Autopsy pathology of infantile neurovisceral ASMD (Niemann-Pick Disease type A): Clinicopathologic correlations of a case report

Abstract

Acid sphingomyelinase deficiency (ASMD; also known as Niemann-Pick Disease [NPD] A and B) is a rare lysosomal storage disease characterized by the pathological accumulation of sphingomyelin within multiple cell types throughout the body. The infantile neurovisceral (ASMD type A, also known as Niemann-Pick Disease type A) form of the disease is characterized by markedly low or absent enzyme levels resulting in both visceral and severe neurodegenerative involvement with death in early childhood. We report here the clinical course and autopsy findings in the case of a 3 year old male patient with infantile neurovisceral ASMD. A comprehensive examination of the autopsy tissue was conducted, including routine paraffin processing and staining, high resolution light microscopy and staining for sphingomyelin, and ultrastructural examination by electron microscopy. Profound sphingomyelin accumulation was present in virtually every organ and cell type. We report the clinicopathologic correlations of these findings and discuss the relevance of these results to the clinical practice of physicians following all patients with ASMD. This case represents one of the most extensive and detailed examinations of ASMD type A to date.

Keywords: Acid sphingomyelinase deficiency; Niemann-Pick Disease type A; Sphingomyelin.

Fig. 1

Sphingomyelin accumulation was present in the heart and lungs. A. In cardiomyocytes of the left ventricular free wall, sphingomyelin appears as purple globules in high resolution microscopy sections (arrow, 1 μm epoxy resin section, modified toluidine blue stain, 1000×). B. Electron microscopy of cardiomyocytes demonstrates the “fingerprint” type whorls (arrow) characteristic of sphingomyelin accumulation in ASMD (electron microscopy, scale bar = 2 μm). C. Alveolar macrophages (arrow) of the lung are engorged with sphingomyelin, panel C. (high resolution light microscopy, 1 μm epoxy resin section, modified toluidine blue stain, 600×). D. Electron microscopy demonstrates the ‘zebra body’ (arrow) and ‘fingerprint’ architecture of the accumulated sphingomyelin within alveolar macrophages (scale bar = 1 μm).

Fig. 2

Sphingomyelin accumulation was present in the liver and spleen. A. Dense portal-portal bridging bands of fibrosis (blue) appear throughout the tissue section, consistent with cirrhosis. (paraffin section, trichrome stain, 20×). B. Clusters of foamy macrophages (arrow) engorged with sphingomyelin are rimmed with pericellular fibrosis in blue (paraffin section, trichrome stain, 200×). C. At higher magnification, hepatocytes also appear foamy due to sphingomyelin accumulation (paraffin section, H & E stain, 600×). D. The spleen was also filled with foamy macrophages (paraffin section, H & E stain, 400×).

Fig. 3

Sphingomyelin is present in multiple cells types of the kidney. A. Sphingomyelin is present in numerous cell types within the renal glomerulus including podocytes (P), mesangial cells (M), capillary endothelial cells (E) and lining cells of Bowman's capsule (B) (1 μm epoxy resin section, modified toluidine blue stain, 1000×). B. Electron microscopy of the renal glomerulus illustrating the electron dense whorls of sphingomyelin within each cell type. (electron microscopy, scale bar = 5 μm). C. Sphingomyelin accumulation is also present within the epithelial cells of the proximal tubules (T) and the surrounding cells of the interstitium (1 μm epoxy resin section, modified toluidine blue stain, 1000×). D. Electron microscopy image of proximal convoluted tubule epithelium with electron dense sphingomyelin accumulation. (electron microscopy, scale bar = 2 μm). The magnitude of substrate accumulation and its specific cellular distribution is strikingly similar to the substrate accumulation observed within renal biopsies of patients with Fabry disease [14].

Fig. 4

Cells of multiple organs exhibited dramatic accumulation of sphingomyelin A. Neurons of the brainstem. B. Cells of the adrenal cortex. C. Ganglion cells of the small intestine. D. The bone marrow was filled with typical “Niemann-Pick’ cells which crowded out the normal hematopoietic elements. E. The cells of the exocrine pancreas are also heavily laden with accumulated substrate. F. Sphingomyelin accumulation is pronounced within the follicular cells of the thyroid, as well as within the interstitial cells and vascular cells between follicles. (High resolution light microscopy, 1 μm epoxy resin sections, modified toluidine blue stain, magnifications 600×, 100×, 600×, 1000×, 600×, and 1000×, respectively).