The Long-term Lung and Respiratory Outcomes of Acid Sphingomyelinase Deficiency: A 10- and 20-year Follow-up Study.

BACKGROUND/AIM: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder characterized by sphingomyelin accumulation causing progressive lung disease, respiratory failure, and death. PATIENTS AND METHODS: This retrospective observational study used the TriNetX database of electronic health records for 15,108 patients with ASMD from 2000-2020. After exclusions, 8,980 individuals were followed for 10 or 20 years. Outcomes included incidence and prevalence of respiratory disorders. Associations of age, sex and race were assessed. RESULTS: Nearly all respiratory outcomes increased significantly over 20 versus 10 years. Other respiratory disorders, specified respiratory disorders and secondary pulmonary hypertension exhibited the greatest increases, reflecting progressive lung damage in ASMD. While outcomes were poor overall, older age, male sex, and racial minority status associated with greater risks, indicating differences in disease progression or care. CONCLUSION: This study confirms the progressive nature of ASMD and need for close monitoring and treatment of pulmonary complications to reduce long-term morbidity and mortality. Genetic testing enabling diagnosis even for milder, adult-onset forms is critical to optimize outcomes.

Glycoprotein non-metastatic protein B (GPNMB) plasma values in patients with chronic visceral acid sphingomyelinase deficiency.

Acid sphingomyelinase deficiency (ASMD) is a rare LSD characterized by lysosomal accumulation of sphingomyelin, primarily in macrophages. With the recent availability of enzyme replacement therapy, the need for biomarkers to assess severity of disease has increased. Glycoprotein non-metastatic protein B (GPNMB) plasma levels were demonstrated to be elevated in Gaucher disease. Given the similarities between Gaucher disease and ASMD, the hypothesis was that GPNMB might be a potential biochemical marker for ASMD as well. Plasma samples of ASMD patients were analyzed and GPNMB plasma levels were compared to those of healthy volunteers. Visceral disease severity was classified as severe when splenic, hepatic and pulmonary manifestations were all present and as mild to moderate if this was not the case. Median GPNMB levels in 67 samples of 19 ASMD patients were 185 ng/ml (range 70-811 ng/ml) and were increased compared to 10 healthy controls (median 36 ng/ml, range 9-175 ng/ml, p < 0.001). Median plasma GPNMB levels of ASMD patients with mild to moderate visceral disease compared to patients with severe visceral disease differed significantly and did not overlap (respectively 109 ng/ml, range 70-304 ng/ml and 325 ng/ml, range 165-811 ng/ml, p < 0.001). Correlations with other biochemical markers of ASMD (i.e. chitotriosidase activity, CCL18 and lysosphingomyelin, respectively R = 0.28, p = 0.270; R = 0.34, p = 0.180; R = 0.39, p = 0.100) and clinical parameters (i.e. spleen volume, liver volume, diffusion capacity and forced vital capacity, respectively R = 0.59, p = 0.061, R = 0.5, p = 0.100, R = 0.065, p = 0.810, R = -0.38, p = 0.160) could not be established within this study. The results of this study suggest that GPNMB might be suitable as a biomarker of visceral disease severity in ASMD. Correlations between GPNMB and biochemical or clinical markers of ASMD and response to therapy have to be studied in a larger cohort.

Importance to include differential diagnostics for acid sphingomyelinase deficiency (ASMD) in patients suspected to have to Gaucher disease.

The clinical manifestation of sphingolipidosis leads often to misclassification between acid sphingomyelinase deficiency (ASMD) and Gaucher disease. In this multicenter, prospective study, we investigated a cohort of 31,838 individuals suspected to have Gaucher disease, due to clinical presentation, from 61 countries between 2017 and 2022. For all samples, both Acid-ß-glucocerebrosidase and acid sphingomyelinase enzyme activities were measured in dried blood spot specimens by tandem mass spectrometry followed by genetic confirmatory testing in potential positive cases. In total, 5933 symptomatic cases showed decreased enzyme activities and were submitted for genetic confirmatory testing. 1411/5933 (24%) cases were finally identified with Gaucher disease and 550/5933 (9%) with ASMD. Most of the confirmed ASMD cases were newborns and children below 2 years of age (63%). This study reveals that one in four cases suspected for Gaucher disease is diagnosed with ASMD. An early appropriate diagnostic work-up is essential because of the availability of a recently approved enzyme replacement therapy for ASMD. In conclusion, a diagnostic strategy using differential biochemical testing including genetic confirmatory testing in clinically suspected cases for sphingolipidosis is highly recommended.

Acid sphingomyelinase deficiency (ASMD): addressing knowledge gaps in unmet needs and patient journey in Italy-a Delphi consensus.

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare disease, and several gaps of knowledge on various issues remain, particularly at a regional/national level. Expert opinions collected through well-defined consensus methodologies are increasingly used to make available reliable information in the context of rare/ultra-rare diseases. With the aim to provide indications on infantile neurovisceral ASMD (also formerly known as Niemann-Pick disease type A), chronic neurovisceral ASMD (formerly known as Niemann-Pick disease type A/B) and chronic visceral ASMD (formerly known as Niemann-Pick disease type B) in Italy, we conducted a Delphi consensus of experts focused on five main areas: (i) patients and disease characteristics; (ii) unmet needs and quality of life; (iii) diagnostic issues; (iv) treatment-related aspects; and (v) patient journey. Pre-specified, objective criteria were used to outline the multidisciplinary panel, based on 19 Italian experts in ASMD in paediatric and adult patients from different Italian Regions, including both clinicians (n = 16) and ASMD patients' advocacy or payors with expertise in rare diseases (n = 3). During two Delphi rounds, a high ratio of agreement was found on several topics related to ASMD characteristics, diagnosis, management and disease burden. Our findings may provide valuable indications for management of ASMD at a public health level in Italy.

SMPD1 expression profile and mutation landscape help decipher genotype-phenotype association and precision diagnosis for acid sphingomyelinase deficiency.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) disorder, also known as Niemann-Pick disease (NPD) is a rare genetic disease caused by mutations in SMPD1 gene, which encodes sphingomyelin phosphodiesterase (ASM). Except for liver and spleen enlargement and lung disease, two subtypes (Type A and B) of NDP have different onset times, survival times, ASM activities, and neurological abnormalities. To comprehensively explore NPD's genotype-phenotype association and pathophysiological characteristics, we collected 144 NPD cases with strict quality control through literature mining. RESULTS: The difference in ASM activity can differentiate NPD type A from other subtypes, with the ratio of ASM activity to the reference values being lower in type A (threshold 0.045 (4.45%)). Severe variations, such as deletion and insertion, can cause complete loss of ASM function, leading to type A, whereas relatively mild missense mutations generally result in type B. Among reported mutations, the p.Arg3AlafsX76 mutation is highly prevalent in the Chinese population, and the p.R608del mutation is common in Mediterranean countries. The expression profiles of SMPD1 from GTEx and single-cell RNA sequencing data of multiple fetal tissues showed that high expressions of SMPD1 can be observed in the liver, spleen, and brain tissues of adults and hepatoblasts, hematopoietic stem cells, STC2_TLX1-positive cells, mesothelial cells of the spleen, vascular endothelial cells of the cerebellum and the cerebrum of fetuses, indicating that SMPD1 dysfunction is highly likely to have a significant effect on the function of those cell types during development and the clinicians need pay attention to these organs or tissues as well during diagnosis. In addition, we also predicted 21 new pathogenic mutations in the SMPD1 gene that potentially cause the NPD, signifying that more rare cases will be detected with those mutations in SMPD1. Finally, we also analysed the function of the NPD type A cells following the extracellular milieu. CONCLUSIONS: Our study is the first to elucidate the effects of SMPD1 mutation on cell types and at the tissue level, which provides new insights into the genotype-phenotype association and can help in the precise diagnosis of NPD.

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.

Peripheral neuropathy as a very rare symptom in a patient with Niemann-Pick type C with negative enzymatic evaluation: a case report.

BACKGROUND: Niemann-Pick is a rare metabolic disease distinguished by lysosomal storage defects. This disease is characterized by sphingomyelinase acid deficiency, causing its accumulation in various organs such as the kidneys, spleen, liver, brain, and nerves. Niemann-Pick disease is categorized into four groups: A, B, C, and D. Peripheral neuropathy is an extremely rare complication in patients with Niemann-Pick type C, which certainly leads to neurologic deterioration. CASE PRESENTATION: We report a case of Niemann-Pick type C disease in a 3-year-old Iranian Azeri female patient who was hospitalized twice. The first time was at 1 month of age with symptoms of splenomegaly, jaundice, and elevated liver enzymes, and the second time was at around age 2 for loss of mental and physical abilities. The patient presented with failure to thrive. According to paraclinical examinations, mildly delayed myelination along with a nonspecific periventricular hypersignal intensity was seen. Interestingly, the patient's Niemann-Pick type C enzymatic function was evaluated twice and was negative on both occasions, while she was positive for NPC1 and NPC2 gene examinations. CONCLUSIONS: In this study, despite the enzymatic study being negative, Niemann-Pick type C disease was finally confirmed, revealing the importance of mutations in Niemann-Pick type C pathogenesis. Besides, peripheral neuropathy was diagnosed in this patient as a very rare symptom of Niemann-Pick type C.

A novel association between angiokeratoma corporis diffusum and acid sphingomyelinase deficiency.

Angiokeratoma corporis diffusum refers to symmetrical clusters of minute red papules in a "bathing trunk" distribution and is considered the cutaneous hallmark of Fabry disease. Acid sphingomyelinase deficiency is an autosomal recessive sphingolipidosis, which presents with massive hepatosplenomegaly, pulmonary infiltrates, and skeletal abnormalities. We present the unusual case of a 12-year-old girl with acid sphingomyelinase deficiency who developed characteristic lesions of angiokeratoma corporis diffusum.

Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD).

BACKGROUND: Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1, the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease. OBJECTIVES: To provide a contemporary guide of clinical assessments for disease monitoring and symptom management across the spectrum of ASMD phenotypes. METHODS: An international group of ASMD experts in various research and clinical fields used an evidence-informed consensus process to identify optimal assessments, interventions, and lifestyle modifications. RESULTS: Clinical assessment strategies for major organ system involvement, including liver, spleen, cardiovascular, pulmonary, and neurological/developmental are described, as well as symptomatic treatments, interventions, and/or life style modifications that may lessen disease impact. CONCLUSIONS: There is currently no disease-specific treatment for ASMD, although enzyme replacement therapy with a recombinant human ASM (olipudase alfa) is in clinical development. Current monitoring addresses symptoms and multisystem involvement. Recommended interventions and lifestyle modifications are designed to address morbidity and disease complications and improve patient quality of life. While infantile neurovisceral ASMD is uniformly fatal in early childhood, patients with chronic visceral and chronic neurovisceral ASMD require appropriate management throughout childhood and adulthood by an interdisciplinary clinical team.

Deep sequencing of SMPD1 gene revealed a heterozygous frameshift mutation (p.Ser192Alafs) in a Palestinian infant with Niemann-Pick disease type A: a case report.

BACKGROUND: Niemann-Pick disease is caused by reduced level of the lysosomal enzyme acid sphingomyelinase. Children can survive between 2 and 12 years based on the disease type. Two main types are well known: type A and B. Niemann-Pick disease type A is characterized by severe central nervous system deterioration and hepatosplenomegaly while type B is a progressive hypersplenism accompanied with gradual deterioration of pulmonary function. CASE PRESENTATION: We describe an 11-month-old Palestinian baby boy with hepatosplenomegaly, hypotonia, delayed motor development, laryngomalacia, bilateral cherry-red spots, and failure to thrive. Metabolic screening, blood count, differential tests, immunology screen, infectious disease screen, urine, biochemical tests as well as molecular diagnosis were performed. The molecular diagnosis was done by amplifying the whole sphingomyelin phosphodiesterase 1 (SMPD1) gene, followed by deep sequencing. The obtained sequences were aligned, de novo assembled and compared to human reference gene (GenBank GeneID: NG_011780.1, Ensembl version ENSG00000166311 and protein identified as UniProtKB - P17405). Two known mutations were identified in our patient: the pathogenic frameshift mutation NM_000543.4(SMPD1):c.573delT (p.Ser192Alafs) and the benign polymorphism NM_000543.4(SMPD1):c.107T>C (p.Val36Ala). The enzyme study showed a very low level of enzymatic activity of acidic sphingomyelinase (0.1 nmol/ml per hour). Correlations between clinical findings, laboratory data, and sequence analysis are presented. CONCLUSIONS: In conclusion, this is the first report about a heterozygote frameshift p.Ser192AlafsX65 in a Palestinian patient with Niemann-Pick disease type A, emphasizing the importance of deep sequencing in genetic diagnosis of this rare inherited disease.

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.

Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.

Disclaimer:This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases. BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease. The underlying metabolic defect is deficiency of the enzyme acid sphingomyelinase that results in progressive accumulation of sphingomyelin in target tissues. ASMD manifests as a spectrum of severity ranging from rapidly progressive severe neurovisceral disease that is uniformly fatal to more slowly progressive chronic neurovisceral and chronic visceral forms. Disease management is aimed at symptom control and regular assessments for multisystem involvement. PURPOSE AND METHODS: An international panel of experts in the clinical and laboratory evaluation, diagnosis, treatment/management, and genetic aspects of ASMD convened to review the evidence base and share personal experience in order to develop a guideline for diagnosis of the various ASMD phenotypes. CONCLUSIONS: Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers because it is important for primary care providers (e.g., pediatricians and internists) and specialists (e.g., pulmonologists, hepatologists, and hematologists) to be able to identify ASMD.Genet Med advance online publication 13 April 2017.

Quantitation of plasmatic lysosphingomyelin and lysosphingomyelin-509 for differential screening of Niemann-Pick A/B and C diseases.

Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Herein we present results of simultaneous LC-ESI-MS/MS measurements of lysosphingomyelin and lysosphingomyelin 509 in plasma and dried blood spots (DBS) collected from ASMd and NPC patients and suggest that the plasma but not DBS levels of the two analytes allow differential biochemical screening of ASMd and NPC.

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.

[Adult psychiatric aspects of Niemann-Pick disease]. / A Niemann-Pick betegség felnött pszichiátriai vonatkozásai.

Niemann-Pick disease (NPD) is a group of distinct rare disorders (i.e. NPD-A; NPD-B; NPD-C) - with autosomal recessive inheritance pattern - within the class of the inborn disorders of the sphingolipid metabolism (called sphingolipidoses). Since patients with NPD-A do not survive into adulthood and most patients with NPD-B are free from neuropsychiatric symptoms we discuss only briefly type-A and -B NPD and mainly constrict our review discussing the neuropsychiatric symptoms along with the pathomechanism and the treatment of NPD-C. NPD-C is clinically heterogeneous, with notable variations in age at onset, course and symptoms. Along with systemic signs, neurologic and psychiatric symptoms are quite frequent in NPD-C and in its adult form sometimes psychiatric symptoms are the first ones appearing. Unfortunately, the majority of clinicans (including adult psychiatrists and neurologists) are not aware of the symptom group characteristic to NPD-C so patients with this disorder are frequently misdiagnosed in the clinical practice. Since neuropsychiatric manifestations of NPD-C may be treated with a substrate reduction agent (miglustat) with greater awareness of the identification of neuropsychiatric symptoms in due course is the prerequisite of proper and early diagnosis and treatment.

Niemann-Pick disease type A presenting as unilateral tremors.

Niemann-Pick group of diseases are rare lysosomal storage disorders. The clinical phenotype is variable. We report a child who first time presented with tremors of tongue and tremors of one side of the body. On examination child had hemiparesis and hepatosplenomegaly. Bone marrow examination shows storage cells suggestive of Niemann-Pick cells and enzyme assay confirmed the diagnosis.

R542X mutation in SMPD1 gene: genetically novel mutation with phenotypic features intermediate between type A and type B Niemann-Pick disease.

Niemann-Pick disease (NPD) is a heterogenous group of progressive neurovisceral disorder characterised by lysosomal accumulation of sphingomyelin. NPD types A and B are caused by mutations involving sphingomyelin-phosphodiesterase-1 (SMPD1) gene and are characterised by deficiency of acid sphingomyelinase activity. We present a case of a 9-month infant with clinical manifestations intermediate between types A and B NPD and genetically illustrating a novel R542X mutation in the exon 6 of SMPD1.

Infant with type A Niemann Pick disease and undetectable Niemann Pick cells in bone marrow.

Bone marrow aspiration is the preliminary investigation in Niemann Pick disease type A when enzyme assays and mutation studies are unavailable. We report an infant with typical phenotype and enzyme deficiency, but undetectable Niemann Pick cells in the bone marrow. A new mutation R542X in SMPD gene was also detected.