Clinical evaluation and treatment of tauopathic syndromes remain a challenge. There is a growing interest in theories concerning their possible associations with metabolic diseases. The possible connection between those diseases might be linked with cerebrovascular dysfunction. The endothelial cell damage and impairment of the blood-brain barrier observed in atherosclerosis or diabetes may play a role in contributing to tauopathic syndrome development. Additionally, the inflammation evoked by pathological metabolic changes may also be involved in this process. Multiple cases indicate the coexistence of metabolic disorders and tauopathic syndromes. These findings suggest that modifying the evolution of metabolic and cerebrovascular diseases may impact the course of neurodegenerative diseases. Obtained data could indicate the possible benefits of introducing routine carotid artery sonography, revascularization operation or antihypertensive medications among patients at high risk for tauopathies. This review has identified this understudied area, which is currently associated with several diseases for which there is no treatment. Due to the pathomechanisms linking metabolic diseases and tauopathies, further investigation of this area of research, including cohort studies, is recommended and may provide new pharmacological perspectives for treatment.

Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann-Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or had a first- or second-degree relative affected by the disorder. No specific criteria were set for the age of the participants. All were between 15 and 18 weeks of gestation. Using amplicon-based next-generation sequencing (NGS), we analyzed the zygosity and variants in cffDNA extracted from maternal peripheral blood. After amplicon NGS, analysis was completed by a custom data analysis pipeline that included in-house-built data processing scripts and commonly used software packages. Importantly, the results were not disclosed to the patients. Our findings showed that in all three cases, AR cffDNA screening results were consistent with standard invasive diagnostic testing. This screening method offers several advantages: it provides critical information to families earlier in the pregnancy compared to invasive diagnostic tests, and it helps to alleviate parental anxiety. Moreover, this non-invasive method can determine pregnancy status in the first trimester for known familial variants. Future research may extend this approach to screen for known disease-causing variants in common AR conditions.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease types A, A/B, and B is a progressive, life-limiting, autosomal recessive disorder caused by sphingomyelin phosphodiesterase 1 (SMPD1) gene mutations. There is a need to increase the understanding of morbidity and mortality across children to adults diagnosed with ASMD.
METHODS: This observational retrospective survey analysed medical records of patients with ASMD with retrievable data from 27 hospitals in France, diagnosed/followed up between 1st January 1990 and 31st December 2020. Eligible records were abstracted to collect demographic, medical/developmental history, and mortality data. Survival outcomes were estimated from birth until death using Kaplan-Meier survival analyses; standardised mortality ratio (SMR) was also explored.
RESULTS: A total of 118 medical records of patients with ASMD (type B [n = 94], type A [n = 15], and type A/B [n = 9]) were assessed. The majority of patients were males (63.6%); the median [range] age at diagnosis was 8.0 [1.0-18.0] months (type A), 1.0 [0-3] year (type A/B), and 5.5 [0-73] years (type B). Overall, 30 patients were deceased at the study completion date; the median [range] age at death for patients with ASMD type A (n = 14) was 1 [0-3.6] year, type A/B (n = 6) was 8.5 [3.0-30.9] years, and type B (n = 10) was 57.6 [3.4-74.1] years. The median [95% confidence interval (CI)] survival age from birth in patients with ASMD type A and type A/B was 2.0 [1.8-2.7] years and 11.4 [5.5-18.5] years, respectively. Survival analysis in ASMD type B was explored using SMR [95% CI] analysis (3.5 [1.6-5.9]), which showed that age-specific deaths in the ASMD type B population were 3.5 times more frequent than those in the general French population. The causes of death were mostly severe progressive neurodegeneration (type A: 16.7%), cancer (type B: 16.7%), or unspecified (across groups: 33.3%).
CONCLUSIONS: This study illustrated a substantial burden of illness with high mortality rates in patients with ASMD, including adults with ASMD type B, in France.

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.

Biomarkers are molecules that can be used to observe changes in an individual\'s biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer\'s disease, Parkinson\'s disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.

UNASSIGNED: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients.
UNASSIGNED: This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan-Meier survival analyses from birth until death.
UNASSIGNED: The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD \"non-type A\" (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications.
UNASSIGNED: Patients with chronic ASMD in the United States have poor survival and significant burden of illness.

Cyclodextrins are often used as molecular carriers for small active ingredients in medicine. Recently, the intrinsic medicinal activity of some of these compounds has been under investigation, mainly related to their ability to interfere with cholesterol and, therefore, prevent and treat cholesterol-related diseases such as cardiovascular disease and neuronal diseases arising from altered cholesterol and lipid metabolism. One of the most promising compounds within the cyclodextrin family is 2-hydroxypropyl-β-cyclodextrin (HPβCD), owing to its superior biocompatibility profile. This work presents the most recent advances in the research and clinical use of HPβCD against Niemann-Pick disease, a congenital condition involving cholesterol accumulation inside lysosomes in brain cells, Alzheimer\'s and Parkinson\'s. HPβCD plays a complex role in each of these ailments, going beyond the mere sequestering of cholesterol molecules and involving an overall regulation of protein expression that helps restore the normal functioning of the organism.

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.
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.
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.
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).

Niemann-Pick (NPD) is a rare autosomal recessive disease, caused by deficiency of acid sphingomyelinase enzyme leading to accumulation of lipids mainly in the reticuloendothelial system and lungs. We describe the case of a 29-year-old primigravida, recently diagnosed with NPD type B. At initial evaluation, her platelets were normal, liver enzymes slightly elevated and splenomegaly on scan. Pregnancy care was by a multidisciplinary team which routinely monitored her liver and pulmonary functions along with platelets. Labor was induced at 37 + 1 weeks of gestation because of fetal growth restriction. She underwent an cesarean section for failed induction and delivered a healthy male baby. Conclusion: Successful outcomes in such pregnancies depend upon close monitoring by a multidisciplinary team.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a progressive neurodegenerative disorder with early infantile (< 2 years), late infantile (2-6 years), juvenile (7-15 years) and adolescent (> 15 years) onset. The mainstay of therapy for NP-C patients with neurological symptoms is miglustat, a drug that may modify the course of the disease.
OBJECTIVE: Our aim was to evaluate the cost-effectiveness of miglustat in comparison to symptomatic therapy in patients with NP-C in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy.
METHODS: The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was eighty years. The main outcomes of the study were quality-adjusted life years gained with miglustat and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Discrete-Event Simulation model. The model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients.
RESULTS: Treatment with miglustat was not cost-effective when compared with symptomatic therapy and was associated with negative values of net monetary benefit regardless of the onset of neurological manifestations (- 110,447,627.00 ± 701,614.00 RSD, - 343,871,695.00 ± 2,577,441.00 RSD, - 1,397,908,502.00 ± 23,084,235.00 RSD and - 2,953,680,879.00 ± 33,297,412.00 RSD) for early infantile, late infantile, juvenile and adolescent cohorts, respectively).
CONCLUSIONS: When traditional pharmacoeconomic evaluation is employed, miglustat is not a cost-effective option in comparison to symptomatic therapy for the treatment of NP-C. However, given the proven efficacy of miglustat, there is a need to find ways to make this drug available to all patients with NP-C.