Brain stem auditory evoked potentials in two siblings with Niemann-Pick disease

Niemann-Pick disease is a disorder of sphingomyelin metabolism, which produces organomegaly and progressive generalized neurologic dysfunction. In two brothers with Niemann-Pick disease type C brain stem auditory evoked potentials (BAEPs) produced prolongation of waves I-III interpeak latencies.     

Type C Niemann-Pick disease in a boxer dog

Summary Pathological and biochemical studies were performed on a 9-month-old boxer dog with progressive neurological abnormality. Histological examination revealed marked neuronal storage throughout the central nervous system and histiocytic storage in the reticuloendothelial system. Ultrastructurally, the neuronal storage consited of accumulation of concentric membranous inclusions and clusters of dense bodies. The biochemically unesterified cholesterol content was high in the liver and spleen. The brain showed increased levels of lactosylceramide and two gangliosides, GM₃ and GM₂. These findings indicate that this dog was affected with a heterogeneous lipid storage disease similar to the human Niemann-Pick type C disease.     

Niemann-Pick disease type C

Summary A complex neuropathological study of two cases of Niemann-Pick disease (NPD) type C (NPDC) revealed some novel features in the chemical pathology of the neuronal storage. Lipid histochemistry showed the presence of a lipid which met the criteria of a neuronal glycosphingolipid. Sphingomyelin (SM) was not detected in the neurones in any of the regions examined. Lipid chemical analysis of total extracts and of partially purified lysosomal fraction of the brain cortex showed markedly increased levels of neutral ceramide hexosides especially of glucosylceramide and ceramide dihexoside (mostly of its slower band). Phospholipids were not significantly increased. Monosialogangliosides GM₂ and GM₃ were increased only slightly. The storage process displayed the well known fine structure and was accompanied by a marked secondary increase in some lysosomal enzyme activities. There was neuroaxonal dystrophy (NAD) of considerable intensity and extent. Many spheroids contianed masses of degenerated organelles and neurofilaments in various proportions and displayed variable activities of acid phosphatase, nonspecific esterase and dehydrogenases. There was marked brain atrophy accompanied in one case by severe demyelination. Enzyme studies revealed partial decrease of sphingomyelinase (SMase) and betaglucosidase activities in cultured fibroblasts, as well as lack of cathodic SMase activity on isoelectric focusing. No defects of these enzymes were found in the brain samples. The findings are regarded as significant since they indicate a biochemical defect in which SM is not primarily involved and which may thus be fundamentally different from that in type A of NPD.     

Cerebellar degeneration in the Niemann-Pick type C mouse

Summary Chronological morphological changes and topographical distribution of degenerating Purkinje cells were studied in the murine model of Niemann-Pick disease type C (NPC mouse). Loss of Purkinje cells can be detected in the anterior vermis as early as 60 days of age, coinciding with early neurological signs, and progressed to total absence in the entire hemisphere and vermis with exception of nodules. Ultrastructurally, concentric lamellar inclusions were detected in the perikarya of degenerating Purkinje cells as well as in the focally enlarged branching points of their dendrites. Calbindin immunocytochemistry demonstrated dendritic pathology characterized by irregular contour of dendritic trees and decreased number of dendritic spines. Ubiquitin immunoreactivity revealed granular reaction products in the perikarya, dendrites and axons of Purkinje cells. Our studies demonstrated unique pathological features of Purkinje cells that involve perikarya, dendrites and axons in the NPC mouse.Supported in party by USPHS grants NS-24453, HD-03110 and ES-01104     

Feline sphingolipidosis resembling Niemann-Pick disease type C

Summary A 9-week old domestic short-hair kitten with progressive neurological dysfunction had histopathological lesions consistent with a lysosomal storage disease. Light microscopy of the brain, spinal cord, and ganglia revealed distention and vacuolation of many neuronal populations, and extensive neuroaxonal dystrophy. Large numbers of foamy macrophages were observed in the liver, spleen, lymph nodes, and lung. Hepatocytes appeared pale and swollen. Ultrastructural examination of all affected tissues and organs revealed heterogeneous membranous inclusions. Lipid analysis of liver revealed an excess of cholesterol, glucosylceramide, lactosylceramide and phospholipids including sphingomyelin. There was some increase in the levels of brain GM₂ and GM₃ gangliosides. Sphingomyelinase activity in liver was partially deficient or low normal. Skin fibroblasts were cultured from two affected cats from the colony established with littermates of the subject of this report. The cultured skin fibroblasts had partially decreased sphingomyelinase activity and a greatly decreased ability to esterify exogenous cholesterol. Clinical, morphological, and biochemical findings suggest that this cat had sphingolipidosis similar to human Niemann-Pick disease type C, a disease not previously described in the cat. The feline form of this storage disease may provide a useful model for studies on the human disease.Supported by Research Grants RR02599, AI07227, AR37095 and DK38795 from the National Institutes of Health, by an anonymous foundation, and by a grant from Zipporah S. Fleisher for Canine Neurologic Research     

Maladie de Niemann-Pick type “C” de Crocker

Summary The authors report electron microscopic findings in brain, bone marrow and liver biopsies in a case of juvenile Niemann-Pick disease (Crocker's type C). The diagnosis was supported by clinical data increase of blood sphingomyelin and vacuolated histiocytes in bone marrow and liver. Neurons and glial cells were filled with two types of cytosomes: classical multilamellar bodies and unusual pleiomorphic bodies. The latter type probably showed some lipofuscinic component. The relationship between type C and classical Niemann-Pick disease is discussed.

     

Systematic review of psychiatric signs in Niemann-Pick disease type C

Objectives: We conducted the first systematic literature review and analysis of psychiatric manifestations in Niemann-Pick disease type C (NPC) to describe: (1) time of occurrence of psychiatric manifestations relative to other disease manifestations; and (2) frequent combinations of psychiatric, neurological and visceral disease manifestations.

Methods: A systematic EMBase literature search was conducted to identify, collate and analyze published data from patients with NPC associated with psychiatric symptoms, published between January 1967 and November 2015.

Results: Of 152 identified publications 40 were included after screening that contained useable data from 58 NPC patients (mean [SD] age at diagnosis of NPC 27.8 [15.1] years). Among patients with available data, cognitive, memory and instrumental impairments were most frequent (90% of patients), followed by psychosis (62%), altered behavior (52%) and mood disorders (38%). Psychiatric manifestations were reported before or at neurological disease onset in 41 (76%) patients; organic signs (e.g., hepatosplenomegaly, hearing problems) were reported before psychiatric manifestations in 12 (22%). Substantial delays to diagnosis were observed (5–6 years between psychiatric presentation and NPC diagnosis).

Conclusions: NPC should be considered as a possible cause of psychiatric manifestations in patients with an atypical disease course, acute-onset psychosis, treatment failure, and/or certain combinations of psychiatric/neurological/visceral symptoms.     

Unusually prominent horizontal gaze palsy in a case of Niemann-Pick type C disease

Niemann-Pick Type C disease (NPC) is a rare inherited metabolic disorder characterized by lipid accumulation and systemic manifestations due to multiple organ involvement. Only a few cases of NPC have been reported so far from India. Varying presentations and often lack of access to complex diagnostic tests have leaded to initial misdiagnosis on few occasions. We here report a provisionally diagnosed case of NPC with prominent horizontal gaze palsy along with characteristic vertical gaze palsy and normal findings on microscopic examination of skin biopsy specimen.     

A case of Niemann-Pick disease type C with neonatal liver failure initially diagnosed as neonatal hemochromatosis

Background

Niemann-Pick type C (NPC) is a lysosomal lipid storage disease with mutation of NPC1/NPC2 genes, which transport lipids in the endosome and lysosome, and various neurological symptoms. NPC patients also develop hepatosplenomegaly or liver disorder in the neonatal period, and 10% suffer severe liver failure. Neonatal hemochromatosis (NH) is a liver disorder characterized by hepatic and extrahepatic siderosis. Although the etiology of NH is unclear, recent reports suggest that the gestational alloimmune mechanism is the cause of NH. Herein, we report a Japanese NPC patient initially diagnosed as NH.

抑制细胞周期依赖性蛋白激酶-5表达对C型尼曼-皮克病小鼠的神经保护作用

目的:观察抑制细胞周期依赖性蛋白激酶-5(cdk5)的表达对C型尼曼-皮克病(NPC)小鼠(npc-/-)的治疗作用。方法:采用携带cdk5特异性小干扰RNA(cdk5-siRNA)的重组腺相关病毒rAAV-cdk5-siRNA-GFP,对出生三天内的npc-/-小鼠进行双侧侧脑室注射,以rAAV-GFP注射组及非手术的同龄npc小鼠为对照(n=6～10/组);采用免疫组织化学染色、HE染色和小鼠衣架悬挂试验来评价小鼠脑内的神经病理改变和运动功能。结果:rAAV2-cdk5-siR-NA-GFP能显著减少轴突球状体的数量,延缓浦肯野细胞的死亡并改善npc-/-小鼠的运动功能。结论:降低cdk5的活性对npc-/-小鼠的神经元有一定的保护作用。     

Treatable metabolic psychoses that go undetected: What Niemann-Pick type C can teach us

Objective. The objective of this review is to raise awareness of the prevalence of inborn errors of metabolism, in particular NP-C, in psychiatric populations. Methods. This review summarises research presented at a satellite symposium held on 28 August 2010 at the 23rd European College of Neuropsychopharmacology (ECNP) meeting. Results and Conclusion. Organic causes of psychoses may have an unrecognised yet notable prevalence, particularly in adolescent or adult patients. Several inherited metabolic disorders can present with psychiatric signs. In some disorders, such as Niemann-Pick type C (NP-C), the disease may remain unrecognised for many years due to a heterogeneous and subtle clinical presentation. In patients presenting with psychoses, subtle signs such as vertical supranuclear gaze palsy, ataxia and splenomegaly should raise the suspicion of NP-C. Miglustat is so far the only approved treatment for NP-C. Miglustat can stabilise neurological disease, particularly in adolescent or adult-onset patients who are detected as early as possible, before irreversible neurological damage occurs.     

C型Niemann-Pick病神经原纤维缠结的形成与特征

目的 探讨C型尼曼-皮克病(NPC)脑部神经原纤维缠结(NFT)形成的时相特征.方法 以17例年龄7个月至55岁的NPC患者为研究对象,采用tau蛋白和有丝分裂期相关抗体进行免疫组织化学染色和银染,分析患者脑内NFT形成的特点.结果 最早可在4岁的患者海马旁回发现典型的NFT形成,随年龄增长数量逐渐增多.在形态上与阿尔茨海默病(AD)所见高度相似,但未发现老年斑.在NPC中,有丝分裂期磷酸化表位早于tau蛋白过度磷酸化及NFT形成.结论NFT形成并非老龄化过程的结果 ,且与老年斑的存在与否并无关联.cdc2/cyclinB1可能是NFT形成的关键性早期事件,针对其活性的抑制剂对于早期干预NPC NFT的形成有重要意义.     

Niemann-Pick C disease in Spain: clinical spectrum and development of a disability scale

OBJECTIVES: To describe the clinical evolution of Niemann-Pick C disease to identify possible factors involved in the diagnosis and severity of the disease. METHODS: A clinical database and a severity scale was created to evaluate 45 patients diagnosed with Niemann-Pick type C in the last 28 years in Spain. RESULTS: Complete clinical data were obtained from 30 patients, all were confirmed to have mutations in the NPC1 gene. Regarding clinical form, 3 were perinatal, 7 severe infantile, 6 late infantile, 11 juvenile and 3 adult. Biochemical phenotype was classic in 26. Splenomegaly was present in 28 patients (93%) with a wide range of age at detection. The first symptom of neurological disease was clumsiness, followed in 2-4 years by cerebellar signs. Ophthalmoplegia appeared 2-4 years later and became complete 1-2 years after onset. Dysarthria appeared by the time of complete ophthalmoplegia. Diagnosis was made before the onset of neurological signs in patients with the severe infantile form, at the time of onset of cerebellar signs in the late infantile form and complete ophthalmoplegia in late onset forms. CONCLUSIONS: In our series, splenomegaly is present in 96% of patients, even in late onset forms during the first years of life. Clumsiness in children with otherwise normal motor development precedes the onset of ataxia by 2-4 years in Niemann Pick type C. A disability scale could be useful for monitoring evolution, establishing possible phenotypic correlations and evaluating future therapies.     

Presentation of Niemann-Pick type C disease with psychiatric disturbance in an adult

INTRODUCTION: Niemann-Pick Type C disease (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder. CASE REPORT: A 31-year-old right-handed woman had suffered from schizophrenia for 13 years. At 25 years of age, she developed a gait disorder with a static and kinetic cerebellar syndrome, dysarthria, vertical supranuclear gaze palsy and cognitive impairment. Brain MRI was normal. Abdominal ultrasonography was performed because of hypercholesterolemia and elevated transaminases and revealed hepatosplenomegaly, which in conjunction with other signs and symptoms, suggested the diagnosis of NPC. The diagnosis was confirmed by demonstration of lysosomal storage of unesterified cholesterol (filipin staining) and of a reduced rate of LDL-induced cholesterol esterification. Implication of the NPC1 gene was assessed by genetic complementation analysis. DISCUSSION: The phenotypic presentation of NPC is remarkably variable. The rarer adult-onset form has a slowly progressive course. Psychotic manifestations are often prominent and may precede neurologic symptoms. Exposure to neuroleptics delays the diagnosis of NPC. CONCLUSION: Psychotic manifestations associated with cerebellar syndrome, vertical supranuclear gaze palsy, and splenomegaly are very suggestive of NPC disease which can be reliably diagnosed on cultured skin fibroblasts by filipin staining.     

Roscovitine对C型尼曼-皮克病小鼠的神经保护作用

目的 观察细胞周期依赖性蛋白激酶特异性抑制剂Roscovitine对C型尼曼-皮克病（NPC）小鼠（npc^-/-）的治疗作用。方法 采用72、144、300和600nmol／d的Roscovitine对5周龄的npc^-/-小鼠（n=6～10）进行2周侧脑室灌注，以DMSO灌注的同龄npc^-/-小鼠（n=6～10）为对照；采用免疫组织化学染色、H＆．E染色和小鼠衣架悬挂试验来进行检测。结果 Roscovitine能显著减少球状轴突的数量，延缓浦肯野细胞的死亡并改善npc^-/-小鼠的运动功能。结论 Roscovitine对NPC的神经系统变性有一定的保护作用。     

Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry

Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry.

Methods: Treating physicians’ data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists.

Results: Out of 386?NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5–67.9; n?=?15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2–69.8; n?=?34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment.

Conclusions: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.     

Establishment and characterization of immortalized Schwann cells from murine model of Niemann-Pick disease type C (spm/spm)

Niemann-Pick disease type C (NPC) is characterized by an accumulation of unesterified cholesterol in the endosomal/lysosomal (E/L) system, resulting in progressive neurodegeneration and death during early childhood. To investigate the cellular pathomechanism of nervous system involvement in NPC, continuous neural cell lines are desirable. In this study, we obtained neuronal and Schwann cell cultures and established spontaneously immortalized Schwann cell lines from dorsal root ganglia and peripheral nerves of NPC model mouse (spm/spm). One of the cell lines, designated SPMS9, had distinct Schwann cell phenotypes and was maintained over 10 months without phenotypic alterations. The level of Npc1 mRNA was markedly decreased, and NPC1 protein was not detectable in SPMS9 cells. These cells contained intracytoplasmic granules positive for filipin cholesterol staining and immunoreactive for GM2 ganglioside. Electron-microscopically, intracytoplasmic polymorphous membranous inclusions and vacuoles were demonstrated in SPMS9 cells. The treatment with an inhibitor of ceramide-specific glucosyltransferase, N-butyldeoxynojirimysin (NB-DNJ) markedly reduced the intracytoplasmic granular immunofluorescence for GM2 ganglioside in SPMS9 cells, whereas the amount of filipin-positive granules remained unchanged. The SPMS9 cells retained vesicular fluorescence of cationic dye acriflavine 16-24 hours after loading, indicating the defect of transmembrane efflux pump activity of NPC1 in the E/L compartment in these cells. These immortalized Schwann cells can be useful in studies on the nervous system lesions in NPC.     

冠心病与脑梗塞并存102例分析

冠心病和脑梗塞是老年人最常见威胁生命和健康的疾病。本文总结了我科近七年冠心病与脑梗塞并存102例进行分析，结果表明，88．2％为老年期病人，70．5％为无症状性脑梗塞，82％为多发腔隙性梗塞灶，部位多位于基底节区和深部白质区，分析了冠心病与脑梗塞相互间的发病机理．结论：在幼脉粥样硬化基础上，高龄和缺血性心脏病是无症状性脑梗塞校危险因素。老年冠心病需同时防治脑梗塞。