Mannosidosis: A clinical and histopathologic study

Kjellman, Bengt; Gamstorp, Ingrid; Brun, Arne; Öckerman, P.A.; Palmgren, Bertil

doi:10.1016/s0022-3476(69)80260-x

Cited by 118 publications

(33 citation statements)

References 13 publications

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“…2C). The presence of storage vacuoles is a prominent feature of alpha‐mannosidosis in mice15, 16 and men 21, 22. Ultrastructural analyses revealed comparable presence of storage vacuoles in neurons of the ganglion trigeminale, hippocampus, and Purkinje cells of the cerebellum (Fig.…”

Section: Resultsmentioning

confidence: 85%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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ObjectiveThe lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.MethodsHere, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.ResultsChronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.InterpretationOur data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.

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Section: Resultsmentioning

confidence: 85%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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“…Furthermore, two AMD patients showed bilateral hypointensities in the thalamic region on T2-weighted images, but the authors state that the intensity of the basal ganglia was normal (Gutschalk et al 2004). Iron accumulation has not been shown in postmortem pathology studies of young patients with AMD (Kjellman et al 1969;Sung et al 1977). As far as we know, there are no published pathology studies of older patients with AMD.The combination of brain atrophy and hypointensities in the basal ganglia on MRI is referred to as NBIA.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration with Brain Iron Accumulation on MRI: An Adult Case of α-Mannosidosis

et al. 2011

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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 a-mannosidosis (AMD), a lysosomal storage disorder.Background: AMD is a rare genetic disorder that causes a-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.

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“…This pattern of accelerated, then diminished physical growth had been observed in other patients. 4,[18][19][20][21] In mannosidosis, mannose-containing oligosaccharides accumulate in the brain. 2 Data on both brain autopsy and CT scan are scanty.…”

Section: Discussionmentioning

confidence: 99%

Mannosidosis in a Sudanese Child: Report of a Case with Review of the Literature

et al. 1989

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MA Abdullah, PT Ozand, M Al-Nasser, S Meshhadani, Mannosidosis in a Sudanese Child: Report of a Case with Review of The Literature. 1989; 9(1): 82-87 Mannosidosis is an autosomal recessive glycoprotein storage disease described by Ockerman 1 and caused by a deficiency of lysosomal isozymes (A and B) of α-D-mannosidase. 2 The clinical and pathological changes occurring during the course of the disease have recently been summarized. [3][4][5] Biochemical verification of the diagnosis requires proof of mannosidase deficiency and analysis of the urinary mannose-containing oligosaccharides. [3][4][5] Most of the cases have been reported from Europe and the United States. Apart from one family report, 6 we are not aware of case reports from Africa or the Middle East. This is a report of a Sudanese child whom we recently encountered. Case ReportA 16-month-old Sudanese boy was the offspring of healthy consanguineous Sudanese parents of Arab-Nubian origin. He had two other normal siblings and was the product of a normal pregnancy and normal spontaneous vaginal delivery. Growth and development had apparently been normal until the age of 4 months, when his problems started as severe wheezing which was later diagnosed as bronchial asthma.When first seen by us at the age of 5 months, he had a head circumference above the 97th percentile, but there was no clinical evidence of increased intracranial pressure; both his height and weight were above the 90th percentile. He was labeled as developmentally normal for his age. At this time a CT scan of the brain showed evidence of cerebral atrophy and ventricular dilatation (Figure 1). The x-ray film of his wrist was reported as showing mild rickets which could not be documented biochemically. The patient was readmitted at the age of 16 months with severe bronchial asthma and pneumonia. On this occasion, both his parents and his doctors were concerned about his delayed development. He was developmentally assessed as follows: personal 8/16, fine motor 12/16, gross motor 4/16, and language 10/16 months. Physical examination otherwise showed coarse Hurler's-like facies with flat nasal bridge, mandibular prognathism, prominent epicanthic folds, and prominent tongue. There were bilateral spotty whitish corneal opacities with markedly bluish and darkly pigmented scleral spots. There were no lenticular opacities, and the intraocular pressure as well as the funduscopy were normal. His skin showed many large bluish mongolian-spot-like areas all over the body. Heart showed clinical evidence of cardiomegaly and grade 3/6 murmur of mitral regurgitation with cardiac decompensation needing treatment. There was hepatomegaly of 4 cm with no splenomegaly as confirmed by ultrasound. He was hypotonic and had lumbar lordosis. He was not deaf. There were no joint contractures. At this admission, his height and head circumference were below the 90th percentile while his height was at the 50th percentile.Skeletal survey showed evidence of dysostosis multiplex with no evidence of rickets (Figure 2). A re...

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Mannosidosis: A clinical and histopathologic study

Cited by 118 publications

References 13 publications

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Neurodegeneration with Brain Iron Accumulation on MRI: An Adult Case of α-Mannosidosis

Mannosidosis in a Sudanese Child: Report of a Case with Review of the Literature

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