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Cells Jun 2020The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis,... (Review)
Review
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
Topics: Animals; Enzyme Replacement Therapy; Glycoproteins; Hematopoietic Stem Cell Transplantation; Humans; Lysosomal Storage Diseases
PubMed: 32517081
DOI: 10.3390/cells9061411 -
The FEBS Journal Apr 2019β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated...
β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated proteins, and plays an important role in the polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β-mannosidase, can lead to the lysosomal storage disease β-mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β-mannosidase in both the apo- and mannose-bound forms. The structure is similar to previously determined β-mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other ligand-bound β-mannosidases from bacterial and fungal sources where bound sugars were in a boat-like conformation, we find the mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of therapeutics for treating diseases caused by β-mannosidase deficiency. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 6DDT and 6DDU.
Topics: Amino Acid Sequence; Animals; Catalytic Domain; Glycosylation; Humans; Mannose; Mice; Mutation; Nystagmus, Pathologic; Phenotype; Protein Conformation; Sequence Homology; Substrate Specificity; beta-Mannosidase; beta-Mannosidosis
PubMed: 30552791
DOI: 10.1111/febs.14731 -
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 -
SAGE Open Medical Case Reports 2021β-mannosidosis is a rare autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of β-mannosidase. Clinical presentation...
β-mannosidosis is a rare autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of β-mannosidase. Clinical presentation includes intellectual deficits, hearing loss, and recurrent respiratory infections. This report describes the dental treatment and follow-up dental care of a child with β-mannosidosis. The patient presented to the dental clinic at the age of 6 years with a localized swelling of his lower posterior teeth. Sickle cell disease and physical and mental developmental delays were noted. Clinical examination revealed a flattened nasal bridge, large head, short neck, open bite, gingival overgrowth, macroglossia, enlarged pulp chambers, and poor oral hygiene. Surgical treatment under general anesthesia included extractions, pulp therapy, and restorations. Four years later, the child returned with generalized gingival inflammation and new carious lesions. Periodontal and restorative treatment was provided, and a preventive dental regimen was established. Mannosidosis cases require complex dental procedures, consultations, and prompt follow-up.
PubMed: 34925842
DOI: 10.1177/2050313X211065796 -
Orphanet Journal of Rare Diseases Aug 2020The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose...
Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant.
BACKGROUND
The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelic MANBA variants have been described worldwide.
RESULTS
We now report on further 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA. MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2, regarded as the most frequent variant causing deafness in Roma populations.
CONLCUSION
Beta-mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.
Topics: Czech Republic; Deafness; Ethnicity; Hearing Loss; Humans; Minority Groups; Roma; Slovakia; beta-Mannosidosis
PubMed: 32847582
DOI: 10.1186/s13023-020-01508-3 -
Journal of Pediatric Neurosciences 2021β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the gene. Two Indian...
β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the gene. Two Indian siblings born out of a third-degree consanguineous marriage presented during late infancy with global developmental delay. On examination, both the siblings had hypotonia; hepatosplenomegaly was present in the first sibling whereas it was absent in the second sibling. Fundus evaluation, hearing assessment, and skeletal survey were normal in both siblings. Enzyme assay showed the absence of the β-mannosidase enzyme. Next-generation sequencing showed a homozygous variation of c.1317 + 1G>A in intron 10 of the MANBA (-) gene in the elder sibling. Sanger sequencing confirmed the same mutation in the homozygous state in both siblings and in the heterozygous state in both parents.
PubMed: 35018184
DOI: 10.4103/jpn.JPN_65_20 -
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 -
Gene Jan 2024A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested...
A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested the disorder was likely to be hereditary, although the signs were not consistent with any previously described inherited disorders in cats. Due to the progression of disease signs including severely impaired motor function and cognitive decline, the cat was euthanized at approximately 10.5 months of age. Whole genome sequence analysis identified a homozygous missense variant c.2506G > A in MANBA that predicts a p.Gly836Arg alteration in the encoded lysosomal enzyme β -mannosidase. This variant was not present in the whole genome or whole exome sequences of any of the 424 cats represented in the 99 Lives Cat Genome dataset. β -Mannosidase enzyme activity was undetectable in brain tissue homogenates from the affected cat, whereas α-mannosidase enzyme activities were elevated compared to an unaffected cat. Postmortem examination of brain and retinal tissues revealed massive accumulations of vacuolar inclusions in most cells, similar to those reported in animals of other species with hereditary β -mannosidosis. Based on these findings, the cat likely suffered from β -mannosidosis due to the abolition of β -mannosidase activity associated with the p.Gly836Arg amino acid substitution. p.Gly836 is located in the C-terminal region of the protein and was not previously known to be involved in modulating enzyme activity. In addition to the vacuolar inclusions, some cells in the brain of the affected cat contained inclusions that exhibited lipofuscin-like autofluorescence. Electron microscopic examinations suggested these inclusions formed via an autophagy-like process.
Topics: Cats; Animals; beta-Mannosidosis; beta-Mannosidase; Mutation, Missense
PubMed: 37913889
DOI: 10.1016/j.gene.2023.147941 -
Cold Spring Harbor Molecular Case... Jun 2019β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is...
β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is caused by mutations in and is extremely rare in humans. Although the clinical presentation is heterogeneous, common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections. We report a 15-yr-old girl presenting with mild intellectual disability, sensorineural hearing loss, severe behavioral disturbances, dysmorphic traits, and evolving angiokeratomas. Copy-number variation analysis of next-generation sequencing (NGS) data indicated increased coverage in exons 8-11 of Low β-mannosidase activity (1 µkatal/kg protein, refv 25-40) established the diagnosis of β-mannosidosis. Whole-genome sequencing (WGS) and cDNA analysis revealed a novel homozygous intragenic inverted duplication in where a 13.1-kb region between introns 7 and 11 was duplicated and inserted in an inverted orientation, creating a 67-base nonduplicated gap at the insertion point. Both junctions showed microhomology regions. The inverted duplication resulted in exon skipping of exons 8-9 or 8-10. Our report highlights the importance of copy-number variation analysis of data from NGS and in particular the power of WGS in the identification and characterization of copy-number variants.
Topics: Adolescent; Angiokeratoma; DNA Copy Number Variations; DNA, Complementary; Exons; Female; Gene Duplication; Hearing Loss; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Intellectual Disability; Mannosidases; Mutation; Phenotype; Sequence Analysis, DNA; Whole Genome Sequencing; beta-Mannosidosis
PubMed: 30886116
DOI: 10.1101/mcs.a003954 -
Orphanet Journal of Rare Diseases Jan 2021Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause...
BACKGROUND
Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders.
METHODS
The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation.
RESULTS
The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/β-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS.
CONCLUSION
This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.
Topics: Chromatography, High Pressure Liquid; Fucosidosis; Glycogen Storage Disease Type II; Humans; Lysosomal Storage Diseases; Oligosaccharides; Tandem Mass Spectrometry
PubMed: 33422100
DOI: 10.1186/s13023-020-01662-8