Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An unusual case of Niemann-Pick disease type C is reported. The disease was first manifested in utero with hepatomegaly and ascitis. At the age of 3 months, respiratory signs were noted due to diffuse alveolar and interstitial pneumonia. Both bronchoalveolar lavage and blood serologic studies revealed respiratory infection by respiratory syncitial virus and Chlamydia trachomatis. These concomitant infections delayed the diagnosis of Niemann-Pick disease which was finally made by the electronic microscopic studies of liver biopsy and bone marrow specimens. Type C was identified by biochemical characterization of lipid accumulation in hepatocytes and by lipid enzyme profiles obtained from cutaneous fibroblast cultures. The child died at the age of 6 months from respiratory failure. Post mortem examination of the lung showed the presence of numerous overloaded alveolar macrophages in the alveolar spaces and walls. The severity of the lung issue disease is unusual in type C Niemann-Pick disease, in which neurologic involvement is usually the main prognosis factor.
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PMID:[A fatal respiratory form of type C Niemann-Pick disease]. 236 71

The records of 52 children with Niemann-Pick disease type C were reviewed to establish whether the disease process and outcome varied with the initial clinical pattern; 34 children (65%) had cholestatic liver disease and hepatosplenomegaly in infancy; 18 were seen at a mean age of 4 years with splenomegaly or neurologic disease or both. Of the 34 children with early cholestatic liver disease, three died in the neonatal period; cholestasis and hepatomegaly subsided in the remaining 31 children, although splenomegaly persisted. Of these 31 children, 15 had persistent liver disease with elevated aminotransferase values. Serial liver biopsy specimens showed that 3 of the 15 children had normal architecture and 12 had hepatic fibrosis, with progression to cirrhosis in 5. No other significant morbidity or additional deaths were associated with the liver disease. The clinical importance of persistent liver disease was overshadowed by the subsequent development of severe neurologic disease. There was no difference in the age at onset of the disease (mean, 4.5 years) or in the pattern of neurologic disease, including supranuclear ophthalmoplegia, whether or not the child had early liver disease. Overt neurologic disease has not yet developed in seven surviving children with liver disease at onset. Sixty-seven percent of children died during the study; the main cause of death was bronchopneumonia. We conclude that the diagnosis of Niemann-Pick disease type C should be considered in patients with unexplained neonatal hepatitis, especially if splenomegaly is a persistent feature. Because liver biopsy specimens may not demonstrate storage cells, bone marrow aspiration to detect the characteristic storage cells is recommended in such patients.
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PMID:Niemann-Pick disease type C: diagnosis and outcome in children, with particular reference to liver disease. 815 88

Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease.
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PMID:Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease. 1617 10

Laboratory diagnosis of lysosomal storage disorders, especially sphingomyelinase deficiency (Niemann-Pick disease type A/B) and Niemann-Pick disease type C (NPC) can be challenging. We therefore aimed to analyse the feasibility of first-step screening with specific chitotriosidase cut-off values in children </= 10 years of age with visceral organomegaly (hepatomegaly, splenomegaly, or hepatosplenomegaly) in whom a storage disorder was suspected. We conducted a retrospective, cross-sectional, referral, single-centre study to assess diagnostic test properties in 106 individuals. Median chitotriosidase activity was 12 655 nmol/h per ml (interquartile range 4693-20982) in Gaucher disease (GD); 780 (465-1298) in SMD (sphingomyelinase deficiency); 925 (319-1215) in NPC and 50 (29-54) in patients with miscellaneous diseases. To restrict the differential diagnosis to GD, SMD or NPC, chitotriosidase activity above 200 nmol/h per ml had a sensitivity of 96%, specificity of 100%, positive predictive value (PPV) of 100%, and negative predictive value (NPV) of 95%. For GD alone, chitotriosidase activity above 4000 nmol/h per ml had a sensitivity of 77%, specificity of 100%, PPV of 100% and NPV of 92%. Of the 44 patients analysed, 4.5% were homozygous and 36.4% heterozygous for chitotriosidase gene duplication. Adjusting for the chitotriosidase genotype, chitotriosidase activities were higher in GD type III than in GD type I. We conclude that, in the above setting, the degree of elevation of chitotriosidase activity can be applied to increase the likelihood of GD, SMD, or NPC and guide the choice of the appropriate confirmatory assay.
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PMID:Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C. 1697 72

Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids and other molecules but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. Based upon a comprehensive study of 13 unrelated adult patients diagnosed in France over the past 20 years as well as the analysis of the 55 other cases published since 1969, we have attempted to delineate the major clinical, radiological, biochemical and genotypic characteristics of adult NPC. Overall, mean age at onset (+/-SD) of neuropsychiatric symptoms was 25 +/- 9.7 years. The diagnosis of NPC was established after a mean delay of 6.2 +/- 6.4 years and the mean age at death (calculated from 20 cases) was 38 +/- 10.2 years. Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). Less frequent signs were epilepsy and cataplexy. During the course of the disease, clinical features could be subdivided into (i) visceral signs (hepatomegaly or splenomegaly), (ii) cortical signs (psychiatric cognitive disorders and epilepsy); and (iii) deep brain signs (VSO, ataxia, movement disorders, dysarthria, dysphagia, cataplexy) which exhibited different evolution patterns. Asymptomatic and non-evolutive visceral signs were often noticed since early childhood (38.5% of our patients), followed by mild cortical signs in childhood (learning difficulties) and early adulthood (62% of cases among which 38% were psychiatric disorders). Deep brain signs were observed in 96% of patients and were usually responsible for death. In general, there was a good correlation between clinical signs and the localization of brain atrophy on MRI. The 'variant' biochemical phenotype characterized by mild abnormalities of the cellular trafficking of endocytosed cholesterol was over-represented in the adult form of NPC and seemed associated with less frequent splenomegaly in childhood and lesser psychiatric signs. Involvement of the NPC1 gene was shown in 33 families and of the NPC2 gene in one. Improving the knowledge of the disease among psychiatrists and neurologists appears essential since emerging treatments should be more efficient at the visceral or cognitive/psychiatric stages of the disease, before the occurrence of widespread deep brain neurological lesions.
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PMID:The adult form of Niemann-Pick disease type C. 1700 72

Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis.
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PMID:The clinical spectrum of fetal Niemann-Pick type C. 1920 79

Loss of function of Niemann-Pick C1 (NPC1) leads to lysosomal free cholesterol storage, resulting in the neurodegenerative disease Niemann-Pick disease type C (NPC). Significant numbers of patients with NPC also suffer from liver disease. Currently, no treatments exist that alter patient outcome, and it is unknown if recovery from tissue damage can occur even if a treatment were found. Our laboratory developed a strategy to test whether mice can recover from NPC liver disease. We used antisense oligonucleotides to knock down hepatic expression of NPC1 in BALB/C mice for either 9 or 15 weeks. This recapitulated liver disease with hepatomegaly, cell death, and fibrosis. Then, antisense oligonucleotide treatment was halted for an additional 4, 9, or 15 weeks. We report that significant liver recovery occurred even when NPC1 protein expression only partially returned to normal. Several pathological phenotypes were alleviated, including hepatomegaly, cholesterol storage, and liver cell death. Histological examination revealed that foamy cell accumulation was relieved; however, liver fibrosis increased. Additionally, resolution of cholesterol storage and liver cell death took longer in mice with long-term knockdown. Finally, we found that transcription of cholesterol homeostatic genes was significantly disrupted during the recovery phase after long-term knockdown.
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PMID:Recovery from liver disease in a Niemann-Pick type C mouse model. 2041 40

Niemann-Pick type C (NPC) disease is a recessive disorder that results in unesterified cholesterol accumulating in the lysosomal and late endosomal system. It is caused by mutations in NPC1 or NPC2 genes and leads to systemic and neurodegenerative symptoms. Few cases of prenatal presentation of NPC have been reported and only two cases in the absence of previous family history, indicating the diagnosis is particularly difficult in such a situation. We report a prenatal diagnosis of NPC in a couple without family history. An ultrasound screening at 22 weeks of gestation (WG) detected fetal ascites and hepatomegaly, which were still present at 25, 27, and 29 WG, and a splenomegaly progressively appeared. No placentomegaly or other signs of hydrops fetalis were observed. The diagnostic of NPC was prenatally confirmed by a filipin test and NPC1 sequencing and multiplex ligation-dependent probe amplification assay which revealed a maternal missense mutation (c.2608T>C; p.Ser870Pro) and a paternal deletion of exons 5 to 25. This additional prenatal case of NPC suggests that even in the absence of family history, fetal ascites associated with splenomegaly but no hydrops should nonetheless arouse suspicion concerning this disease as a possible diagnosis.
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PMID:In Utero Diagnosis of Niemann-Pick Type C in the Absence of Family History. 2656 27

Niemann-Pick C disease is a neurovisceral disorder caused by mutations in the NPC gene that result in systemic accumulation of intracellular cholesterol. Although neurodegeneration defines the disease's severity, in most patients it is preceded by hepatic complications such as cholestatic jaundice or hepatomegaly. To analyze the contribution of the hepatic disease in Niemann-Pick C disease progression and to evaluate the degree of primary and secondary hepatic damage, we generated a transgenic mouse with liver-selective expression of NPC1 from embryonic stages. Hepatic NPC1 re-expression did not ameliorate the onset and progression of neurodegeneration of the NPC1-null animal. However, the mice showed reduced hepatomegalia and dramatic, although not complete, reduction of hepatic cholesterol and serum bile salts, bilirubin, and transaminase levels. Therefore, hepatic primary and secondary cholesterol deposition and damage occur simultaneously during Niemann-Pick C disease progression.
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PMID:Hepatic Primary and Secondary Cholesterol Deposition and Damage in Niemann-Pick Disease. 2678 26