Asymptomatic Pulmonary Involvement in 2 Children with Niemann-Pick Disease Type B

Niggemann, B.; Rebien, Wolfgang; Rahn, W; Wahn, Ulrich

doi:10.1159/000196305

Cited by 29 publications

(19 citation statements)

References 3 publications

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“…The typical chest radiograph has interstitial infiltrates with reticulonodular changes and areas of ground glass density, often out of proportion to clinical manifestations. 13 Studies in ASM knockout mice, which have histopathologic and clinical changes similar to human NPD-B patients, 14 reveal that inflammation, abnormal surfactant catabolism, and abnormal surfactant composition all contribute to lung abnormalities. 15 However, more detailed studies of lung function are required to understand better the pathophysiology of the pulmonary disease in NPD-B.…”

Section: Discussionmentioning

confidence: 99%

“…Patients who were Ͼ18 years old and did not have pulmonary signs were given a score of 1, those with cyanosis or clubbing were given a score of 2, and those with oxygen dependence were given a score of 3. The sum of the scores from each category was the overall phenotypic severity score, which was categorized as mild (overall score 6 -11), moderate (overall score [12][13][14] or severe (overall score Ͼ15).…”

Section: Determination Of Phenotypic Severity Score and Genotype/phenmentioning

confidence: 99%

See 1 more Smart Citation

The Natural History of Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study

Wasserstein¹,

Desnick²,

Schuchman³

et al. 2004

Pediatrics

160

168

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ABSTRACT. Objectives. Type B Niemann-Pick disease (NPD-B) caused by acid sphingomyelinase deficiency is a rare, autosomal recessive, lysosomal storage disorder with a broad range of disease severity. The objectives of this study were to document the natural history of the disease in a large, clinically heterogeneous patient population that was followed for a period of 10 years and to determine how genotype influences phenotype.Methods. Twenty-nine patients with NPD-B had serial evaluations at least 9 months apart. Organ volumes, hematologic indices, lipid concentrations, pulmonary function, and hepatic activity were studied, and individual phenotypic severity was compared with genotype.Results. All patients with intact spleens had splenomegaly (mean value: 12.7 multiples of normal [MN]; range: 4.5-27.3 MN), and all but 1 had hepatomegaly (mean volume: 1.91 MN; range: 0.93-3.21 MN). At initial visit, 39% had thrombocytopenia and 3% had leukopenia. At final visit, the percentages increased to 54% and 34%, respectively. Mean annual decreases in platelet count and leukocyte count were 7 ؋ 10 3 and 0.2 ؋ 10 3 per mm 3 , respectively. The typical atherogenic lipid profile was worse in older patients. A total of 69% of patients had low diffusion capacity for carbon monoxide, and more than one third had low forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity at initial visit. All measurements of pulmonary function showed a gradual deterioration over time. Liver dysfunction was characterized by stable elevation of hepatic transaminases and bilirubin. Homozygotes for ⌬R608, P323A, and P330R had milder disease than patients with all other genotypes.Conclusions. N iemann-Pick disease (NPD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM; sphingomyelin phosphodiesterase; EC 3.1.4.12) and the accumulation of sphingomyelin within cells of the monocyte-macrophage system. 1 Types A and B NPD are inherited as autosomal recessive traits and result from allelic mutations in the ASM gene. Type A disease (NPD-A), which has an Ashkenazi Jewish predilection, is a fatal neurodegenerative disorder of infancy. In contrast, type B NPD (NPD-B), which is panethnic, is a nonneuronopathic disease characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement, with most patients living into adulthood. Other, more variable features of NPD-B may include liver dysfunction, cardiac disease, retinal stigmata, and growth retardation. [2][3][4][5][6] There is a broad spectrum of disease manifestations among NPD-B patients, ranging from onset in childhood with massive organomegaly, secondary hypersplenism, growth restriction, and later pulmonary involvement or liver failure to a milder, attenuated course. As in other lysosomal storage diseases, this marked phenotypic variability is influenced by genotype, 7,8 although other factors such as gender and age may also contribute to disease severity. To date, the phenotypic variab...

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Section: Discussionmentioning

confidence: 99%

Section: Determination Of Phenotypic Severity Score and Genotype/phenmentioning

confidence: 99%

The Natural History of Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study

Wasserstein¹,

Desnick²,

Schuchman³

et al. 2004

Pediatrics

160

168

View full text Add to dashboard Cite

show abstract

“…8 Chest radiographs in affected patients reveal interstitial infiltrates with reticulonodular changes and areas of ground-glass density that may be out of proportion to clinical findings. 16 Severely affected patients may exhibit cough, shortness of breath, and recurrent respiratory infections, 17 and some patients develop chronic oxygen dependence with progressive pulmonary failure. 18 The pathophysiology of the pulmonary disease is presumably related to the accumulation of sphingomyelin in the alveolar macrophages, although studies in the ASM knockout mouse also have shown that inflammation, abnormal surfactant catabolism, and abnormal surfactant composition all contribute to lung abnormalities.…”

Section: Genetics In Medicine | Volume 15 | Number 8 | August 2013mentioning

confidence: 99%

Morbidity and mortality in type B Niemann–Pick disease

McGovern

Lippa

Bagiella

et al. 2013

Genetics in Medicine

114

168

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“…Respiratory function testing also can be useful in alerting patients and physicians to pulmonary involvement in later stages of the disease, but young NPD patients often present with normal lung function (Ferretti et al, 1996;Niggemann et al, 1994). Characteristics of the BALF have been sparsely documented in incidental cases, and BAL is not a routine procedure in type B NPD diagnosis.…”

Section: Dhami Et Almentioning

confidence: 99%

“…Respiratory infections and pulmonary function decline are a common cause of morbidity among type B NPD individuals (Lever and Ryder, 1983;Schuchman and Desnick, 2001), and may lead to death in severely affected patients. The lung pathology of type B NPD patients has been routinely characterized by radiography showing evidence of reticulonodular infiltrates (Bouziani et al, 1990;Ferretti et al, 1996;Gerbaux et al, 1971;Gogus et al, 1994;Niggemann et al, 1994). Histologic examination of autopsy lungs has also demonstrated the presence of "foamy cells" (large macrophages with cytoplasmic inclusions) in the alveolar spaces (reviewed in Minai et al, 2000).…”

mentioning

confidence: 99%

Analysis of the Lung Pathology and Alveolar Macrophage Function in the Acid Sphingomyelinase–Deficient Mouse Model of Niemann-Pick Disease

Dhami

Gordon

et al. 2001

Laboratory Investigation

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SUMMARY:Types A and B Niemann-Pick disease (NPD) are lipid storage diseases caused by the deficient activity of the lysosomal enzyme, acid sphingomyelinase (ASM). Type B NPD is associated with progressive pulmonary function decline and frequent respiratory infections. ASM knock-out (ASMKO) mice are available as a model for NPD, but the lung pathology in these mice has not been adequately characterized. This study shows that by 10 weeks of age ASMKO mice have a significantly higher number of cells in their pulmonary airspaces than normal mice, consisting primarily of enlarged and often multinucleated macrophages. These mice also have much higher levels of sphingomyelin in their airspaces at 10 weeks of age, and both cell numbers and sphingomyelin concentrations remain elevated until 26 weeks of age. In these older mice an increased number of neutrophils is also seen. The alveolar cell population in the ASMKO mice produces less superoxide when stimulated, but this can be corrected by providing recombinant ASM to the culture media. Elevated levels of the chemokines macrophage inflammatory protein-2 and macrophage inflammatory protein-1␣ were also present in the bronchoalveolar lavage fluid of ASMKO mice, and this correlated with increased production of these chemokines by cultured macrophages and enhanced immunostaining in situ. Also, lung histology showed increased cellularity in the alveolar walls of ASMKO mice, but no evidence of fibrosis. Ultrastructural analysis of the lungs showed that the ASMKO mice have similar pathologic features to human NPD patients, with variable lipid storage evident in type I pneumocytes, endothelial cells, and airway ciliated epithelia. The alveolar macrophage, however, was the most dramatically affected cell type in both mice and humans. These studies indicate that the ASMKO mice can be used as a model to study the lung pathology associated with NPD, and demonstrate that the cellular and biochemical analysis of pulmonary airspaces may be a useful approach to monitoring disease progression and/or treatment. (Lab Invest 2001, 81:987-999).

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Asymptomatic Pulmonary Involvement in 2 Children with Niemann-Pick Disease Type B

Cited by 29 publications

References 3 publications

The Natural History of Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study

The Natural History of Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study

Morbidity and mortality in type B Niemann–Pick disease

Analysis of the Lung Pathology and Alveolar Macrophage Function in the Acid Sphingomyelinase–Deficient Mouse Model of Niemann-Pick Disease

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