In 1914 the German pediatrician Albert Niemann described a Jewish child with damage to the brain and nervous system. Subsequently, in 1927, Ludwig Pick analyzed the tissues from deceased children and provided evidence of a new storage disease, not previously described. Currently, the term "Niemann-Pick disease" (NPD) refers to a group of genetic diseases of the metabolism, characterized by lipid storage and autosomal recessive inheritance. Alan Crocker, in 1958, was the first to propose a classification of this series of metabolic disorders, based on biochemical and clinical features (1). Types A and B of Niemann-Pick disease (NPD-A and NPD-B) are due to a lack of acid sphingomyelinase (A-SMase) activity, a lysosomal enzyme encoded by the SMPD1 gene (sphingomyelin phosphodiesterase 1) located on chromosome 11 (11p15.1-p15.4). The enzyme defect results in a pathological accumulation of sphingomyelin (SM) and other lipids, particularly within the tissues of the reticulo-endothelial system (RES) – including the spleen, lymph nodes, bone marrow, thymus and mononuclear phagocytes - which, along with the liver and lungs, is deeply affected by the disease. Progressive accumulation of sphingomyelin in the RES cells determines systemic symptoms, including pulmonary progressive involvement; when the accumulation occurs in the cells of the central nervous system as well, it causes the neurodegenerative course of the disease observed in type A. Molecular genetic studies demonstrate that both forms depend on allelic mutations in the SMPD1 gene; so far, approximately one hundred different mutations have been described. The Niemann-Pick disease type C (NPD-C) is a chronic neuropathy, with clinical, biochemical and molecular features distinct from those of NPD-A and -B (primary sphingolipidosis). In approximately 95% of cases, the primary genetic defect resides in the NPC1 gene (chromosome 18q11, 57 Kb, 25 exons), whereas, for the remaining 5% of cases, mutations have been identified in a second gene, called NPC2 or HE1 (chromosome 14q23.3, 13.5 Kb, 5 exons). NPC1 and NPC2 proteins seem to interact in the endo-lysosomal system to facilitate intracellular transport of cholesterol and of other molecules. Pathological mutations usually cause a typical cellular lesion, consisting of an abnormal intracellular transport of exogenous cholesterol (LDL), a lysosomal accumulation of unesterified cholesterol and dysregulated cholesterol homeostasis as well as lipid metabolism. The excess of unesterified cholesterol, sphingomyelin, phospholipids and glycolipids are accumulated in the liver, spleen and central nervous system, especially in the cerebellum, the latter resulting the main target organ of the disease. Common symptoms are hepatosplenomegaly and neurodegeneration, resulting in progressive motor dysfunction, cognitive decay and psychic disorders. The NPD-C is divided into 3 subgroups according to the age of clinical onset and the respective phenotype: childhood presentation, late-childhood presentation and adolescent and adult presentation.

Emotional wounds: NIEMANN – PICK DISEASE

PALMA, FULVIO;
2010-01-01

Abstract

In 1914 the German pediatrician Albert Niemann described a Jewish child with damage to the brain and nervous system. Subsequently, in 1927, Ludwig Pick analyzed the tissues from deceased children and provided evidence of a new storage disease, not previously described. Currently, the term "Niemann-Pick disease" (NPD) refers to a group of genetic diseases of the metabolism, characterized by lipid storage and autosomal recessive inheritance. Alan Crocker, in 1958, was the first to propose a classification of this series of metabolic disorders, based on biochemical and clinical features (1). Types A and B of Niemann-Pick disease (NPD-A and NPD-B) are due to a lack of acid sphingomyelinase (A-SMase) activity, a lysosomal enzyme encoded by the SMPD1 gene (sphingomyelin phosphodiesterase 1) located on chromosome 11 (11p15.1-p15.4). The enzyme defect results in a pathological accumulation of sphingomyelin (SM) and other lipids, particularly within the tissues of the reticulo-endothelial system (RES) – including the spleen, lymph nodes, bone marrow, thymus and mononuclear phagocytes - which, along with the liver and lungs, is deeply affected by the disease. Progressive accumulation of sphingomyelin in the RES cells determines systemic symptoms, including pulmonary progressive involvement; when the accumulation occurs in the cells of the central nervous system as well, it causes the neurodegenerative course of the disease observed in type A. Molecular genetic studies demonstrate that both forms depend on allelic mutations in the SMPD1 gene; so far, approximately one hundred different mutations have been described. The Niemann-Pick disease type C (NPD-C) is a chronic neuropathy, with clinical, biochemical and molecular features distinct from those of NPD-A and -B (primary sphingolipidosis). In approximately 95% of cases, the primary genetic defect resides in the NPC1 gene (chromosome 18q11, 57 Kb, 25 exons), whereas, for the remaining 5% of cases, mutations have been identified in a second gene, called NPC2 or HE1 (chromosome 14q23.3, 13.5 Kb, 5 exons). NPC1 and NPC2 proteins seem to interact in the endo-lysosomal system to facilitate intracellular transport of cholesterol and of other molecules. Pathological mutations usually cause a typical cellular lesion, consisting of an abnormal intracellular transport of exogenous cholesterol (LDL), a lysosomal accumulation of unesterified cholesterol and dysregulated cholesterol homeostasis as well as lipid metabolism. The excess of unesterified cholesterol, sphingomyelin, phospholipids and glycolipids are accumulated in the liver, spleen and central nervous system, especially in the cerebellum, the latter resulting the main target organ of the disease. Common symptoms are hepatosplenomegaly and neurodegeneration, resulting in progressive motor dysfunction, cognitive decay and psychic disorders. The NPD-C is divided into 3 subgroups according to the age of clinical onset and the respective phenotype: childhood presentation, late-childhood presentation and adolescent and adult presentation.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2506924
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