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.

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.

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.

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.

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

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.

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.

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.

Analysis of growth, reproductive and blood physiological and biochemical parameters in Niemann-Pick disease type C1 mice / 中国实验动物学报

Objective To investigate the growth curve,breeding rate,and blood physiological and biochemical parameters in Npc1 gene mutant mice (Npc1-/-) for providing theoretical evidence in research on Niemann-Pick disease type C1 (NPC1) patient.Methods 1) The body mass of Npc1-/-,Npc1+/-,and Npc1+/+ mice (n=120;60♀,60♂) was measured from 0 to 77 days;(2) As Npc1-/-mice were born only by the mating Npc1+/-mice,the breeding rate of Npc1+/-mice was counted here from the 1st to 4th generation;(3) The blood physiological and biochemical parameters were measured on both Npc1-/-and Npc1+/+ mice at 60 days.Results 1) Compared with the wild type controls,the body weight of Npc1-/-mice was progressively increased up to 7 weeks and then decreased,and died around 11 weeks.The body weight of the Npc1+/-and Npc1+/+ mice was increased as time went on.After 4 weeks,the male mice showed a higher weight gain than the females;(2) The generations of Npc1+/-mice had no significant difference in mating-parturition interval,litter size,weaning litter and the number of male and female (P>0.05),but the weaning rate of the 2nd generation was significantly higher than that of the 1st generation (P0.05).Among the biochemical parameters,aspartate aminotransferase (AST),glucose (GLU),lactate dehydrogenase (LDH),potassium (K) and copper (Cu) had a significant difference between the Npc1-/-and Npc1+/+ mice (P<0.05).Conclusions 1) The growth curves of Npc1-/-,Npc1+/-,and Npc1+/+ mice are different due to different genotype and sex;(2) The reproduction rates of Npc1+/-mice have no significant difference among different generations;(3) The blood physiological parameters (MCH,MPXI) and biochemical parameters (UREA,AST,GLU,LDH,K,Cu) are significantly different between Npc1-/-and Npc1+/+ mice.

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.

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.

Renal function and pathological changes in Niemann-Pick disease type C1 mice / 中国病理生理杂志

AIM:To investigate the renal function and pathological changes in Npc1 mutant ( Npc1-/-) mice. METHODS:Different genotypes of Niemann-Pick disease type C1 (Npc1) mice were identified by PCR.Subsequently, the renal function of Npc1-/-and Npc1 +/+mice at postnatal day 60 ( P60) was evaluated by measuring the activity and con-tent of important indicators in the serum including ALT , AST, LDH, urea, UA and Cr.Furthermore,β-galactosidase stai-ning and Masson staining were performed to examine the aging and fibrosis of the renal tissues , respectively .RESULTS:Compared with the Npc1 +/+mice, the body weight and kidney weight had a significant reduction ( P<0.01) in the Npc1-/-mice.The results of hepatic and renal functions showed that the activities of ALT , AST and LDH, and contents of urea, UA and Cr had marked increases (P<0.05) in the Npc1-/-mice.Moreover, the results of senescence-associatedβ-galacto-sidase staining in the renal tissues demonstrated accelerated aging in the Npc1-/-mice (P<0.01), and these results were confirmed by Masson staining, which clearly showed the formation of collagen fibers (P<0.01).CONCLUSION:Muta-tion of the Npc1 gene results in abnormal lipid metabolism , which accelerates kidney senescence by promoting fibrosis in the renal tissue and subsequently causes reduction in renal function .

Two Siblings with Adolescent/Adult Onset Niemann-Pick Disease Type C in Korea

Niemann-Pick disease, type C (NP-C), is caused by NPC1 or NPC2 gene mutations. Progressive neurological, psychiatric, and visceral symptoms are characteristic. Here, we present cases of a brother (Case 1) and sister (Case 2) in their mid-20s with gait disturbance and psychosis. For the Case 1, neurological examination revealed dystonia, ataxia, vertical supranuclear-gaze palsy (VSGP), and global cognitive impairment. Case 2 showed milder, but similar symptoms, with cortical atrophy. Abdominal computed tomography showed hepatosplenomegaly in both cases. NPC1 gene sequencing revealed compound heterozygote for exon 9 (c.1552C>T [R518W]) and exon 18 (c.2780C>T [A927V]). Filipin-staining tests were also positive. When a young patient with ataxia or dystonia shows VSGP, NP-C should be considered.

A SEVEN-MONTH-OLD INFANT WITH NIEMANN PICK DISEASE:A CASE REPORT / 现代医院

Objective To study the various clinical manifestations of niemann pick disease, and to improve the ability of diagnosis and differential diagnosis in order to reduce misdiagnosis or missed diagnosis.Methods The onset and diagnostic procedure of a seven-month-old infant with niemann pick disease were reported and relative literature were reviewed and studied.Results The infant demonstrated severe hepatosplenomegaly, abnormity of liver function, anemia and development backwardness.Bone marrow examination indicated storage cells suggestive of niemann pick cells.Conclusion Niemann pick disease is a group of rare diseases with various clinical manifestations. Clinical suspected cases need further bone marrow examination, pathologcal biopsy and gene tests.

Distinct Niemann-Pick Disease Type C Clinical, Cytological, and Biochemical Phenotype in an Adult Patient With 1 Mutated, Overexpressed NPC1 Allele

Abstract Niemann-Pick disease type C (NP-C) is a rare autosomal-recessive neurovisceral lysosomal storage disease. We report on a juvenile onset, now 25-year-old female patient with typical neurologic symptoms, including vertical gaze palsy, of NP-C. The diagnosis was supported by a positive filipin test ("variant biochemical phenotype" of cholesterol accumulation) in cultured fibroblasts, high numbers of "Niemann-Pick cells" in the bone marrow, and 1 positive out of 3 NP-C biomarkers tested, but NP-C was not definitely confirmed genetically. She showed only 1 known NPC1 variant (3 bp deletion in exon 18; p.N916del); this allele, however, being distinctly overexpressed at the messenger RNA level as compared to the wild-type allele, as a not as yet clarified (copathogenic?) phenomenon. The patient's mother, also carrying the p.N916del allele but without overexpression, has a chronic inflammatory disease of the central nervous system classified as multiple sclerosis. However, her severe clinical phenotype includes some signs also consistent with NP-C. The laboratory diagnosis of NP-C can be challenging in detecting novel disease constellations.

Niemann-Pick disease type C: a case series of Brazilian patients / Doenca de Niemann-Pick tipo C: serie de casos de pacientes brasileiros

The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis. .

O objetivo desse estudo foi analisar uma série de casos de pacientes brasileiros com doença de Niemann-Pick tipo C (NP-C). Método Correlação entre manifestações clínicas, alterações laboratoriais, estudo molecular e resposta ao tratamento foram realizadas. Resultado A amostra consiste de 5 pacientes com idade entre 8 e 26 anos. Paralisia do olhar vertical supranuclear, ataxia cerebelar, demência, distonia e disartria estavam presentes em todos os casos. Coloração de filipina na cultura de fibroblastos mostrou padrão “clássico” em dois pacientes e padrão “variante” em três casos. O estudo molecular encontrou mutações no gene NPC1 em todos os alelos. O tratamento com miglustate foi realizado em 4 pacientes. Conclusão Embora coloração de filipina seja utilizada para confirmar o diagnóstico, o histiócito azul-marinho no aspirado de medula óssea frequentemente auxilia a confirmar o diagnóstico de NP-C. A mutação p.P1007A está correlacionada com o padrão “ variante” na coloração de filipina. A resposta ao tratamento com miglustate parece estar correlacionada com a idade e escore de desabilidade no momento do diagnóstico. .