Cases Of Niemann-Pick Disease Type Research Articles

P283: A case of Niemann-Pick disease type C from suspected uniparental disomy of chromosome 18

P283: A case of Niemann-Pick disease type C from suspected uniparental disomy of chromosome 18

Niemann–Pick Disease Type C Associated with Fuchs Heterochromic Iridocyclitis

In this study, we report a 26-year-old female case of Niemann–Pick disease type C in association with Fuchs heterochromic iridocyclitis who was admitted with the complaint of ocular pain and redness following trauma. She had mild inflammatory signs and also vertical ocular motility limitations.

Three Chinese children with Niemann-Pick disease type C with neonatal cholestasis as initial presentation

To analyze the clinical characteristics of three Chinese cases of Niemann-Pick disease type C patients with neonatal cholestasis as initial presentation, and enhance awareness of Niemann-Pick disease type C among pediatricians. Three sporadic cases with confirmed Niemann-Pick disease type C initially presented as neonatal cholestasis were retrospectively reviewed in this study. Their peripheral blood specimens were collected after obtaining informed consent. All exons and the intron-exon boundaries of NPC1 gene were examined by bi-directional sequencing. Three patients, 1 female and 2 males, aged from 2 months to 5 years and 10 months, all first complained of jaundice in the neonatal period. Laboratory tests showed total bilirubin and direct bilirubin significantly increased with predominant increase of direct bilirubin. Total bile acid, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were also increased, while high-density lipoprotein cholesterol decreased. All patients were also accompanied by hepatosplenomegaly, with two of them having increased bronchovascular markings in chest X-ray. Two heterozygous changes of NPC1 gene, c.2741G>T +c.3020C>G (p. C914F + p. P1007R), c.2177G>C + c.3734_ 3735delCT (p.R726T + p. P1245RfsX12), and c.2054T>C + c.2128C>T(p.I685T + p.Q710X), were identified in patient 1, 2 and 3, respectively. We reported three cases suffered from Niemann-Pick disease type C with initial presentation as neonatal cholestasis in the mainland of China. For newborns with prolonged jaundice in the neonatal period, as well as neonatal cholestasis, hepatosplenomegaly, Niemann-Pick type C should be included in consideration of differential diagnosis. Genetic testing can identify causative mutations for diagnosis.

Editorial Comment: Cerebellar Ataxia, Vertical Supranuclear Gaze Palsy, Sensorineural Deafness, Epilepsy, Dementia and Hallucinations in an Adolescent Male

The authors describe a case of Niemann-Pick disease type C, which features many typical findings. The history of difficulty with vertical gaze beginning at 2 years of age and the confirmation of a vertical supranuclear gaze palsy at 13 years, together with cerebellar dysfunction, epilepsy, cognitive decline, sensorineural hearing loss and spasticity should have pointed immediately to Niemann-Pick disease type C as the most likely diagnosis. It is not clear from the protocol if the patient had splenomegaly or if imaging studies were performed to seek evidence of organomegaly. If splenomegaly was present, the diagnosis would be confirmed for

A case of Niemann-Pick disease type A

Niemann-Pick disease is a group of autosomal recessive disorders associated with hepatosplenomegaly, variable neurologic deficits, and the storage of sphingomyelin and other lipids. Seven cases have been reported in Korea. We report an additional case presenting with hypotonia, early neurodevelopmental delay, hepatosplenomegaly and death by persistent pneumonia and asphyxia at the age of 23 months. MRI of brain and fundoscopic findings of our case at 4 months of age were normal. However, abnormal intensity of the thalamus and atrophy of the right temporal lobe on the MRI and macular cherry red spots were noticed at the age of 17 months. A bone marrow biopsy showed large foamy cells, while hexosaminidase A and B levels were normal. Although biochemical or molecular workup was not done, these findings led to the diagnosis of infantile onset Niemann-Pick disease, probably type A. A brief review of the related literatures was made

Sea-blue histiocytosis in bone marrow in a home TPN patient

Patients and heterozygous carriers of Niemann-Pick disease types A and B as . well as the primary (genetic) sea-blue histiocyte syndrome were investigated for their leukocyte sphingomyelinase activity. In parallel, glucocerebrosidase activity was determined in all cases studied. [3H]Sphingomyelin and [14C]glucocerebroside served as substrates for sphingomyelinase and glucocerebrosidase activity measurements, respectively. Conditions for these enzymes' assays are discussed.Sphingomyelinase activity was completely absent in three cases of NiemannPick disease type A and significantly diminished in one patient with NiemannPick disease type B and two with the sea-blue histiocyte syndrome. Sphingomyelinase activity in obligatory heterozygotes of all variants investigated represented about 40 to 70 per cent of normal activity. Nevertheless, some overlapping with normal values occasionally occurred. Interestingly, glucocerbrosidase activity was elevated in patients with Niemann-Pick disease variants.

Neurofibrillary tangles in Niemann—Pick disease type C

Post-mortem neuropathological examination of five cases of Niemann-Pick disease type C revealed neurofibrillary tangles in many parts of the brain. Tangles were a consistent finding in the hippocampus, hypothalamus, substantia innominata, midbrain pons and medulla. Other regions of the brain in which tangles were present included neocortex, basal ganglia, thalamus, cerebellar cortex in one case, and dentate nucleus in another. The tangles were argyrophilic, fluoresced under ultraviolet light when stained with thioflavin S, and reacted strongly with antibody to tau protein. Some of the tangles could be immunostained for ubiquitin. Electron microscopy, performed in one of the cases, showed the tangles to consist of paired helical filaments ultrastructurally identical to those of Alzheimer's disease. The distribution of the tangles in the central nervous system as a whole and also within many individual neurons corresponded fairly closely with that of the abnormal storage material. Both the tangles and the storage material extended into, and distended, the proximal parts of many dendrites and axons. No A4/beta protein, either in the form of plaques or in the walls of blood vessels, was detected in any of the cases. Our findings suggest that neurofibrillary tangles are a common feature of Niemann-Pick disease type C and that their formation may be a reaction to the abnormal storage material.

Liver findings in Niemann-Pick disease type C.

A complex analysis of liver from a series of eight cases of Niemann-Pick disease type C showed practically generalized storage of glycolipids and phosphoglycerides by chemical and histochemical techniques. In six of the eight cases the storage process was of low degree, barely recognizable by routine histology, but well recognizable by histochemistry and electron-microscopy. In two cases it was marked and led to early functional impairment of the liver. Changes in various enzyme activities and in ultrastructural features of the storage process are described. Sphingomyelin was found to participate to a very low low degree and its accumulation was not proportional to the extent of overall storage. In two cases with prominent involvement of the liver normal levels of sphingomyelin were found. In other cases sphingomyelin was found, by lipid histochemistry, to be stored only in macrophages. To stress that the storage process in Niemann-Pick disease type C is qualitatively different a comparison was made with liver findings in sphingomyelinase-deficient patients. This feature is of practical as well as theoretical importance.

Chromatofocusing of skin fibroblast sphingomyelinase: Alterations in Niemann-Pick disease type C shared by G M1-gangliosidosis

Sphingomyelinase activity of cultivated skin fibroblast extracts from normal individuals was resolved by Chromatofocusing in the pH range 8-5 into three major components with pI's of 7.3, 6.3 and 5.9, respectively. Chromatofocusing proved a more efficient and reproducible separation technique than preparative flat-bed isoelectric focusing and it gave a constant profile even when detergent concentration varied. In skin fibroblasts from five patients with Niemann-Pick disease type C, a varying degree of reduction in the proportion of the 7.3 peak was observed. In a patient with clinical features of Niemann-Pick disease type C, the finding of such a profile would thus be a good argument for the diagnosis, but it is not pathognomonic as we found similar changes in two cases with G M1-gangliosidosis, while some cases of Niemann-Pick disease type C have borderline normal profiles. These results challenge the concept of a specific sphingomyelinase isoenzyme deficiency as the basic defect in Niemann-Pick disease type C.

A case of Niemann-Pick disease type C with liver cirrhosis

A case of Niemann-Pick disease type C with liver cirrhosis

In situ degradation of sphingomyelin by cultured normal fibroblasts and fibroblasts from patients with Niemann-Pick disease type A and C

Cultured normal human skin fibroblasts actively degraded sphingomyelin [choline-methyl- 14C] introduced in ethanolic solution in the culture medium. After 17 h incubation, about 65 to 80 % of the cellular radioactivity was recovered in phosphatidylcholine. In fibroblasts from Niemann-Pick disease type A the in situ degradation of sphingomyelin was less than 2 % of controls, which was in good agreement with the strong decrease of the sphingomyelinase activity measured in vitro by conventional methods. In the two cases of Niemann-Pick disease type C studied, the in situ degradation of sphingomyelin was significantly but not dramatically decreased compared to controls.

Sphingomyelinase activity levels in human peripheral blood leukocytes, using [ 3H]sphingomyelin as substrate: study of heterozygotes and homozygotes for Niemann-pick disease variants

Patients and heterozygous carriers of Niemann-Pick disease types A and B as . well as the primary (genetic) sea-blue histiocyte syndrome were investigated for their leukocyte sphingomyelinase activity. In parallel, glucocerebrosidase activity was determined in all cases studied. [ 3H]Sphingomyelin and [ 14C]glucocerebroside served as substrates for sphingomyelinase and glucocerebrosidase activity measurements, respectively. Conditions for these enzymes' assays are discussed. Sphingomyelinase activity was completely absent in three cases of NiemannPick disease type A and significantly diminished in one patient with NiemannPick disease type B and two with the sea-blue histiocyte syndrome. Sphingomyelinase activity in obligatory heterozygotes of all variants investigated represented about 40 to 70 per cent of normal activity. Nevertheless, some overlapping with normal values occasionally occurred. Interestingly, glucocerbrosidase activity was elevated in patients with Niemann-Pick disease variants.

Sphingomyelinases in Human Tissues. III. Expression of Niemann-Pick Disease in Cultured Skin Fibroblasts

Extract: Sphingomyelinase was effectively extracted from cultured fibroblasts homogenized in 1% glycine. The average specific activity was 24.6 nmol substrate hydrolyzed per hr per mg protein. Cultured cells from two cases of Niemann-Pick disease type A and one case of type B had markedly reduced enzyme activity, whereas, in type E cells, total activity was twice normal. Sphingomyelinase was resolved by isoelectric focusing into three peaks of activity (I-III), where I and II were the major forms. Species I had a pI of 4.6, II a pI of 4.8, and III a pI of 5.0. All three peaks, although markedly reduced, were present in cell extracts from both types A and B. All species of enzyme in B cells were found at higher levels than in A cells. Cultured cells from a case of type E contained sphingomyelinase I at a level several fold higher than normal, species II was absent, whereas III was found at near normal levels. Speculation: The data suggest that multiple forms of sphingomyelinase exist in cultured cells. Each species may contain polypeptide sequences in common since all forms are affected in fibroblasts in both types A and B. It is also likely that each sphingomyelinase species possesses some unique structure since a specific deficiency of species II was found in a case of type E. Type C and type E Niemann-Pick disease appear to be related since both involve a specific deficiency of sphingomyelinase II.

Sphingomyelinases in Human Tissues. III. Expression of Niemann-Pick Disease in Cultured Skin Fibroblasts

Sphingomyelinase was effectively extracted cultured fibroblasts homogenized in 1% glycine. The average specific activity was 24.6 nmol substrate hydrolyzed per hr per mg protein. Cultured cells from two cases of Niemann-Pick disease type A and one case of type B had markedly reduced enzyme activity, whereas, in type E cells, total activity was twice normal. Sphingomyelinase was resolved by isoelectric focusing into three peaks of activity (I-II), where I and II were the major forms. Species I had a pI of 4.6, II a pI of 4.8, and III a pI of 5.0. All three peaks, although markedly reduced, were present in cell extracts from both types A and B. All species of enzyme in B cells were found at higher levels than in A cells. Cultured cells from a case of type E contained sphingomyelinase I at a level several fold higher than normal, species II was absent, whereas III was found at near normal levels.