Niemann-Pick disease type B and heterogeneous manifestations of its liver involvement： A case report / 临床肝胆病杂志

This article reports a case with the chief complaint of “hepatosplenomegaly to be investigated” and a confirmed diagnosis of Niemann-Pick disease type B after various tests， and a literature review was conducted to summarize the heterogeneous manifestations of liver involvement in type B Niemann-Pick disease， in order to improve the clinical management of difficult and rare liver diseases.

Consenso Argentino sobre Diagnóstico y Tratamiento de la Enfermedad de Niemann-Pick tipo C / Argentinean Consensus on the Diagnosis and Treatment of Niemann-Pick Disease type C

Resumen La enfermedad de Niemann-Pick tipo C (NPC) es un trastorno del metabolismo lisosomal que se debe a la presencia de variantes patogénicas bialélicas en los genes NPC1 o NPC2. El depósito intracelular de lípidos, especialmente colesterol no esterificado, provoca daño oxidativo en diversos tejidos, especialmente neuronas, bazo e hígado. Esto, a su vez, induce la aparición de un conjunto de síntomas neurológicos/psiquiátricos y viscerales, con una amplia variabilidad de edad de apa rición, desde formas prenatales/neonatales hasta otras de aparición en la vida adulta. En los últimos años ha habido avances considerables en la comprensión sobre esta enfermedad y su manejo. En el presente consenso un grupo de expertos argentinos abordan los enfoques actuales de diagnóstico, seguimiento y tratamiento de NPC, incluyendo el uso de miglustat como única terapia específica aprobada en la actualidad.

Abstract Niemann-Pick type C (NPC) is a disorder of the lyso somal metabolism due to biallelic pathogenic variants in NPC1 or NPC2. Intracellular deposit of lipids, mainly unesterified cholesterol, gives rise to oxidative damage in several tissues, mainly neurons, spleen and liver. This, in turn, is associated with a myriad of neurologi cal/psychiatric and visceral symptoms, with wide vari ability in age of presentation, from prenatal/neonatal to adult-onset forms of the disease. The last few years have seen considerable progress in understanding this disease and its management. In this consensus, current approaches to the diagnosis, follow-up and treatment of NPC (including the use of miglustat, the only specific drug approved at the time) are discussed by an Argentin ian panel of experts.

Utility of morphologic assessment of bone marrow biopsy in diagnosis of lysosomal storage disorders

Introduction: Lysosomal storage disorders (LSDs) are rare disorders and pose a diagnostic challenge for clinicians owing to their generalized symptomatology. In this study, we aim to classify LSDs into two broad categories, namely, Gaucher disease (GD) and Niemann–Pick/Niemann–Pick-like diseases (NP/NP-like diseases) based on the morphology of the storage cells in the bone marrow (BM) aspiration smears and trephine biopsy sections. Materials and Method: This retrospective study includes 32 BM specimens morphologically diagnosed as LSDs at our institute, in the last 10 years. Subsequently, they were subclassified into GD and NP/NP-like diseases. Further, we have compared and analyzed the clinical, hematological, and biochemical parameters for the two groups of LSDs. Results: Based on BM morphology, 59.4% (n = 19) cases were diagnosed as NP/NP-like diseases and 40.6% (n = 13) cases as GD. Abdominal distension and failure to thrive were the most common clinical manifestations in both groups of LSDs. Anemia and thrombocytopenia were frequently seen in either of the LSDs. On the assessment of metabolic profile, elevated total/direct bilirubin and liver enzymes were more commonly seen in NP/NP-like diseases when compared with GD. Conclusion: We have classified LSDs into GD and NP/NP-like diseases based on the morphology of the storage cells in the BM specimen. The hallmark findings on BM biopsy annexed with the comparative features of the two proposed categories can aid the clinician in clinching the diagnosis. Formulation of such a methodology will prove instrumental for patient care in an underresourced setting.

A family of Niemann-Pick disease type C caused by compound heterozygous mutations in NPC1 gene / 中华神经科杂志

Objective:To report the clinical and genetic characteristics of a family with Niemann-Pick disease type C caused by novel compound heterozygous mutations in the NPC1 gene to improve the clinicians′ recognition of the disease. Methods:Two patients from the family with non-consanguineous marriages admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University in 2020 were examined in detail. Peripheral blood DNA was extracted, and whole exome sequencing was performed on the patients, combined with Sanger sequencing for verification. The mutation and protein function predictor softwares were applied to analyze the mutation sites.Results:The inheritance was autosomal recessive in this family. The onset age of the proband was 9 years, and the main clinical manifestations were dysarthria, dysphagia, cognitive impairment, ataxia, bilateral pyramidal tract impairment, vertical supranuclear gaze palsy and splenomegaly. The clinical phenotype of the proband′s younger brother was similar to that of the proband, but it was more severe than that of the proband. The younger brother of the proband had an earlier age of onset and severe psychomotor retardation. Whole exome sequencing showed that both brothers carried 2 rare variants of NPC1 gene:1 pathogenic, stop gain at c.352_353del, p.Gln119ValfsTer8, and a missense change, c.593A>G, p.Asn198Ser, of suspected pathogenic. Sanger sequencing confirmed that compound heterozygous mutations were derived from the proband′s parents. According to the American College of Medical Genetics and Genomics guidelines, the above variants were rated as pathogenic and suspected pathogenic, respectively. And the c.593A>G, p.Asn198Ser mutation found in this family was a novel one which had not been reported yet. The proband had delayed diagnosis for 7 years from the onset of symptoms. After taking megastat for 1 year, the symptoms of dysphagia, ataxia and vertical eye movement disorder were significantly improved. Conclusions:The clinical phenotype of the pedigree was consistent with the clinical phenotype of Niemann-Pick disease type C. Compound heterozygous mutations of NPC1 gene (c.352_353del; c.593A>G) were found to be the genetic cause of the family.

Molecular and functional study of pediatric patients with Niemann-Pick C in Argentina / Estudio molecular y funcional de pacientes pediátricos con Niemann-Pick C en Argentina

Abstract Niemann-Pick type C (NP-C) is a rare, autosomal recessive disorder. At least 95% of all the cases with this disease are due to mutations in the NPC1 gene. The clinical signs and symptoms of NP-C are classified into visceral, neurological and psychiatric. Our aim is to report the clinical findings, molecular results and filipin staining of 4 patients. The age of onset, expressed as median and range, was 0.2 (0.08-4.0) years and the age of diagnosis was 4.0 (2.5-8.9) years. Neurological and/or visceral manifestations were presented in our patients. Foamy cells in bone marrow biopsy were found in two patients. Through a molecular analysis of NPC1 gene, one non-reported (novel) and 4 previously described mutations were found. The filipin staining showed a positive pattern in all the patients. The diagnostic confirmation of these pediatric patients means a contribution to the casuistry of this disease in Argentina.

Resumen Niemann-Pick tipo C (NP-C) es una enfermedad poco frecuente, con un patrón de herencia au tosómico recesivo. Al menos el 95% de los casos se producen por mutaciones en el gen NPC1. Los signos y síntomas clínicos de NP-C se clasifican en viscerales, neurológicos y psiquiátricos. En este trabajo presentamos los hallazgos clínicos, los resultados moleculares y la tinción con filipina de 4 pacientes con NP-C. La edad de presentación de los primeros síntomas, expresada como mediana y rango, fue de 0.2 años (0.08-4.0) años y la edad del diagnóstico fue 4.0 (2.5-8.9) años. Los pacientes presentaron manifestaciones neurológicas y / o vis cerales. Se encontraron células espumosas en la biopsia de médula ósea en 2 pacientes. El análisis molecular del gen NPC1 encontró 1 variante nueva y 4 previamente publicadas. La tinción de filipina mostró un patrón positivo en todos los pacientes. La confirmación diagnóstica de este grupo de pacientes pediátricos significa un aporte a la casuística de esta enfermedad en Argentina.

Advances in the diagnosis of acid sphingomyelinase deficiency / 中国医师杂志

Acid sphingomyelinase deficiency (ASMD), also known as type A and B Niemann-Pick disease, is a group of intra-lysosomal lipid storage diseases caused by mutations in the SMPD1 gene that decrease acid sphingomyelinase activity or even cause deletion, resulting in abnormal deposition of sphingolipids. This disease can be diagnosed by bone marrow aspiration, pathological biopsy, acid sphingomyelinase activity measurement and SMPD1 gene testing. In recent years, with the rapid progress of molecular diagnostic techniques, new insights have been gained in the laboratory diagnosis of ASMD by means of molecular genetic tests, biomarkers and acid sphingomyelinase activity assay. This article will review the diagnostic progress of ASMD, aiming to reduce the misdiagnosis and leakage of the disease and improve the clinicians′ understanding of the disease.

Advance in Niemann-Pick disease type C / 国际儿科学杂志

Niemann-Pick disease type C is a lipid storage disorder associated with impaired intracellular cholesterol trafficking, caused by mutations of either NPC1 or NPC2 genes.According to the age at onset of symptoms, it is divided into 5 categories, including neonatal, early-infantile, late-infantile, juvenile and adult type.There are differences in clinical manifestations and prognoses among each category.The characteristic clinical manifestations are hepatosplenomegaly, lung infiltration, vertical supranuclear gaze palsy and gelastic cataplexy.The definite diagnosis requires demonstration of unesterified cholesterol accumulated in fibroblasts cultured from skin biopsies with filipin staining and(or) of pathogenic mutation of NPC1/NPC2 genes.There is no effective treatment for this disease yet, therefore the overall prognosis is still poor.Miglustat can delay onset of the neurological symptoms, and prolong survival of partial patients.

The influence of hematopoietic stem cell transplant on pulmonary involvement in pediatric type B Niemann-Pick disease: high resolution CT findings / 中华放射学杂志

Objective:To analyze the pulmonary high resolution CT (HRCT) images before and after hematopoietic stem cell transplantation (HSCT) in 6 children with Niemann-Pick disease(NPD) type B, and to investigate the effect of HSCT on lung lesions.Methods:Data of 6 children who were diagnosed with NPD type B and underwent HSCT treatment in Children′s Hospital Affiliated to Capital Institute of Pediatric from March 2019 to June 2021 were retrospectively enrolled, including 5 males and 1 female, with ages ranging from 1 year and 2 months to 5 years, and a median age of 2 years and 1month. The follow-up time of HRCT after HSCT was 7-20.5 months, the median time was 5 months, and the number of follow-up was 2-7 per patients, a total of 27 times. The pulmonary lesions (including interstitial lung disease, airway lesions and alveolar lesions) on aortic arch level, tracheal carina level and right diaphragmatic surface level were evaluated and scored respectively by two experienced pediatric radiologists, and the average score between them would be the final score. The Kruskal-Wallis H test was used to compare the scores of the three kinds of lung lesions before HSCT. The linear regression method was used to analyze the impact of HSCT duration on the degree of different lesions. To control possible confounding factors in the study, a generalized linear mixed model was used to evaluate the effects of HSCT duration, age, gender and whether co-infection on different types of lesions after HSCT. Results:Before HSCT treatment, all of the 6 children had different degree of airway, interstitial and alveolar lesions, with a median score of 3.0, 14.0 and 5.8 points, respectively (χ2=11.95, P=0.003). Interstitial disease was the most extensive and serious lesion among those three pulmonary involvements in pediatric NPD type B. After HSCT treatment, the scores of interstitial and airway lesions in all of the 6 children reduced, in varying degree, with the increase of time after HSCT. Except case 4, the alveolar lesion in 5 patients also showed a decreasing trend over time. The linear regression equation between the score of airway, interstitial, alveolar lesions and the HSCT duration was: airway lesion, Y=1.94-0.15X; interstitial lesion, Y=12.73-0.78X; and alveolar lesion, Y=3.31-0.27X. The results of the generalized linear mixed model showed that the main effect of HSCT duration significantly affected on the three kinds of lung lesions, and the scores of interstitial lesions, airway lesions and alveolar lesions were decreased by 0.688, 0.245, and 0.338 points for each 1 month increase of HSCT duration (all P<0.05). The alveolar lesion score decreased by 1.135 points for each 1 year increase in age at presentation ( P=0.012). The main effects of gender and co-infection were not statistically significant in all of the pulmonary lesions (both P>0.05). Conclusion:HSCT alleviates pulmonary lesions of children with NPD type B significantly and consistently, with interstitial lesions were the most prominent.

Novel compound heterozygous mutation in NPC1 gene cause Niemann–Pick disease type C with juvenile onset

Niemann–Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the NPC1 (in 95% of cases) or NPC2 (in *5% of cases) genes, inherited in an autosomal recessive manner. We report the case of a 38-year-old woman with learning disorder from her first year of schooling, and could notice slow progressed cognitive impairment, social withdrawal, apathy, handwriting alterations, deterioration of language skills and dysphagia. Brain magnetic resonance imaging showed severe cerebellar atrophy, hypoplasia of the corpus callosum, asymmetric lateral ventricular enlargement, and severe enlargement of frontal and parietal subarachnoid spaces. Next generation sequencing for NPC genes (NPC1 and NPC2) detected compound heterozygous mutations in NPC1 gene, including c.1553G [A (p.Arg518Gln), paternally inherited, and c.1270C [ T (p.Pro424Ser) maternally inherited. The first mutation has been already described in literature and correlated to NPC, while the second mutation is still unknown. Moreover, filipin test and quantification of plasma oxysterols confirmed NPC diagnosis. We can suggest the missense mutation c.1270C [ T (p.Pro424Ser) as a new causative mutation of NPC

Enfermedad de Niemann-Pick en una escolar / Niemann-Pick Disease in a scholar girl

Introducción: La enfermedad de Niemann-Pick tipo C es una enfermedad poco frecuente, autosómica recesiva, caracterizada por el depósito de lípidos a nivel lisosomal, que, a pesar de ser tratable, es mortal en todos los casos y representa una importante carga para los pacientes y sus familias. Objetivo: Contribuir al conocimiento de esta rara enfermedad neurovisceral progresiva de curso fatal. Presentación del caso: Se trata de una niña de 7 años de edad, que a los 2 años asistió a consulta por trastornos de la marcha, con deterioro progresivo de esta, así como del lenguaje y el comienzo de crisis epilépticas. Evolutivamente presentó cataplejías gelásticas, paresia de la mirada vertical y esplenomegalia. Estos elementos clínicos evolutivos fueron lo suficientemente distintivos para orientar la sospecha clínica y las investigaciones necesarias para llegar al diagnóstico definitivo de la enfermedad. Con la confirmación de que se trataba de la enfermedad de Niemann-Pick tipo C, se comenzó tratamiento con miglustad a dosis de 100 mg dos veces al día. Conclusiones: El deterioro neurológico progresivo, la cataplejía gelástica, la paresia de la mirada vertical y la esplenomegalia, unido a los resultados del medulograma y el estudio genético permitieron el diagnóstico de esta entidad(AU)

Introduction: Niemann-Pick type C disease is a non-frequent, recessive autosomal one, which is characterized by lipids deposit in the lysosomal level. Although this disease is treatable, it is fatal in all the cases and it represents a important burden to patients and their families. Objective: To contribute to the knowledge on this rare, progressive neurovisceral disease with fatal evolution. Case presentation: Seven- years- old girl, whom at two years old attended to a consultation for walk disorders presenting a progressive worsening of it, as well of the speech, and also presented an onset of epileptic crisis. In the evolution she presented gelastic cataplexy, vertical look´s paresia and splenomegaly. These clinical evolutive elements were sufficiently distinctive to indicate the clinical suspicion and the necessary research to reach its definitive diagnostic. With the confirmation of Niemann-Pick type C disease, miglustad was used as treatment with a dose of 100 mg twice in the day. Conclusions: Progressive neurological worsening, gelastic cataplexy, vertical look´s paresia and splenomegaly joined with the results of a medulogram and the genetic study permitted this disease to be identified(AU)

Niemann-Pick disease type C-presenting as persistent neonatal jaundice: a rare case report

Neimann-Pick disease (NPD) is an autosomal recessive lysosomal storage disorder caused by inherited deficiency of acid sphingomyelinase enzyme or its transport which leads to deposition of sphingomylin and cholesterol in the lysosomes of reticuloendothelial system. It is characterized by failure to thrive, hepatospleenomeagaly and neurodegenerative changes. There are four subgroups of neimann pick disease, type A, B, C and D. Here authors are reporting a case of 5 months old female child presenting with persistent jaundice since neonatal period, progressive abdominal distention and failure to thrive. On examination patient had significant abdominal distension with moderate hepatosplenomegaly. On laboratory evaluation child diagnosed to have NPD type C. This case emphasizes the need to keep NPD in differential diagnosis of children presenting with persistent neonatal jaundice, hepatosplenomegaly, failure to thrive.

Effect of Shuangyu Tiaozhi Decoction on NPC1L1 and ABCG8 in Intestine of Hyperlipemic Model Rats / 中国实验方剂学杂志

Objective:To observe the expression levels of niemann-pick C1-like 1 (NPC1L1) and adenosine triphosphate-binding cassette transporters G8 (ABCG8) in intestine of hyperlipidemic model rats, in order to investigate the therapeutic mechanism of Shuangyu Tiaozhi decoction on hyperlipidemia. Method:A total of 40 SD rats were selected, including 8 for normal control group. The remaining 32 rats were used to establish hyperlipemic model. After modeling, the rats were randomly divided into the model group (equivalent normal saline), the high and low-dose Shuangyu Tiaozhi groups (15.6, 7.8 g·kg-1), and the Simvastatin group (4 mg·kg-1), with 8 in each group. They were given drugs by gavage for 8 weeks. The levels of total cholesterol (TC), triglyceride (TG) in serum and total cholesterol (TTC), free cholesterol (FTC) in liver of rats in each group were determined by biochemical and enzymatic methods. The morphological changes of liver were observed by hematoxylin-eosin (HE) staining, and the levels of expressions of NPC1L1, ABCG8 and liver X receptor-α (LXR-α) in intestine were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) and Western blot. The expression of ABCG8 protein was determined by immunohistochemistry. Result:After successful replication of the hyperlipidemia model, the blood lipid level was abnormally increased, and the liver steatosis became obvious in the model group compared with the normal control group. The expression levels of NPC1L1, LXR-α and ABCG8 increased significantly (PPα were significantly down-regulated, but ABCG8 was obviously up-regulated in a dose-dependent manner (PPPPPPConclusion:Shuangyu Tiaozhi decoction can reduce the blood lipid level of hyperlipemic rat model by reducing the absorption of cholesterol. Its mechanism may be correlated with the down-regulation of NPC1L1 expression and the up-regulation of ABCG8 expression.

Niemann-Pick Disease Type C Misdiagnosed as Cerebral Palsy: A Case Report

Niemann-Pick disease type C (NP-C) is a rare autosomal recessive neurovisceral lysosomal lipid storage disorder. The clinical manifestations of the disorder are variable. This report describes the case of a 27-month-old girl with NP-C whose condition had been misdiagnosed as spastic cerebral palsy (CP). She had spasticity, particularly at both ankles, and gait disturbance. Magnetic resonance imaging of the brain revealed findings suspicious of sequelae from a previous insult, such as periventricular leukomalacia, leading to the diagnosis of CP. However, she had a history of hepatosplenomegaly when she was a fetus and her motor development had deteriorated, with symptoms of vertical supranuclear gaze palsy, cataplexy, and ataxia developing gradually. Therefore, NP-C was considered and confirmed with a genetic study, which showed mutation of the NPC1 gene. Thus, if a child with CP-like symptoms presents with a deteriorating course and NP-C-specific symptoms, NP-C should be cautiously considered.

In Vivo Assessment of Neurodegeneration in Type C Niemann-Pick Disease by IDEAL-IQ

OBJECTIVE: To noninvasively assess the neurodegenerative changes in the brain of patients with Niemann-Pick type C (NPC) disease by measuring the lesion tissue with the iterative decomposition of water and fat with echo asymmetry and least square estimation-iron quantification (IDEAL-IQ). MATERIALS AND METHODS: Routine brain MRI, IDEAL-IQ and 1H-proton magnetic resonance spectroscopy (1H-MRS, served as control) were performed on 12 patients with type C Niemann-Pick disease (4 males and 8 females; age range, 15–61 years; mean age, 36 years) and 20 healthy subjects (10 males and 10 females; age range, 20–65 years; mean age, 38 years). The regions with lesion and the normal appearing regions (NARs) of patients were measured and analyzed based on the fat/water signal intensity on IDEAL-IQ and the lipid peak on 1H-MRS. RESULTS: Niemann-Pick type C patients showed a higher fat/water signal intensity ratio with IDEAL-IQ on T2 hyperintensity lesions and NARs (3.7–4.9%, p < 0.05 and 1.8–3.0%, p < 0.05, respectively), as compared to healthy controls (HCs) (1.2–2.3%). After treatment, the fat/water signal intensity ratio decreased (2.2–3.4%), but remained higher than in the HCs (p < 0.05). The results of the 1H-MRS measurements showed increased lipid peaks in the same lesion regions, and the micro-lipid storage disorder of NARs in NPC patients was detectable by IDEAL-IQ instead of 1H-MRS. CONCLUSION: The findings of this study suggested that IDEAL-IQ may be useful as a noninvasive and objective method in the evaluation of patients with NPC; additionally, IDEAL-IQ can be used to quantitatively measure the brain parenchymal adipose content and monitor patient follow-up after treatment of NPC.

Microglial involvement in the development of olfactory dysfunction

Olfactory impairment is the most common clinical manifestation among the elderly, and its prevalence increases sharply with age. Notably, growing evidence has shown that olfactory dysfunction is the first sign of neurodegeneration, indicating the importance of olfactory assessment as an early marker in the diagnosis of neurological disorders. In this review, we describe the nature of olfactory dysfunction and the advantage of using animal models in olfaction study, and we include a brief introduction to olfactory behavior tests widely used in this field. The contribution of microglia in the neurodegenerative processes including olfactory impairment is then discussed to provide a comprehensive description of the physiopathological role of interactions between neurons and microglia within the olfactory system.

Immune system dysfunction in Niemann-Pick type C1 mice / 中华微生物学和免疫学杂志

Objective To analyze the differences in immune system between Npc1 gene mutant (Npc1-/ -) and wild-type (Npc1+/ +) mice for better understanding the pathogenesis of Niemann-Pick disease type C1 (NPC1) from an immunological perspective and providing reference for NPC1 treatment in clinic.Methods Body, thymus and spleen weight of Npc1-/ -and Npc1+/ + mice aged (14±2) days, (42±2) days and (63±2) days (Day14±2 , Day42±2 and Day63±2 ) were recorded and the associated organ index were calcu-lated. White blood cell count in peripheral blood of mice aged Day42±2 was examined by routine blood test. Expression of cytokines at mRNA level in mouse peripheral blood was detected by qPCR. Percentages of CD4+, CD8+ and CD19+ lymphocytes in peripheral blood and spleen of mice aged Day42±2 were measured by flow cytometry. Apoptosis and senescence of spleen in mice aged Day63±2 were examined by immunofluores-cence and β-galactosidase staining. Results Compared with Npc1+/ + mice, there was no significant differ-ence in the weight of spleen and thymus in Npc1-/ - mice aged Day14±2; the weight of spleen in Npc1-/ - mice aged Day42±2 significantly increased, but the weight of thymus showed a significant decrease; furthermore, both the weight of spleen and thymus in Npc1-/ - mice aged Day63±2 significantly decreased; and the body weight of Npc1-/ - mice of each age group significantly decreased. Moreover, compared with Npc1+/ + mice, the absolute number of lymphocytes in the peripheral blood of Npc1-/ - mice aged Day42±2 showed no signifi-cant difference, but the percentage in whole white blood cells significantly decreased due to the significantly increased neutrophils. Expression of cytokines ( IL-1, IL-2, IFN-γ, TNF-α, IL-4, granzyme A and granzyme B) at mRNA level in the peripheral blood leukocytes of Npc1-/ - mice aged Day42±2 was abnormal as compared with that in Npc1+/ + mice. The number of T (CD4+ and CD8+) lymphocytes in Npc1-/ - mice aged Day42±2 significantly decreased, while the number of B (CD19+) lymphocytes increased significantly as com-pared with those in the Npc1+/ + mice. Compared with Npc1+/ + mice, apoptosis and senescence of the spleen in Npc1-/ - mice aged Day63±2 aggravated significantly. Conclusion The abnormal lipid metabolism triggered by Npc1 gene mutation causes severe immune dysfunction in Npc1-/ - mice. Therefore, immune dysfunction should be taken into full consideration when treating patients with NPC1, which might help improve the life quality and prolong the survival time.

A case of Kazakh adolescent Niemann-Pick disease type C / 中华神经科杂志

The clinical data and genetic results of a case of Xinjiang Kazakh adolescent Niemann-Pick disease type C (NPC) with neurological lesions as the first and main clinical manifestations were analyzed, and the literatures at home and abroad were reviewed and summarized. The main clinical manifestations of the patient were unstable walking, frequent falls, slow progression of the disease, difficulty in independent walking, and involuntary movements of the limbs and face, inability to concentrate and dysarthria. Skull MRI revealed abnormal signals in the posterior horn of bilateral lateral ventricles. Abdominal ultrasound splenomegaly was found. Niemann-Pick cells and navy tissue cells were seen in the bone marrow smear. The result of the patient gene sequencing showed that the exon 23 in NPC1 gene had a homozygous mutation c.3493G>A (p.V1165M), which was a missense mutation;the patient′s father and mother performed Sanger generation sequencing verification and were found that they all carried the disease-causing mutation. NPC is a rare autosomal recessive lysosomal storage disease with no specific clinical symptoms. For adolescents with ataxia, dystonia, or psychiatric symptoms, there is a high degree of suspicion of NPC when there is isolated splenomegaly and no liver disease.

Niemann-Pick disease type B: HRCT assessment of pulmonary involvement / Doença de Niemann-Pick tipo B: avaliação do comprometimento pulmonar por TCAR

ABSTRACT Objective: To analyze HRCT findings in patients with Niemann-Pick disease (NPD) type B, in order to determine the frequency of HRCT patterns and their distribution in the lung parenchyma, as well as the most common clinical characteristics. Methods: We studied 13 patients (3 males and 10 females) aged 5 to 56 years. HRCT images were independently evaluated by two observers, and disagreements were resolved by consensus. The inclusion criteria were presence of abnormal HRCT findings and diagnosis of NPD type B confirmed by histopathological examination of a bone marrow, lung, or liver biopsy specimen. Results: The most common clinical findings were hepatosplenomegaly and mild to moderate dyspnea. The most common HRCT patterns were smooth interlobular septal thickening and ground-glass opacities, which were both present in all patients. Intralobular lines were present in 12 patients (92.3%). A crazy-paving pattern was observed in 5 patients (38.4%), and areas of air trapping were identified in only 1 case (7.6%). Pulmonary involvement was bilateral in all cases, with the most affected area being the lower lung zone. Conclusions: Smooth interlobular septal thickening, with or without associated ground-glass opacities, in patients with hepatosplenomegaly is the most common finding in NPD type B.

RESUMO Objetivo: Analisar os achados de TCAR em pacientes com doença de Niemann-Pick (DNP) tipo B a fim de avaliar a frequência dos padrões tomográficos e sua distribuição no parênquima pulmonar, além das características clínicas mais frequentes. Métodos: Foram estudados 13 pacientes (3 do sexo masculino e 10 do sexo feminino) com idades variando de 5 a 56 anos. As imagens de TCAR foram avaliadas por dois observadores de forma independente, e os casos discordantes foram resolvidos por consenso. Os critérios de inclusão foram presença de anormalidades na TCAR e diagnóstico confirmado de DNP tipo B por exame anatomopatológico através de biópsias de medula óssea, pulmão ou fígado. Resultados: Os achados clínicos mais comuns foram hepatoesplenomegalia e dispneia leve a moderada. Os padrões tomográficos mais frequentes foram espessamento liso de septos interlobulares e opacidades em vidro fosco, presentes em todos os pacientes. Linhas intralobulares estiveram presentes em 12 pacientes (92,3%). O padrão de pavimentação em mosaico foi observado em 5 pacientes (38,4%). Áreas de aprisionamento aéreo foram identificadas em 1 dos casos (7,6%). O comprometimento pulmonar foi bilateral em todos os casos, sendo o terço inferior dos pulmões a região mais envolvida. Conclusões: O achado de espessamento liso de septos interlobulares, com ou sem opacidades em vidro fosco associadas, em pacientes com hepatoesplenomegalia é o achado mais frequente na DNP tipo B.

Aberrant Activation of Cdc2/cyclin B1 Is Involved in Initiation of Cytoskeletal Pathology in Murine Niemann-Pick Disease Type C / 华中科技大学学报（医学）（英德文版）

Niemann-Pick disease type C (NPC) is a fatal,neurovisceral lipid storage disease,neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons,progressive neuronal loss,neurofibrillary tangles (NFTs) formation,and axonal spheroids (AS).Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC (npc mice).With a goal of elucidating the mechanisms underlying the lesion formation,we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2,cdk4,and cdk5 in lesion formation in young npc mice.Cytoskeletal lesions were detectable in npc mice at three weeks of age.Importantly,concomitant activation of cdc2/cyclin B 1 kinase and accumulation of a subsequently generated cohort of phospho-epitopes were detected.The activation of cdk4/cyclin D1 and cdk5/p25 kinases was observed during the fourth week of life in npc mice,and this activation contributed to the lesion formation.We concluded that the progression of cytoskeletal pathology in npc mice older than four weeks is accelerated by the cumulative effect of cdc2,cdk4,and cdk5 activation.Furthermore,cdc2/cyclin B1 may act as a key initial player one week earlier.Targeting cell cycle activation may be beneficial to slow down the NPC pathogenesis.

Effect of intracerebellar microinjection of cdc2-siRNA on the coordination of mice with Niemann-Pick disease type C / 中华行为医学与脑科学杂志

Objective To observe the effect of inhibiting the abnormal activation of cdc2 gene on the coordination of mice with Niemann-Pick disease type C(NPC).Methods Recombinant adeno-associated virus(rAAV) encoding cdc2-siRNA was packaged,and then was injected into the cerebellum of 2 weeks old npc-/-mice.Footprint test and vertical screen test were performed to assess the coordination of mice at the age of 8 weeks.Purkinje cells visualized by HE staining in cerebellum were counted,and the phosphorylation of microtubule-associated protein Tau recognized by PHF-1 antibody was detected by immunoblotting technology.Results (1) Footprint test showed that the stride length in cdc2-siRNA npc-/-group((4.92±0.31)cm) was markedly longer than that in empty vector npc-/-group((4.05 ± 0.19) cm) (P＜ 0.05).(2) Vertical screen test showed that the latency to turn head upwards or reach the upper edge of the screen in cdc2-siRNA npc-/-group((26.01± 1.82) s,(50.93±1.98) s) was significantly shorter than that in the empty vector npc-/-group ((31.96± 3.47) s,(56.89 ± 2.97) s),respectively (P＜ 0.05 for all comparisons).(3) The number of Purkinje cells in cerebellum was dramatically increased in cdc2-siRNA npc-/-group(11.0±2.5) compared with the empty vector npc-/-group (5.1 ± 2.2) (P＜0.05).(4)The relative optical densities of cdc2 and phosphorylated Tau immunoreactive bands in cdc2-siRNA npc-/-group(1.42±0.22,0.95±0.31)were significantly lower than those in the empty vector npc-/-group(2.11±0.29,2.61±0.62),respectively (P＜0.05 for all comparisons).Conclusion Inhibiting the abnormal activation of cdc2 gene can improve the coordination of npc-/-mice by ameliorating Purkinje cell's loss and reducing the hyperphosphorylation of Tau in cerebellum.