Niemann-Pick Research Articles

Differently increased volumes of multiple brain areas in Npc1 mutant mice following various drug treatments.

Niemann-Pick disease type C1 (NPC1, MIM 257220) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of Npc1-/- displays a rapidly progressing form of Npc1 disease, which is characterized by weight loss, ataxia, and increased cholesterol storage. Npc1-/- mice receiving a combined therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) showed prevention of Purkinje cell loss, improved motor function and reduced intracellular lipid storage. Although therapy of Npc1-/- mice with COMBI, MIGLU or HPßCD resulted in the prevention of body weight loss, reduced total brain weight was not positively influenced. In order to evaluate alterations of different brain areas caused by pharmacotherapy, fresh volumes (volumes calculated from the volumes determined from paraffin embedded brain slices) of various brain structures in sham- and drug-treated wild type and mutant mice were measured using stereological methods. In the wild type mice, the volumes of investigated brain areas were not significantly altered by either therapy. Compared with the respective wild types, fresh volumes of specific brain areas, which were significantly reduced in sham-treated Npc1-/- mice, partly increased after the pharmacotherapies in all treatment strategies; most pronounced differences were found in the CA1 area of the hippocampus and in olfactory structures. Volumes of brain areas of Npc1-/- mice were not specifically changed in terms of functionality after administering COMBI, MIGLU, or HPßCD. Measurements of fresh volumes of brain areas in Npc1-/- mice could monitor region-specific changes and response to drug treatment that correlated, in part, with behavioral improvements in this mouse model.

Niemann-Pick Disease, Type A: Clinical Case of 5 Months Old Patient

Background. Niemann-Pick disease, type A is a rare hereditary disease from the group of lysosomal storage diseases, it is characterized by early onset and progressive course. Description of this disease’s clinical cases is crucial for early diagnosis and adequate management due to its rarity, rapid progression, and the development of new pathogenetic therapy methods.Clinical case description. The disease manifested on the second month of the patient’s life with poor weight gain, frequent pneumonia, hepatosplenomegaly, diffuse muscular hypotonia, delayed motor development, and progressive neurological symptoms. Laboratory testing has revealed significant decrease in sphingomyelinase activity in blood. The heterozygous deletion c.996del in exon 2 of the SMPD1 gene has been revealed via direct automatic sequencing; it leads to frameshifting p.F333Sfs*52 (inherited from mother). Moreover, the previously described pathogenic nucleotide variant c.1252C>T (heterozygous) has been revealed in exon 3 of the SMPD1 gene; it leads to translation arrest p.Arg418* (inherited from father). Cherry-red spots were diagnosed at fundospcopy. The diagnosis of Niemann-Pick disease, type А was established according to clinical signs and molecular genetic testing results.Conclusion. The detection of physical and motor development delay, diffuse muscular hypotonia, hepatosplenomegaly, cherry-red spots at ophthalmological examination, lung involvement, recurrent pneumonia, and progressive neurological symptoms in a child during the first months of life indicates that this patient has Niemann-Pick disease, type А. Early molecular genetic testing is crucial for timely choosing the management approach and further genetic counselling of the family.

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.

Clinical and genetic analysis of Niemann-Pick disease type C with a novel NPC1 variant

BackgroundNiemann-Pick disease type C poses a significant challenge within the landscape of rare genetic disorders, marked by its connection to variants in the NPC1 or NPC2 genes. This autosomal recessive lipid storage disorder unfolds with a relentless progression of neurological deterioration and a distinctive hallmark of hepatosplenomegaly.Case presentationThis case report delves into the intricate presentation of a 9-year-old Iraqi boy exhibiting heightened walking instability and speech slurring. His medical history unfolds a series of challenges, including neonatal hyperbilirubinemia, hepatosplenomegaly, and recurrent nasal bleeding. A comprehensive physical examination reveals motor and neurological abnormalities such as an inability to squat and rise, vertical gaze palsy, and dysdiadochokinesia. Further investigations, encompassing laboratory tests and imaging studies, coupled with the identification of foamy cells in bone marrow smears, raise significant concerns about Niemann-Pick disease type C. By utilizing whole exome sequencing, we pinpointed a previously unreported homozygous variant—c.2925_2928delCTGC; p.Cys976PhefsTer6—found within exon 20 (NM_000271.5) of the proband’s NPC1 gene.ConclusionsThis study significantly advances our understanding of the c.2925_2928del (C976Ffs*6) variant in the NPC1 gene, shedding light on the complexities of Niemann-Pick disease type C. Beyond its scientific significance, the findings provide crucial insights for familial genetic counseling and prenatal diagnoses. This research expands our knowledge of the variant’s genetic landscape, making it a valuable resource in both academic and clinical settings, particularly for families dealing with Niemann-Pick disease type C.

Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.

Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.

Duo-Chol: A Photoconvertible Live Cell Imaging Tool for Tracking Cholesterol.

Investigating cholesterol trafficking pathways continues to be of significant scientific interest owing to its homeostasis being associated with several debilitating cardiovascular and neurodegenerative diseases including atherosclerosis, Niemann-Pick's disease, Alzheimer's disease, and Parkinson's disease. To further our understanding of cholesterol trafficking, it is imperative to develop new fluorescent probes that possess improved photostability, low efflux, and high spatial and temporal resolution for live-cell imaging. In this study, we developed a photoconvertible fluorescent cholesterol analog, Duo-Chol, enabling the improved spatiotemporal fluorescence imaging of the dynamic localization of cholesterol in live cells. This tool provides a unique and powerful approach to interrogating cholesterol dynamics, addressing the limitations of existing methods, and expanding our ability to probe the biological role of sterols in living cells.

Ratiometric fluorescence nanoscopy and lifetime imaging of novel Nile Red analogs for analysis of membrane packing in living cells

Subcellular membranes have complex lipid and protein compositions, which give rise to organelle-specific membrane packing, fluidity, and permeability. Due to its exquisite solvent sensitivity, the lipophilic fluorescence dye Nile Red has been used extensively to study membrane packing and polarity. Further improvement of Nile Red can be achieved by introducing electron-donating or withdrawing functional groups. Here, we compare the potential of derivatives of Nile Red with such functional substitutions for super-resolution fluorescence microscopy of lipid packing in model membranes and living cells. All studied Nile Red derivatives exhibit cholesterol-dependent fluorescence changes in model membranes, as shown by spectrally resolved stimulated emission depletion (STED) microscopy. STED imaging of Nile Red probes in cells reveals lower membrane packing in fibroblasts from healthy subjects compared to those from patients suffering from Niemann Pick type C1 (NPC1) disease, a lysosomal storage disorder with accumulation of cholesterol and sphingolipids in late endosomes and lysosomes. We also find small but consistent changes in the fluorescence lifetime of the Nile Red derivatives in NPC1 cells, suggesting altered hydrogen-bonding capacity in their membranes. All Nile Red derivatives are essentially non-fluorescent in water but increase their brightness in membranes, allowing for their use in MINFLUX single molecule tracking experiments. Our study uncovers the potential of Nile Red probes with functional substitutions for nanoscopic membrane imaging.

Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice.

Systemic AAV9- hNPC1 gene therapy in null Npc1 m1N mice at higher doses or with earlier administration and treatment of hypomorphic Npc1 I1061T mice delays disease progression and increases lifespan.

PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease.

Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles (ILVs) and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. Although BMP synthase was recently discovered, it has long been thought that BMP's unique stereochemistry confers resistance to acid phospholipases, a requirement for its role in the lysosome. Here, we demonstrate that PLA2G15, a major lysosomal phospholipase, efficiently hydrolyzes BMP with primary esters regardless of stereochemistry. Interestingly, we discover that BMP's unique esterification position is what confers resistance to hydrolysis. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates. Conversely, BMP with secondary esters is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient tissues and cells accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. Increasing BMP levels by targeting PLA2G15 reverses the cholesterol accumulation phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorate disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and as a potential target for modulating BMP levels for therapeutic intervention.

Intracerebroventricular 2-hydroxypropyl-γ-cyclodextrin alleviates hepatic manifestations without distributing to the liver in a murine model of Niemann–Pick disease type C

Niemann–Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood–brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC.

Recent and anticipated novel drug approvals (Q2 2024 through Q1 2025).

Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. Selected drug approvals anticipated in the 12-month period covering the second quarter of 2024 through the first quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. New cellular and gene therapies for cancers continued to strengthen the pipeline, in addition to new drugs targeting previously untreatable conditions. Several novel drugs are being developed for rare and ultra-rare diseases such as hemophilia, Niemann-Pick disease type C, hereditary angioedema, and aromatic l-amino acid decarboxylase deficiency. The current drug pipeline includes new drugs with various indications for cancers and rare diseases as well as diabetes, acute coronary syndrome, chronic skin disorder, and chronic obstructive pulmonary disease.

Analysis of Metabolic Changes in Endogenous Metabolites and Diagnostic Biomarkers for Various Diseases Using Liquid Chromatography and Mass Spectrometry.

Analysis of endogenous metabolites in various diseases is useful for searching diagnostic biomarkers and elucidating the molecular mechanisms of pathophysiology. The author and collaborators have developed some LC/tandem mass spectrometry (LC/MS/MS) methods for metabolites and applied them to disease-related samples. First, we identified urinary conjugated cholesterol metabolites and serum N-palmitoyl-O-phosphocholine serine as useful biomarkers for Niemann-Pick disease type C (NPC). For the purpose of intraoperative diagnosis of glioma patients, we developed the LC/MS/MS analysis methods for 2-hydroxyglutaric acid or cystine and found that they could be good differential biomarkers. For renal cell carcinoma, we searched for various biomarkers for early diagnosis, malignancy evaluation and recurrence prediction by global metabolome analysis and targeted LC/MS/MS analysis. In pathological analysis, we developed a simultaneous LC/MS/MS analysis method for 13 steroid hormones and applied it to NPC cells, we found 6 types of reductions in NPC model cells. For non-alcoholic steatohepatitis (NASH), model mice were prepared with special diet and plasma bile acids were measured, and as a result, hydrophilic bile acids were significantly increased. In addition, we developed an LC/MS/MS method for 17 sterols and analyzed liver cholesterol metabolites and found a decrease in phytosterols and cholesterol synthetic markers and an increase in non-enzymatic oxidative sterols in the pre-onset stage of NASH. We will continue to challenge themselves to add value to clinical practice based on cutting-edge analytical chemistry methodology.

Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models

Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.

Adult niemann-pick disease: A case report

Adult niemann-pick disease: A case report

Drug‐refractory epilepsy as presenting feature of Niemann–Pick disease

AbstractNiemann–Pick disease type C (NPC) is a lipid storage disorder having varied neurological, psychiatric, and visceral manifestations. Twenty‐seven‐year‐old female presented to the hospital with recurrent episodes of seizures for the last one and half year. She had delayed motor and language milestones and was scholastically poor in school. On examination, vertical saccades were slow with downgaze restriction. Higher mental function examination revealed predominant impairment of frontal and temporal lobe functions. She also had intermittent oromandibular dyskinesis. Cerebrospinal fluid analysis showed nil cells with protein 28 mg/dL and glucose 54 mg/dL. MRI brain showed diffuse supratentorial cerebral atrophy with atrophy of corpus callosum and multiple subcortical and periventricular T2/FLAIR hyperintensities. A clinical suspicion of NPC was considered and genetic analysis showed homozygous mutation of the NPC‐2 gene on Exon 3. So, our case was unique in terms of drug‐refractory epilepsy was the presenting feature that led to the diagnosis of NPC.

Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function.

Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the pathogenesis of Alzheimer disease (AD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in the lysosomes of embryonic fibroblasts from Psen1-knockout (PS1-KO) and Psen2-KO (PS2-KO) mice and was associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport in late endosomal/lysosomal compartments. Mass spectrometry and complementary biochemical analyses also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes and decreased NPC1, thereby resembling the changes in PS1-KO and PS2-KO cells. In turn, treatment of PS1-KO and PS2-KO mouse embryonic fibroblasts (MEFs) with the chaperone inducer arimoclomol partially normalized NPC1 expression and rescued lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by overexpression of NPC1. Collectively, these data indicate that a loss of PS function results in impaired protein N-glycosylation, which eventually causes decreased expression of NPC1 and intracellular cholesterol accumulation. This mechanism could contribute to the neurodegeneration observed in PS KO mice and potentially to the pathogenesis of AD.

Insect Chemosensory Proteins against COVID-19

This article describes a novel strategy to fight SARS-CoV-2 infection by employing tiny soluble binding proteins called “Odorant Binding Proteins” (OBPs), “Niemann-Pick Type C2 (NPC2s)”, and “Chemosensory Proteins” (CSPs). The possible interactions between these proteins and sensory receptors are not relevant to COVID-19. We concentrate on the interaction between the protein-binding site and C18 lipids in COVID. Extended lipid chains, like palmitic acid (C18), oleic acid (C18:1), and linoleic acid (C18:2) resemble the primary components of membrane viral particles. The virus’s surface is covered in C18 lipids. In light of this, OBPs’, NPC2s’ and CSPs’ capacity to interact with C18-lipids and transfer them to Degradative Enzymes (ODEs) may provide a novel molecular strategy for combating coronavirus infection, regardless of the course of viral mutation. In order to confine COVID virus variations in a hydrophobic pocket and/or produce viral particles devoid of an outer protective envelope, proteins with the ability to bind long lipid chains on viral surfaces or peplos may show great promise.

Case report of the perinatal form of Nieman-Pick disease type С against the backdrop of pathogenetic off-label therapy

Background. Niemann–Pick disease type C is a multisystem orphan disease caused by mutations in the NPC1 and NPC2 genes and characterized by clinical polymorphism. The difficulties of managing such patients lie in the diagnosis and differential diagnostic search with other conditions with cholestasis, as well as the initiation of substrate-reducing therapy in young children. Case report. Previously, a case report of Niemann–Pick disease type C, with the manifestation of the disease in infancy and the appointment of off-label pathogenetic therapy was described. The article presents the results of dynamic monitoring of the child on this therapy, its effectiveness and safety. The leading syndromes in the clinical presentation of the disease were cholestasis, cytolysis, hepatosplenomegaly, as well as psychomotor retardation. An extensive differential diagnostic search was conducted with the exception of diseases such as toxic, viral hepatitis, alpha-1-antitrypsin deficiency, autoimmune liver diseases, aminoacidopathy, Alagille syndrome. Genetic testing on the “Cholestasis” panel revealed a mutation in the NPC1 gene. Biochemical diagnostics showed an increase in the concentration of lysosphingomyelin-509 and increased activity of chitotriosidase in dry blood spots. When sequencing the NPC1 gene by Sanger, the nucleotide substitution chr18:21131617G> A in the homozygous state was detected in the child. At 9 months, by the decision of the medical board, the child was prescribed pathogenetic therapy, the effectiveness of which was confirmed by clinical and laboratory relief of cholestasis, positive dynamics of neurological manifestations, in addition, the drug is satisfactorily tolerated by the patient, despite the preservation of an isolated increase in the level of aspartate aminotransferase. Conclusion. The presented case report confirms the need for a thorough differential diagnostic search with the inclusion of a wide range of diseases with the leading cholestasis for the timely detection of infants with Niemann- Pick disease type C, as well as the importance and effectiveness of early administration of pathogenetic therapy.

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India

BackgroundCurrent clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India.Results903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood.ConclusionWe developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

Overview of clinical, molecular, and therapeutic features of Niemann-Pick disease (types A, B, and C): Focus on therapeutic approaches.

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.