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

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.

Pulmonary involvement in selected lysosomal storage diseases and the impact of enzyme replacement therapy: A state-of-the art review.

Lysosomal storage disorders (LSDs) are multisystemic, progressive and clinically very heterogeneous. Respiratory complications are not regarded as the principal problems of LSDs, but significantly impact morbidity. In this review, we focus on pulmonary complications observed in late-onset LSDs, their milder forms that are recognised in adulthood. We also discuss the effects of enzyme replacement therapy (ERT) on the respiratory system in patients with particular LSDs. We searched the PubMed database, retrieving research papers on pulmonary complications of LSDs currently treated with ERT (the conditions are abbreviated GD3; NPDB; LOPD; MPS I, II, IVA, VI; and FD) and the effects of such treatment. Although some studies indicated that ERT was helpful in terms of reducing chest computed tomography abnormalities, infection frequency and organomegaly, the data are not conclusive, and the mechanism of action of ERT in the respiratory system remains unclear for some LSDs including late-onset Pompe disease and Gaucher disease type III. The optimal timing of treatment for pre-symptomatic or symptomatic patients, treatment duration and whether such treatment modulates inflammation (as has been suggested in patients with Fabry disease), remain to be explored.

Hematopoietic stem cell transplantation in Niemann-Pick disease type B monitored by chitotriosidase activity.

Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness.

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

Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Here, using polystyrene and poly(lactic-co-glycolic acid) nanocarriers, we optimized lung delivery by varying enzyme dose and nanocarrier concentration, verified endocytosis and lysosomal trafficking in vivo, and evaluated delivered activity and effects. Raising the enzyme load of nanocarriers progressively increased absolute enzyme delivery to all lung, liver, and spleen, over the naked enzyme. Varying nanocarrier concentration inversely impacted lung versus liver and spleen uptake. Mouse intravital and postmortem examination verified endocytosis, transcytosis, and lysosomal trafficking using nanocarriers. Compared to naked enzyme, nanocarriers increased enzyme activity in organs and reduced lung sphingomyelin storage and macrophage infiltration. Although old mice with advanced disease showed reactivity (pulmonary leukocyte infiltration) to injections, including buffer without carriers, antibody, or enzyme, younger mice with mild disease did not. We conclude that anti-ICAM nanocarriers may result in effective lung enzyme therapy using low enzyme doses.

Types A and B Niemann-Pick Disease.

Two distinct metabolic abnormalities are included under the eponym Niemann-Pick disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick disease (NPD). Type A NPD patients exhibit hepatosplenomegaly, frequent pulmonary infections, and profound central nervous system involvement in infancy. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and progressive alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second category are designated as having type C NPD. Impaired intracellular trafficking of cholesterol causes type C NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed.

Types A and B Niemann-Pick disease.

Two distinct metabolic abnormalities are encompassed under the eponym Niemann-Pick disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick disease (NPD). Type A NPD patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second NPD category are designated as having types C and D NPD. These patients may have mild hepatosplenomegaly, but the central nervous system is profoundly affected. Impaired intracellular trafficking of cholesterol causes types C and D NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed.

[Acid sphingomyelinase deficiency and spleen trauma: splenectomy or not splenectomy?]. / Déficit en sphingomyélinase acide et rupture splénique : splénectomie ou traitement conservateur ?

INTRODUCTION: Acid sphingomyelinase deficiency leads to a severe infantile disease (Niemann-Pick disease type A) or an attenuated form of the disease encountered in adults (Niemann-Pick type B), including pulmonary fibrosis and splenomegaly. CASE REPORT: A 52-year-old man with Niemann-Pick disease type B was admitted with splenic rupture. Embolization of the splenic artery was initially performed. Three months later, the splenic volume had increased and functional asplenia was diagnosed. Splenic scintigraphy showed 20% of functional splenic tissue. Splenectomy was finally performed because of complete necrosis of the spleen. CONCLUSION: Despite its theoretical contra-indication in Niemann-Pick disease due to a risk of respiratory insufficiency, splenectomy must sometimes be considered.

Psychosocial aspects of patients with Niemann-Pick disease, type B.

Health-care providers have only begun to understand the medical aspects of Niemann-Pick disease type B (NPDB), a relatively rare disease. Even less information is known about the psychological effects of living with NPDB. Patients with NPDB and their families face numerous psychological stressors including extensive medical testing, uncertainty of diagnosis, living and coping with a chronic illness, and grief and bereavement surrounding this progressively debilitating, and, ultimately, fatal disease. We used a qualitative case study approach to explore the human experiences of NPDB patients and families. To assess psychosocial adjustment, all participants were administered a semi-structured, qualitative interview, as well as quantitative measures. Five major findings emerged: (1) limited physical activity, social isolation, and peer rejection were identified as significant stressors; (2) stressors had a specific impact during the age span of 10-16 years; (3) parents and adult patients expressed frustration regarding the lack of available information and treatment; (4) patients described close family relationships as a way of coping with illness; and (5) adult patients identified early medical experiences as having a considerable psychological impact. The results of this investigation highlight and expand awareness of the psychological and social needs of NPDB patients and families. This study calls for a collaborative, multidisciplinary effort in the treatment of these patients and their families.

Correction of enzyme levels with allogeneic hematopoeitic progenitor cell transplantation in Niemann-Pick type B.

Niemann-Pick type B (NP) is an autosomal recessive lysosomal storage disorder with variable phenotypes for which few patients have undergone hematopoietic progenitor cell (HPC) transplantation. We present an 18-month old with NP type B who underwent two allogeneic HPC transplants from her HLA-identical sister. Sphingomyelinase in the peripheral leucocytes and skin fibroblasts was absent at diagnosis. Engraftment failed following initial transplant; therefore a second with the same donor was performed. Engraftment since has been durable; all subsequent sphingomyelinase levels have been normal. Our experience indicates that HPC transplantation for patients with NP type B is feasible and beneficial.

The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease.

Patients with types A and B Niemann-Pick disease (NPD) have an inherited deficiency of acid sphingomyelinase (ASM) activity. The clinical spectrum of this disorder ranges from the infantile, neurological form that results in death by 3 years of age (type A NPD) to the non-neurological form (type B NPD) that is compatible with survival into adulthood. Intermediate cases also have been reported, and the disease is best thought of as a single entity with a spectrum of phenotypes. ASM deficiency is panethnic, but appears to be more frequent in individuals of Middle Eastern and North African descent. Current estimates of the disease incidence range from approximately 0.5 to 1 per 100,000 births. However, these approximations likely under estimate the true frequency of the disorder since they are based solely on cases referred to biochemical testing laboratories for enzymatic confirmation. The gene encoding ASM (SMPD1) has been studied extensively; it resides within an imprinted region on chromosome 11, and is preferentially expressed from the maternal chromosome. Over 100 SMPD1 mutations causing ASM-deficient NPD have been described, and some useful genotype-phenotype correlations have been made. Based on these findings, DNA-based carrier screening has been implemented in the Ashkenazi Jewish community. ASM 'knockout' mouse models also have been constructed and used to investigate disease pathogenesis and treatment. Based on these studies in the mouse model, an enzyme replacement therapy clinical trial has recently begun in adult patients with non-neurological ASM-deficient NPD.