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.

Similarities and differences between Gaucher disease and acid sphingomyelinase deficiency: An algorithm to support the diagnosis.

Lysosomal storage disorders are a group of inborn errors of metabolism due to defects in proteins crucial for lysosomal function. Gaucher disease is the most common autosomal recessive lysosomal storage disorder due to mutations in the GBA1 gene, resulting in the lysosomal deficiency of glucocerebrosidase activity. Gaucher disease is characterized by the toxic accumulation of glucosylceramide in the reticuloendothelial system. Acid sphingomyelinase deficiency (ASMD), previously known as Niemann Pick A/B disease, is also an autosomal recessive lysosomal storage disorder due to mutations in the SMPD1 gene, which result in acid sphingomyelinase deficiency and the accumulation of sphingomyelin in mononuclear phagocytic system and hepatocytes. The phenotypic expression of Gaucher disease type 1 (GD1), the most common type, and chronic visceral ASMD may overlap for several signs or symptoms. Splenomegaly is detectable in approximately 90% of the patients in both conditions; however, since GD1 is more frequent than ASMD, clinicians are more prone to suspect it, often neglecting the diagnosis of ASMD. Based on previous experience, a group of experts in the clinical and laboratory diagnosis, management, and treatment of lysosomal storage disorders developed an algorithm for both GD1 and ASMD to support physicians, including primary care providers, internists, and specialists (e.g., hepatologists, hematologists, and pulmonologists) to suspect and differentiate GD1 and ASMD and to provide the appropriate referral.

Three-years misdiagnosis of Niemann Pick disease type B with novel mutations in SMPD1 gene as Budd-Chiari syndrome.

BACKGROUND: The chronic visceral subtype of acid sphingomyelinase deficiency, commonly known as Niemann Pick disease type B (NPDB), is a relatively rare autosomal recessive genetic disorder that is caused by mutations in the SMPD1 gene. NPDB with sea-blue histiocytes (SBH) clinically mimics Budd-Chiari syndrome (BCS), as it lacks specific clinical characteristics. This makes its diagnosis difficult. CASE PRESENTATION: Here, we report a case of NPDB with SBH that was misdiagnosed as BCS for three years. A 20-year-old female with abdominal distension, hepatosplenomegaly, and haematological anomalies was initially diagnosed with BCS based on her imaging finding of a thin hepatic vein and rapid blood flow at the confluence of the hepatic vein and inferior vena cava. Her bone marrow cytology found sea-blue histiocytes. Liver biopsy showed foamy cytoplasm in hepatocytes surrounded by numerous Kupffer cells. Sequencing analysis of the SMPD1 gene led to the finding of two missense mutations in the heterozygous state: C.829 T > C (p.Trp277Arg) in exon 2 (novel) and c.1805G > A (p.Arg602His) in exon 6 (already described). These findings established the diagnosis of NPDB. CONCLUSION: The patient presented with hepatosplenomegaly, haematological anomalies, and dyslipidaemia. Thus, NPDB should be considered following the exclusion of related diseases. The diagnosis of NPDB was suspected by clinical symptoms and routine laboratory tests and was confirmed by liver biopsy and gene sequencing. The novel mutation c.829 T > C in exon 2 of the SMPD1 gene has never been reported and needs to be further investigated.

Spontaneous splenic rupture as the first clinical manifestation of Niemann-Pick disease type B: A case report and review of the literature.

Splenomegaly is the most common phenotype for Niemann-Pick disease type B (NPD-B), an autosomal recessive lipid storage disease caused by deficiency of the lysosomal enzyme acid sphingomyelinase. Although a spleen of massive volume is common in NPD-B, splenic rupture in this disease is rarely reported. We describe a patient with NPD-B who initially presented with spontaneous splenic rupture. Microscopic examination of the spleen specimen revealed expansion of the red pulp by abundant foamy histiocytes. A literature review revealed that splenic rupture resulting from latent splenomegaly may occur in middle adulthood in a mild form of NPD-B associated with SMPD1 variants of lower pathogenicity. We suggest that unexplained splenomegaly or splenic rupture should raise the possibility of a lysosomal storage disease, including NPD. For patients with NPD-B, spleen size should be evaluated periodically, and the risk of splenic rupture should always be considered.

Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency.

Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+ macrophages and expansion of airspace/alveolar CD11c+ CD11b- macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+ cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden-like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.

Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family.

OBJECTIVES: Ochoa syndrome (UFS1; Urofacial syndrome-1) is a very rare autosomal recessive disorder caused by mutations in the HPSE2 gene that results bladder voiding dysfunction and somatic motor neuropathy affecting the VIIth cranial nerve. Niemann-Pick disease is a rare autosomal recessive lysosomal storage disorder with systemic involvement resulting from sphingomyelinase deficiency and generally occurs via mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). CASE PRESENTATION: Here, we report a 6-year-old girl with symptoms such as urinary incontinence, recurrent urinary tract infections, peculiar facial expression, mainly when smiling, hypertelorism, constipation, incomplete closure of eyelids during sleep and splenomegaly. Homozygote mutations in two different genes responsible for two distinct syndromes were detected in the patient. Homozygous NM_000543.5:c.502G>A (p.Gly168Arg) mutation was found in the SMPD1 gene causing Niemann-Pick disease. In addition, some of the clinical features were due to a novel homozygous mutation identified in the HPSE2 gene, NM_021828.5:c.755delA (p.Lys252SerfsTer23). CONCLUSIONS: Here, we discuss about the importance of considering dual diagnosis in societies where consanguineous marriages are common. Accurate diagnosis of the patient is very important for the management of the diseases and prevention of complications.

Niemann-Pick Disease Type B in Traumatic Splenic Rupture.

The rupture of spleen is common in clinical and forensic practice. Trauma is the most common cause of splenic rupture. Although rare, traumatic splenic rupture may occur in these individuals with asymptomatic underlying disease, and clinical and forensic pathologists may neglect the disease and diagnose only the traumatic splenic rupture. Here, we present a case of postinjury splenic rupture resulting in splenectomy, where the patient was diagnosed with Niemann-Pick disease type B through histopathological examination and genetic testing. In forensic practice, in cases of isolation splenic rupture, full microscopy should be done to differentiate traumatic rupture from a spontaneous bleed due to an underlying disease process.

Niemann-Pick disease type-B: a unique case report with compound heterozygosity and complicated lipid management.

BACKGROUND: Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by deficient activity of acid sphingomyelinase. CASE PRESENTATION: We present a case of NPD type B with a unique compound heterozygosity for SMPD1 (NM_000543.4:c.[84delC];[96G > A]) in which both mutations that induce an early stop codon are located before the second in-frame initiation codon. The clinical presentation of the patient is compatible with NPD type B. She was initially diagnosed of Gaucher Disease, but her altered lipid profile led to a clinical suspicion of NPD. Combined high doses of atorvastatin and ezetimibe were given to treat the severe hypercholesterolemia. CONCLUSIONS: The pharmacological management of the lipid profile in these patients is important. A unique compound mutation in SMPD1 gene is described.

Novel mutations in the SMPD1 gene in Jordanian children with Acid sphingomyelinase deficiency (Niemann-Pick types A and B).

Acid sphingomyelinase (ASM) deficiency (ASMD) is a spectrum that includes Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). ASMD is characterized by intracellular accumulation of unesterified cholesterol and gangliosides within the endosomal-lysosomal system. It is caused by different mutations in SMPD1 gene that result in reduction or complete absence of acid sphingomyelinase activity in the cells. Herein, four unrelated consanguineous families with two NPD A and three NPD B patients were assessed for their genotypes via sequencing of the SMPD1 gene and their acid sphingomyelinase enzymatic activity. Among the eight identified mutations, three were novel and reported for the first time in Jordanian families (c.120_131delGCTGGCGCTGGC or c.132_143delGCTGGCGCTGGC, c.1758T > G, and c.1344T > A). All the patients displayed ASM activity lower than 1.3 µmol/l/h (P < 0.001). Genotyping and enzymatic assessment might play a significant role in disease identification in people at risk to facilitate genetic counseling in the future.

Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population.

INTRODUCTION AND OBJECTIVES: Niemann-Pick disease type A (NPD-A) and B (NPD-B) are lysosomal storage diseases with a birth prevalence of 0.4-0.6/100,000. They are caused by a deficiency in acid sphingomyelinase, an enzyme encoded by SMPD1. We analyzed the phenotype and genotype of four unrelated Mexican patients, one with NPD-A and three with NPD-B. PATIENTS AND METHODS: Four female patients between 1 and 7 years of age were diagnosed with NPD-A or NPD-B by hepatosplenomegaly, among other clinical characteristics, and by determining the level of acid sphingomyelinase enzymatic activity and sequencing of the SMPD1 gene. Additionally, a 775bp amplicon of SMPD1 (from 11:6393835_6394609, including exons 5 and 6) was analyzed by capillary sequencing in a control group of 50 unrelated healthy Mexican Mestizos. RESULTS: An infrequent variant (c.1343A>G p.Tyr448Cys) was observed in two patients. One is the first NPD-A homozygous patient reported with this variant and the other a compound heterozygous NPD-B patient with the c.1829_1831delGCC p.Arg610del variant. Another compound heterozygous patient had the c.1547A>G p.His516Arg variant (not previously described in affected individuals) along with the c.1805G>A p.Arg602His variant. A new c.1263+8C>T pathogenic variant was encountered in a homozygous state in a NPD-B patient. Among the healthy control individuals there was a heterozygous carrier for the c.1550A>T (rs142787001) pathogenic variant, but none with the known pathogenic variants in the 11:6393835_6394609 region of SMPD1. CONCLUSIONS: The present study provides further NPD-A or B phenotype-genotype correlations. We detected a heterozygous carrier with a pathogenic variant in 1/50 healthy Mexican mestizos.

Generation of an induced pluripotent stem cell line (TRNDi004-I) from a Niemann-Pick disease type B patient carrying a heterozygous mutation of p.L43_A44delLA in the SMPD1 gene.

Niemann-Pick disease type B (NPB) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 1-year old male patient with NPB that has a heterozygous mutation of a p.L43_A44delLA of SMPD1 using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPB.

Utility of amniotic fluid chitotriosidase in the prenatal diagnosis of lysosomal storage disorders.

OBJECTIVE: Plasma chitotriosidase is a documented biomarker for certain lysosomal storage disorders. However, its clinical utility for prenatal samples is not elucidated yet. METHODS: We have established Reference intervals for amniotic fluid chitotriosidase using control amniotic fluids (n = 47) and compared the activity with amniotic fluids affected by lysosomal storage disorders (n = 25). RESULTS: The reference interval established was 0-6.76 nmol/h/ml. The amniotic fluids affected with LSDs exhibited elevation of chitotriosidase. The area under the curve (AUC) of receiver operating characteristic curve for affected vs. healthy was 0.987 indicating 98.6% accuracy of chitotriosidase in identifying pregnancies affected with LSDs. Among the different LSDs, Gaucher (202.00 ±â€¯35.27 nmol/h/ml) and Niemann-pick A/B (60.33 ±â€¯21.59 nmol/h/ml) showed very high levels of chitotriosidase. CONCLUSION: Amniotic fluid chitotriosidase has the potential to serve as a diagnostic marker for lysosomal storage disorders, more specifically for Gaucher and Niemann-Pick A/B.

Unravelling new pathways of sterol metabolism: lessons learned from in-born errors and cancer.

PURPOSE OF REVIEW: To update researchers of recently discovered metabolites of cholesterol and of its precursors and to suggest relevant metabolic pathways. RECENT FINDINGS: Patients suffering from inborn errors of sterol biosynthesis, transport and metabolism display unusual metabolic pathways, which may be major routes in the diseased state but minor in the healthy individual. Although quantitatively minor, these pathways may still be important in healthy individuals. Four inborn errors of metabolism, Smith-Lemli-Opitz syndrome, cerebrotendinous xanthomatosis and Niemann Pick disease types B (NPB) and C (NPC) result from mutations in different genes but can generate elevated levels of the same sterol metabolite, 7-oxocholesterol, in plasma. How this molecule is metabolized further is of great interest as its metabolites may have an important role in embryonic development. A second metabolite, abundant in NPC and NPB diseases, cholestane-3ß,5α,6ß-triol (3ß,5α,6ß-triol), has recently been shown to be metabolized to the corresponding bile acid, 3ß,5α,6ß-trihydroxycholanoic acid, providing a diagnostic marker in plasma. The origin of cholestane-3ß,5α,6ß-triol is likely to be 3ß-hydroxycholestan-5,6-epoxide, which can alternatively be metabolized to the tumour suppressor dendrogenin A (DDA). In breast tumours, DDA levels are found to be decreased compared with normal tissues linking sterol metabolism to cancer. SUMMARY: Unusual sterol metabolites and pathways may not only provide markers of disease, but also clues towards cause and treatment.

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.

[Acid sphingomyelinase deficiency (Niemann-Pick disease type B) in adulthood: A retrospective multicentric study of 28 adult cases]. / Déficit en sphingomyélinase acide (maladie de Niemann-Pick B) : une étude rétrospective multicentrique de 28 patients adultes.

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease with a clinical spectrum ranging from a neurovisceral infantile form (Niemann-Pick disease type A) to a chronic visceral form also encountered in adults (Niemann-Pick disease type B, NP-B). METHODS: Retrospective multicentric analysis of French adult patients with ASMD over the period 1985-March 2015. Clinical, biological, and imaging data were analyzed. RESULTS: Twenty-eight patients (19 males, 9 females) were analyzed. Diagnosis was made before the age of 10 years in 16 cases. Main symptoms at diagnosis were spleen/liver enlargement and interstitial lung disease. Biological abnormalities included: thrombocytopenia (platelet count <150 000/mm3) in 24 cases including 4 patients with platelet count <60 000/mm3, constantly low high-density lipoprotein (HDL) cholesterol, polyclonal hypergammaglobulinemia (n=6), monoclonal gammopathy of unknown significance (n=5), normal prothrombin level discordant with low factor V (n=5), elevated chitotriosidase level (n=11). The diagnosis was confirmed in all cases by deficient acid sphingomyelinase enzyme activity. SMPD1 gene sequencing was performed in 25 cases. The frequent p.R610del mutation was largely predominant, constituting 62% of the non-related alleles. During the follow-up period, three patients died before 50 years of age from cirrhosis, heart failure and lung insufficiency, respectively. CONCLUSION: ASMD in adulthood (NP-B) associates spleen/liver enlargement and interstitial lung disease. Early diagnosis and appropriate management are essential for reducing the risk of complications, improving quality of life, and avoiding inappropriate procedures such as splenectomy. To date, only symptomatic therapy is available. A phase 2/3 therapeutic trial with IV infusion of recombinant enzyme is on-going.

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.

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.

Niemann-Pick Types A and B (NPA/B) diseases are autosomal recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase (ASM) because of the mutations in the SMPD1 gene. Here, we provide a comprehensive updated review of already reported and newly identified SMPD1 variants. Among them, 185 have been found in NPA/B patients. Disease-causing variants are equally distributed along the SMPD1 gene; most of them are missense (65.4%) or frameshift (19%) mutations. The most frequently reported mutation worldwide is the p.R610del, clearly associated with an attenuated NP disease type B phenotype. The available information about the impact of 52 SMPD1 variants on ASM mRNA and/or enzymatic activity has been collected and whenever possible, phenotype/genotype correlations were established. In addition, we created a locus-specific database easily accessible at http://www.inpdr.org/genes that catalogs the 417 SMPD1 variants reported to date and provides data on their in silico predicted effects on ASM protein function or mRNA splicing. The information reviewed in this article, providing new insights into the genotype/phenotype correlation, is extremely valuable to facilitate diagnosis and genetic counseling of families affected by NPA/B.