Question

    Niemann-Pick Disease (Niemann Pick Disease)

    Niemann-Pick disease (NPD) is an autosomal recessive disorder, observed most frequently in Ashkenazi Jews, where there is a deficiency of the lysosomal enzyme sphingomyelinase, leading to accumulation of sphingomyelin in cells of the monocyte-macrophage system and reticular endothelial cells.

    The disease is induced by this process: metabolic.

    Presentation

    Patients with type A NPD appear normal at birth but start to display signs, such as hepatosplenomegaly, in early infancy. In type A NPD less than 5% or sphingomyelinase activity is observed and along with hepatosplenomegaly, patients display a failure to thrive, feeding problems, interstitial lung disease resulting in recurrent respiratory tract infections, motor and intellectual developmental delays followed by regression, irritability, cherry-red macula, pancytopenia, progressive neurodegeneration and eventually death by age two or three. Progressive hepatosplenomegaly is usually apparent by three months and mild hypotonia may appear by 6 months leading to loss of tone and deep tendon reflexes (previously achieved milestones may be lost). Psychomotor skills of type A patients do not progress beyond the 12 month level (eg. sit with assistance). The final stage of type A NPD is characterized by spasticity and rigidity. Although uncommon, some patients present unilateral tremors and ipsilateral hemiparesis [8].

    Patients with type B NPD have 5-10% of normal sphingomyelinase activity and display more variable severity of symptoms, clinical findings and age of onset than type A. Hepatosplenomegaly is a hallmark of both types of NPD and lymphadenopathy may occur in patients with type B. Patients with type B NPD have minimal neurologic involvement but pancytopenia is common. Pulmonary involvement may be observed in type B NPD patients which is detected on chest radiographs as diffuse reticular or finely nodular infiltration. Severe pulmonary complications may arise in patients with type B NPD due to progressive pulmonary infiltrates. It is common for type B NPD patients to survive into adulthood and often it is hard to distinguish these patients from patients with Gaucher disease type 1. Growth retardation may be observed in patients with moderate-to-severe type B NPD [7] [8].
    Mildly affected patients may have minimal disease manifestations and hepatosplenomegaly may not be detected until adulthood.

    Liver, Gall & Pancreas
    Hepatomegaly
    • Hepatomegaly and/or splenomegaly may or may not be present.[genedx.com]
    • Often observed is isolated unexplained splenomegaly (with or without hepatomegaly).[hindawi.com]
    • Enlargement of the liver (hepatomegaly) or spleen (splenomegaly) is present in a high percentage of affected individuals in this age group.[rarediseases.org]
    Hepatosplenomegaly
    • Hepatosplenomegaly is a hallmark of both types of NPD and lymphadenopathy may occur in patients with type B.[symptoma.com]
    • Niemann-P ick disease (NPD) is actually a collection of a number of distinct autosomal recessive lysosomal storage diseases . deficiency of acid sphingomyelinase 1 Niemann-Pick disease type A (NPA) severe hepatosplenomegaly in infancy severe central nervous[radiopaedia.org]
    • Hepatosplenomegaly develops by age 6 months and development does not progress beyond age 12 months.[emedicine.medscape.com]
    • Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension, and pain.[en.wikipedia.org]
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  • Entire body system
    Anemia
    • Other examples include the defective gene that causes sickle cell anemia.[geneticliteracyproject.org]
    • Caused by deficiency of sphingomyelinase, resulting in accumulation of sphingomyelin in the reticuloendothelial system, mental and physical retardation, enlarged liver and spleen, anemia, and blindness.[icd10data.com]
    • Niemann-Pick disease: A biochemical disorder affecting a lipid (fat) called sphingomyelin, resulting usually in progressive enlargement of the liver and spleen (hepatosplenomegaly), "swollen glands" (lymphadenopathy), anemia and mental and physical deterioration[medicinenet.com]
    • The disease, which in the United States and Canada is most common among Jewish people, begins in infancy or childhood and is characterized by enlargement of liver and spleen, anemia, lymphadenopathy, and progressive mental and physical deterioration.[medical-dictionary.thefreedictionary.com]
    • Presence of anemia defined as two standard deviations below normal for age and gender.[clinicaltrials.gov]
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  • neurologic
    Hyporeflexia
    Mental Deterioration
    • As the disease progresses, it becomes clear that the child is mentally deteriorating.[ncbi.nlm.nih.gov]
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  • Immune System
    Splenomegaly
    • INTRODUCTION Niemann-Pick disease (NPD) is a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of sphingomyelin.[uptodate.com]
    • Absence of splenomegaly does not exclude NP-C.[hindawi.com]
    • Isolated splenomegaly may be the presenting symptom in some adolescents or adults.[rarediseases.org]
    • […] definition Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly[orpha.net]
    • Patients with splenomegaly have increased risk of splenic rupture, therefore, contact sports should be avoided.[symptoma.com]
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  • Skin
    Xanthoma
    • Xanthoma tuberosum References Millat et al., (2005) Mol Genet Metab 86:220-232 Park et al., (2003) Hum Mut 22:313 Verot et al., (2007) Clin Genet 71:320-30 Sevin et al., (2007) Brain 130:120-133 Fernandez-Valero et al., (2005) Clin Genet 68 :245-254[genedx.com]
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  • respiratoric
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  • gastrointestinal
    Failure to Thrive
    • Type A NPD is a fatal disorder in young children characterized by failure to thrive, hepatosplenomegaly and progressive neurodegeneration resulting in death by age three.[symptoma.com]
    • Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms.[uniprot.org]
    • The disease is characterized by hepatosplenomegaly, failure to thrive, and rapidly progressive neurodegeneration.[merckmanuals.com]
    • Mortality/morbidity Patients with NPD type A develop progressive failure to thrive, sphingomyelin accumulation, liver dysfunction, and neurodegeration beginning at age 3 months and ending with death by age 3 years.[emedicine.medscape.com]
    • Niemann Pick C Cell Line Collection Niemann Pick type C (NPC) disease is an autosomal recessive disorder of lipid storage which can lead to neurological, psychiatric, and visceral problems as well as the failure to thrive.[catalog.coriell.org]
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  • musculoskeletal
    Muscle Weakness
    • There is a gradual decline of motor and intellectual function resulting in a degenerative muscle weakness and floppiness.[en.wikibooks.org]
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  • Eyes
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  • Workup

    NPD may be suspected due to familial history along with identification of hepatosplenomegaly upon physical examination. Diagnosis may be confirmed pre or postnatal, using a sphingomyelinase assay on amniocentesis or chorionic villus sampling and white blood cells (WBCs), respectively. The hallmark of NPD is characteristic lipid-laden foam cell on bone marrow examination, although, genetic tests are needed for definitive diagnosis [10]. Along with hepatosplenomegaly patients often display pancytopenia (secondary to splenomegaly), elevated transaminase, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Patients with type B NPD commonly have reduced high-density lipoprotein (HDL-C) fraction and these patients often display hypertriglyceridemia. Pulmonary reticulonodular patterns of infiltration and calcified nodules may be observed in chest radiographs of NPD patients with or without pulmonary symptoms. Patients often display decreased oxygen diffusion, restrictive lung disease and exercise intolerance. A lag in bone age of up to two and a half years may be observed in NPD type B patients. Myocardial dysfunction and valvular heart disease can be diagnosed with an echocardiogram (ECHO), which are especially prevalent in NPD patients with underlying coronary artery disease [10].

    Clinical laboratories are equipped to identify the four most common SMPD1 mutations responsible for NPD. Three common mutations have been identified in type A NPD patients (L302P, R495L and fsP330) and one common allele in type B (deltaR608). Another less common mutation, Gln294Lys, is associated with a milder form of type B NPD. Patients with the Gly294Lys mutation may not show decreased sphingomyelinase function in tests where the artificial substrate is used [9]. Mutation analysis is available for rare or specific gene mutations which can provide useful information for genotype-phenotype correlations and prenatal diagnosis for family members.

    Pathology

    Biopsy
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  • Laboratory

    Serum
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  • Pleura
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  • Imaging

    X-ray
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  • CT
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  • MR
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  • Treatment

    No specific treatments are available for patients with type A NPD and current treatment modalities focused on symptom management. Novel therapies, such as bone marrow, stem cell transplants and enzymatic replacement, are currently being tested as a treatment option for patients with NPD [11] [12]. Liver and amniotic cell transplantation have been attempted in infants with type A NPD with minimal success.

    Adults with type B NPD that have elevated cholesterol should receive treatments to lower cholesterol levels to normal range. If statins are used, liver function should be monitored. Patients with type B NPD that experience acute bleeding secondary to an overactive spleen and thrombocytopenia may require blood transfusions. Affected individuals with pulmonary disorders, including interstitial lung disease, may be administered oxygen or bronchopulmonary lavage (although this has mixed results). Bone marrow transplants have shown some success in treating type B NPD patients by reducing hepatosplenomegaly, increasing peripheral blood counts and decreasing lung infiltration, however, this is not recommended for patients with neurological symptoms.

    Prognosis

    Type A NPD is extremely serious and is characterized by failure to thrive, hepatoslenomegaly, interstitial lung disease, cherry-red macula, progressive neurodegeneration and eventually death by age three. Children with type A NPD appear normal at birth. Severity of symptoms, clinical findings and age of onset for patients with Type B NPD are typically more variable than type A and symptoms are often milder, including neurological signs which may be absent [7].
    Patients are usually diagnosed during early childhood or infancy when physicians notice hepatoslenomegaly upon physical examination. Patients with type A NPD exhibit neurodegeneration beginning at three months of age and death by three years of age. Patients with type B NPD often survive into adulthood [7] [8].

    Complications

    Deafness
    • “We went through a study of trying to decrease the dose to see what dose improved signs of disease but didn’t cause deafness,” Vite said.[news.upenn.edu]
    • NICHD researchers, the NPC project team includes NIH scientists from the Clinical Center, National Human Genome Research Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and National Institute on Deafness[medicalxpress.com]
    • They'd been nearly deaf, and new tests showed their hearing was better.[cnn.com]
    Dementia
    • When it appears in adulthood it can produce psychosis and dementia.[cedars-sinai.edu]
    • - Multi-Infarct Information Page Dementia - Semantic Information Page Dementia - Subcortical Information Page Dementia Information Page Dementia With Lewy Bodies Information Page Dentate Cerebellar Ataxia Information Page Dentatorubral Atrophy Information[ninds.nih.gov]
    • For example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia.[clinicaltrials.gov]
    • This was initially... read more » Dementia may be a drug interaction : A common scenario in aged care is for a patient to show mental decline to dementia .[rightdiagnosis.com]
    • Signs and symptoms include hepatosplenomegaly, pancytopenia, ataxia, dystonia, and dementia.[icd10data.com]
    Hypersplenism
    Loss of Vision
    • These individuals may have only moderate enlargement of the spleen and liver, but brain damage may be extensive and cause an inability to look up and down, difficulty in walking and swallowing and progressive loss of vision and hearing.[nationalstemcellfoundation.org]
    • Affected individuals may have extensive brain damage that can cause an inability to look up and down, difficulty in walking and swallowing, and progressive loss of vision and hearing.[my.clevelandclinic.org]
    • […] of vision or hearing brain damage Type E The symptoms of the type E form of Niemann-Pick disease are present in adults.[healthline.com]
    Mental Retardation
    • There is abnormal accumulation of sphingomyelin causing enlargement of the liver and spleen, anaemia and severe neurological damage leading to physical and mental retardation and often death in early childhood.[medical-dictionary.thefreedictionary.com]
    • Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms.[uniprot.org]
    • The neurological features include mental retardation, spasticity, seizures, jerks, eye paralysis (ophthalmoplegia) and ataxia (wobbliness).[medicinenet.com]
    • Symptoms consist of extreme liver and spleen enlargement, mental retardation , and a brownish-yellow skin discoloration; foamy cells containing phospholipids are found in several organs.[britannica.com]
    • Cognitive impairment may range from a delay in developmental milestones to mental retardation.[hindawi.com]
    Pancytopenia
    • Patients with type B NPD have minimal neurologic involvement but pancytopenia is common.[symptoma.com]
    • Answer 5: Pancytopenia is a feature of Gaucher disease, an autosomal recessive sphingolipidosis caused by deficiency in glucocerebrosidase that presents with pancytopenia and hepatosplenomegaly.[medbullets.com]
    • Signs and symptoms include hepatosplenomegaly, pancytopenia, ataxia, dystonia, and dementia.[icd10data.com]
    • Systemic involvement includes progressive lung disease, hepatosplenomegaly, short stature , and pancytopenia. [3] Individuals with NPD types A and B typically have less than 10% residual acid sphingomyelinase enzyme activity.[emedicine.medscape.com]
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  • Etiology

    NPD is a sphingolipidosis characterized by a deficiency in sphingomyelinase caused by an autosomal recessive gene. Sphingomyelinase deficiency leads to lysosomal accumulation of sphingomyelin. The sphingomyelinase gene is located on chromosome 11 (11p15.1 to p15.4). The primary cell types affected by this disease are cells in the monocyte-macrophage system along with reticuloendothelial cells.

    Type A NPD is extremely serious and is characterized by failure to thrive, hepatoslenomegaly, interstitial lung disease, cherry-red macula, progressive neurodegeneration and eventually death by age three. Type B NPD is regarded as a milder form of the disease, without neurological signs, that has a later-onset, however, there is much overlap between type A and B. A number of mutations have been identified to cause NPD, including deletions and substitutions.

    Epidemiology

    NPD is an autosomal recessive disorder that affects more commonly Ashkenazi Jews, people of Turkish decent and individuals who reside in the Maghreb region of North Africa and Saudi Arabia, however, it does occur rarely in all races and geographical locations [2] [3] [4]. Males and females are affected equally by both types of NPD. The onset and severity of type A and type B NPD vary from early onset and death by age three to later onset and survival into adulthood, respectively.

    Sex distribution
    Age distribution

    Pathophysiology

    NPD is caused by an autosomal recessive mutation of the Sphingomyelin Phosphodiesterase 1 (SMPD1) gene located on chromosome 11 (11p15.1-p15.4) that results in sphingomyelinase deficiency [5] [6]. Genomic studies have revealed that three mutations (L302P, 1bp del fsP330, R496L) are responsible for 90% of type A NPD cases and the deltaR608 mutation is most commonly found in type B NPD. Patients with NPD demonstrate less than 10% of sphingomyelinase activity compared to unaffected individuals. Sphingomyelinase deficiency leads to the accumulation of sphingomyelin in cells of the monocyte-macrophage system as well as reticuloendothelial cells. Systemic manifestations are observed in both type A and type B, including progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia, whereas, neurodegenerative signs are primarily observed in patients with type A [7].

    Prevention

    Dietary supplements are often needed for pediatric patients with type B NPD who experience early satiety due to hepatosplenomegaly. High calorie supplements may be beneficial. Patients with splenomegaly have increased risk of splenic rupture, therefore, contact sports should be avoided. If trauma occurs in NPD patients with hyperslenism, immediate medical care should be administered to address risk of splenic rupture and intracranial bleeding.

    Summary

    Type A and B Niemann-Pick disease (NPD) result from an autosomal recessive gene that causes a deficiency in the enzyme sphingomyelinase which leads to a sphingolipidosis associated with the accumulation of sphingomyelin. Type A NPD is a fatal disorder in young children characterized by failure to thrive, hepatosplenomegaly and progressive neurodegeneration resulting in death by age three. There is much overlap between type A and B NPD, however, type B is generally less severe. Type C NPD is an unrelated disorder associated with abnormal cholesterol storage. The occurrence of NPD is 1 in 248,000 [1].

    Patient Information

    Niemann-Pick disease (NPD) is a genetic disorder associated with a deficiency of the enzyme, sphingomyelinase, which results in the accumulation of sphingomyelin or cholesterol in tissues. There are different forms of NPD, based on the level of sphingomyelinase deficiency, with the most severe form (type A) found to occur most commonly in Jewish patients and the milder form (type B) occurring in any ethnic group (although rarely). Patients with type A NPD experience severe growth complications and neurologic problems starting in infancy and typically don’t survive past age three. Usually, patients with type B NPD survive into adulthood and do not experience neurologic symptoms. Patients with type B NPD may develop fatty growths and areas of dark pigmentation on the skin, enlarged liver, spleen and lymph nodes and in some cases possess intellectual disabilities.

    Some tests can be performed, including amniocentesis and chorionic villus sampling, to diagnose certain forms of NPD in a developing fetus. Diagnosis can be achieved after birth through analysis of tissue samples, including liver and blood, and genetic tests. There is no cure for NPD and in severe cases children die early from central nervous system dysfunction or infection. New therapies are being developed that are showing promise in preclinical studies but none have been approved for treatment of NPD.

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    References

    1. Vanier MT, Rousson R, Garcia I, et al. Biochemical studies in Niemann-Pick disease. III. In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the disease. Clin Genet. 1985; 27(1):20-32.
    2. Cho YU, Chae JD, Lee WM, et al. A Case of a Korean Adult Affected by Type B Niemann-Pick Disease: Secondary Sea-blue Histiocytosis and Molecular Characterization. Korean J Lab Med. 2009; 29(2):97-103.
    3. Rodriguez-Pascau L, Gort L, Schuchman EH, et al. Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum Mutat. 2009; 18
    4. Simonaro CM, Desnick RJ, McGovern MM, et al. The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet. 2002; 71(6):1413-9.
    5. Camoletto PG, Vara H, Morando L, et al. Synaptic vesicle docking: sphingosine regulates syntaxin1 interaction with Munc18. PLoS ONE. 2009; 4(4):e5310.
    6. Jenkins RW, Canals D, Hannun YA. Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal. 200; 21(6):836-46.
    7. Ambrosio C, Serra S, Alexandre M, et al. Arthralgia, bone pain, positive antinuclear antibodies and thrombocytopenia...diagnosis: Niemann-Pick disease. Acta Reumatol Port. 2009; 34(1):102-5.
    8. Vykuntaraju KN, Lokanatha H, Shivananda. Niemann-Pick disease type A presenting as unilateral tremors. Indian Pediatr. 2012; 49(11):919-20.
    9. Wasserstein MP, Aron A, Brodie SE, et al. Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. J Pediatr. 2006; 149(4):554-9.
    10. Hervé A, Marchand-Adam S, Fabre A, et al. Niemann-Pick disease type B identified following an episode of bronchopneumonia. Rev Mal Respir. 2008; 25(7):861-6.
    11. Alizon C, Beucher AB, Gourdier AL, et al. Type B Niemann Pick disease: clinical description of three patients in a same family. Rev Med Interne. 2010; 31(8):562-5
    12. Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. 2007; 30(5):654-63. Epub 2007 Jul 12.

    • Angina pectoris in hereditary xanthomatosis - C Müller - Archives of Internal Medicine, 1939 - archinte.jamanetwork.com
    • Fetal ascites: an unusual presentation of Niemann-Pick disease type C. - IK Maconochie, S Chong, G Mieli-Vergani - disease in childhood, 1989 - adc.bmj.com
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • Niemann-Pick disease type A and B are clinically but also enzymatically heterogeneous: pitfall in the laboratory diagnosis of sphingomyelinase deficiency - K Harzer, A Rolfs, P Bauer, M Zschiesche - , 2003 - albrecht-kossel-institut.de
    • ARD CHOLESTEROL AND HDL INCREASE - U Cornelli - gunainternational.it
    • Adult-onset cerebellar cortical abiotrophy and retinal degeneration in a domestic shorthair cat - G Barone, P Foureman - Journal of the American Animal , 2002 - Am Animal Hosp Assoc
    • Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse - MA Passini, J Bu, JA Fidler, RJ Ziegler - Proceedings of the , 2007 - National Acad Sciences
    • Adult Niemann-Pick disease with sea-blue histiocytes in the spleen - PJ Dawson, G Dawson - Human pathology, 1982 - Elsevier
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • A clinical staging classification for type C Niemann‐Pick disease - JJ Higgins, MC Patterson, JM Dambrosia, AT Pikus - Neurology, 1992 - AAN Enterprises
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • Bone marrow examination in cases of pancytopenia. - A Jha, G Sayami, RC Adhikari, AD Panta, R Jha - 2008 - imsear.hellis.org
    • A disorder of mucopolysaccharide metabolism with articular, respiratory, and neurologic manifestations - SM Bierman, T Edgington, VD Newcomer - Arthritis & , 1966 - Wiley Online Library
    • Hypercholesteremia with predisposition to atherosclerosis: an inborn error of lipid metabolism - D Adlersberg - The American Journal of Medicine, 1951 - Elsevier
    • A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B - MM McGovern, MP Wasserstein, R Giugliani - Pediatrics, 2008 - Am Acad Pediatrics
    • Case report. Pulmonary involvement in Niemann-Pick disease subtype B: CT findings - GR Ferretti, S Lantuejoul, E Brambilla - Journal of computer , 1996 - journals.lww.com
    • A family with visceral course of Niemann-Pick disease, macular halo syndrome and low sphingomyelin degradation rate - W Sperl, G Bart, MT Vanier, H Christomanou - metabolic disease, 1994 - Springer
    • Comparative diagnostic performances of auscultation, chest radiography, and lung ultrasonography in acute respiratory distress syndrome - D Lichtenstein, I Goldstein, E Mourgeon, P Cluzel - , 2004 - journals.lww.com
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders - J De Keyser, JP Mostert, MW Koch - Journal of the neurological sciences, 2008 - Elsevier
    • Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease - M Ikegami, R Dhami - American Journal of , 2003 - Am Physiological Soc
    • A method for enrichment of hybrid somatic cells: complementation studies in certain lysosomal enzymopathies - PV Nelson, WF Carey - Journal of inherited metabolic disease, 1985 - Springer
    • An autopsy case of fetal Gaucher disease - Y Adachi, Y Kobayashi, H Ida, R Yasumizu - Pediatrics , 1998 - Wiley Online Library
    • NUMEROUS PECULIAR MEMBRANE‐STRUCTURES COMPOSED OF COMPOUND LIPID IN BONE AND BONE MARROW AND VARIOUS ADIPOSE TISSUES - T Nasu, Y Tsukahara, K Terayama - Pathology International, 1973 - Wiley Online Library
    • A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B - MM McGovern, MP Wasserstein, R Giugliani - Pediatrics, 2008 - Am Acad Pediatrics
    • Cataplexy in variant forms of Niemann‐Pick disease - RS Kandt, RG Emerson, HS Singer, DL Valle - Annals of , 2004 - Wiley Online Library
    • Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study - MC Patterson, D Vecchio, H Prady, L Abel - The Lancet , 2007 - Elsevier
    • Case report. Pulmonary involvement in Niemann-Pick disease subtype B: CT findings - GR Ferretti, S Lantuejoul, E Brambilla - Journal of computer , 1996 - journals.lww.com
    • Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease - MP Wasserstein, A Aron, SE Brodie, C Simonaro - The Journal of , 2006 - Elsevier
    • " Cataplexy" and muscle ultrasound abnormalities in Coffin-Lowry syndrome. - YJ Crow, SM Zuberi, R McWilliam, JL Tolmie - Journal of medical , 1998 - jmg.bmj.com
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • Clinical approach to inherited peroxisomal disorders - F Poggi-Travert, B Fournier, BT Poll-The - metabolic disease, 1995 - Springer
    • A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation. - RS Howard, R Greenwood, J Gawler - Journal of Neurology, , 1993 - jnnp.bmj.com
    • Adult lipidosis resembling Niemann-Pick's disease - RD Terry, WM Sperry, B Brodoff - The American Journal of , 1954 - ncbi.nlm.nih.gov
    • A progressive neurologic disorder with supranuclear vertical gaze paresis and distinctive bone marrow cells - FL Yan-Go, T Yanagihara, RV Pierre, NP Goldstein - Mayo Clin Proc, 1984 - ukpmc.ac.uk
    • A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C - MC Patterson - The neurologist, 2003 - journals.lww.com
    • STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASE A REPORT OF - BGR Neville, BD LAKE, R STEPHENS, MD Sanders - Brain, 1973 - Oxford Univ Press
    • 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: Follow up using brain spectroscopy - D Galanaud, A Tourbah, S Lehéricy, N Leveque - Molecular genetics and , 2009 - Elsevier

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