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Pediatric Pulmonology Apr 2023
Topics: Humans; beta-Mannosidosis; alpha-Mannosidosis; Hemorrhage
PubMed: 36610029
DOI: 10.1002/ppul.26310 -
The Journal of Veterinary Medical... Feb 2023Locoweeds, a type of poisonous weedare, are widely distributed throughout the world and have a significant impact on the development of herbivore animal husbandry....
Locoweeds, a type of poisonous weedare, are widely distributed throughout the world and have a significant impact on the development of herbivore animal husbandry. Swainsonine (SW), the main toxin in locoweeds, can competitively inhibit lysosomes α-mannosidase (LAM) in animal cells, resulting in α-mannosidosis. However, the specifics of the interaction between SW and LAM are still unclear. Here, we used molecular docking to predicte the interaction points between SW and LAM, built mutated lysosomes α-mannosidase (LAM), and analyzed its biochemical properties changes in presumption points. The Trp at the 28th position and the Tyr at the 599th position of the LAM were interaction point candidates, and the above two amino acids in Capra hircus LAM (chLAM), were successfully mutated to glycine by constructing recombinant yeast GS115/PIC9K- LAM. The results showed that the sensitivity of Capra hircus LAM (chLAM), to SW decreased significantly compared with wild-type LAM, the enzyme activity of LAM decreased approximately threefold, the optimum temperature of LAM decreased from 55°C to 50°C, the optimum pH value increased from 4.5 to 5.0, and the effects of Mn, Fe, Al, Co, Cr, and ethylenediaminetetraacetic acid (EDTA) on LAM enzyme activity before and after point mutation changed significantly. These findings help us better understanding the molecular mechanism of the interaction mechanism between SW and chLAM, and provide new reference for solving locoweeds poisoning.
Topics: Animals; alpha-Mannosidase; Molecular Docking Simulation; Lysosomes; Swainsonine; Goats; Mannosidases
PubMed: 36596563
DOI: 10.1292/jvms.22-0222 -
Orphanet Journal of Rare Diseases Jul 2022Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include... (Review)
Review
BACKGROUND
Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include skeletal dysmorphism, mental impairment, hearing loss and recurrent infections. The severe type of the disease leads to early childhood death, while patients with milder forms can live into adulthood. There are no mortality studies to date. This study aimed to investigate the age at death and the causes of death of patients with alpha-mannosidosis who had not received disease-modifying treatment.
METHODS
Clinicians and LSD patient organisations (POs) from 33 countries were invited to complete a questionnaire between April-May 2021. Cause of death and age at death was available for 15 patients. A literature review identified seven deceased patients that met the inclusion criteria.
RESULTS
Median age at death for patients reported by clinicians/POs was 45 years (mean 40.3 ± 13.2, range 18-56, n = 15); 53% were female. One death occurred during the patient's second decade of life, and 14 out of 15 deaths (93.3%) during or after the patients' third decade, including four (26.7%) during their sixth decade. Median age at death for patients identified from the literature was 4.3 years (mean 15.7 ± 17.0, range 2.2-41, n = 7); two were female. Four of the seven patients (57.1%) died within the first decade of life. Seven of 15 deaths (46.7%) reported by clinicians/POs were recorded as pneumonia and three (20.0%) as cancer. Other causes of death included acute renal failure due to sepsis after intestinal perforation, decrease of red blood cells of unknown origin, kidney failure with systemic lupus erythematosus, aortic valve insufficiency leading to heart failure, and dehydration due to catatonia. Three out of seven causes of death (42.9%) reported in the literature were associated with septicaemia, two (28.6%) with respiratory failure and one to pneumonia following aspiration.
CONCLUSIONS
This study suggests that pneumonia has been the primary cause of death during recent decades in untreated patients with alpha-mannosidosis, followed by cancer. Determining the causes of mortality and life expectancy in these patients is crucial to further improve our understanding of the natural history of alpha-mannosidosis.
Topics: Adult; Child, Preschool; Female; Humans; Male; Middle Aged; alpha-Mannosidase; alpha-Mannosidosis; Hearing Loss; Intellectual Disability
PubMed: 35871018
DOI: 10.1186/s13023-022-02422-6 -
Molecular Genetics and Metabolism... Mar 2022Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study...
INTRODUCTION
Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study was to present the long-term follow-up of 12 Polish patients with AM, evaluate the clinical, biochemical, and molecular findings and progression of the disease.
MATERIAL AND METHODS
The article presents a long-term (over 30 years) observational, retrospective, single-center study of patients with AM.
RESULTS
The hearing loss, as one of the first symptoms, was detected in childhood (mean age of 2 years and 6 months) in 10 patients. The other symptoms include: recurrent infections (all patients), inguinal hernias (6 patients), craniosynostosis (1 patient). The mean age at AM diagnosis was 6 years while median was 4 years (age range: 1 year and 8 months - 12 years). The most commonly identified variant in the 1 gene was c.2245C > T, p.(Arg749Trp). The mean time of follow-up in our study was approximately 14 years (range: 1 year - 26 years). Following birth, children with AM grow slowly, finally reaching the 3rd percentile (or values below the 3rd percentile). Hearing loss was not progressive while a gradual exacerbation of intellectual disability with no developmental regression was observed in all patients. Ataxia was diagnosed in 6 patients in the second decade of life (age range 15-20 years).
CONCLUSIONS
Our study revealed the sensorineural hearing loss as one of the first noted symptom in AM which was congenital and non-progressive during the natural course of disease. A detailed anthropometric phenotype of AM patients was provided with observation of the growth decline during the long-term follow-up. Our study confirmed the existence of two distinguished clinical phenotypes of AM (mild and moderate), and also the lack of clear genotype-phenotype correlation.
PubMed: 35242565
DOI: 10.1016/j.ymgmr.2021.100826 -
Anais Da Academia Brasileira de Ciencias 2021It is well known that several of the swainsonine-containing plant species found widespread around the world have a negative economic impact in each country. In... (Review)
Review
It is well known that several of the swainsonine-containing plant species found widespread around the world have a negative economic impact in each country. In Argentina, most of the information on the poisonous plant species that produce α-mannosidosis is published in Spanish and thus not available to most English-speaking researchers interested in toxic plants. Therefore, the aim of this review is to summarize the information about swainsonine-containing plants in Argentina, which are extensively distributed throughout different ecoregions of the country. To date, five species from three genera have been shown to induce α-mannosidosis in livestock in Argentina: Ipomoea carnea subsp. fistulosa, Ipomoea hieronymi subsp. calchaquina (Convolvulaceae), Astragalus garbancillo, Astragalus pehuenches (Fabaceae), and Sida rodrigoi (Malvaceae). These species contain the indolizidine alkaloid swainsonine, which inhibits the lysosomal enzyme α-mannosidase and consequently affects glycoprotein metabolism, resulting in partially metabolized sugars. The prolonged consumption of these poisonous plants produces progressive weight loss and clinical signs related to a nervous disorder, characterized by tremors of head and neck, abnormalities of gait, difficulty in standing, ataxia and wide-based stance. Histological lesions are mainly characterized by vacuolation of different cells, especially neurons of the central nervous system. The main animal model used to study α-mannosidosis is the guinea pig because, when experimentally poisoned, it exhibits many of the characteristics of naturally intoxicated livestock.
Topics: Animals; Argentina; Guinea Pigs; Plant Poisoning; Plants, Toxic; Ruminants; alpha-Mannosidosis
PubMed: 34787167
DOI: 10.1590/0001-3765202120191496 -
PloS One 2021Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM...
Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.
Topics: Audiometry; Base Sequence; Carrier Proteins; Cognitive Dysfunction; Consanguinity; Family; Female; Genetic Predisposition to Disease; Geography; Humans; Male; Membrane Transport Proteins; Mutation; Pedigree; Phenotype; Tunisia; Exome Sequencing; alpha-Mannosidosis
PubMed: 34614013
DOI: 10.1371/journal.pone.0258202 -
The Canadian Journal of Neurological... Sep 2022
Topics: Contrast Media; Humans; Magnetic Resonance Imaging; Thalamus; alpha-Mannosidosis
PubMed: 34486965
DOI: 10.1017/cjn.2021.208 -
Journal of Pediatric Neurosciences 2021Alpha-mannosidosis is a lysosomal storage disorder caused by mutations in gene. A 7-year-old girl child, born of a consanguineous marriage, presented with developmental...
Alpha-mannosidosis is a lysosomal storage disorder caused by mutations in gene. A 7-year-old girl child, born of a consanguineous marriage, presented with developmental delay, seizures, and hearing impairment. On examination, she had coarse features without hepatosplenomegaly. On investigations, low levels of the enzyme alpha-mannosidase level were observed. Targeted next-generation sequencing revealed a novel pathogenic variant p.Trp469Ter on exon 11 of gene.
PubMed: 36160623
DOI: 10.4103/jpn.JPN_71_20 -
New Zealand Veterinary Journal Sep 2021Over the last 50 years, there have been major advances in knowledge and technology regarding genetic diseases, and the subsequent ability to control them in a... (Review)
Review
Over the last 50 years, there have been major advances in knowledge and technology regarding genetic diseases, and the subsequent ability to control them in a cost-effective manner. This review traces these advances through research into genetic diseases of animals at Massey University (Palmerston North, NZ), and briefly discusses the disorders investigated during that time, with additional detail for disorders of major importance such as bovine α-mannosidosis, ovine ceroid-lipofuscinosis, canine mucopolysaccharidosis IIIA and feline hyperchylomicronaemia. The overall research has made a significant contribution to veterinary medicine, has provided new biological knowledge and advanced our understanding of similar disorders in human patients, including testing various specific therapies prior to human clinical trials.
Topics: Animals; Cat Diseases; Cats; Cattle; Cattle Diseases; Dog Diseases; Dogs; Humans; Neuronal Ceroid-Lipofuscinoses; Sheep; Sheep Diseases; Universities
PubMed: 33969809
DOI: 10.1080/00480169.2021.1928564 -
Diagnostics (Basel, Switzerland) Feb 2021Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26...
Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I ( < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann-Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.
PubMed: 33669444
DOI: 10.3390/diagnostics11020320