A retrospective study of morbidity and mortality of chronic acid sphingomyelinase deficiency in Germany.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, potentially fatal lysosomal storage disease that exhibits a broad spectrum of clinical phenotypes. There is a need to expand the knowledge of disease mortality and morbidity in Germany because of limited information on survival analysis in patients with chronic ASMD (type B or type A/B). METHODS: This observational, multicentre, retrospective cohort study was conducted using medical records of patients with the first symptom onset/diagnosis of ASMD type B or type A/B between 1st January 1990 and 31st July 2021 from four German medical centres. Eligible medical records were abstracted to collect data on demographic characteristics, medical history, hospitalisation, mortality, and causes of death from disease onset to the last follow-up/death. Survival outcomes were estimated using the Kaplan-Meier analysis. Standardised mortality ratio (SMR) was also explored. RESULTS: This study included 33 chart records of patients with ASMD type B (n = 24) and type A/B (n = 9), with a median (interquartile range [IQR]) age of 8.0 [3.0-20.0] years and 1.0 [1.0-2.0] years, respectively, at diagnosis. The commonly reported manifestations were related to spleen (100.0%), liver (93.9%), and respiratory (77.4%) abnormalities. Nine deaths were reported at a median [IQR] age of 17.0 [5.0-25.0] years, with 66.7% of overall patients deceased at less than 18 years of age; the median [IQR] age at death for patients with ASMD type B (n = 4) and type A/B (n = 5) was 31.0 [11.0-55.0] and 9.0 [4.0-18.0] years, respectively. All deaths were ASMD-related and primarily caused by liver or respiratory failures or severe progressive neurodegeneration (two patients with ASMD type A/B). The median (95% confidence interval [CI]) overall survival age since birth was 45.4 (17.5-65.0) years. Additionally, an SMR [95% CI] analysis (21.6 [9.8-38.0]) showed that age-specific deaths in the ASMD population were 21.6 times more frequent than that in the general German population. CONCLUSIONS: This study highlights considerable morbidity and mortality associated with ASMD type B and type A/B in Germany. It further emphasises the importance of effective therapy for chronic ASMD to reduce disease complications.

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

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

Real-life impacts of olipudase alfa: The experience of patients and families taking an enzyme replacement therapy for acid sphingomyelinase deficiency.

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is an ultra-rare autosomal recessive lysosomal storage disorder characterized by intracellular lipid accumulation resulting from reduced function of acid sphingomyelinase. Olipudase alfa, an enzyme replacement therapy, was recently approved in several countries for the treatment of the non-neurologic manifestations of ASMD. Studies demonstrate improvement in organomegaly, pulmonary function and lipid profiles with olipudase alfa, yet little is known about its impact on quality of life (QoL) for patients and caregivers. The purpose of this study is to better understand the real-life impact of ASMD on patients and caregivers and assess how olipudase alfa impacts QoL for pediatric patients and their caregivers. METHODS: Caregivers of pediatric patients (≤ 18 years of age) with a confirmed diagnosis of ASMD that received olipudase alfa for at least 12 months were recruited in early 2022 through national patient organizations to participate in a global online questionnaire followed by semi-structured interviews. Ten caregivers of patients with ASMD who utilized olipudase alfa as an experimental therapy for pediatric patients participated in the study. Quantitative analysis of the results was undertaken, and qualitative data was analyzed using an inductive thematic approach. RESULTS: Ten eligible participants completed questionnaires, and 8 of the 10 went on to participate in structured interviews. Symptom burden of ASMD and impact on symptomatology and quality of life after olipudase alfa use are reported here. Five themes emerged from analysis: (1) ASMD is a systemic disease with a wide array of manifestations that significantly impact QoL; (2) Olipudase alfa was associated with improvements in all non-neurologic manifestations of ASMD; (3) Participants perceived the risk associated with olipudase alfa to be low and the benefits to greatly outweigh any risk or burden; (4) Participants reported an unmet need to treat the neurologic manifestations of the disease despite the benefits of olipudase alfa in the management of non-neurological symptoms; (5) Participants felt all patients with ASMD need access to olipudase alfa based on the life-changing experience they perceived. CONCLUSIONS: These findings highlight the sustained positive impact olipudase alfa had in many domains that are deemed important to patients and families living with ASMD and outline the extensive unmet need for patients and families living with ASMD.

Neurons regulate the esterification of bioactive lipid mediators in the brain of acid sphingomyelinase deficient mice.

Acid sphingomyelinase deficiency is a neurodegenerative lysosomal storage disorder caused by mutations in the sphingomyelin-degrading enzyme acid sphingomyelinase (ASM) gene. Upregulated neuroinflammation has been well-characterized in an ASM knockout mouse model of acid sphingomyelinase deficiency disease, but lipid mediator pathways involved in 'mediating' inflammation and inflammation-resolution have yet to be characterized. In this study, we 1) measured free (bioactive) and esterified (inactive) lipid mediators involved in inflammation and inflammation resolution in cerebellum and neuronal cultures of ASM knockout (ASMko) mice and wildtype (WT) controls, and 2) quantified the esterification of labeled pro-resolving free d11-14(15)-epoxyeicosatrienoic acid in cultured neurons from ASMko and WT mice. We found elevated concentrations of esterified pro-resolving lipid mediators and hydroxyeicosatrienoic acids typically destined for pro-resolving lipid mediator synthesis (e.g. lipoxins) in the cerebellum and neurons of ASMko mice compared to controls. Free d11-14(15)-epoxyeicosatrienoic acid esterification within neurons of ASMko mice was significantly elevated compared to WT. Our findings show evidence of increased inactivation of free pro-resolving lipid mediators through esterification in ASMko mice, suggesting impaired resolution as a new pathway underlying ASM deficiency pathogenesis.

Development and validation of a new genotype-phenotype correlation for Niemann-Pick disease type C1.

Hundreds of NPC1 variants cause highly heterogeneous phenotypes. This study aims to explore the genotype-phenotype correlation of NPC1, especially for missense variants. In a well-characterized cohort, phenotypes are graded into three clinical forms: mild, intermediate, and severe. Missense residue structural location was stratified into three categories: surface, partially, and fully buried. The association of phenotypes with the topography of the amino acid substitution in the protein structure was investigated in our cohort and validated in two reported cohorts. One hundred six unrelated NPC1 patients were enrolled. A significant correlation of genotype-phenotype was found in 81 classified individuals with two or one (the second was null variant) missense variant (p < 0.001): of 25 patients with at least one missense variant of surface (group A), 19 (76%) mild, six (24%) intermediate, and none severe; of 31 cases with at least one missense variant of partially buried without surface variants (group B), 11 (35%) mild, 16 (52%) intermediate, and four (13%) severe; of the remaining 25 patients with two or one buried missense variants (group C), eight (32%) mild, nine (36%) intermediate, and eight (32%) severe. Additionally, 7-ketocholesterol, the biomarker, was lower in group A than in group B (p = 0.024) and group C (p = 0.029). A model was proposed that accurately predicted phenotypes of 72 of 90 (80%), 73 of85 (86%), and 64 of 69 (93%) patients in our cohort, Italian, and UK cohort, respectively. This study proposed a novel genotype-phenotype correlation in NPC1, linking the underlying molecular pathophysiology with clinical phenotype and aiding genetic counseling and evaluation in clinical practice.

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.

Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. RESULTS: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. CONCLUSION: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

[Ocular manifestation of an adult Niemann-Pick disease type B]. / Felnottkori B-típusú Niemann­Pick-betegség szemészeti manifesztációja.

Niemann-Pick disease is a rare, autosomal recessive inherited lysosomal storage disorder. The pathophysiological background for this condition is the deficiency or reduced function of the enzyme sphingomyelinase, as well as a deficiency in the intracellular cholesterol transporter protein. Due to the breakdown defect, sphingomyelin and cholesterol accumulate in the lysosomes of cells. The disease is divided into 5 subtypes (A, A/B, B, C, D). The authors present the case of a 24-year-old young man diagnosed with Niemann-Pick disease type B as a child, focusing on the ophthalmic manifestation of the disease. During the examination of the patient, fundus photographs and fundus autofluorescence imaging were taken, and optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and visual field (perimetry) examinations were performed. The characteristic macular halo and the cherry-red spot in the fovea were clearly visible during ophthalmoscopy and on the fundus photographs. The OCT images showed focal thickening with high reflectivity in the ganglion cell layer corresponding to the macular halo, and the area of the foveola was spared. With visual field examination, an intact field of vision was found on both eyes. Similar to the presented patient, symptoms in patients with the B subtype are milder, and besides the visceral symptoms, there are no neurological symptoms, and the specific ophthalmic abnormalities do not cause visual impairment. Currently, Niemann-Pick disease is considered a rare disease, and the diagnosis of the patients is often delayed or even missed due to non-specific or mild symptoms. Through consultation between medical specialties, ophthalmological examination can also contribute to the correct diagnosis in cases with mild general symptoms. Timely diagnosis can potentially lead to mitigation of symptoms thanks to the ever-expanding therapeutic options, stabilization of the disease progression, and increase of the patients' life expectancy. Orv Hetil. 2023; 164(46): 1838-1844.

Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis.

Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease type A (NPA), type B (NPB) and type A/B (NPA/B), is a rare lysosomal storage disease characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was established by generating liver organoids from a NPB patient carrying the p.Arg610del variant in the SMPD1 gene. Liver organoids were characterized by transcriptomic and lipidomic analysis. We observed altered lipid homeostasis in the patient-derived organoids showing the predictable increase in sphingomyelin (SM), together with cholesterol esters (CE) and triacylglycerides (TAG), and a reduction in phosphatidylcholine (PC) and cardiolipins (CL). Analysis of lysosomal gene expression pointed to 24 downregulated genes, including SMPD1, and 26 upregulated genes that reflect the lysosomal stress typical of the disease. Altered genes revealed reduced expression of enzymes that could be involved in the accumulation in the hepatocytes of sphyngoglycolipids and glycoproteins, as well as upregulated genes coding for different glycosidases and cathepsins. Lipidic and transcriptome changes support the use of hepatic organoids as ideal models for ASMD investigation.

Screening for lysosomal diseases in a selected pediatric population: the case of Gaucher disease and acid sphingomyelinase deficiency.

BACKGROUND: GD and ASMD are lysosomal storage disorders that enter into differential diagnosis due to the possible overlap in their clinical manifestations. The availability of safe and effective enzymatic therapies has recently led many investigators to develop and validate new screening tools, such as algorithms, for the diagnosis of LSDs where the lack of disease awareness or failure to implement newborn screening results in a delayed diagnosis. RESULTS: the proposed algorithm allows for the clinical and biochemical differentiation between GD and ASMD. It is based on enzyme activity assessed on dried blood spots by multiplexed tandem mass spectrometry (MS/MS) coupled to specific biomarkers as second-tier analysis. CONCLUSIONS: we believe that this method will provide a simple, convenient and sensitive tool for the screening of a selected population that can be used by pediatricians and other specialists (such as pediatric hematologists and pediatric hepatologists) often engaged in diagnosing these disorders.

NPC1 plays a role in the trafficking of specific cargo to melanosomes.

Niemann-Pick type C1 (NPC1) protein is a multimembrane spanning protein of the lysosome limiting membrane that facilitates intracellular cholesterol and sphingolipid transport. Loss-of-function mutations in the NPC1 protein cause Niemann-Pick disease type C1, a lysosomal storage disorder characterized by the accumulation of cholesterol and sphingolipids within lysosomes. To investigate whether the NPC1 protein could also play a role in the maturation of the endolysosomal pathway, here, we have investigated its role in a lysosome-related organelle, the melanosome. Using a NPC1-KO melanoma cell model, we found that the cellular phenotype of Niemann-Pick disease type C1 is associated with a decreased pigmentation accompanied by low expression of the melanogenic enzyme tyrosinase. We propose that the defective processing and localization of tyrosinase, occurring in the absence of NPC1, is a major determinant of the pigmentation impairment in NPC1-KO cells. Along with tyrosinase, two other pigmentation genes, tyrosinase-related protein 1 and Dopachrome-tautomerase have lower protein levels in NPC1 deficient cells. In contrast with the decrease in pigmentation-related protein expression, we also found a significant intracellular accumulation of mature PMEL17, the structural protein of melanosomes. As opposed to the normal dendritic localization of melanosomes, the disruption of melanosome matrix generation in NPC1 deficient cells causes an accumulation of immature melanosomes adjacent to the plasma membrane. Together with the melanosomal localization of NPC1 in WT cells, these findings suggest that NPC1 is directly involved in tyrosinase transport from the trans-Golgi network to melanosomes and melanosome maturation, indicating a novel function for NPC1.

Effect of acid sphingomyelinase deficiency in type A Niemann-Pick disease on the transport of therapeutic nanocarriers across the blood-brain barrier.

ASM deficiency in Niemann-Pick disease type A results in aberrant cellular accumulation of sphingomyelin, neuroinflammation, neurodegeneration, and early death. There is no available treatment because enzyme replacement therapy cannot surmount the blood-brain barrier (BBB). Nanocarriers (NCs) targeted across the BBB via transcytosis might help; yet, whether ASM deficiency alters transcytosis remains poorly characterized. We investigated this using model NCs targeted to intracellular adhesion molecule-1 (ICAM-1), transferrin receptor (TfR), or plasmalemma vesicle-associated protein-1 (PV1) in ASM-normal vs. ASM-deficient BBB models. Disease differentially changed the expression of all three targets, with ICAM-1 becoming the highest. Apical binding and uptake of anti-TfR NCs and anti-PV1 NCs were unaffected by disease, while anti-ICAM-1 NCs had increased apical binding and decreased uptake rate, resulting in unchanged intracellular NCs. Additionally, anti-ICAM-1 NCs underwent basolateral reuptake after transcytosis, whose rate was decreased by disease, as for apical uptake. Consequently, disease increased the effective transcytosis rate for anti-ICAM-1 NCs. Increased transcytosis was also observed for anti-PV1 NCs, while anti-TfR NCs remained unaffected. A fraction of each formulation trafficked to endothelial lysosomes. This was decreased in disease for anti-ICAM-1 NCs and anti-PV1 NCs, agreeing with opposite transcytosis changes, while it increased for anti-TfR NCs. Overall, these variations in receptor expression and NC transport resulted in anti-ICAM-1 NCs displaying the highest absolute transcytosis in the disease condition. Furthermore, these results revealed that ASM deficiency can differently alter these processes depending on the particular target, for which this type of study is key to guide the design of therapeutic NCs.

Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency.

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neuroinflammation and neurodegeneration for which there is no effective treatment. Cellular accumulation of sphingomyelin (SM) is a pathological hallmark in all tissues. SM is the only sphingolipid comprised of a phosphocholine group linked to ceramide. Choline is an essential nutrient that must be obtained from the diet and its deficiency promotes fatty liver disease in a process dependent on ASM activity. We thus hypothesized that choline deprivation could reduce SM production and have beneficial effects in ASMD. Using acid sphingomyelinase knock-out (ASMko) mice, which mimic neurovisceral ASMD, we have assessed the safety of a choline-free diet and its effects on liver and brain pathological features such as altered sphingolipid and glycerophospholipid composition, inflammation and neurodegeneration. We found that the choline-free diet was safe in our experimental conditions and reduced activation of macrophages and microglia in the liver and brain, respectively. However, there was no significant impact on sphingolipid levels and neurodegeneration was not prevented, arguing against the potential of this nutritional strategy to assist in the management of neurovisceral ASMD patients.

Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B).

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. METHODS: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. RESULTS: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. CONCLUSION: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).

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.

Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults.

BACKGROUND: Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. RESULTS: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment. CONCLUSIONS: Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .

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.

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.

Optical Coherence Tomography Findings in Cherry-Red Spot: Implications for Understanding Pathophysiology and Visual Prognosis.

PURPOSE: To report optical coherence tomography (OCT) findings of cherry-red spots from Tay-Sachs and Niemann-Pick disease. METHODS: Consecutive patients with Tay-Sachs and Niemann-Pick disease evaluated by the pediatric transplant and cellular therapy team, for whom a handheld OCT scan was obtained, were included. Demographic information, clinical history, fundus photography, and OCT scans were reviewed. Two masked graders evaluated each of the scans. RESULTS: The study included 3 patients with Tay-Sachs disease (5, 8, and 14 months old) and 1 patient with Niemann-Pick disease (12 months old). All patients had bilateral cherry-red spots on fundus examination. In all patients with Tay-Sachs disease, handheld OCT revealed parafoveal ganglion cell layer (GCL) thickening, increased nerve fiber layer, and GCL reflectivity, and different levels of residual normal signal GCL. The patient with Niemann-Pick disease had similar parafoveal findings, but there was a thicker residual GCL. Sedated visual evoked potentials were unrecordable in all 4 patients despite 3 of them demonstrating normal visual behavior for age. Patients with good vision had relative sparing of the GCL on OCT. CONCLUSIONS: The cherry-red spots in lysosomal storage diseases appear as perifoveal thickening and hyperreflectivity of the GCL on OCT. In this case series, residual GCL with normal signal proved to be a better biomarker for visual function than visual evoked potentials and could be considered for future therapeutic trials. [J Pediatr Ophthalmol Strabismus. 2023;60(6):435-440.].