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JIMD Reports 2012A 34-year-old woman was referred to our hospital with progressive movement disorders and neurodegeneration with brain iron accumulation and enlargement of the frontal...
CASE
A 34-year-old woman was referred to our hospital with progressive movement disorders and neurodegeneration with brain iron accumulation and enlargement of the frontal diploe on the MRI. Metabolic testing revealed that she had α-mannosidosis (AMD), a lysosomal storage disorder.
BACKGROUND
AMD is a rare genetic disorder that causes α-mannosidase deficiency resulting in lysosomal accumulation of undigested oligosaccharides. The symptoms of AMD consist of facial and skeletal deformities combined with progressive psychiatric and neurological complaints, especially ataxia and mental retardation. Bilateral patellar dislocation and hearing impairment are frequent.
DISCUSSION
The movement disorders we found in our patient have not been reported previously, but they are likely late symptoms of this progressive disorder. The iron deposits in the basal ganglia have also not been reported in AMD and are yet of unknown significance. Lysosomal storage disorders, such as AMD, should be considered in patients with progressive neurologic conditions and neurodegeneration with brain iron accumulation on MRI.
PubMed: 23430902
DOI: 10.1007/8904_2011_78 -
JIMD Reports 2013Lysosomal storage disorders (LSD) are rare entities of recessive inheritance. The presence of a "founder" mutation in isolated communities with a high degree of...
Lysosomal storage disorders (LSD) are rare entities of recessive inheritance. The presence of a "founder" mutation in isolated communities with a high degree of consanguinity (e.g., tribes in the Middle East North Africa, MENA, region) is expected to lead to unusually high disease prevalence. The primary aim of this study was to estimate the prevalence of LSD and report their mutation spectrum in UAE. Between 1995 and 2010, 119 patients were diagnosed with LSD (65 Emiratis and 54 non-Emiratis). Genotyping was performed in 59 (50 %) patients (39 Emirati from 17 families and 20 non-Emiratis from 17 families). The prevalence of LSD in Emiratis was 26.9/100,000 live births. Sphingolipidoses were relatively common (9.8/100,000), with GM1-gangliosidosis being the most prevalent (4.7/100,000). Of the Mucopolysaccharidoses VI, IVA and IIIB were the predominant subtypes (5.5/100,000). Compared to Western countries, the prevalence of fucosidosis, Batten disease, and α-mannosidosis was 40-, sevenfold, and fourfold higher in UAE, respectively. The prevalence of Pompe disease (2.7/100,000) was similar to The Netherlands, but only the infantile subtype was found in UAE. Sixteen distinct LSD mutations were identified in 39 Emirati patients. Eight (50 %) mutations were reported only in Emirati, of which three were novel [c.1694G>T in the NAGLU gene, c.1336 C>T in the GLB1 gene, and homozygous deletions in the CLN3 gene]. Twenty-seven (42 %) patients were clustered in five of the 70 Emirati tribes. These findings highlight the need for tribal-based premarital testing and genetic counseling.
PubMed: 23430803
DOI: 10.1007/8904_2012_182 -
Genetics and Molecular Research : GMR Aug 2012Although lysosomal storage disorders (LSDs) are considered individually rare, as a group they present a non-negligible frequency. Few studies have been made of...
Although lysosomal storage disorders (LSDs) are considered individually rare, as a group they present a non-negligible frequency. Few studies have been made of populational occurrence of LSDs; they have been conducted predominantly on Caucasian populations. We studied the occurrence of LSDs in Cuba. Data from individuals who had been referred to the Institute of Neurology and Neurosurgery in Havana from hospitals all over the country between January 1990 and December 2005 were analyzed. This institute was the only laboratory to provide enzyme-based diagnostic testing for 19 LSDs in Cuba during this period. Occurrence rates were calculated by dividing the number of postnatal diagnoses by the number of births during the study period. The combined occurrence of LSDs in Cuba was 5.6 per 100,000, lower than that reported in other studies conducted on Caucasian populations. The most frequent individual LSDs were: mucopolysaccharidosis type I (1.01 per 100,000) and, surprisingly, alpha-mannosidosis (0.72 per 100,000) and fucosidosis (0.62 per 100,000). These findings may be related to specific genetic characteristics and admixture of the Cuban population. This is the first comprehensive study of the occurrence of LSDs in Cuba. We conclude that the epidemiology of these diseases can vary regionally, and we stress the need for similar surveys in other Latin American countries.
Topics: Adolescent; Adult; Child; Child, Preschool; Cuba; Fucosidosis; Humans; Incidence; Infant; Middle Aged; Young Adult; alpha-Mannosidosis
PubMed: 22911605
DOI: 10.4238/2012.August.13.9 -
Analytical and Bioanalytical Chemistry Jun 2012Many lysosomal storage diseases are characterized by an increased urinary excretion of glycoconjugates and oligosaccharides that are characteristic for the underlying...
Many lysosomal storage diseases are characterized by an increased urinary excretion of glycoconjugates and oligosaccharides that are characteristic for the underlying enzymatic defect. Here, we have used capillary high-performance anion-exchange chromatography (HPAEC) hyphenated to mass spectrometry to analyze free oligosaccharides from urine samples of patients suffering from the lysosomal storage disorders fucosidosis, α-mannosidosis, G(M1)-gangliosidosis, G(M2)-gangliosidosis, and sialidosis. Glycan fingerprints were registered, and the patterns of accumulated oligosaccharides were found to reflect the specific blockages of the catabolic pathway. Our analytical approach allowed structural analysis of the excreted oligosaccharides and revealed several previously unpublished oligosaccharides. In conclusion, using online coupling of HPAEC with mass spectrometric detection, our study provides characteristic urinary oligosaccharide fingerprints with diagnostic potential for lysosomal storage disorders.
Topics: Anion Exchange Resins; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Humans; Lysosomal Storage Diseases; Mass Spectrometry; Oligosaccharides
PubMed: 22526647
DOI: 10.1007/s00216-012-5968-9 -
PLoS Pathogens Jun 2011C. canimorsus 5 has the capacity to grow at the expenses of glycan moieties from host cells N-glycoproteins. Here, we show that C. canimorsus 5 also has the capacity to...
C. canimorsus 5 has the capacity to grow at the expenses of glycan moieties from host cells N-glycoproteins. Here, we show that C. canimorsus 5 also has the capacity to deglycosylate human IgG and we analyze the deglycosylation mechanism. We show that deglycosylation is achieved by a large complex spanning the outer membrane and consisting of the Gpd proteins and sialidase SiaC. GpdD, -G, -E and -F are surface-exposed outer membrane lipoproteins. GpdDEF could contribute to the binding of glycoproteins at the bacterial surface while GpdG is a endo-β-N-acetylglucosaminidase cleaving the N-linked oligosaccharide after the first N-linked GlcNAc residue. GpdC, resembling a TonB-dependent OM transporter is presumed to import the oligosaccharide into the periplasm after its cleavage from the glycoprotein. The terminal sialic acid residue of the oligosaccharide is then removed by SiaC, a periplasm-exposed lipoprotein in direct contact with GpdC. Finally, most likely degradation of the oligosaccharide proceeds sequentially from the desialylated non reducing end by the action of periplasmic exoglycosidases, including β-galactosidases, β-N-Acetylhexosaminidases and α-mannosidases.
Topics: Bacterial Outer Membrane Proteins; Capnocytophaga; Cell Line; Glycoproteins; Glycosylation; Gram-Negative Bacterial Infections; Humans; Immunoglobulin G; Lipoproteins; Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; N-Acetylneuraminic Acid; Neuraminidase; Polysaccharides; alpha-Mannosidosis; beta-Galactosidase; beta-N-Acetylhexosaminidases
PubMed: 21738475
DOI: 10.1371/journal.ppat.1002118 -
Plant Biotechnology Journal Dec 2011Deficiency in human lysosomal α-mannosidase (MAN2B1) results in α-mannosidosis, a lysosomal storage disorder; patients present a wide range of neurological,...
Deficiency in human lysosomal α-mannosidase (MAN2B1) results in α-mannosidosis, a lysosomal storage disorder; patients present a wide range of neurological, immunological, and skeletal symptoms caused by a multisystemic accumulation of mannose-containing oligosaccharides. Here, we describe the expression of recombinant MAN2B1 both transiently in Nicotiana benthamiana leaves and in the leaves and seeds of stably transformed N. tabacum plants. After purification from tobacco leaves, the recombinant enzyme was found to be N-glycosylated and localized in vacuolar compartments. In the fresh leaves of tobacco transformants, MAN2B1 was measured at 10,200 units/kg, and the purified enzyme from these leaves had a specific activity of 32-45 U/mg. Furthermore, tobacco-produced MAN2B1 was biochemically similar to the enzyme purified from human tissues, and it was internalized and processed by α-mannosidosis fibroblast cells. These results strongly indicate that plants can be considered a promising expression system for the production of recombinant MAN2B1 for use in enzyme replacement therapy.
Topics: Cell Line; Enzyme Activation; Enzyme Assays; Fibroblasts; Glycosylation; Humans; Immunoprecipitation; Mannosidase Deficiency Diseases; Plant Leaves; Plants, Genetically Modified; Plasmids; Protoplasts; Recombinant Proteins; Seeds; Nicotiana; Transformation, Genetic; Vacuoles; alpha-Mannosidase
PubMed: 21645202
DOI: 10.1111/j.1467-7652.2011.00630.x -
Journal of Inherited Metabolic Disease Oct 2011In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chains in the lysosomes in all body tissues, including the brain. With...
In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chains in the lysosomes in all body tissues, including the brain. With ensuing therapeutic modalities in man (BMT and ERT) non-invasive methods of monitoring the effect of treatment are needed. Paramount is the possible effect of the treatment on the brain, since this organ is regarded as difficult to reach because of the blood-brain barrier. We therefore performed proton nuclear magnetic resonance spectroscopy (MRS) of the brain in two untreated patients, and a 16-year-old patient treated with BMT at the age of 10 to assess whether this non-invasive method could be applied in the monitoring of the accumulation of abnormal chemicals in the brain of patients. We found an abnormal peak that was not present in the treated patient. A similar pattern was also found in MRS of urine from patients, reflecting the concentration of oligosaccharides in serum and tissues. We therefore conclude that MRS can be a useful method to monitor the effect of treatment for Alpha-Mannosidosis.
Topics: Adolescent; Adult; Blood-Brain Barrier; Brain; Humans; Magnetic Resonance Spectroscopy; Male; Monitoring, Physiologic; Oligosaccharides; Polysaccharides; Protons; Radiography; Urinalysis; Young Adult; alpha-Mannosidosis
PubMed: 21541723
DOI: 10.1007/s10545-011-9331-7 -
European Journal of Human Genetics :... Jul 2011
Topics: Humans; Mutation; Toxoplasmosis, Congenital; alpha-Mannosidosis
PubMed: 21368911
DOI: 10.1038/ejhg.2011.5 -
Journal of Neuropathology and... Jan 2011α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the... (Comparative Study)
Comparative Study
α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions, and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages, and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-Mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term enzyme replacement therapy partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides, and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures.
Topics: Animals; CHO Cells; Cerebellum; Cricetinae; Cricetulus; Disease Models, Animal; Enzyme Replacement Therapy; Gene Targeting; Humans; Lameness, Animal; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Treatment Outcome; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 21157375
DOI: 10.1097/NEN.0b013e31820428fa -
BMC Genomics Dec 2009Lysosomal alpha-mannosidase is an enzyme that acts to degrade N-linked oligosaccharides and hence plays an important role in mannose metabolism in humans and other... (Comparative Study)
Comparative Study
BACKGROUND
Lysosomal alpha-mannosidase is an enzyme that acts to degrade N-linked oligosaccharides and hence plays an important role in mannose metabolism in humans and other mammalian species, especially livestock. Mutations in the gene (MAN2B1) encoding lysosomal alpha-D-mannosidase cause improper coding, resulting in dysfunctional or non-functional protein, causing the disease alpha-mannosidosis. Mapping disease mutations to the structure of the protein can help in understanding the functional consequences of these mutations and thus indirectly, the finer aspects of the pathology and clinical manifestations of the disease, including phenotypic severity as a function of the genotype.
RESULTS
A comprehensive homology modeling study of all the wild-type and inherited mutations of lysosomal alpha-mannosidase in four different species, human, cow, cat and guinea pig, reveals a significant correlation between the severity of the genotype and the phenotype in alpha-mannosidosis. We used the X-ray crystallographic structure of bovine lysosomal alpha-mannosidase as template, containing only two disulphide bonds and some ligands, to build structural models of wild-type structures with four disulfide linkages and all bound ligands. These wild-type models were then used as templates for disease mutations. All the truncations and substitutions involving the residues in and around the active site and those that destabilize the fold led to severe genotypes resulting in lethal phenotypes, whereas the mutations lying away from the active site were milder in both their genotypic and phenotypic expression.
CONCLUSION
Based on the co-location of mutations from different organisms and their proximity to the enzyme active site, we have extrapolated observed mutations from one species to homologous positions in other organisms, as a predictive approach for detecting likely alpha-mannosidosis. Besides predicting new disease mutations, this approach also provides a way for detecting mutation hotspots in the gene, where novel mutations could be implicated in disease. The current study has identified five mutational hot-spot regions along the MAN2B1 gene. Structural mapping can thus provide a rational approach for predicting the phenotype of a disease, based on observed genotypic variations.
Topics: Amino Acid Sequence; Animals; Catalytic Domain; Cats; Cattle; Computational Biology; Genotype; Guinea Pigs; Humans; Models, Molecular; Molecular Sequence Data; Mutation; Phenotype; Protein Folding; Protein Structure, Tertiary; Sequence Alignment; Structural Homology, Protein; alpha-Mannosidase
PubMed: 19958498
DOI: 10.1186/1471-2164-10-S3-S33