Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011168 (dysphagia)
 15,644 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on a 12-year-old Chinese child with type C Niemann-Pick disease, who presented primarily with neurologic symptoms. He started to develop ataxia and dysarthria at the age of six years. Dementia, dysphagia, dystonia and seizures, in that sequence, followed within a couple of years. He was anarthric and bedridden five years after onset. Supranuclear vertical gaze palsy was found at the beginning of the illness. However, no hepatosplenomegaly or other physical abnormality was noted. Bone marrow aspirates revealed foamy storage cells and sea-blue histiocytes. However, sphingomyelinase activity in the cultured skin fibroblast was normal. The characteristic clinical presentations and typical pathologic and histochemical findings meet the diagnostic criteria of type C Niemann-Pick disease. We report the first Chinese case of type C Niemann-Pick disease and review 73 cases reported previously.
 ...
PMID:Type C Niemann-Pick disease: report of a Chinese case. 790 66

Niemann-Pick disease type C (NPC) is a rare, neurovisceral lipid storage disorder caused by genetic defects in lipid transporting proteins. It is distinct from Niemann-Pick types A and B (sphingomyelin lipidoses) and displays genetic (mutations in the NPC1 or NPC2[=HE1] gene), biochemical, and clinical heterogeneity. Late infantile to juvenile forms of NPC predominate and are characterised by atypical behaviour, ataxia, dysarthria, dysphagia, dystonia, cataplexy, vertical gaze palsy, splenomegaly, and dementia. In adult variants, psychosis and dementia are common, and dysarthria, ataxia, splenomegaly, and vertical gaze palsy are further facultative signs. Routine laboratory results including serum cholesterol are normal. In bone marrow smears, sea-blue histiocytes are often demonstrated and foam cells sometimes seen. The diagnosis is confirmed by detecting free cholesterol accumulation in perinuclear granules (lysosomes) and reduced cholesterol esterification after challenge with exogenous low-density lipoprotein in fibroblasts. Alternatively or additionally, mutational analysis can be performed. Treatment is restricted to symptomatic measures, since there is no specific therapy.
 ...
PMID:[Niemann-Pick disease type C--a neurometabolic disease through disturbed intracellular lipid transport]. 1455 97

Niemann-Pick type C1 (NPC1) disease is an autosomal recessive disorder characterized clinically by neonatal jaundice, hepatosplenomegaly, vertical gaze palsy, ataxia, dystonia, and progressive neurodegeneration. The present study provides basic clinical and health information from the National Niemann-Pick C1 disease database that was obtained using a clinical questionnaire of 83 questions mailed to families affected by NPC1 disease living in the United States. The study was conducted over a 1-year period, during which time parents/caregivers and physicians completed the clinical questionnaire. Sixty-four percent (87/136) of the questionnaires were returned, with 53% and 47% representing male and female NPC1 patients, respectively. The average age of diagnosis for NPC1 disease was 10.4 years, with one-half of patients being diagnosed before the age of 6.9 years. The average age of death for NPC1 disease was 16.2 years, with one-half of patients dying before the age of 12.5 years. A common clinical symptom reported at birth was neonatal jaundice (52%), followed by enlargement of the spleen (36%) and liver (31%); ascites (19%) and neonatal hypotonia (6%) were much less frequent. With respect to developmental difficulties, the most common findings included clumsiness (87%), learning difficulties (87%), ataxia (83%), dysphagia (80%), and vertical gaze palsy (81%). Together, these findings confirm and extend previous reports investigating the clinical features associated with NPC1 disease.
 ...
PMID:The National Niemann-Pick C1 disease database: report of clinical features and health problems. 1749 24

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.
 ...
PMID:Niemann-Pick disease type C. 2052 56

The Niemann-Pick disease group is now divided into two distinct entities: (1) acid sphingomyelinase-deficient Niemann-Pick disease (ASM-deficient NPD) resulting from mutations in the SMPD1 gene and encompassing type A and type B as well as intermediate forms; (2) Niemann-Pick disease type C (NP-C) including also type D, resulting from mutations in either the NPC1 or the NPC2 gene. Both Niemann-Pick diseases have an autosomal recessive inheritance and are lysosomal lipid storage disorders, with visceral (type B) or neurovisceral manifestations. The clinical knowledge is updated taking into account recent surveys in large cohort of patients, particularly for type B and type C. The diagnosis of NP-C is often delayed due to the wide spectrum of clinical phenotypes. Systemic manifestations, if present, always precede onset of neurological manifestations. Most common neurological signs are vertical supranuclear gaze palsy, cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures, and dystonia are other common features of NP-C. For both ASM-deficient NPD and NP-C, strategies for laboratory diagnosis of patients and prenatal diagnosis are discussed. Recent progress towards enzyme replacement therapy in type B patients and management of the neurological disease in type C patients are finally highlighted.
 ...
PMID:Niemann-Pick diseases. 2362 94

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder resulting from mutations in either the NPC1 (95%) or NPC2 (5%) genes. NPC typically presents in childhood with visceral lipid accumulation and complex progressive neurodegeneration characterized by cerebellar ataxia, dysphagia, and dementia, resulting in a shortened lifespan. While cholesterol is widely acknowledged as the principal storage lipid in NPC, multiple species of sphingolipids accumulate as well. This accumulation of sphingolipids led to the initial assumption that NPC disease was caused by a deficiency in a sphingolipid catabolism enzyme, similar to sphingomyelinase deficiencies with which it shares a family name. It took about half a century to determine that NPC was in fact caused by a cholesterol trafficking defect, and still as we approach a century after the initial identification of the disease, the mechanisms by which sphingolipids accumulate remain poorly understood. Here we focus on the defects of sphingolipid catabolism in the endolysosomal compartment and how they contribute to the biology and pathology observed in NPC disease. This review highlights the need for further work on understanding and possibly developing treatments to correct the accumulation of sphingolipids in addition to cholesterol in this currently untreatable disease.
 ...
PMID:Niemann-Pick type C disease: The atypical sphingolipidosis. 3020 42

Changes in gene expression profiles were investigated in 23 patients with Niemann-Pick C1 disease (NPC). cDNA expression microarrays with subsequent validation by qRT-PCR were used. Comparison of NPC to control samples revealed upregulation of genes involved in inflammation (MMP3, THBS4), cytokine signalling (MMP3), extracellular matrix degradation (MMP3, CTSK), autophagy and apoptosis (CTSK, GPNMB, PTGIS), immune response (AKR1C3, RCAN2, PTGIS) and processes of neuronal development (RCAN2). Downregulated genes were associated with cytoskeletal signalling (ACTG2, CNN1); inflammation and oxidative stress (CNN1); inhibition of cell proliferation, migration and differentiation; ERK-MAPK pathway (COL4A1, COL4A2, CPA4); cell adhesion (IGFBP7); autophagy and apoptosis (CDH2, IGFBP7, COL4A2); neuronal function and development (CSRP1); and extracellular matrix stability (PLOD2). When comparing NPC and Gaucher patients together versus controls, upregulation of SERPINB2 and IL13RA2 and downregulation of CSRP1 and CNN1 were characteristic. Notably, in NPC patients, the expression of PTGIS is upregulated while the expression of PLOD2 is downregulated when compared to Gaucher patients or controls and potentially could serve to differentiate these patients. Interestingly, in NPC patients with (i) jaundice, splenomegaly and cognitive impairment/psychomotor delay-the expression of ACTG2 was especially downregulated; (ii) ataxia-the expression of ACTG2 and IGFBP5 was especially downregulated; and (iii) VSGP, dysarthria, dysphagia and epilepsy-the expression of AKR1C3 was especially upregulated while the expression of ACTG2 was downregulated. These results indicate disordered apoptosis, autophagy and cytoskeleton remodelling as well as upregulation of immune response and inflammation to play an important role in the pathogenesis of NPC in humans.
 ...
PMID:Changes in global gene expression indicate disordered autophagy, apoptosis and inflammatory processes and downregulation of cytoskeletal signalling and neuronal development in patients with Niemann-Pick C disease. 3192 69

Sea-blue histiocytes in bone marrow can be associated with a number of conditions and have indeed often been reported in Niemann-Pick diseases, mostly in Niemann-Pick type B, but also Niemann-Pick type C. Rarely, it was reported to be related to a progressive neurological condition. In this work, early bone marrow aspirations in a boy following the discovery of hepatosplenomegaly at 1 month of age and later isolated splenomegaly did not reveal abnormal cells (which is not uncommon). Numerous sea-blue histiocytes were found in a repeated exam when the child was 10-year old, at a time he had developed a progressive neurological condition with frequent falls, clumsiness, slow and slurred speech, intellectual disability, dystonic movements, and dysphagia. Acquired sea-blue histiocytes should be considered initially on the basis of clinical symptoms. Whole-exome sequencing identified two variants in the NPC1 gene, leading to the diagnosis of Niemann-Pick type C1. This case points out the presence of sea-blue histiocytes in the bone marrow and has helped to reach a diagnosis of NPC1 which was very difficult to establish even after years of study. Given the rarity of this pathology and the variety of clinical presentations, it is important to communicate the possible forms of presentation of this syndrome.
 ...
PMID:A progressive neurological condition with acquired sea-blue histiocytosis further the diagnosis of Niemann-Pick type C1 in a 10-year-old boy. 3231 43

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0-24) and 7.5 (0-24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.
 ...
PMID:Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease. 3270 31