The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann-Pick Disease: A Comprehensive Review

Abstract

Niemann-Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase α is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies.

Keywords: NPC1; NPC2; Niemann–Pick Disease; Olipudase α; SMPD1; acid sphingomyelinase deficiency; lung transplant; miglustat.

Figure 1

Molecular pathogenetic mechanisms in ASMD (NPD type A and B) and NPD type C. ASMDs (NPD type A and B) are due to acid sphingomyelinase (ASMase) deficiency. This leads to accumulation of sphingomyelin in lysosomes. As a consequence, a secondary sequestration of cholesterol in lysosomes occurs. ASMase acts as a trigger for endoplasmic reticulum stress. The consequent reduced endoplasmic reticulum stress signaling causes a decrease in reactive oxygen species (ROS) in mitochondria. NPD type C is characterized by defects of NPC1 and NPC2. This leads to accumulation of cholesterol in lysosomes, which is sustained by decreased activity of acid ceramidase (ACDase). As a consequence, via a poorly understood mechanism involving endoplasmic reticulum signals, mitochondrial cholesterol levels increase. The mitochondrial cholesterol accumulation determines an increase in ROS-induced oxidative stress.