A case of Niemann Pick disease type-A with associated neonatal thrombosis

Background: Niemann-Pick Disease (NPD) is a rare autosomal recessive disorder associated with intracellular deposition of sphingomyelin and cholesterol storage within the lysosome. There are mainly three types of NPD namely types A, B, and C. NPD type B is generally later in onset with a good prognosis for survival into adulthood and usually with no neurological abnormalities.Case Presentation: The patient, male, was born in 35 weeks of pregnancy. Failure to thrive started at around 4 months and the diagnosis of type B Niemann-Pick disease was made approximately at the age of 2 years. Currently, the patient is 10 years old and having undergone 3 years of Traditional Persian Diet, has had obvious improvement in growth and laboratory tests.Conclusion: The NPD is no specific treatment, especially in modern medicine. Considering the significant improvement in the patient’s condition after an appropriate diet and traditional medicines, it seems that traditional medicinal therapies have great results in the treatment of NPD. In this study, we presented an innovation for NPD treatment by the use of a Traditional Persian diet.

Background: Niemann–Pick (NP) disease is a genetically heterogeneous metabolic disorder caused by bi-allelic variants in NPC1, NPC2, or SMPD1, with initial symptoms and age at onset varying widely. The interpretation of variants in NP disease genes is challenging when these alterations have never been observed before, and when parental samples are not available. Case Presentation: We clinically, genetically, and biochemically characterized an infant with a complex presentation and a negative family history. Clinical and paraclinical observations were consistent with NP disease. Genetic screening identified two previously unreported SMPD1 missense variants, which were initially classified as variants of unknown significance. Based on strongly increased plasma levels of lysosphingomyelin-509, both variants could be re-classified as likely pathogenic, thus establishing a diagnosis of NP disease type A/B. Conclusion: A combination of genetics with biochemical approaches facilitates conclusive diagnosis of metabolic disorders including NP disease. Blood-based biomarkers are particularly promising in this respect.

Niemann–Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 μL) and cisterna magna (10 μL) of Npc1 homo-knockout (Npc1−/−) mice. Each mouse received total 1.35 × 1011 vector genome on days 4 or 5 of life. AAV-treated Npc1−/− mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1−/− mice (n = 11) and untreated Npc1−/− mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1−/− mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1−/− mice increased until 15 weeks. AAV-treated Npc1−/− mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1−/− mice. In contrast, untreated Npc1−/− mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1−/− mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1−/− mice. Our results suggest the feasibility of gene therapy for patients with NPC1.

Background. Niemann – Pick disease (NPD) is a rare autosomal recessive disease caused by acid sphingomyelinase deficiency and characterized by impaired intracellular lipids’ transport leading to accumulation of cholesterol and glycosphingolipids in the cells. Olipudase alfa was registered as the drug for enzyme replacement therapy in 2022. There are only two studies and one observation published on the results of its implementation in children. Olipudase alfa efficacy and safety have not been studied in Russian studies.Clinical case description. Girl, 1 year 5 months old, was diagnosed with insufficient weight gain and dyspeptic syndrome. Subsequently the child was followed up with various gastroenterological diagnoses for 1.5 years. Diagnosis of NPD type B was established at the age of 3 years 4 months, it was confirmed by revealing acid sphingomyelinase activity decrease to 0.11 mmol/l/h and nucleotide variant in the SMPD1 gene. Therapy with olipudase alfa was initiated at the age of 3 years 10 months with increasing dosage (from 0.03 mg/kg to therapeutic — 3 mg/kg of body weight, 11 injections in total), intravenously, drop infusion, once in 2 weeks. Clinical progression of the disease has stopped (with persistent hepatosplenomegaly), positive changes in laboratory parameters of the disease activity were revealed (with persistence of high (66 U/L) aspartate aminotransferase activity), and increasing of body weight (however, physical development remains below average, –1 to –2 SD) was noted within 24 weeks of therapy.Conclusion. The combination of hepatosplenomegaly, increased transaminase activity and cholesterol levels, gastroenterological symptoms, and insufficient body weight gain should rise doctors’ awareness of orphan disease in a child. Timely diagnosis of NPD is crucial for early enzyme replacement therapy initiation (that is currently available). We have shown that olipudase alfa can help us to maintain child’s vital activity, to achieve positive clinical and laboratory dynamics, and to reach slow recovery of the child’s physical development.

Deficient leucocyte sphingomyelinase activity has been demonstrated in a patient with the sea-blue histiocyte syndrome. Family studies revealed that two other cases previously diagnosed on clinical and histochemical criteria also had a pronounced diminution of sphingomyelinase activity. Both parents of the affected individuals were carriers of the disease as indicated by sphingomyelinase activity intermediate between normal and diseased subjects. Additional heteroxygous carriers were found among the siblings and other relatives of the patients. This family study supports further the hypothesis that the sea-blue histiocyte syndrome and chronic Niemann-Pick (Type B) disease are the same.

Niemann-Pick disease type C1 (NPC1) is a genetic neurovisceral disorder characterized by abnormalities in intracellular sterol trafficking. A knockout mouse model (NPC1) is an important tool for the study of pathogenesis and treatment strategies. In the present study, NPC1 mice were examined for pathological changes in the cornea. Fifteen inbred homozygous NPC1 knockout mice (NPC1, 5-10 weeks old), 5 age-matched heterozygous mice (NPC1), and 14 wild-type control mice (NPC1) were examined. In vivo confocal laser scanning microscopy (CLSM) was performed on both eyes of each animal; afterward, the eyes were processed for histology, electron microscopy, and lipid analysis. In vivo CLSM disclosed hyperreflective intracellular deposits in the intermediate and basal cell layers of corneal epithelium in all NPC1 mice. At the electron microscopy level, however, vacuolated cytoplasmic structures, 200-500 nm in diameter, with electron-dense material appeared in all structures investigated, including all epithelial layers and stromal keratocytes. These deposits were negative for filipin, a marker for unesterified cholesterol. Lipid analysis showed a marked increase in disialotetrahexosylganglioside 2 (GM2) level in NPC1 mice corneas, whereas no changes were detected in free cholesterol and disialotetrahexosylganglioside 3 (GM3) levels when compared with controls. Morphological changes characteristic for the NPC1 mouse cornea were visualized in all epithelial layers and keratocytes. In vivo CLSM findings were confirmed by other techniques. In vivo detection of ocular manifestations and analysis of ocular tissue have the potential to aid the diagnosis of NPC1 disease and to monitor the efficacy of treatment.

Treating central nervous system (CNS) diseases is complicated by the incapability of numerous therapeutics to cross the blood-brain barrier (BBB), mainly composed of brain endothelial cells (BECs). Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC-specific adeno-associated viral vector (AAV-BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an in vitro BBB model with mixed glial cells, and in healthy BALB/c mice. Transduced primary BECs had significantly increased NPC2 gene expression and secreted NPC2 after viral transduction, which significantly reversed cholesterol deposition in NPC2 deficient fibroblasts. Mice receiving an intravenous injection with AAV-BR1-NCP2-eGFP were sacrificed 8 weeks later and examined for its biodistribution and transgene expression of eGFP and NPC2. AAV-BR1-NPC2-eGFP was distributed mainly to the brain and lightly to the heart and lung, but did not label other organs including the liver. eGFP expression was primarily found in BECs throughout the brain but occasionally also in neurons suggesting transport of the vector across the BBB, a phenomenon also confirmed in vitro. NPC2 gene expression was up-regulated in the brain, and recombinant NPC2 protein expression was observed in both transduced brain capillaries and neurons. Our findings show that AAV-BR1 transduction of BECs is possible and that it may denote a promising strategy for future treatment of NPC2.

Objective: To describe the course of type B Niemann- Pick disease (ENP-B) by following the evolution of three pediatric patients. Methods: Three patients, two of them male, age be- tween two and eleven years, with type B Niemann-Pick disease were evaluated periodically by physic exam and laboratory: hematologic indices, lipid profile, hepatic function tests; Radiologic studies: chest X-ray, abdominal ultrasound, cranial computed tomography, echocardiogram. Histologic exams: hepatic biopsy, bone marrow aspirate. We also obtained information on intercurrent pathologies. Results: Symptoms started ~3 years (2-5 years) and the diagnosis was made at the age of ~5 years 3 months (2-11 years), based on clinical findings suggestive of ENP-B; on foam cells in bone marrow aspirate in the three patients, hepatic biopsy in two; acid sphingomyelinase determination in three. The clinical manifestations were: hepatosplenomegaly in three; neurologic involvement in two; bone involvement in one; pulmonary involvement in two; liver involvement in three; affected hematological indices in three; lipid abnormalities in three; cardiac involvement in one; ocular manifestations in one; growth retardation in three. In none of the families were detected consan- guinity nor endogamy. Conclusions: This study shows the multisystemic involvement and the clinic variability in the type B Niemann-Pick disease, which is characterized es- sentially by hepatosplenomegaly with the possibility of development of liver dysfunction. Patients have a progressive hypersplenism. They present an athero- genic lipid profile. A gradual pulmonary affection, and other systemic manifestations are observed. The diagnosis confirmation, requires the determination of acid sphyngomyelinase. To date, there are no useful biomarkers to evaluate the disease activity. Enzyme replacement therapy is still on research.

The Niemann Pick disease type C1 (NPC1) is a lysosomal storage disorder caused by a mutation in the NPC1 gene. The mutation disrupts the normal cholesterol traficking and induces cholesterol accumulation in cells of the liver and the brain. Till now, no therapy exists for NPC1 patients. But recently, pneumococci immunization has shown to reduce inflammation in Non-alcoholic steatohepatitis (NASH), another lipid storage disorder. Therefore, pneumococci immunization was also tested on NPC1mut mice. The results indicate an improved pathology in the NPC1 mice after the immunization

Mitochondrial cholesterol enrichment affects PINK1-PRKN-mediated mitophagy in Alzheimer's disease

The main topic discussed during the Prague Symposium on Niemann- Pick disease in 1982 was the prominent heterogeneity of the chemical pathology of the complex urgently calling for revision of the original Croker’s scheme (Croker, 1961) in which all the types were considered as sphingomyelinoses differing only in the degree of storage of the critical lipid (Elleder and Jirasek, 1983). Recent biochemical investigations on Niemann- Pick disease explained its chemical heterogeneity in terms of enzymology, i.e. succeeded in finding out the metabolic error of the second part of the Niemann-Pick disease complex (Butler et al., 1987)

Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 is associated with neuroinflammation; however, attempts to therapeutically target neuroinflammation in NPC1 have had mixed success. We show here that NPC1 neuroinflammation is characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- microglia demonstrated altered morphology, reduced levels of lineage markers and a shift toward glycolytic metabolism. Treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a drug currently being studied in a phase 2b/3 clinical trial, reversed all microglia-associated defects in Npc1-/- animals. In addition, impairing microglia mediated neuroinflammation by genetic deletion of IRF8 led to decreased symptoms and increased lifespan. We identified CD22 as a marker of dysregulated microglia in Npc1 mutant mice and subsequently demonstrated that elevated cerebrospinal fluid levels of CD22 in NPC1 patients responds to HPβCD administration. Collectively, these data provide the first in-depth analysis of microglia function in NPC1 and suggest possible new therapeutic approaches.

Niemann-Pick disease, type C1 (NPC1), which arises from a mutation in the NPC1 gene, is characterized by abnormal cellular storage and transport of cholesterol and other lipids that leads to hepatic disease and progressive neurological impairment. Oxidative stress has been hypothesized to contribute to the NPC1 disease pathological cascade. To determine whether treatments reducing oxidative stress could alleviate NPC1 disease phenotypes, the in vivo effects of the antioxidant N-acetylcysteine (NAC) on two mouse models for NPC1 disease were studied. NAC was able to partially suppress phenotypes in both antisense-induced (NPC1ASO) and germline (Npc1-/-) knockout genetic mouse models, confirming the presence of an oxidative stress-related mechanism in progression of NPC1 phenotypes and suggesting NAC as a potential molecule for treatment. Gene expression analyses of NAC-treated NPC1ASO mice suggested NAC affects pathways distinct from those initially altered by Npc1 knockdown, data consistent with NAC achieving partial disease phenotype suppression. In a therapeutic trial of short-term NAC administration to NPC1 patients, no significant effects on oxidative stress in these patients were identified other than moderate improvement of the fraction of reduced CoQ10, suggesting limited efficacy of NAC monotherapy. However, the mouse model data suggest that the distinct antioxidant effects of NAC could provide potential treatment of NPC1 disease, possibly in concert with other therapeutic molecules at earlier stages of disease progression. These data also validated the NPC1ASO mouse as an efficient model for candidate NPC1 drug screening, and demonstrated similarities in hepatic phenotypes and genome-wide transcript expression patterns between the NPC1ASO and Npc1-/- models.

Metabolic disorders of the liver

Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer's disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.