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Niemann-Pick disease is a rare, autosomal recessive inherited lysosomal storage disorder. The pathophysiological background for this condition is the deficiency or reduced function of the enzyme sphingomyelinase, as well as a deficiency in the intracellular cholesterol transporter protein. Due to the breakdown defect, sphingomyelin and cholesterol accumulate in the lysosomes of cells. The disease is divided into 5 subtypes (A, A/B, B, C, D). The authors present the case of a 24-year-old young man diagnosed with Niemann-Pick disease type B as a child, focusing on the ophthalmic manifestation of the disease. During the examination of the patient, fundus photographs and fundus autofluorescence imaging were taken, and optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and visual field (perimetry) examinations were performed. The characteristic macular halo and the cherry-red spot in the fovea were clearly visible during ophthalmoscopy and on the fundus photographs. The OCT images showed focal thickening with high reflectivity in the ganglion cell layer corresponding to the macular halo, and the area of the foveola was spared. With visual field examination, an intact field of vision was found on both eyes. Similar to the presented patient, symptoms in patients with the B subtype are milder, and besides the visceral symptoms, there are no neurological symptoms, and the specific ophthalmic abnormalities do not cause visual impairment. Currently, Niemann-Pick disease is considered a rare disease, and the diagnosis of the patients is often delayed or even missed due to non-specific or mild symptoms. Through consultation between medical specialties, ophthalmological examination can also contribute to the correct diagnosis in cases with mild general symptoms. Timely diagnosis can potentially lead to mitigation of symptoms thanks to the ever-expanding therapeutic options, stabilization of the disease progression, and increase of the patients' life expectancy. Orv Hetil. 2023; 164(46): 1838-1844.

Background: The chronic visceral subtype of acid sphingomyelinase deficiency, commonly known as Niemann Pick disease type B (NPDB), is a relatively rare autosomal recessive genetic disorder that is caused by mutations in the SMPD1 gene. NPDB with sea-blue histiocytes (SBH) clinically mimics Budd-Chiari syndrome (BCS), as it lacks specific clinical characteristics. This makes its diagnosis difficult., Case Presentation: Here, we report a case of NPDB with SBH that was misdiagnosed as BCS for three years. A 20-year-old female with abdominal distension, hepatosplenomegaly, and haematological anomalies was initially diagnosed with BCS based on her imaging finding of a thin hepatic vein and rapid blood flow at the confluence of the hepatic vein and inferior vena cava. Her bone marrow cytology found sea-blue histiocytes. Liver biopsy showed foamy cytoplasm in hepatocytes surrounded by numerous Kupffer cells. Sequencing analysis of the SMPD1 gene led to the finding of two missense mutations in the heterozygous state: C.829 T > C (p.Trp277Arg) in exon 2 (novel) and c.1805G > A (p.Arg602His) in exon 6 (already described). These findings established the diagnosis of NPDB., Conclusion: The patient presented with hepatosplenomegaly, haematological anomalies, and dyslipidaemia. Thus, NPDB should be considered following the exclusion of related diseases. The diagnosis of NPDB was suspected by clinical symptoms and routine laboratory tests and was confirmed by liver biopsy and gene sequencing. The novel mutation c.829 T > C in exon 2 of the SMPD1 gene has never been reported and needs to be further investigated., (© 2022. The Author(s).)

Background: Niemann-Pick disease (NPD) is caused by abnormal storage of sphingomyelin. NPD may affect the pulmonary system and cause hypoxia. In the present case, both hepatopulmonary syndrome (HPS) and pulmonary arteriovenous fistulas (PAVFs) developed in a child with NPD and were successfully treated with repeated embolization. Case Presentation: We have reported the case of a 16-year-old-girl with NPD who suffered severe hypoxia, dyspnea, fatigue, had multiple PAVFs, and was diagnosed with type 2 HPS. To improve oxygenation, 10 PAVFs were embolized. She needed re-embolization after 9 months because of hypoxia redevelopment. Conclusions: Pulmonary involvement, HPS, and/or PAVFs could be responsible for hypoxemia in patients with NPD, who should, therefore, be investigated for HPS and PAVFs. Embolization could be beneficial. Some patients may need repeated embolization.

Background: Typically, patients with Acid Sphingomyelinase Deficiency (ASMD) because of p.Arg610del mutation, have mild phenotype with normal linear growth., Observation: We reported the case of 2 Tunisian brothers who have been referred for splenomegaly, polyadenopathies, pubertal, and growth delay. Molecular testing of SMPD1 gene revealed the presence of a homozygous p.Arg610del mutation. Lysosphingomyelin and its isoform-509 were both increased confirming ASMD for both cases. Growth hormone deficiency was highly suspected but growth hormone response after stimulating tests was acceptable for both patients., Conclusions: There is no correlation between phenotype-genotype in case of p.Arg610del mutation that could be associated to a severe delay of growth.

Competing Interests: Competing interests: None declared.

Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication., (Copyright © 2019 SPLF and Elsevier Masson SAS. All rights reserved.)

Niemann-Pick disease type C (NPC) is a rare lysosomal storage disorder causing an intracellular lipid trafficking defect and varying damage to the spleen, liver, and central nervous system. The adult form, representing approximately 20% of the cases, is associated with progressive cognitive decline. Intriguingly, brains of adult NPC patients exhibit neurofibrillary tangles, a characteristic hallmark of Alzheimer's disease (AD). However, the cognitive, psychiatric, and neuropathological features of adult NPC and their relation to AD have yet to be explored. We systematically reviewed the literature on adult NPC with a particular focus on cognitive and neuroanatomical abnormalities. The careful study of cognition in adult NPC allows drawing critical insights in our understanding of the pathophysiology of AD as well as normal cognition.

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.

Niemann-Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1 Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS). WGS results were obtained 16 d before return of the standard clinical genetic test results and prompted initiation of targeted therapy., (© 2017 Hildreth et al.; Published by Cold Spring Harbor Laboratory Press.)

Niemann-Pick disease is a rare autosomal recessive lysosomal storage disease with three subtypes. Types A and B result from a deficiency of acid sphingomyelinase activity, associated with the accumulation of lipid-laden macrophages (so-called Niemann-Pick cells) in various tissues, especially the liver and spleen. Type A is a fatal neurodegenerative disorder of infancy. Type B Niemann-Pick disease is a less severe form with milder neurological involvement, characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement; most patients live into adulthood. Type C Niemann-Pick disease is a complex lipid storage disorder caused by defects in cholesterol trafficking, resulting in a clinical presentation dominated by neurological involvement. Pulmonary involvement occurs in all three types of Niemann-Pick disease, but most frequently in type B. Respiratory manifestations range from a lack of symptoms to respiratory failure. Progression of respiratory disease is slow, but inexorable, due to the accumulation of Niemann-Pick cells in the alveolar septa, bronchial walls, and pleura, potentially leading to a progressively worsening restrictive pattern on pulmonary function testing. Bronchoalveolar lavage has important diagnostic value because it shows the presence of characteristic Niemann-Pick cells. Radiographic findings consist of a reticular or reticulonodular pattern and, eventually, honeycombing, involving mainly the lower lung zones. The most common changes identified by high-resolution computed tomography are ground-glass opacities, mild smooth interlobular septal thickening, and intralobular lines. The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann-Pick disease, with a focus on pulmonary involvement.

Niemann-Pick disease is an inherited lipid storage disorder caused by the deficiency of acid sphingomyelinase, which results in accumulation of sphingomyelin within cells of several organs and consequent tissue damage. The broad clinical spectrum of this disorder may overlap with that of systemic lupus erythematosus, hindering differential diagnosis. Herein, we report the case of a patient affected by Niemann-Pick type B disease intertwined with clinical and serological features of systemic lupus erythematosus. Two novel mutations in the SMPD1 gene were found in compound heterozygosity: p.A36V and IVS2 + 8 T > G., (© The Author(s) 2015.)

Niemann-Pick C (NPC) disease is a rare autosomal recessive lipid storage disorder. We report here the unique occurrence of three adult heterozygous carriers of mutations in the NPC1 gene who also have a parkinsonism syndrome. This suggests the possibility that mutations in NPC1 could be a risk factor for Parkinson's disease similar to the phenomenon that is now recognized with Gaucher disease and the glucocerebrosidase (GBA) gene. This report should be a stimulus for larger more detailed epidemiological studies., (© 2013.)

Background: Niemann-Pick disease (NPD) and Gaucher disease (GD) are well-known lysosomal storage diseases. Respiratory system involvement is an important cause of morbidity and mortality in patients with NPD and GD., Objectives: We tried to assess the clinical, radiological, and histological features of GD and NPD patients with lung involvement., Methods: We reviewed medical history, physical examination, radiological, and histological data of 10 NPD and 7 GD patients., Results: The most common respiratory symptoms were recurrent lung infection and dyspnea. Although lung examination results in 6 NPD patients were normal, they had lung involvement; 3 patients were diagnosed as NPD directly via lung biopsy during investigation of recurrent lung infection or interstitial lung disease. All GD patients but 1 had respiratory system symptoms at the time of diagnosis. Hepatopulmonary syndrome was present in 4 GD patients. A ground-glass pattern and atelectasis were 2 important high-resolution computed tomography features in the NPD and GD patients. Flexible bronchoscopy and bronchoalveolar lavage were used for emergency extraction of bronchial casts in 1 NPD patient., Conclusions: Lung involvement in NPD and GD patients should be included in the differential diagnosis of interstitial lung disease. Besides interstitial appearance on HRCT, atelectasis related to bronchial cast and bronchiectasis are other radiological findings in these group of patients. Analysis of bronchoalveolar fluid and lung biopsy provide very important clues for diagnosis. Hepatopulmonary syndrome is an important vascular complication observed in GD patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency-dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.

A case of a 19 year-old female with the Niemann-Pick disease and transient left ventricular dysfunction following epileptic seizures is presented. Electrocardiographic features and differentid diagnosis of this condition are presented.

Niemann-Pick type C (NP-C) disease is a devastating developmental disorder with progressive and fatal neurodegeneration. We have used a mouse model of Niemann-Pick type C (NP-C) disease to evaluate the effects of direct intracerebral transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) on the progression of neurological disease in this order. Here, we show that hUCB-MSCs transplantation into NP-C mice prevents the loss of Purkinje neurons and inhibits cerebellar apoptotic cell death. Interestingly, these effects were associated with the modulation of inflammatory responses, as evidenced by increased anti-inflammatory cytokine IL-10, and reduced abnormal astrocytic activation. Furthermore, our results show that the hUCB-MSCs transplantation reduced the cholesterol accumulation level in neurons in NP-C mice compared with sham-transplanted animals. This study provides the first evidence that hUCB-MSCs can improve neurological symptoms in NP-C disease, suggesting it as a potential therapeutic agent against neurodegenerative diseases.

This report describes a solitary syringocystadenoma papilliferum, a rare skin tumor, in a 9-year-old boy who was known to have Niemann-Pick disease. To our knowledge, this association has not been described in the medical literature and this is the first report describing such association.

Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C-1 (NPC1)-deficient (NPCD) cells, wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments. We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release. Further, NPCD Epstein-Barr virus-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly compared to normal cells. Infection of the NPCD fibroblasts with a vesicular stomatitis virus G-pseudotyped strain of HIV-1 produced similar results, suggesting a postentry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release. Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.

Niemann-Pick type C1 (NPC) disease is an autosomal recessive neurodegenerative disorder. One feature of the mouse model of NPC1 is it's infertility. We have made transgenic mice which express the Npc1 protein exclusively in fibrillary astrocytes, using the glial fibrillary acidic protein (GFAP) promoter. This selective expression of Npc1 corrects sterility in GFAP-Npc1(-/-), Npc1(-/-) mice. Counts of acidophils in the pituitary of GFAP-Npc1E, Npc1(-/-) mice, as compared Npc1(-/-) mice, and measurements of dopamine D2 receptor (DRD2) mRNA in the pituitary, suggest mechanisms for fertility enhancement. We conclude that the correction of sterility in GFAP-Npc1E, Npc1(-/-) mice is a result of restoring hypothalamic control of the pituitary.

The lysosomal storage disorders are a heterogeneous group of inherited metabolic diseases resulting from defects in the degradation or transport of several distinct by-products of cellular turnover. The various subtypes are characterized by multi-systemic involvement; the wide range in patient ages at symptom onset is only partly explained by the underlying mutation(s). Neurodegenerative features and musculoskeletal complications are often seen in the most severe variants, and are features of the disease that have the most significant impact on patients' physical and functional well-being. Until recently, the care of affected individuals relied mainly on palliative or supportive measures. The introduction of therapies directed at correcting the primary defect (i.e., deficient enzyme activity) in several of these disorders has led to modification of the phenotype and natural history or disease course; however, clinical problems arising from brain and bone involvement remain major sources of morbidity. Factors that might influence therapeutic outcome include pre-existing pathology at the time of treatment initiation, drug access to tissues sites of pathology, and - in the case of enzyme therapy - antibody formation. Increasing understanding of the pathogenesis or relevant mechanism(s) of diseases is providing insights into additional therapeutic targets, enabling the potential for optimized patient outcomes with the use of adjunctive or supplemental agents. Physical and occupational therapy remain critical components of a comprehensive approach to patient care.

Niemann-Pick disease (NPD) is an inherited metabolic disorder, which has been classified into types A, B, C, and D. Niemann-Pick disease rarely causes spontaneous splenic rupture: to our knowledge, only four such cases have ever been reported. We report the case of a 53-year-old man with NPD manifesting as spontaneous splenic rupture. Ultrasound showed a ruptured large spleen with hemoperitoneum, and he underwent emergency splenectomy. Histopathological examination confirmed that there were numerous accumulated "Pick cells," defined as foamy histiocytes, in the spleen.

Background: Lung involvement in children with Niemann-Pick disease has rarely been studied systematically., Objective: To assess the involvement of the lung and the value of bronchoalveolar lavage in children with Niemann-Pick diseases., Design: Retrospective analysis of patient records., Patients: Thirteen patients, with type A (n = 1), type B (n = 10), and type C (n = 2) Niemann-Pick disease, aged 2 months to 9 years at diagnosis, were included in the study., Interventions: Lung involvement was assessed by clinical evaluation, chest radiograph, lung computed tomography (CT) scan, pulmonary function tests, and bronchoalveolar lavage fluid analysis., Results: Respiratory symptoms were present at diagnosis in 10 patients and developed during follow up in the three other patients. All patients showed signs of interstitial lung disease on chest X-ray and lung CT scan. Bronchoalveolar lavage fluid analysis (n = 7) revealed a marked accumulation of foamy macrophages (Niemann-Pick cells) in all patients. At follow up, one patient died of respiratory failure, five patients required long term oxygen therapy and seven other patients presented a chronic obstructive pulmonary disease (n = 6) or chronic cough (n = 1)., Conclusion: Lung disease was observed in all the patients included in the present study. Bronchoalveolar lavage may be useful in Niemann-Pick diseases by showing the presence of characteristic Niemann-Pick cells.

Niemann-Pick disease (NPD), an autosomal recessive disorder resulting from mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, is subdivided into the acute, lethal neuronopathic type A, and the chronic visceral type B, explained by the different residual activity levels of acid sphingomyelinase (ASMase). An increasing number of reports on intermediate forms, challenging this traditional clinical classification, have described a broad range of neurological manifestations; however genotype-phenotype correlations have been compromised by relatively small sample sizes and/or allelic heterogeneity. Here we present a genetically homogeneous group of 20 Gypsy patients with intermediate NPD, where we observed a surprising diversity of neurological features. All affected subjects were homozygous for the same ancestral mutation, W391G in SMPD1, yet displayed the entire spectrum of phenotypic variation observed previously in unrelated affected subjects of diverse ethnicity and disease-causing mutations, ranging from subclinical retinal involvement to severe ataxia, cognitive deficits and psychiatric disorders. The clinical heterogeneity of W391G homozygotes points to additional factors, beyond SMPD1 and residual ASMase, which determine the localization, extent and severity of neural involvement. The phenotype similarity of affected relatives suggests a possible role of genetic modifying factors. In practical terms, W391 is common in the Gypsy population and the diagnosis of NPD should be borne in mind despite the atypical course of the disease. Generally, our findings indicate that mutation analysis is of limited value in predicting brain damage, and the option of enzyme replacement therapy should be considered in intermediate NPD.

Sea-blue histiocytosis is a rare disorder seen in patients with lipid metabolic or ceroid storage diseases. Sea-blue histiocytes are ceroid-laden macrophages detectable by May-Giemsa staining. We report a case of a 28-year-old woman diagnosed with Niemann-Pick disease at 2 or 3 years of age. To confirm this diagnosis, we examined her bone marrow, which revealed scattered foci containing aggregates of foamy macrophages. May-Giemsa staining identified blue-staining foamy macrophages, referred to as sea-blue histiocytes. In summary, we report the detection of sea-blue histiocytosis in an adult with Niemann-Pick disease.

Background: Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lysosomal storage disease which may present in infancy with cholestatic jaundice and/or hepatosplenomegaly. In cholestatic patients with splenomegaly, a bone marrow aspirate has been advocated as a relatively accessible tissue to demonstrate storage phenomena. Typically in patients with NPC, macrophages with abnormal cholesterol storage, so called foam cells, can be detected in the bone marrow., Aim: To review our experience of bone marrow aspiration in children with NPC presenting with infantile liver disease., Methods: A retrospective analysis of 11 consecutive children (8 males) from Birmingham Children's Hospital with NPC presenting with infantile liver disease was undertaken. The diagnosis of NPC was confirmed in all cases by demonstrating undetectable or low rates of cholesterol esterification and positive filipin staining for free cholesterol in cultured fibroblasts., Results: The median age at presentation was 1.5 months (range 0.5-10). Bone marrow aspirates showed storage cells in only 7/11 cases. Bone marrow aspirates which had storage cells were undertaken at a median age of 11 months while those with no storage cells were undertaken at median age 2.3 months. The overall sensitivity of bone marrow aspirates for detecting storage cells in children presenting with infantile liver disease was 64%; however, for children who had bone marrow aspirates in the first year of life it was only 57%., Conclusions: The sensitivity of bone marrow aspirate for the diagnosis of NPC disease in patients presenting with infantile liver disease was lower than previously reported. Where NPC is suspected clinically, definitive investigations should be undertaken promptly. There is a need to develop sensitive screening methods for NPC in children presenting with infantile liver disease.

Objective: To document the prevalence of neurologic disease in Niemann-Pick disease (NPD) NPD-B., Study Design: Sixty-four patients with NPD-B had detailed neurologic and ophthalmologic evaluations. The presence of neurologic abnormalities was compared with genotype., Results: Nineteen of 64 patients (30%) had neurologic abnormalities, which were minor and nonprogressive in 14 (22%), and global and progressive in 5 (8%). In these five patients, the onset of neurologic difficulties occurred between 2 and 7 years of age and was associated with peripheral neuropathy, retinal abnormalities, and the Q292K mutation. No patients with at least one copy of DeltaR608 had neurologic involvement., Conclusions: The majority of patients with NPD-B have no neurologic abnormalities. In patients with neurologic abnormalities, the findings can be minor and static or severe and progressive. The latter phenotype follows a course distinct from that of classic NPD-A and is associated with the Q292K mutation and characteristic retinal findings. Thus, similar to other lysosomal storage disorders, there is a broad spectrum of neurologic abnormalities in acid sphingomyelinase deficiency, which makes the current classification scheme inaccurate.

Cataplexy in childhood is a rare and often misdiagnosed symptom. It is described as a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions and in particular with unexpected laughter. This report presents a 9-year old male with progressive cerebellar and pyramidal symptoms and a cognitive decline since the age of 4. His recently developed "drop attacks" on laughter were recognized as cataplexy and led to the diagnosis of Niemann-Pick type C disease. With biochemical studies this diagnosis, a lysosomal storage disease, was confirmed. With cataplexy narcolepsy, Niemann-Pick type C disease, Norrie disease, Prader-Willi syndrome, and Coffin-Lowry syndrome are associated disorders. Recognition of cataplexy in children with concomitant neurologic symptoms may lead to an early and straight diagnosis of one of these disorders.

Objective: To describe the disease course and natural history of Type A Niemann-Pick disease (NPD)., Methods: Ten patients with NPD-A (six male, four female; age range at entry: 3 to 6 months) were serially evaluated including clinical neurologic, ophthalmologic, and physical examinations, and assessment of development. Laboratory analyses, abdominal and brain ultrasounds, and chest radiographs also were obtained and information on intercurrent illnesses and cause of mortality was collected., Results: All affected infants had a normal neonatal course and early development. The first symptom detected in all patients was hepatosplenomegaly. Developmental age did not progress beyond 10 months for adaptive behavior, 12 months for expressive language, 9 months for gross motor skills, and 10 months for fine motor skills. Non-neurologic symptoms included frequent vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbance. Neurologic examination at the time of presentation was normal in most patients. Later neurologic examinations revealed progressive hypotonia with loss of the deep tendon reflexes. All patients had cherry red spots by 12 months. The median time from diagnosis to death was 21 months. The cause of death was respiratory failure in nine patients and complications from bleeding in the tenth., Conclusions: The clinical course in Type A Niemann-Pick disease is similar among affected patients and is characterized by a relentless neurodegenerative course that leads to death, usually within 3 years.

Transthoracic echocardiography is a useful tool in the evaluation of patients with intrapulmonary and intracardiac shunts. We describe a case of a 49-year-old female with severe hypoxemia in the setting of aortic stenosis and cirrhosis of the liver. The use of agitated saline contrast during an echocardiography study helped to establish the diagnosis of intrapulmonary arteriovenous shunting consistent with the hepatopulmonary syndrome, thereby confirming the etiology of her symptoms and laboratory findings. This case report highlights the utility of echocardiography in diagnosing intrapulmonary shunts and assists in the understanding of the pathophysiology of hypoxemia in such patients.

Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mice). We confirmed previous results showing that a single injection of 250 microg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1(-/-) mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1(-/-) mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice. Similar effects of allopregnanolone treatment were observed in Npc1(-/-), mdr1a(-/-) double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity.

Idiopathic nodular panniculitis is a condition characterized by the recurrent appearance of inflammatory nodules in the subcutaneous fat. In this report, an infant affected with Niemann-Pick disease and recurrent lobular panniculitis is described and discussed.

Systemic diseases affecting the lung are fortunately relatively rare in paediatric practice. A number of conditions do, however, cause significant respiratory complications, which can result in serious morbidity and mortality in this age group. These include connective tissue disorders such as systemic lupus erythematosus, dermatomyositis and scleroderma, inherited connective tissue disorders such as Ehlers-Danlos and Marfan's syndrome, lysosomal storage disorders such as mucopolysaccharidoses, familial dysautonomia, Langerhans cell histocytosis, pulmonary lymphangiomatosis, sarcoidosis and sickle cell disease. The investigations of these conditions are often complex but form part of the overall multisystem review of each individual patient. Treatment is individualised but often requires the extended use of corticosteroids and other immunosuppressants. The outcome is variable and depends on the ability to control the underlying condition. Long-term chronic lung damage is not unusual and these diseases, when they affect the lung, carry a small but significant mortality.

Niemann-Pick disease (NPD) is a rare, autosomal-recessively inherited lipid storage disease which is characterized by intracellular deposition of sphingomyelin in various body tissues. The disease is heterogeneous and classified into six groups. Pulmonary parenchymal involvement may be a feature of several subtypes of NPD, including type B. Progressive pulmonary involvement in NPD type B is a major cause of morbidity and mortality. It is usually diagnosed at older ages. Only a few cases with early pulmonary involvement have been reported. In this report, a patient with NPD type B, hospitalized with the diagnosis of pneumonia at age 3 months, is presented. Following treatment for pneumonia, she continued to have persistent respiratory symptoms and became oxygen-dependent. High-resolution computed tomography of the chest revealed diffuse interstitial changes. During follow-up, the patient developed hepatosplenomegaly. Lung, liver, and bone marrow biopsies showed characteristic findings for NPD. Biochemical studies also confirmed the diagnosis, and the sphingomyelinase enzyme level of the patient was low. Unilateral lung lavage was performed in order to decrease lipid storage as a treatment modality. However, there was no clinical or radiological improvement. The patient died at age 15 months due to progressive respiratory failure. Pulmonary involvement is a rare entity in early childhood in patients with NPD type B, but should be considered in the differential diagnosis of persistent interstitial lung disease. It may cause progressive respiratory failure, but the treatment options remain limited., (Copyright 2005 Wiley-Liss, Inc.)

Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1-/- mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol ("high-fat") diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. gamma-Glutamyltransferase was also elevated in Npc1-/- mice, more so on the high-fat diet. Mrps 1-5 were elevated in Npc1-/- liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1-/- liver and were suppressed by the high-fat diet. In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.