Dataset Information

Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in ?-Mannosidosis.

ABSTRACT: ?-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic ?-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9½ months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5½ years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.

SUBMITTER: Danielsen ER

PROVIDER: S-EPMC3755547 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in α-Mannosidosis.

Danielsen Else R ER Lund Allan M AM Thomsen Carsten C

JIMD reports 20130424

α-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic α-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a ha ...[more]

PMID: 23613340

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Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

Project description:Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.

Dataset Information

Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in ?-Mannosidosis.

Publications

Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in α-Mannosidosis.

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