as 'walking with assistance', one as 'wheelchair-dependent', and two as 'severely immobile'. In addition to best supportive care, three patients had received haematopoietic stem cell transplantation (HSCT) and one had received velmanase alfa enzyme replacement therapy (ERT). Patient HRQoL results for the EQ-5D-5 L questionnaire and the Health Utilities Index-3 showed that patients with more severe ambulatory health states reported lower utility values than patients who were more mobile. Patients who received HSCT or ERT experienced improved HRQoL. Carer HRQoL results for the Hospital Anxiety and Depression Scale and Caregiver Strain Index demonstrated that carers experience high levels of stress and anxiety from their caregiving responsibilities.
CONCLUSIONS
This survey confirmed the heterogeneity of alpha-mannosidosis and the large impact of the disease and treatment on patients, carers, and families. Early diagnosis and access to treatment offers the best chance of slowing the disease progression and may provide some relief to patients and carers.
PubMed: 31198684
DOI: 10.1016/j.ymgmr.2019.100480 -
Journal of Veterinary Diagnostic... Jul 2019is a small subshrub that is distributed throughout Brazil and is responsible for lysosomal storage disease and occasional reproductive problems in cattle, goats,...
is a small subshrub that is distributed throughout Brazil and is responsible for lysosomal storage disease and occasional reproductive problems in cattle, goats, equids, sheep, and deer. We describe herein the clinical, epidemiologic, and pathologic features of hydrallantois in 3 cows naturally poisoned by in Rio Grande do Sul State, Brazil. Clinically, all cows had marked abdominal distension and mild ataxia. After natural death or euthanasia, autopsies revealed that the abdominal distension in all 3 cases was caused by severe enlargement of the uterus, which contained 100-120 L of translucent fluid within the allantois, in addition to adventitial placentation. Microscopic evaluation of the placenta revealed marked diffuse edema, sometimes with a myxomatous appearance. Neurons in the cerebellum and obex were swollen, with mild-to-moderate cytoplasmic granular vacuolation. Histochemical examination with lectins ConA, WGA, and sWGA revealed mild-to-marked staining in the cytoplasm of neurons of the cerebellum and medulla at the level of the obex, indicating the occurrence of α-mannosidosis.
Topics: Allantois; Animals; Brain Diseases; Brazil; Cattle; Cattle Diseases; Female; Malvaceae; Plant Poisoning
PubMed: 31122163
DOI: 10.1177/1040638719850610 -
Molecular Genetics & Genomic Medicine Jul 2019Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency...
BACKGROUND
Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available.
METHODS
We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease.
RESULTS
We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers.
CONCLUSION
Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge.
Topics: Brain; Child, Preschool; Chromatography, High Pressure Liquid; Cord Blood Stem Cell Transplantation; Dried Blood Spot Testing; Humans; Intellectual Disability; Leukocytes; Magnetic Resonance Imaging; Male; Tandem Mass Spectrometry; beta-Mannosidase; beta-Mannosidosis
PubMed: 31115173
DOI: 10.1002/mgg3.712 -
Blood Cell Therapy May 2019Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMDs). We examined the...
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMDs). We examined the overall survival (OS) and engrafted survival (ES) of children with IMDs, who received first HCT at Royal Manchester Children's hospital from 1985 to 2016. A total of 137 children with IMDs were included in this analysis (historical cohort [1985-2006], n=65; current cohort [2007-2016], n=72). Primary diagnoses included mucopolysaccharidoses (81%), X-linked adrenoleukodystrophy (6%), metachromatic leukodystrophy (4%), mannosidosis (3%), Wolman disease (2%), and other conditions (4%). The five-year OS has increased from 65% (95% confidence interval [CI], 52%-76%) in the historical cohort to 91% (95% CI, 81%-96%) in the current cohort (<0.001). Moreover, the five-year ES, which was 64% (95 CI%, 56%-72%) for the entire cohort, has doubled from 41% (95% CI, 29%-53%) in the historical cohort to 85% (95% CI, 75%-92%) in the current cohort (<0.001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (<0.001). In patients who received a second transplant, 13 out of 20 patients (65%) in the historical cohort and all four in the current cohort were alive and engrafted. Of 82 survivors followed-up at Manchester, 80% and 20% had full and mixed chimerism, respectively. Although this study was restricted to a single center, our findings show that HCT is an increasingly safe procedure and provides long-lasting endogenous enzyme replacement therapy for children with IMDs in the modern era of HCT.
PubMed: 37885827
DOI: 10.31547/bct-2018-012