RARE DISEASE
Chronic neurovisceral acid sphingomyelinase deficiency
Chronic neurovisceral acid sphingomyelinase deficiency
Chronic neurovisceral acid sphingomyelinase deficiency
Synonyms: Chronic neurovisceral ASMD, NPD-A/B, Niemann-Pick disease type A/B
Synonyms: Chronic neurovisceral ASMD, NPD-A/B, Niemann-Pick disease type A/B
Synonyms: Chronic neurovisceral ASMD, NPD-A/B, Niemann-Pick disease type A/B
Drug discovery
82
papers
On emerging therapies
Overview
Chronic neurovisceral acid sphingomyelinase deficiency (ASMD type A/B) is a rare autosomal recessive lysosomal storage disorder caused by SMPD1 mutations, leading to sphingomyelin accumulation. This intermediate phenotype combines chronic visceral manifestations (hepatosplenomegaly, interstitial lung disease, dyslipidemia) with progressive neurodegeneration (developmental delay, motor regression). Onset typically occurs in childhood with variable progression, often resulting in premature death from respiratory/liver failure or neurological decline [1][2][7].
Burden
Multisystem complications: 50% require outpatient/home healthcare; 40% experience developmental delays [4][7]
Major mortality drivers: Respiratory insufficiency (40%), liver failure (30%), and neurocognitive decline [3][7][13]
Socioeconomic impact: 22% of adults have compromised work ability; 16% require home schooling [4][7]
Therapies
Enzyme replacement therapy: Olipudase alfa improves visceral symptoms (hepatosplenomegaly, lung function) but does not address neurodegeneration [3][8][11]
Supportive care: Nutritional support, infection management, respiratory interventions, and physical/neurodevelopmental therapies [2][13]
Emerging approaches: Clinical trials investigating CNS-targeted therapies; genetic counseling for families [8][12]
Categories: rare endocrine diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
82 drug discovery papers about Chronic neurovisceral acid sphingomyelinase deficiency, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
82 drug discovery papers about Chronic neurovisceral acid sphingomyelinase deficiency, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-10-12 | Current and Emerging Treatments for Acid Sphingomyelinase Deficiency.
Acid sphingomyelinase deficiency is an ultra-rare disease characterised by generalised storage of sphingomyelin, caused by deficiency of the lysosomal enzyme acid sphingomyelinase, owing to the presence of biallelic pathogenic variants in the SMPD1 gene. The main disease manifestations are in the liver, spleen, lung and bone - with some patients having also involvement of the central nervous system. Patients show variable degrees of anaemia, thrombocytopenia and lipid abnormalities, among other findings. Clinically, acid sphingomyelinase deficiency spans from an acute neurovisceral form, with neurological involvement and early death (type A), to a chronic visceral disease, with no or minimal neurological manifestations (type B). An intermediate form, with chronic neurovisceral involvement, is presented by some patients (type A/B). Diagnosis involves the measurement of biomarkers, an assay of enzyme activity and genetic testing. Until a few years ago, treatment was mainly dependent on symptomatic management and bone marrow or solid organ (liver and/or lung) transplantation. In 2022, a specific enzyme replacement therapy with olipudase alfa was approved, and the results available indicate that it changed the therapeutic landscape for patients with acid sphingomyelinase deficiency type B and A/B. Research is being developed to address the needs of patients with acid sphingomyelinase deficiency type A, with gene therapy remaining as a promising approach.
2025-01-01 | Unraveling Genetic Complexity in Consanguineous Families: Integrating Pedigree Analysis and Genomic Testing for Rare Disease Diagnosis in Libya
Consanguinity makes rare autosomal genetic disorders more common. This issue remainsunstudied in Libyan populations. We investigated eight extended Libyan families fromMisurata, with a focus on families G and H from the third generation, who exhibited complexsyndromic presentations. Whole-exome sequencing (WES), Sanger validation, and clinicalphenotyping were employed to identify the molecular basis of disease. In Family G, three malesiblings were diagnosed with Niemann-Pick disease type A/B (NPD A/B) and a female siblingwith hypertrophic cardiomyopathy type 4 (HCM4). Genetic analysis revealed a homozygouspathogenic variant in SMPD1 consistent with NPD A/B, and a homozygous MYBPC3 variant(c.1483C>T, p.Arg495Trp) linked to HCM4. In Family H, double first-cousin consanguinitysegregated Joubert syndrome type 4 (JS4) in three siblings due to homozygous deletions in theNPHP1 gene. Additional heterozygous variants in NPC1 and MYBPC3 were detected acrossboth families, raising the possibility of polygenic modifiers and variable expressivity. Ourfindings reveal that the complexity of rare diseases in consanguineous populationsdemonstrates the co-occurrence of multiple diseases within the same family. This studyhighlights the diagnostic utility of WES in low-resource settings and endorses equitable,culturally informed genetic counselling frameworks to advance disparities in rare diseasemanagement and precision health interventions in Libya.
2024-10-23 | Chronic acid sphingomyelinase deficiency diagnosed in infancy/childhood in Polish patients: 2024 update.
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disease (LSD) associated with biallelic pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. The aim of this study was to provide the 2024 update on chronic visceral and neurovisceral ASMD diagnosed in the infancy/childhood in Polish patients. All the patients diagnosed in the pediatric age (0-18 years) with ASMD, both chronic neurovisceral and visceral type, and then systematically followed up, were enrolled into the study. A total number of 7 patients were enrolled into the study. Four patients were previously reported. Two patients were newly recognized with ASMD - 1 with chronic visceral and 1 with chronic neurovisceral ASMD. Splenomegaly was noted in all the patients while a mild liver enlargement was observed in 4 of 7 patients. All patients presented with decreased high-density lipoprotein cholesterol (HDL-C) and decreased serum 25-hydroxy-vitamin D concentration while almost all (6 of 7) with hypercholesterolemia. Cherry-red spot was observed in 5 of 7 patients, including 1 patient with neurovisceral type. Seven various SMPD1 gene variants were identified and missense variants were the most common types of genetic lesions, comprising 71% of all alleles. In all the screened patients, lyso-sphingomyelin (lyso-SM) in dried blood spot (DBS) was found elevated; however, the greater values were observed for patients with chronic neurovisceral type. Chronic acid sphingomyelinase deficiency (ASMD) is a slowly progressive disease. Pediatric ASMD is characterized by spleno-hepatomegaly, dyslipidemia (with decreased HDL-C as the most characteristic) and infiltrative (interstitial) lung disease. Both visceral and neurovisceral chronic ASMD patients could present with cherry-red spot. Both acid spingomyelinase activity and lyso-spingomyelin concentration in DBS should be regarded as a first-tier screening method into ASMD.
2024-05-07 | Overview of clinical, molecular, and therapeutic features of Niemann–Pick disease (types A, B, and C): Focus on therapeutic approaches
Abstract Niemann–Pick disease (NPD) is another type of metabolic disorder that is classified as lysosomal storage diseases (LSDs). The main cause of the disease is mutation in the SMPD1 (type A and B) or NPC1 or NPC2 (type C) genes, which lead to the accumulation of lipid substrates in the lysosomes of the liver, brain, spleen, lung, and bone marrow cells. This is followed by multiple cell damage, dysfunction of lysosomes, and finally dysfunction of body organs. So far, about 346, 575, and 30 mutations have been reported in SMPD1 , NPC1 , and NPC2 genes, respectively. Depending on the type of mutation and the clinical symptoms of the disease, the treatment will be different. The general aim of the current study is to review the clinical and molecular characteristics of patients with NPD and study various treatment methods for this disease with a focus on gene therapy approaches.
2024-01-12 | Niemann-Pick Disease: Seven Questions about it
Acid sphingomyelinase deficiency is a rare hereditary disease caused by enzyme deficiency due to mutations in the SMPD1 gene. Decreased enzyme activity leads to accumulation of sphingomyelin in lysosomes. This disease is characterized by wide diversity of clinical manifestations: from infantile neurovisceral form (Niemann-Pick disease type A) with severe rapidly progressive neurodegeneration to chronic visceral form (Niemann-Pick disease type B) with almost no central nervous system involvement. There is also intermediate phenotype: chronic neurovisceral form (Niemann-Pick disease type A/B) that includes manifestations two other forms, both visceral and neurological. The disease course is most commonly progressive and multi-system due to sphingomyelin accumulation in cells of the monocyte-macrophage system, as well as in other cells such as hepatocytes.
cell therapies
2024-07-09 | Course of Niemann – Pick disease type A/B in the context of hematopoietic stem cell transplantation
Niemann – Pick disease type A/B (NPAB) is a rare severe inherited disease from the group of accumulation diseases with a defect in the acid sphingomyelinase gene (Niemann-Pick disease types B, A/B) (ASMD). Symptoms of damage to the nervous system and internal organs manifest in infancy, leading to disability, fatalities in childhood. NPAB is so far incurable. Optimal management of the disease requires a multidisciplinary team of physicians, specialists. The basis of therapy is the elimination of existing/forming complications, symptomatic treatment. Enzyme replacement therapy as a means of modifying the course of this disease is expected to slow down the progression of pathologic manifestations of the disease not related to the central nervous system lesions. Single cases of hematopoietic stem cell transplantation (HSCT) have been described in the treatment of ASMD, which is one of the new methods aimed at normalizing the level of acid sphingomyelinase, blood parameters, as well as reducing the severity of pathological visceral manifestations. However, the development of complications during HSCT, absence of positive therapeutic effect in severe CNS lesions does not allow to widely implement this method. Taking into account the contradictory data on the efficacy of HSCT in ASMD, further clinical studies are required. Analysis of 2 clinical cases of NPAB in children from the same family allowed us to reveal differences in the course and outcomes of the disease at verification of the diagnosis at birth followed by HSCT. Difficulties in diagnosing this extremely rare pathology, which requires a multidisciplinary approach, justify the need to improve methods of early diagnosis, including the organization of genetic risk determination, introduction of prenatal genetic testing before pregnancy.
2019-06-16 | Pulmonary Type B Niemann-Pick Disease Successfully Treated with Lung Transplantation
Niemann-Pick Disease (NPD) type B is a rare autosomal recessive disease characterised by hepatosplenomegaly and pulmonary disease, highlighted by preserved volumes and diminished diffusion capacity of the lung for carbon monoxide (DLCO) on pulmonary function tests (PFTs). There is no current accepted treatment for the disease. We present a case of a successful bilateral lung transplant in a patient with a DLCO of 14%, and significant pulmonary changes attributable to NPD type B on computed tomography (CT) chest, and both microscopic and macroscopic assessment of the lung explant. To the author's knowledge this is only the third case of lung transplantation in a patient with NPD type B and is one of two current living patients post lung transplantation for NPD type B.A 64-year-old male patient underwent bilateral lung transplantation for NPD type B. Preoperative PFTs demonstrated preserved volumes with significantly decreased DLCO, with imaging showing a diffuse reticular interstitial pattern, typical of chronic fibrotic lung disease. The patient suffered from primary graft dysfunction type 3 in the postoperative period as well as rejection managed with methylprednisolone and intravenous immunoglobulin. The patient improved steadily and was discharged 80 days post-transplantation.This case is only the third reported case of lung transplantation in a patient with NPD type B and the second case of a patient with NPD type B currently living post-transplantation, being at postoperative day (POD) 267 at the time of manuscript drafting. It demonstrates that lung transplantation, although hazardous, is a viable strategy for treatment in patients with NPD type B who have significant pulmonary involvement.
2015-12-01 | Liver Transplantation in Patients With Niemann-Pick Disease – Single-Center Experience
Niemann-Pick disease (NPD) is a rare syndrome caused by abnormal intracellular sphingomyelin lipid storage in cells known as "Pick cells." NPD can start in childhood or develop insidiously, with a predilection for reticuloendothelial cells and the nervous system. NPD is a heterogeneous clinical, and biomolecular disorder which has 6 variants. There is no curable treatment for NPD. Generally, the treatment for all types of Niemann-Pick disease is to support. Type B NPD (NPD-B) is mostly characterized by hepatosplenomegaly, which can evolve to hepatic cirrhosis. In patients who progress to liver failure, liver transplantation may be improve liver function. The Transplant Service of Hospital Universitário Walter Cantídio performed its first liver transplants in patients with NPD-B with good results, demonstrating the efficacy of this procedure in selected cases.
2012-12-11 | NIEMANN PICK DISEASE – A CASE REPORT
Niemann Pick Disease ( NPD) is a rare autosomal recessive metabolic disease characterized by lysosomal lipid storage.The disease is caused by deficiency of enzyme, acid sphingomyelinase (ASM) which leads to accumulation of sphingomyelin & other lipids in reticuloendothelial cells of various organs like liver, spleen, bone marrow, lymph node, brain, nerves and kidney.Four types of the disease have been identified which are A, B, C and D. The type C is divided into types C1 and C2, each caused by a different gene mutation.We report a case of Niemann Pick Disease type B. The patient was a 10 month male child who presented with repeated episodes of vomiting and loose motions.His blood counts revealed pancytopenia.Bone marrow (BM) aspiration was performed which showed many large histiocytes with foamy cytoplasm-Niemann Pick cells which are characteristic of this disease.Further confirmatory investigations were not done because of nonaffordability of parents.At present no definite treatment is available however newer treatment modalities like Bone Marrow transplant, enzyme replacement therapy and gene therapy are likely to be useful especially in NPD type B. However such treatment is unlikely to prevent or reverse the major neurological complications of NPD type A. Supportive treatment through nutrition,medication, physical therapy can help to improve quality of life.
2003-12-01 | Niemann–Pick disease: Sixteen‐year follow‐up of allogeneic bone marrow transplantation in a type B variant
Abstract Summary : Allogenic bone marrow transplantation (BMT) was carried out on a 3‐year‐old white caucasian girl with Niemann–Pick disease (NPD) type B. The donor was her unaffected brother. The patient was neurologically normal at the time of transplantation. Engraftment was based on cytogenetic studies and increased leukocyte acid sphingomyelinase (ASM) activity. However, liver biopsies taken up to 33 months post transplantation showed only a moderate reduction in stored sphingomyelin and no significant increase in ASM activity. The post‐transplantation period was complicated by severe graft‐versus‐host disease and a respiratory arrest. By 6 years of age, neurological involvement was observed, including bilateral cherry red spots. The proband is now severely mentally and physically disabled. Liver cirrhosis has continued to progress despite the BMT, and haematemesis due to portal hypertension occurred at 17 years of age. However, pulmonary infiltration regressed after BMT and there has been no clinical evidence of pulmonary insufficiency.
proteins
2026-09-03 | Targeting of Acid Sphingomyelinase, a Lysosomal Membrane Protein, Using Apolipoprotein E3-containing Nanodiscs.
We developed a nanodisc (ND)-based platform with recombinant acid sphingomyelinase (ASM) embedded in a bilayer of phospholipids that are circumscribed by apolipoprotein E3 (apoE3) for targeted delivery to lysosomes. We designed a fusion protein comprising essential catalytic segments of ASM with a transmembrane helix at one end (TM-ASMcat). Purified TM-ASMcat was reconstituted with phospholipids and the N-terminal (NT) domain of apoE3 to promote the formation of NDs (TM-ASMcat-ND). Physicochemical characterization revealed the presence of both TM-ASMcat (35 kDa) and apoE3NT (24 kDa) in the preparations, and formation of large complexes (400-600 kDa). Transmission electron microscopy of TM-ASMcat-ND revealed discoidal complexes (major/minor axes of 30.9 ± 11.9/8.6 ± 2.0 nm, respectively), while atomic force microscopy showed NDs ~ 14 nm high. The TM-ASMcat-ND displayed a significant ability to hydrolyze sphingomyelin at pH 5. LC-MS/MS of glioblastoma cells treated with TM-ASMcat-ND revealed a significant decrease (22.3%) in total sphingomyelin content compared to cells treated with PBS. Sphingolipidomic analysis showed a trend of decrease in specific sphingomyelin species compared to empty ND-treated cells. Immunofluorescence analysis revealed perinuclear vesicles showing colocalization of ASM with apoE3 and Lysotracker, indicative of successful targeting of TM-ASMcat-ND to the lysosomes. Taken together, our data indicate that TM-ASMcat has been embedded in ND, and that it retains catalytic activity in solution and inside the cells. Our findings bear the potential to treat ASM deficiency in Niemann-Pick disease Type A and B, which are lysosomal storage disorders characterized by the accumulation of sphingomyelin.
2026-04-28 | Adults With Acid Sphingomyelinase Deficiency Have Sustained Improvements in Clinical Outcomes With up to 5 Years of Olipudase Alfa Enzyme Replacement Therapy: ASCEND Trial Final Results.
Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.
2026-04-24 | Improvement in quality of life and general functions in pediatric acid sphingomyelinase deficiency patients after receiving olipudase alfa: A single-center experience in Taiwan.
The ultra-rare lysosomal storage disease, Acid sphingomyelinase deficiency (ASMD), is currently managed with olipudase alfa, an enzyme replacement therapy (ERT). Specifically targeting the non-neurological manifestations in chronic ASMD cases, olipudase alfa has demonstrated efficacy in reducing disease burdens through clinical trials and real-world studies. However, data on the impact of olipudase alfa on quality of life and its real-world influences are limited. By May 2024, two pediatric patients-Patient 1 (P1) and Patient 2 (P2)-diagnosed with chronic neurovisceral ASMD A/B had undergone three years of olipudase alfa treatment in a single tertiary medical center in southern Taiwan. Throughout the treatment course, major outcomes including neurocognitive function and functional capability assessments were measured regularly. The primary caregivers completed the PedsQL™ version 4.0 questionnaire for the evaluation of the quality of life of the patients. Additionally, the progress of major symptoms was independently assessed using a customized questionnaire. Following treatment with olipudase alfa, the six-minute walking distance improved from zero to 127.7 m in P1 and from zero to 340 m in P2. Functional capability, measured by the EDSS and pmRS scales, showed no decline in either patient. Quality of life, evaluated using the PedsQL 4.0 generic scales, which measures the frequency of discomfort caused by the disease, showed improvement for both patients. The total score decreased from 64 to 55 in P1 and from 58 to 39 in P2, with the greatest improvement observed in physical functioning. Among the major symptoms and signs, abdominal fullness and growth failure showed the most notable improvements. However, the caregiver noted increased emotional challenges in P1, particularly due to fear of needle injections following treatment. For P1, the full-scale IQ score fell from the 0.2nd percentile at baseline to below the 0.1st percentile after three years of enzyme replacement therapy (ERT). In P2, Bayley III scores for cognitive, language, and motor domains remained below the 1st percentile compared to age- and gender-matched controls, showing no obvious improvement or deterioration after treatment. ERT improves functional capacity and quality of life in two pediatric patients with chronic neurovisceral ASMD A/B. Further data from larger samples are required to confirm these findings.
2026-04-15 | Features of liver damage in Niemann — Pick disease type A, A/B and B (deficiency of acidic sphingomyelinase)
Background. Acid sphingomyelinase deficiency (Niemann – Pick disease) leads to the intracellular accumulation of sphingomyelin within the mononuclear phagocyte system, including liver, spleen, lungs and bone marrow. Liver involvement represents one of the earliest and persistent visceral manifestations of the disease. Foamy macrophages featuring prominent cytoplasmic vacuolation are generated within the liver. Intracellular accumulation of pathological substrates in hepatocytes results in several pathological changes, including inflammation and cytokine release, remodeling of the sinusoidal network, periportal and bridging fibrosis and progressive portal hypertension. Dyslipidemia, associated with Niemann – Pick disease, is characterised by elevated levels of various lipid fractions. Gradual lipid accumulation leads to the liver enlargement (hepatomegaly) and the development of hepatic steatosis. Hepatomegaly, biochemical abnormalities and progressive fibrosis significantly impair the patients' quality of life and adversely affect the prognosis of the disease. Objective. To analyze current data on the pathogenesis, clinical manifestations, morphological features, and treatment of liver damage in Niemann – Pick disease types A, A/B, and B. Materials and methods. A systematic review of publications from 2013-2025 on the clinical presentation, histopathology, and treatment of acid sphingomyelinase deficiency was conducted, including the impact of enzyme replacement therapy on liver pathology. Results. The liver is a key target organ in Niemann – Pick disease types A, A/B, and B. The spectrum of liver changes includes hepatomegaly, parenchymal infiltration with foamy macrophages, progressive fibrosis, cirrhosis, hepatic steatosis, and the possible development of portal hypertension and liver failure requiring transplantation. The severity of liver damage and the age at onset of changes depend on the disease phenotype. Liver failure, in addition to respiratory disease, is the leading cause of death in chronic forms of Niemann – Pick disease. Modern enzyme replacement therapy can reduce liver volume, improve biochemical parameters, and slow the progression of fibrosis. Conclusion. Early diagnosis and pathogenetic therapy are key to slowing the progression of liver disease in acid sphingomyelinase deficiency.
2026-02-16 | Pathogenic Variants and Olipudase Alfa Treatment of Patients With Acid Sphingomyelinase Deficiency in Taiwan.
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal disorder with diverse clinical presentations and often delayed diagnosis. This study investigates the clinical features, genetic variants, and treatment outcomes in Taiwanese patients. We retrospectively reviewed nine ASMD cases in Taiwan, including genetic data and responses to olipudase alfa. Newborn screening data using the NeoLSD MS/MS kit for dried blood spot enzyme activity, followed by lyso-sphingomyelin and molecular testing, were also analysed. The SMPD1 c.1497_1498inv variant was found in 62.5% of alleles among chronic neurovisceral ASMD cases, while c.995C > G appeared in 37.5% of chronic visceral ASMD cases and was also frequent in partial ASMD from newborn screening. Four patients received olipudase alfa; Patient 1, treated for 3 years starting at age 41, showed improved pulmonary function despite persistent thrombocytopenia and splenomegaly. Patients 2, 6, and 7, treated from early childhood, exhibited marked improvements in hepatosplenomegaly, interstitial lung disease, and growth within 1 year of therapy. This study highlights distinct genotype-phenotype correlations in ASMD and supports the clinical benefits of olipudase alfa. Increased awareness and early diagnosis, potentially through newborn screening, are essential for optimizing outcomes in ASMD.
small molecules
2026-04-26 | Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann–Pick type C disease
Abstract Background and Purpose Niemann–Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small‐molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol‐lowering effects via regulating intestinal cholesterol absorption and liver cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic Ca 2+ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal cholesterol has not been fully clarified. Experimental Approach Effects of curcumin on lysosomal cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin‐induced cholesterol reduction. Key Results CUR alleviates lysosomal cholesterol accumulation in NPC1 cells in a TFEB‐ and TFE3‐dependent manner. CUR enhanced lysosomal acidity and promoted calcium‐dependent lysosomal exocytosis, which contributed to CUR‐mediated lysosomal cholesterol clearance. The combination of CUR with specific agonists (ML‐SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal cholesterol clearance. Conclusion and Implications CUR reduces lysosomal cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting Ca 2+ ‐ and TRPML1‐dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and other diseases of lysosomal storage.
2026-04-09 | Zuclopenthixol inhibits residual activity of acid sphingomyelinase in Niemann pick disease type B: a case report with in vitro validation
Niemann-Pick disease type B (NPD-B) is a rare lysosomal storage disorder characterized by residual activity of acid sphingomyelinase (ASM). While functional inhibitors of ASM (FIASMAs) are widely prescribed as psychotropic medications, they may pose a particular risk to patients with NPD-B by further reducing the already impaired enzymatic function. Here, we report the case of a 20-year-old male with genetically confirmed NPD-B who experienced rapid clinical deterioration following the administration of zuclopenthixol, a drug not previously associated with FIASMA activity. Within 48 hours of treatment initiation, the patient developed profound lethargy and markedly elevated creatine kinase (CK) levels of up to 22,000 U/L, consistent with rhabdomyolysis. Symptoms resolved quickly after discontinuation of zuclopenthixol. In vitro experiments using a radioactive [1 4 C]-sphingomyelin assay in Jurkat cells demonstrated that zuclopenthixol dose-dependently inhibited ASM activity by up to 71.5%. Zuclopenthixol had not previously been recognized as a FIASMA and might therefore have been considered a rational choice for treating patients with NPD-B. Our findings challenge this assumption by identifying zuclopenthixol as a potent inhibitor of ASM activity. This novel insight is of high clinical relevance, given the frequent use of antipsychotics in the management of neuropsychiatric symptoms in lysosomal storage disorders. We propose that zuclopenthixol and other potential FIASMAs be carefully re-evaluated for use in this vulnerable patient population.
2026-04-03 | Discovery of Autophagy Modulators that Increase I1061T NPC1 Expression and Promote Cholesterol Efflux in Niemann-Pick Type C Patient-Derived Fibroblasts
Autophagy, an evolutionarily conserved catabolic process, has been implicated as a potential therapeutic target in Niemann-Pick Type C (NPC) disease, a fatal lysosomal storage disorder. Our goal was to identify autophagy modulators that positively impact NPC-relevant phenotypes to further evaluate the role of autophagy in this disease. Using a phenotypic high-throughput screen for autophagy modulation and a subsequent secondary assay in homozygous I1061T NPC1 patient-derived fibroblasts, two compounds, 1 and 2, were identified that induced autophagy and reduced unesterified cholesterol accumulation to a level comparable to the reduction achieved by 2-hydroxypropyl-β-cyclodextrin. Global protein expression changes were evaluated in I1061T NPC1 fibroblasts following treatment with compounds 1 and 2 to identify affected pathways, and we observed a significant reduction of lysosomal hydrolase levels induced by compound 2. Additional mechanistic studies revealed that the expression of NPC1 protein is required for compound-induced amelioration of cholesterol accumulation and that compound 2 increases expression levels of I1061T NPC1 without broadly inhibiting proteasomal activity or exacerbating ER stress. These results have led to the hypothesis that compound 2 may serve as a proteostasis modulator or small-molecule chaperone that upregulates autophagy to a level that is predominantly cytoprotective and increases the proportion of properly folded mutant NPC1, thus increasing NPC1 expression levels and alleviating cholesterol accumulation and associated phenotypes. This work, along with future mechanistic studies, contributes to the development of novel strategies to modulate autophagy and proteostasis with potentially broad therapeutic applications.
2026-01-01 | Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study
Abstract Background Acid sphingomyelinase deficiency (ASMD) A and B, historically known as Niemann-Pick (NP) types A (NPA) and B (NPB), are life-threatening and rare inherited lysosomal storage disorders, caused by a deficiency in the acid sphingomyelinase enzyme activity. The negative outcome of this deficiency is the sphingomyelin (SM) accumulation in different organs and tissues. Trehalose is a natural disaccharide with neuroprotective and autophagy-inducing abilities that has recently been shown to improve clinical and biochemical features of patients with ASMD A/B. We previously showed that trehalose can reduce the serum levels of sphingomyelins and improve disease symptoms caused by lipid accumulation in ASMD A/B patients. Aim The aim of this study was to investigate the serum metabolome changes in five patients with ASMD A/B, who received 15 g/week of trehalose intravenously for three months, using an untargeted gas chromatography-mass spectrometry (GC-MS) method. Methods and materials GC-MS technique was used to assess the serum metabolic profile of patients with ASMD A/B. MSDIAL was used for data processing, and multivariate data analysis including Principal Component Analysis (PCA), and Orthogonal projections to latent structures discriminant analysis (OPLS-DA) algorithms were carried out using SIMCA. Results OPLS-DA model revealed significant changes in several serum metabolites including phosphate (P = 0.0019), sorbitol (P = 0.00009), myoinositol (P = 0.02), threonine (P = 0.01), lactic acid (P = 0.0001), 1-monopalmitin (P = 0.01), threitol (P = 0.002), ribitol (P = 0.008), and D-ribose (P = 0.007) following trehalose treatment. Conclusion The findings revealed that the beneficial effects of trehalose in patients with ASMD might be mediated by metabolic alterations. A clear shift in glucose metabolism in favor of less fatty acid production together with facilitating the breakdown of sphingomyelins is involved in the observed protective activity.
2025-02-07 | Short Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects During LPS-induced Lung Injury in Mice
Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick Disease (NPD) that, in Type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional Smpd1 (Smpd1-/- mice) deletion causes lung inflammation with foamy dysfunctional macrophages, but is protective against acute lung injury. It is unknown whether these manifestations are from progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, Smpd1fl/flxCAGG-CreERTM, induced by tamoxifen (5 weeks), with decreased Smpd1 expression (by 75%) and ASM activity (by up to 40%). We investigated how brief post-developmental ASM insufficiency affects lung sphingolipids and pathology including following lipopolysaccharide (LPS)-induced injury. Compared to controls, Smpd1fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios, increased de novo sphingolipid synthesis and sphingosine-1 phosphate levels. At 3 days following LPS instillation (20μg) control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1fl/fl mice showed more exuberant inflammation with reduced apoptosis, particularly in endothelial cells. During repair (6-9 days), Smpd1fl/fl lungs had increased cell proliferation with reduced autophagosome-tagging p62/SQSTM1. These results indicate that prior to significant lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and stimulates repair following inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of NPD and the role of distinct sphingolipid metabolites in lung injury and repair.
gene therapies
2025-10-12 | Current and Emerging Treatments for Acid Sphingomyelinase Deficiency.
Acid sphingomyelinase deficiency is an ultra-rare disease characterised by generalised storage of sphingomyelin, caused by deficiency of the lysosomal enzyme acid sphingomyelinase, owing to the presence of biallelic pathogenic variants in the SMPD1 gene. The main disease manifestations are in the liver, spleen, lung and bone - with some patients having also involvement of the central nervous system. Patients show variable degrees of anaemia, thrombocytopenia and lipid abnormalities, among other findings. Clinically, acid sphingomyelinase deficiency spans from an acute neurovisceral form, with neurological involvement and early death (type A), to a chronic visceral disease, with no or minimal neurological manifestations (type B). An intermediate form, with chronic neurovisceral involvement, is presented by some patients (type A/B). Diagnosis involves the measurement of biomarkers, an assay of enzyme activity and genetic testing. Until a few years ago, treatment was mainly dependent on symptomatic management and bone marrow or solid organ (liver and/or lung) transplantation. In 2022, a specific enzyme replacement therapy with olipudase alfa was approved, and the results available indicate that it changed the therapeutic landscape for patients with acid sphingomyelinase deficiency type B and A/B. Research is being developed to address the needs of patients with acid sphingomyelinase deficiency type A, with gene therapy remaining as a promising approach.
2025-01-01 | Unraveling Genetic Complexity in Consanguineous Families: Integrating Pedigree Analysis and Genomic Testing for Rare Disease Diagnosis in Libya
Consanguinity makes rare autosomal genetic disorders more common. This issue remainsunstudied in Libyan populations. We investigated eight extended Libyan families fromMisurata, with a focus on families G and H from the third generation, who exhibited complexsyndromic presentations. Whole-exome sequencing (WES), Sanger validation, and clinicalphenotyping were employed to identify the molecular basis of disease. In Family G, three malesiblings were diagnosed with Niemann-Pick disease type A/B (NPD A/B) and a female siblingwith hypertrophic cardiomyopathy type 4 (HCM4). Genetic analysis revealed a homozygouspathogenic variant in SMPD1 consistent with NPD A/B, and a homozygous MYBPC3 variant(c.1483C>T, p.Arg495Trp) linked to HCM4. In Family H, double first-cousin consanguinitysegregated Joubert syndrome type 4 (JS4) in three siblings due to homozygous deletions in theNPHP1 gene. Additional heterozygous variants in NPC1 and MYBPC3 were detected acrossboth families, raising the possibility of polygenic modifiers and variable expressivity. Ourfindings reveal that the complexity of rare diseases in consanguineous populationsdemonstrates the co-occurrence of multiple diseases within the same family. This studyhighlights the diagnostic utility of WES in low-resource settings and endorses equitable,culturally informed genetic counselling frameworks to advance disparities in rare diseasemanagement and precision health interventions in Libya.
2024-10-23 | Chronic acid sphingomyelinase deficiency diagnosed in infancy/childhood in Polish patients: 2024 update.
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disease (LSD) associated with biallelic pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. The aim of this study was to provide the 2024 update on chronic visceral and neurovisceral ASMD diagnosed in the infancy/childhood in Polish patients. All the patients diagnosed in the pediatric age (0-18 years) with ASMD, both chronic neurovisceral and visceral type, and then systematically followed up, were enrolled into the study. A total number of 7 patients were enrolled into the study. Four patients were previously reported. Two patients were newly recognized with ASMD - 1 with chronic visceral and 1 with chronic neurovisceral ASMD. Splenomegaly was noted in all the patients while a mild liver enlargement was observed in 4 of 7 patients. All patients presented with decreased high-density lipoprotein cholesterol (HDL-C) and decreased serum 25-hydroxy-vitamin D concentration while almost all (6 of 7) with hypercholesterolemia. Cherry-red spot was observed in 5 of 7 patients, including 1 patient with neurovisceral type. Seven various SMPD1 gene variants were identified and missense variants were the most common types of genetic lesions, comprising 71% of all alleles. In all the screened patients, lyso-sphingomyelin (lyso-SM) in dried blood spot (DBS) was found elevated; however, the greater values were observed for patients with chronic neurovisceral type. Chronic acid sphingomyelinase deficiency (ASMD) is a slowly progressive disease. Pediatric ASMD is characterized by spleno-hepatomegaly, dyslipidemia (with decreased HDL-C as the most characteristic) and infiltrative (interstitial) lung disease. Both visceral and neurovisceral chronic ASMD patients could present with cherry-red spot. Both acid spingomyelinase activity and lyso-spingomyelin concentration in DBS should be regarded as a first-tier screening method into ASMD.
2024-05-07 | Overview of clinical, molecular, and therapeutic features of Niemann–Pick disease (types A, B, and C): Focus on therapeutic approaches
Abstract Niemann–Pick disease (NPD) is another type of metabolic disorder that is classified as lysosomal storage diseases (LSDs). The main cause of the disease is mutation in the SMPD1 (type A and B) or NPC1 or NPC2 (type C) genes, which lead to the accumulation of lipid substrates in the lysosomes of the liver, brain, spleen, lung, and bone marrow cells. This is followed by multiple cell damage, dysfunction of lysosomes, and finally dysfunction of body organs. So far, about 346, 575, and 30 mutations have been reported in SMPD1 , NPC1 , and NPC2 genes, respectively. Depending on the type of mutation and the clinical symptoms of the disease, the treatment will be different. The general aim of the current study is to review the clinical and molecular characteristics of patients with NPD and study various treatment methods for this disease with a focus on gene therapy approaches.
2024-01-12 | Niemann-Pick Disease: Seven Questions about it
Acid sphingomyelinase deficiency is a rare hereditary disease caused by enzyme deficiency due to mutations in the SMPD1 gene. Decreased enzyme activity leads to accumulation of sphingomyelin in lysosomes. This disease is characterized by wide diversity of clinical manifestations: from infantile neurovisceral form (Niemann-Pick disease type A) with severe rapidly progressive neurodegeneration to chronic visceral form (Niemann-Pick disease type B) with almost no central nervous system involvement. There is also intermediate phenotype: chronic neurovisceral form (Niemann-Pick disease type A/B) that includes manifestations two other forms, both visceral and neurological. The disease course is most commonly progressive and multi-system due to sphingomyelin accumulation in cells of the monocyte-macrophage system, as well as in other cells such as hepatocytes.
cell therapies
2024-07-09 | Course of Niemann – Pick disease type A/B in the context of hematopoietic stem cell transplantation
Niemann – Pick disease type A/B (NPAB) is a rare severe inherited disease from the group of accumulation diseases with a defect in the acid sphingomyelinase gene (Niemann-Pick disease types B, A/B) (ASMD). Symptoms of damage to the nervous system and internal organs manifest in infancy, leading to disability, fatalities in childhood. NPAB is so far incurable. Optimal management of the disease requires a multidisciplinary team of physicians, specialists. The basis of therapy is the elimination of existing/forming complications, symptomatic treatment. Enzyme replacement therapy as a means of modifying the course of this disease is expected to slow down the progression of pathologic manifestations of the disease not related to the central nervous system lesions. Single cases of hematopoietic stem cell transplantation (HSCT) have been described in the treatment of ASMD, which is one of the new methods aimed at normalizing the level of acid sphingomyelinase, blood parameters, as well as reducing the severity of pathological visceral manifestations. However, the development of complications during HSCT, absence of positive therapeutic effect in severe CNS lesions does not allow to widely implement this method. Taking into account the contradictory data on the efficacy of HSCT in ASMD, further clinical studies are required. Analysis of 2 clinical cases of NPAB in children from the same family allowed us to reveal differences in the course and outcomes of the disease at verification of the diagnosis at birth followed by HSCT. Difficulties in diagnosing this extremely rare pathology, which requires a multidisciplinary approach, justify the need to improve methods of early diagnosis, including the organization of genetic risk determination, introduction of prenatal genetic testing before pregnancy.
2019-06-16 | Pulmonary Type B Niemann-Pick Disease Successfully Treated with Lung Transplantation
Niemann-Pick Disease (NPD) type B is a rare autosomal recessive disease characterised by hepatosplenomegaly and pulmonary disease, highlighted by preserved volumes and diminished diffusion capacity of the lung for carbon monoxide (DLCO) on pulmonary function tests (PFTs). There is no current accepted treatment for the disease. We present a case of a successful bilateral lung transplant in a patient with a DLCO of 14%, and significant pulmonary changes attributable to NPD type B on computed tomography (CT) chest, and both microscopic and macroscopic assessment of the lung explant. To the author's knowledge this is only the third case of lung transplantation in a patient with NPD type B and is one of two current living patients post lung transplantation for NPD type B.A 64-year-old male patient underwent bilateral lung transplantation for NPD type B. Preoperative PFTs demonstrated preserved volumes with significantly decreased DLCO, with imaging showing a diffuse reticular interstitial pattern, typical of chronic fibrotic lung disease. The patient suffered from primary graft dysfunction type 3 in the postoperative period as well as rejection managed with methylprednisolone and intravenous immunoglobulin. The patient improved steadily and was discharged 80 days post-transplantation.This case is only the third reported case of lung transplantation in a patient with NPD type B and the second case of a patient with NPD type B currently living post-transplantation, being at postoperative day (POD) 267 at the time of manuscript drafting. It demonstrates that lung transplantation, although hazardous, is a viable strategy for treatment in patients with NPD type B who have significant pulmonary involvement.
2015-12-01 | Liver Transplantation in Patients With Niemann-Pick Disease – Single-Center Experience
Niemann-Pick disease (NPD) is a rare syndrome caused by abnormal intracellular sphingomyelin lipid storage in cells known as "Pick cells." NPD can start in childhood or develop insidiously, with a predilection for reticuloendothelial cells and the nervous system. NPD is a heterogeneous clinical, and biomolecular disorder which has 6 variants. There is no curable treatment for NPD. Generally, the treatment for all types of Niemann-Pick disease is to support. Type B NPD (NPD-B) is mostly characterized by hepatosplenomegaly, which can evolve to hepatic cirrhosis. In patients who progress to liver failure, liver transplantation may be improve liver function. The Transplant Service of Hospital Universitário Walter Cantídio performed its first liver transplants in patients with NPD-B with good results, demonstrating the efficacy of this procedure in selected cases.
2012-12-11 | NIEMANN PICK DISEASE – A CASE REPORT
Niemann Pick Disease ( NPD) is a rare autosomal recessive metabolic disease characterized by lysosomal lipid storage.The disease is caused by deficiency of enzyme, acid sphingomyelinase (ASM) which leads to accumulation of sphingomyelin & other lipids in reticuloendothelial cells of various organs like liver, spleen, bone marrow, lymph node, brain, nerves and kidney.Four types of the disease have been identified which are A, B, C and D. The type C is divided into types C1 and C2, each caused by a different gene mutation.We report a case of Niemann Pick Disease type B. The patient was a 10 month male child who presented with repeated episodes of vomiting and loose motions.His blood counts revealed pancytopenia.Bone marrow (BM) aspiration was performed which showed many large histiocytes with foamy cytoplasm-Niemann Pick cells which are characteristic of this disease.Further confirmatory investigations were not done because of nonaffordability of parents.At present no definite treatment is available however newer treatment modalities like Bone Marrow transplant, enzyme replacement therapy and gene therapy are likely to be useful especially in NPD type B. However such treatment is unlikely to prevent or reverse the major neurological complications of NPD type A. Supportive treatment through nutrition,medication, physical therapy can help to improve quality of life.
2003-12-01 | Niemann–Pick disease: Sixteen‐year follow‐up of allogeneic bone marrow transplantation in a type B variant
Abstract Summary : Allogenic bone marrow transplantation (BMT) was carried out on a 3‐year‐old white caucasian girl with Niemann–Pick disease (NPD) type B. The donor was her unaffected brother. The patient was neurologically normal at the time of transplantation. Engraftment was based on cytogenetic studies and increased leukocyte acid sphingomyelinase (ASM) activity. However, liver biopsies taken up to 33 months post transplantation showed only a moderate reduction in stored sphingomyelin and no significant increase in ASM activity. The post‐transplantation period was complicated by severe graft‐versus‐host disease and a respiratory arrest. By 6 years of age, neurological involvement was observed, including bilateral cherry red spots. The proband is now severely mentally and physically disabled. Liver cirrhosis has continued to progress despite the BMT, and haematemesis due to portal hypertension occurred at 17 years of age. However, pulmonary infiltration regressed after BMT and there has been no clinical evidence of pulmonary insufficiency.
proteins
2026-09-03 | Targeting of Acid Sphingomyelinase, a Lysosomal Membrane Protein, Using Apolipoprotein E3-containing Nanodiscs.
We developed a nanodisc (ND)-based platform with recombinant acid sphingomyelinase (ASM) embedded in a bilayer of phospholipids that are circumscribed by apolipoprotein E3 (apoE3) for targeted delivery to lysosomes. We designed a fusion protein comprising essential catalytic segments of ASM with a transmembrane helix at one end (TM-ASMcat). Purified TM-ASMcat was reconstituted with phospholipids and the N-terminal (NT) domain of apoE3 to promote the formation of NDs (TM-ASMcat-ND). Physicochemical characterization revealed the presence of both TM-ASMcat (35 kDa) and apoE3NT (24 kDa) in the preparations, and formation of large complexes (400-600 kDa). Transmission electron microscopy of TM-ASMcat-ND revealed discoidal complexes (major/minor axes of 30.9 ± 11.9/8.6 ± 2.0 nm, respectively), while atomic force microscopy showed NDs ~ 14 nm high. The TM-ASMcat-ND displayed a significant ability to hydrolyze sphingomyelin at pH 5. LC-MS/MS of glioblastoma cells treated with TM-ASMcat-ND revealed a significant decrease (22.3%) in total sphingomyelin content compared to cells treated with PBS. Sphingolipidomic analysis showed a trend of decrease in specific sphingomyelin species compared to empty ND-treated cells. Immunofluorescence analysis revealed perinuclear vesicles showing colocalization of ASM with apoE3 and Lysotracker, indicative of successful targeting of TM-ASMcat-ND to the lysosomes. Taken together, our data indicate that TM-ASMcat has been embedded in ND, and that it retains catalytic activity in solution and inside the cells. Our findings bear the potential to treat ASM deficiency in Niemann-Pick disease Type A and B, which are lysosomal storage disorders characterized by the accumulation of sphingomyelin.
2026-04-28 | Adults With Acid Sphingomyelinase Deficiency Have Sustained Improvements in Clinical Outcomes With up to 5 Years of Olipudase Alfa Enzyme Replacement Therapy: ASCEND Trial Final Results.
Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.
2026-04-24 | Improvement in quality of life and general functions in pediatric acid sphingomyelinase deficiency patients after receiving olipudase alfa: A single-center experience in Taiwan.
The ultra-rare lysosomal storage disease, Acid sphingomyelinase deficiency (ASMD), is currently managed with olipudase alfa, an enzyme replacement therapy (ERT). Specifically targeting the non-neurological manifestations in chronic ASMD cases, olipudase alfa has demonstrated efficacy in reducing disease burdens through clinical trials and real-world studies. However, data on the impact of olipudase alfa on quality of life and its real-world influences are limited. By May 2024, two pediatric patients-Patient 1 (P1) and Patient 2 (P2)-diagnosed with chronic neurovisceral ASMD A/B had undergone three years of olipudase alfa treatment in a single tertiary medical center in southern Taiwan. Throughout the treatment course, major outcomes including neurocognitive function and functional capability assessments were measured regularly. The primary caregivers completed the PedsQL™ version 4.0 questionnaire for the evaluation of the quality of life of the patients. Additionally, the progress of major symptoms was independently assessed using a customized questionnaire. Following treatment with olipudase alfa, the six-minute walking distance improved from zero to 127.7 m in P1 and from zero to 340 m in P2. Functional capability, measured by the EDSS and pmRS scales, showed no decline in either patient. Quality of life, evaluated using the PedsQL 4.0 generic scales, which measures the frequency of discomfort caused by the disease, showed improvement for both patients. The total score decreased from 64 to 55 in P1 and from 58 to 39 in P2, with the greatest improvement observed in physical functioning. Among the major symptoms and signs, abdominal fullness and growth failure showed the most notable improvements. However, the caregiver noted increased emotional challenges in P1, particularly due to fear of needle injections following treatment. For P1, the full-scale IQ score fell from the 0.2nd percentile at baseline to below the 0.1st percentile after three years of enzyme replacement therapy (ERT). In P2, Bayley III scores for cognitive, language, and motor domains remained below the 1st percentile compared to age- and gender-matched controls, showing no obvious improvement or deterioration after treatment. ERT improves functional capacity and quality of life in two pediatric patients with chronic neurovisceral ASMD A/B. Further data from larger samples are required to confirm these findings.
2026-04-15 | Features of liver damage in Niemann — Pick disease type A, A/B and B (deficiency of acidic sphingomyelinase)
Background. Acid sphingomyelinase deficiency (Niemann – Pick disease) leads to the intracellular accumulation of sphingomyelin within the mononuclear phagocyte system, including liver, spleen, lungs and bone marrow. Liver involvement represents one of the earliest and persistent visceral manifestations of the disease. Foamy macrophages featuring prominent cytoplasmic vacuolation are generated within the liver. Intracellular accumulation of pathological substrates in hepatocytes results in several pathological changes, including inflammation and cytokine release, remodeling of the sinusoidal network, periportal and bridging fibrosis and progressive portal hypertension. Dyslipidemia, associated with Niemann – Pick disease, is characterised by elevated levels of various lipid fractions. Gradual lipid accumulation leads to the liver enlargement (hepatomegaly) and the development of hepatic steatosis. Hepatomegaly, biochemical abnormalities and progressive fibrosis significantly impair the patients' quality of life and adversely affect the prognosis of the disease. Objective. To analyze current data on the pathogenesis, clinical manifestations, morphological features, and treatment of liver damage in Niemann – Pick disease types A, A/B, and B. Materials and methods. A systematic review of publications from 2013-2025 on the clinical presentation, histopathology, and treatment of acid sphingomyelinase deficiency was conducted, including the impact of enzyme replacement therapy on liver pathology. Results. The liver is a key target organ in Niemann – Pick disease types A, A/B, and B. The spectrum of liver changes includes hepatomegaly, parenchymal infiltration with foamy macrophages, progressive fibrosis, cirrhosis, hepatic steatosis, and the possible development of portal hypertension and liver failure requiring transplantation. The severity of liver damage and the age at onset of changes depend on the disease phenotype. Liver failure, in addition to respiratory disease, is the leading cause of death in chronic forms of Niemann – Pick disease. Modern enzyme replacement therapy can reduce liver volume, improve biochemical parameters, and slow the progression of fibrosis. Conclusion. Early diagnosis and pathogenetic therapy are key to slowing the progression of liver disease in acid sphingomyelinase deficiency.
2026-02-16 | Pathogenic Variants and Olipudase Alfa Treatment of Patients With Acid Sphingomyelinase Deficiency in Taiwan.
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal disorder with diverse clinical presentations and often delayed diagnosis. This study investigates the clinical features, genetic variants, and treatment outcomes in Taiwanese patients. We retrospectively reviewed nine ASMD cases in Taiwan, including genetic data and responses to olipudase alfa. Newborn screening data using the NeoLSD MS/MS kit for dried blood spot enzyme activity, followed by lyso-sphingomyelin and molecular testing, were also analysed. The SMPD1 c.1497_1498inv variant was found in 62.5% of alleles among chronic neurovisceral ASMD cases, while c.995C > G appeared in 37.5% of chronic visceral ASMD cases and was also frequent in partial ASMD from newborn screening. Four patients received olipudase alfa; Patient 1, treated for 3 years starting at age 41, showed improved pulmonary function despite persistent thrombocytopenia and splenomegaly. Patients 2, 6, and 7, treated from early childhood, exhibited marked improvements in hepatosplenomegaly, interstitial lung disease, and growth within 1 year of therapy. This study highlights distinct genotype-phenotype correlations in ASMD and supports the clinical benefits of olipudase alfa. Increased awareness and early diagnosis, potentially through newborn screening, are essential for optimizing outcomes in ASMD.
small molecules
2026-04-26 | Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann–Pick type C disease
Abstract Background and Purpose Niemann–Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small‐molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol‐lowering effects via regulating intestinal cholesterol absorption and liver cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic Ca 2+ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal cholesterol has not been fully clarified. Experimental Approach Effects of curcumin on lysosomal cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin‐induced cholesterol reduction. Key Results CUR alleviates lysosomal cholesterol accumulation in NPC1 cells in a TFEB‐ and TFE3‐dependent manner. CUR enhanced lysosomal acidity and promoted calcium‐dependent lysosomal exocytosis, which contributed to CUR‐mediated lysosomal cholesterol clearance. The combination of CUR with specific agonists (ML‐SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal cholesterol clearance. Conclusion and Implications CUR reduces lysosomal cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting Ca 2+ ‐ and TRPML1‐dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and other diseases of lysosomal storage.
2026-04-09 | Zuclopenthixol inhibits residual activity of acid sphingomyelinase in Niemann pick disease type B: a case report with in vitro validation
Niemann-Pick disease type B (NPD-B) is a rare lysosomal storage disorder characterized by residual activity of acid sphingomyelinase (ASM). While functional inhibitors of ASM (FIASMAs) are widely prescribed as psychotropic medications, they may pose a particular risk to patients with NPD-B by further reducing the already impaired enzymatic function. Here, we report the case of a 20-year-old male with genetically confirmed NPD-B who experienced rapid clinical deterioration following the administration of zuclopenthixol, a drug not previously associated with FIASMA activity. Within 48 hours of treatment initiation, the patient developed profound lethargy and markedly elevated creatine kinase (CK) levels of up to 22,000 U/L, consistent with rhabdomyolysis. Symptoms resolved quickly after discontinuation of zuclopenthixol. In vitro experiments using a radioactive [1 4 C]-sphingomyelin assay in Jurkat cells demonstrated that zuclopenthixol dose-dependently inhibited ASM activity by up to 71.5%. Zuclopenthixol had not previously been recognized as a FIASMA and might therefore have been considered a rational choice for treating patients with NPD-B. Our findings challenge this assumption by identifying zuclopenthixol as a potent inhibitor of ASM activity. This novel insight is of high clinical relevance, given the frequent use of antipsychotics in the management of neuropsychiatric symptoms in lysosomal storage disorders. We propose that zuclopenthixol and other potential FIASMAs be carefully re-evaluated for use in this vulnerable patient population.
2026-04-03 | Discovery of Autophagy Modulators that Increase I1061T NPC1 Expression and Promote Cholesterol Efflux in Niemann-Pick Type C Patient-Derived Fibroblasts
Autophagy, an evolutionarily conserved catabolic process, has been implicated as a potential therapeutic target in Niemann-Pick Type C (NPC) disease, a fatal lysosomal storage disorder. Our goal was to identify autophagy modulators that positively impact NPC-relevant phenotypes to further evaluate the role of autophagy in this disease. Using a phenotypic high-throughput screen for autophagy modulation and a subsequent secondary assay in homozygous I1061T NPC1 patient-derived fibroblasts, two compounds, 1 and 2, were identified that induced autophagy and reduced unesterified cholesterol accumulation to a level comparable to the reduction achieved by 2-hydroxypropyl-β-cyclodextrin. Global protein expression changes were evaluated in I1061T NPC1 fibroblasts following treatment with compounds 1 and 2 to identify affected pathways, and we observed a significant reduction of lysosomal hydrolase levels induced by compound 2. Additional mechanistic studies revealed that the expression of NPC1 protein is required for compound-induced amelioration of cholesterol accumulation and that compound 2 increases expression levels of I1061T NPC1 without broadly inhibiting proteasomal activity or exacerbating ER stress. These results have led to the hypothesis that compound 2 may serve as a proteostasis modulator or small-molecule chaperone that upregulates autophagy to a level that is predominantly cytoprotective and increases the proportion of properly folded mutant NPC1, thus increasing NPC1 expression levels and alleviating cholesterol accumulation and associated phenotypes. This work, along with future mechanistic studies, contributes to the development of novel strategies to modulate autophagy and proteostasis with potentially broad therapeutic applications.
2026-01-01 | Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study
Abstract Background Acid sphingomyelinase deficiency (ASMD) A and B, historically known as Niemann-Pick (NP) types A (NPA) and B (NPB), are life-threatening and rare inherited lysosomal storage disorders, caused by a deficiency in the acid sphingomyelinase enzyme activity. The negative outcome of this deficiency is the sphingomyelin (SM) accumulation in different organs and tissues. Trehalose is a natural disaccharide with neuroprotective and autophagy-inducing abilities that has recently been shown to improve clinical and biochemical features of patients with ASMD A/B. We previously showed that trehalose can reduce the serum levels of sphingomyelins and improve disease symptoms caused by lipid accumulation in ASMD A/B patients. Aim The aim of this study was to investigate the serum metabolome changes in five patients with ASMD A/B, who received 15 g/week of trehalose intravenously for three months, using an untargeted gas chromatography-mass spectrometry (GC-MS) method. Methods and materials GC-MS technique was used to assess the serum metabolic profile of patients with ASMD A/B. MSDIAL was used for data processing, and multivariate data analysis including Principal Component Analysis (PCA), and Orthogonal projections to latent structures discriminant analysis (OPLS-DA) algorithms were carried out using SIMCA. Results OPLS-DA model revealed significant changes in several serum metabolites including phosphate (P = 0.0019), sorbitol (P = 0.00009), myoinositol (P = 0.02), threonine (P = 0.01), lactic acid (P = 0.0001), 1-monopalmitin (P = 0.01), threitol (P = 0.002), ribitol (P = 0.008), and D-ribose (P = 0.007) following trehalose treatment. Conclusion The findings revealed that the beneficial effects of trehalose in patients with ASMD might be mediated by metabolic alterations. A clear shift in glucose metabolism in favor of less fatty acid production together with facilitating the breakdown of sphingomyelins is involved in the observed protective activity.
2025-02-07 | Short Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects During LPS-induced Lung Injury in Mice
Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick Disease (NPD) that, in Type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional Smpd1 (Smpd1-/- mice) deletion causes lung inflammation with foamy dysfunctional macrophages, but is protective against acute lung injury. It is unknown whether these manifestations are from progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, Smpd1fl/flxCAGG-CreERTM, induced by tamoxifen (5 weeks), with decreased Smpd1 expression (by 75%) and ASM activity (by up to 40%). We investigated how brief post-developmental ASM insufficiency affects lung sphingolipids and pathology including following lipopolysaccharide (LPS)-induced injury. Compared to controls, Smpd1fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios, increased de novo sphingolipid synthesis and sphingosine-1 phosphate levels. At 3 days following LPS instillation (20μg) control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1fl/fl mice showed more exuberant inflammation with reduced apoptosis, particularly in endothelial cells. During repair (6-9 days), Smpd1fl/fl lungs had increased cell proliferation with reduced autophagosome-tagging p62/SQSTM1. These results indicate that prior to significant lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and stimulates repair following inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of NPD and the role of distinct sphingolipid metabolites in lung injury and repair.
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