8 years of age. B. Progression of coxarthrosis at age 13.<b>Copyright information:</b>... more 8 years of age. B. Progression of coxarthrosis at age 13.<b>Copyright information:</b>Taken from "Alpha-mannosidosis"http://www.ojrd.com/content/3/1/21Orphanet Journal of Rare Diseases 2008;3():21-21.Published online 23 Jul 2008PMCID:PMC2515294.
Ith skeletal abnormalities of all vertebrae. B. Orthopedic correction of kyphosis.<b>Copyri... more Ith skeletal abnormalities of all vertebrae. B. Orthopedic correction of kyphosis.<b>Copyright information:</b>Taken from "Alpha-mannosidosis"http://www.ojrd.com/content/3/1/21Orphanet Journal of Rare Diseases 2008;3():21-21.Published online 23 Jul 2008PMCID:PMC2515294.
Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-m... more Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-mannosidosis: a method of monitoring treatment
Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of ... more Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed. Methods: In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed. Results: Data analysis revealed a wi...
This is an Open Access article distributed under the terms of the Creative Commons Attribution Li... more This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Clinical findings in acute portal vein thrombosis are often limited and non-specific. Many portal... more Clinical findings in acute portal vein thrombosis are often limited and non-specific. Many portal vein thromboses probably remain undiagnosed during the acute stage, and some of these may be discovered later because of complications such as variceal bleeding. Ultrasound with pulsed Doppler and colour Doppler is useful in the diagnosis of the thrombus, and for evaluation of its extension, hemodynamic significance and complications. We present a case of acute portal vein thrombosis associated with protein S deficiency, and review the findings of ultrasound and Doppler in the light of those previously reported. We describe the lack of Doppler signal in the splenic vein and inability to visualize the portal vein and its intra-hepatic branches as one normally can. Further observations include a thrombosed portal vein branch within the liver, prominent branches of the hepatic artery, splenomegaly, partial recanalization and development of collaterals. In the hepatic veins, we found pathologic blood flow with reduced heart-synchronous variations of velocity, as often found in portal hypertension due to cirrhosis. This is not previously reported in portal vein thrombosis, and may be a sign of a portal vein thrombosis with a large degree of obstruction to blood flow and development of portal hypertension. This phenomenon can be explained using hemodynamics.
Alpha-mannosidosis is characterized by mild to moderate intellectual disability (ID), moderate to... more Alpha-mannosidosis is characterized by mild to moderate intellectual disability (ID), moderate to severe neurosensory hearing loss, frequent infections, psychomotor disturbances and skeletal World Health Organisation (WHO) (1993) The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research. WHO, Geneva.
Complexes between CD1 molecules and self or microbial glycolipids represent important immunogenic... more Complexes between CD1 molecules and self or microbial glycolipids represent important immunogenic ligands for specific subsets of T cells. However, the function of one of the CD1 family members, CD1e, has yet to be determined. Here, we show that the mycobacterial antigens hexamannosylated phosphatidyl- myo -inositols (PIM 6 ) stimulate CD1b-restricted T cells only after partial digestion of the oligomannose moiety by lysosomal α-mannosidase and that soluble CD1e is required for this processing. Furthermore, recombinant CD1e was able to bind glycolipids and assist in the digestion of PIM 6 . We propose that, through this form of glycolipid editing, CD1e helps expand the repertoire of glycolipidic T cell antigens to optimize antimicrobial immune responses.
Nths. Note enlarged head, short neck, rounded eyebrows, saddle nose, and prominent forehead. B. S... more Nths. Note enlarged head, short neck, rounded eyebrows, saddle nose, and prominent forehead. B. Same twins aged 8 years. Note slight muscular atrophy of the hands. C. Boy, aged 27. Note: Hearing aid.<b>Copyright information:</b>Taken from "Alpha-mannosidosis"http://www.ojrd.com/content/3/1/21Orphanet Journal of Rare Diseases 2008;3():21-21.Published online 23 Jul 2008PMCID:PMC2515294.
UNLABELLED Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosoma... more UNLABELLED Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Here, we report two sisters with alpha-mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of alpha-mannosidosis and SLE are discussed with regard to both clinical and molecular findings. CONCLUSION alpha-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.
In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chai... more 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 ...
Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of ... more Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed. Methods: In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed. Results: Data analysis revealed a wide spectrum of clinical presentation regarding the severity and disease progression. Most clinical abnormalities were observed in the musculoskeletal and neurological system. All patients showed mental retardation and hearing loss from early childhood. An impairment in physical endurance was revealed by the 6-minute walk and 3-minute stair stair climb tests. There was only slight progression of a few clinical findings: Psychiatric troubles in both groups essentially, and respiratory dysfunction under 18 years. The serum and urinary oligosaccharide levels were increased in all affected individuals and correlated well with the 6-minute walk and 3-minute stair climb test results. Conclusions: This study confirms that alpha-Mannosidosis is a very heterogeneous disorder regarding both, disease severity and progression. As it has been shown that Mannosidosis patients are able to perform lung function tests and the 6MWT and stair-climb test, these clinical parameters apparently can be used as clinical endpoints for clinical trials. Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to treatment. Trial registration: ClinicalTrials.gov Identifier = NCT00498420 and EuropeanCommission FP VI contract LHSM-CT-2006-018692.
a-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal a-mannosidase... more a-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal a-mannosidase (LA-MAN). The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency. Recently, we reported the first amannosidosis-causing mutation affecting two Palestinian siblings. In the present study 21 novel mutations and four polymorphic amino acid positions were identified by the screening of 43 patients, from 39 families, mainly of European origin. Disease-causing mutations were identified in 72% of the alleles and included eight splicing, six missense, and three nonsense mutations, as well as two small insertions and two small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in two or three families, except for a missense mutation resulting in an R750W substitution. This mutation was found in 13 patients, from different European countries, and accounted for 21% of the disease alleles. Although there were clinical variations among the patients, no significant LAMAN activity could be detected in any of the fibroblast cultures. In addition, no correlation between the types of mutations and the clinical manifestations was evident.
α-Mannosidosis (MIM 248500) is an autosomal recess- ive lysosomal storage disorder resulting from... more α-Mannosidosis (MIM 248500) is an autosomal recess- ive lysosomal storage disorder resulting from deficient activity of lysosomal α-mannosidase (LAMAN) (EC 3.2.1.24). The disease is characterized by massive in- tracellular accumulation of mannose-rich oligosac- charides with resulting mental retardation, hearing loss, immune deficiency and skeletal changes. We re- port here the purification and characterization of human placenta LAMAN. The enzyme is
α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MA... more α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene, encoding the lysosomal α-mannosidase. The disorder is characterized by a range of clinical phenotypes of which the major manifestations are mental impairment, hearing impairment, skeletal changes and immunodeficiency. Here we report an α-mannosidosis mutation database, amamutdb.no, which has been constructed as a publicly accessible online resource for recording and analyzing MAN2B1 variants (http://amamutdb.no). Our aim has been to offer structured and relational information on MAN2B1 mutations and genotypes along with associated clinical phenotypes. Classifying missense mutations, as pathogenic or benign, is a challenge. Therefore, they have been given special attention as we have compiled all available data that relate to their biochemical, functional and structural properties. The α-mannosidosis mutation database is comprehensive and relational in the sense that informatio...
8 years of age. B. Progression of coxarthrosis at age 13.<b>Copyright information:</b>... more 8 years of age. B. Progression of coxarthrosis at age 13.<b>Copyright information:</b>Taken from "Alpha-mannosidosis"http://www.ojrd.com/content/3/1/21Orphanet Journal of Rare Diseases 2008;3():21-21.Published online 23 Jul 2008PMCID:PMC2515294.
Ith skeletal abnormalities of all vertebrae. B. Orthopedic correction of kyphosis.<b>Copyri... more Ith skeletal abnormalities of all vertebrae. B. Orthopedic correction of kyphosis.<b>Copyright information:</b>Taken from "Alpha-mannosidosis"http://www.ojrd.com/content/3/1/21Orphanet Journal of Rare Diseases 2008;3():21-21.Published online 23 Jul 2008PMCID:PMC2515294.
Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-m... more Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-mannosidosis: a method of monitoring treatment
Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of ... more Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed. Methods: In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed. Results: Data analysis revealed a wi...
This is an Open Access article distributed under the terms of the Creative Commons Attribution Li... more This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Clinical findings in acute portal vein thrombosis are often limited and non-specific. Many portal... more Clinical findings in acute portal vein thrombosis are often limited and non-specific. Many portal vein thromboses probably remain undiagnosed during the acute stage, and some of these may be discovered later because of complications such as variceal bleeding. Ultrasound with pulsed Doppler and colour Doppler is useful in the diagnosis of the thrombus, and for evaluation of its extension, hemodynamic significance and complications. We present a case of acute portal vein thrombosis associated with protein S deficiency, and review the findings of ultrasound and Doppler in the light of those previously reported. We describe the lack of Doppler signal in the splenic vein and inability to visualize the portal vein and its intra-hepatic branches as one normally can. Further observations include a thrombosed portal vein branch within the liver, prominent branches of the hepatic artery, splenomegaly, partial recanalization and development of collaterals. In the hepatic veins, we found pathologic blood flow with reduced heart-synchronous variations of velocity, as often found in portal hypertension due to cirrhosis. This is not previously reported in portal vein thrombosis, and may be a sign of a portal vein thrombosis with a large degree of obstruction to blood flow and development of portal hypertension. This phenomenon can be explained using hemodynamics.
Alpha-mannosidosis is characterized by mild to moderate intellectual disability (ID), moderate to... more Alpha-mannosidosis is characterized by mild to moderate intellectual disability (ID), moderate to severe neurosensory hearing loss, frequent infections, psychomotor disturbances and skeletal World Health Organisation (WHO) (1993) The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research. WHO, Geneva.
Complexes between CD1 molecules and self or microbial glycolipids represent important immunogenic... more Complexes between CD1 molecules and self or microbial glycolipids represent important immunogenic ligands for specific subsets of T cells. However, the function of one of the CD1 family members, CD1e, has yet to be determined. Here, we show that the mycobacterial antigens hexamannosylated phosphatidyl- myo -inositols (PIM 6 ) stimulate CD1b-restricted T cells only after partial digestion of the oligomannose moiety by lysosomal α-mannosidase and that soluble CD1e is required for this processing. Furthermore, recombinant CD1e was able to bind glycolipids and assist in the digestion of PIM 6 . We propose that, through this form of glycolipid editing, CD1e helps expand the repertoire of glycolipidic T cell antigens to optimize antimicrobial immune responses.
Nths. Note enlarged head, short neck, rounded eyebrows, saddle nose, and prominent forehead. B. S... more Nths. Note enlarged head, short neck, rounded eyebrows, saddle nose, and prominent forehead. B. Same twins aged 8 years. Note slight muscular atrophy of the hands. C. Boy, aged 27. Note: Hearing aid.<b>Copyright information:</b>Taken from "Alpha-mannosidosis"http://www.ojrd.com/content/3/1/21Orphanet Journal of Rare Diseases 2008;3():21-21.Published online 23 Jul 2008PMCID:PMC2515294.
UNLABELLED Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosoma... more UNLABELLED Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Here, we report two sisters with alpha-mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of alpha-mannosidosis and SLE are discussed with regard to both clinical and molecular findings. CONCLUSION alpha-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.
In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chai... more 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 ...
Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of ... more Background: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed. Methods: In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed. Results: Data analysis revealed a wide spectrum of clinical presentation regarding the severity and disease progression. Most clinical abnormalities were observed in the musculoskeletal and neurological system. All patients showed mental retardation and hearing loss from early childhood. An impairment in physical endurance was revealed by the 6-minute walk and 3-minute stair stair climb tests. There was only slight progression of a few clinical findings: Psychiatric troubles in both groups essentially, and respiratory dysfunction under 18 years. The serum and urinary oligosaccharide levels were increased in all affected individuals and correlated well with the 6-minute walk and 3-minute stair climb test results. Conclusions: This study confirms that alpha-Mannosidosis is a very heterogeneous disorder regarding both, disease severity and progression. As it has been shown that Mannosidosis patients are able to perform lung function tests and the 6MWT and stair-climb test, these clinical parameters apparently can be used as clinical endpoints for clinical trials. Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to treatment. Trial registration: ClinicalTrials.gov Identifier = NCT00498420 and EuropeanCommission FP VI contract LHSM-CT-2006-018692.
a-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal a-mannosidase... more a-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal a-mannosidase (LA-MAN). The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency. Recently, we reported the first amannosidosis-causing mutation affecting two Palestinian siblings. In the present study 21 novel mutations and four polymorphic amino acid positions were identified by the screening of 43 patients, from 39 families, mainly of European origin. Disease-causing mutations were identified in 72% of the alleles and included eight splicing, six missense, and three nonsense mutations, as well as two small insertions and two small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in two or three families, except for a missense mutation resulting in an R750W substitution. This mutation was found in 13 patients, from different European countries, and accounted for 21% of the disease alleles. Although there were clinical variations among the patients, no significant LAMAN activity could be detected in any of the fibroblast cultures. In addition, no correlation between the types of mutations and the clinical manifestations was evident.
α-Mannosidosis (MIM 248500) is an autosomal recess- ive lysosomal storage disorder resulting from... more α-Mannosidosis (MIM 248500) is an autosomal recess- ive lysosomal storage disorder resulting from deficient activity of lysosomal α-mannosidase (LAMAN) (EC 3.2.1.24). The disease is characterized by massive in- tracellular accumulation of mannose-rich oligosac- charides with resulting mental retardation, hearing loss, immune deficiency and skeletal changes. We re- port here the purification and characterization of human placenta LAMAN. The enzyme is
α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MA... more α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene, encoding the lysosomal α-mannosidase. The disorder is characterized by a range of clinical phenotypes of which the major manifestations are mental impairment, hearing impairment, skeletal changes and immunodeficiency. Here we report an α-mannosidosis mutation database, amamutdb.no, which has been constructed as a publicly accessible online resource for recording and analyzing MAN2B1 variants (http://amamutdb.no). Our aim has been to offer structured and relational information on MAN2B1 mutations and genotypes along with associated clinical phenotypes. Classifying missense mutations, as pathogenic or benign, is a challenge. Therefore, they have been given special attention as we have compiled all available data that relate to their biochemical, functional and structural properties. The α-mannosidosis mutation database is comprehensive and relational in the sense that informatio...
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