Pulmonary Involvement in Niemann–Pick Disease: A State-of-the-Art Review

Abstract

Niemann-Pick disease is a rare autosomal recessive lysosomal storage disease with three subtypes. Types A and B result from a deficiency of acid sphingomyelinase activity, associated with the accumulation of lipid-laden macrophages (so-called Niemann-Pick cells) in various tissues, especially the liver and spleen. Type A is a fatal neurodegenerative disorder of infancy. Type B Niemann-Pick disease is a less severe form with milder neurological involvement, characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement; most patients live into adulthood. Type C Niemann-Pick disease is a complex lipid storage disorder caused by defects in cholesterol trafficking, resulting in a clinical presentation dominated by neurological involvement. Pulmonary involvement occurs in all three types of Niemann-Pick disease, but most frequently in type B. Respiratory manifestations range from a lack of symptoms to respiratory failure. Progression of respiratory disease is slow, but inexorable, due to the accumulation of Niemann-Pick cells in the alveolar septa, bronchial walls, and pleura, potentially leading to a progressively worsening restrictive pattern on pulmonary function testing. Bronchoalveolar lavage has important diagnostic value because it shows the presence of characteristic Niemann-Pick cells. Radiographic findings consist of a reticular or reticulonodular pattern and, eventually, honeycombing, involving mainly the lower lung zones. The most common changes identified by high-resolution computed tomography are ground-glass opacities, mild smooth interlobular septal thickening, and intralobular lines. The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann-Pick disease, with a focus on pulmonary involvement.

Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice

“…Type B Niemann-Pick disease (NPD-B) (OMIM 607616) is an inherited lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid sphingomyelinase (ASM) (EC 3.1.4.12). 1,2 Its prevalence is thought to be 0.5-1 in every 100,000 live births, 1 although this may be underestimated due to under-or mis-diagnosis. 1,3 ASM is a 57-to 75-kDa enzyme (depending on post-translational modifications and proteolytic maturation), 1,3 which hydrolyzes sphingomyelin into ceramide and phosphocholine.…”

“…3,[5][6][7] The lungs, liver, and spleen are primary targets for intervention, as compromised pulmonary function, liver failure, and splenic rupture are causes of death in NPD-B patients. 2,3,6,7 Sphingomyelin accumulates in cells of the reticuloendothelial system, vascular component, and tissue-specific cells in these organs, including alveolar macrophages, Kupffer cells, epithelial and endothelial cells, vascular smooth muscle cells, hepatocytes, fibroblasts, etc. 2,3,6,7 Due to the main role that sphingomyelin-ceramide signaling pathways play in endothelial and immune cells, inflammation is also a hallmark in NPD-B.…”

“…2,3,6,7 Sphingomyelin accumulates in cells of the reticuloendothelial system, vascular component, and tissue-specific cells in these organs, including alveolar macrophages, Kupffer cells, epithelial and endothelial cells, vascular smooth muscle cells, hepatocytes, fibroblasts, etc. 2,3,6,7 Due to the main role that sphingomyelin-ceramide signaling pathways play in endothelial and immune cells, inflammation is also a hallmark in NPD-B. 3 This causes increased lung permeability with cellular infiltration, accumulation of lipidladen macrophages in alveoli and septa, and alterations in surfactant composition.…”

“…5,6 Neurological symptoms are either absent or minor in NPD-B, leading to slow, mild disease progression. 2,3,6 This contributes to the lateonset and chronic form of NPD-B, which associates with residual ASM activity in patients. 3 This is in contrast to type A NPD (NPD-A), an early-onset, severe phenotypic manifestation of ASM deficiency, characterized by rapid neurological decline and fatality within the first years of life.…”

Initial and Final Status of the Patients with Niemann Pick A and B: Ege University Experience

“…We found similar findings; two patients had low weight SDS, three patients had low height SDS and five patients had both low weight and height SDS. NPD-B is most commonly associated with pulmonary involvement, expressed through interstitial lung disease (10,11). In our study, 10 patients had interstitial lung disease.…”