Forme respiratoire néonatale létale de la maladie de Niemann-Pick C2 et diagnostic anténatal par l'étude des mutations du gène HE1/NPC2

Morisot, C.; Millat, Gilles; Coeslier, Anne Dieux; Bourgois, Béatrice; Fontenoy, E.; Dobbelaere, Dries; Vérot, Lucie; Haouari, N.; Vaillant, C. Le; Gottrand, Frédéric; Bogaert, Evelien; Thelliez, P; Klosowski, S; Djebara, Az-Eddine; Bachiri, A.; Manouvrier, Sylvie; Vanier, Marie T.

doi:10.1016/j.arcped.2005.01.015

Cited by 12 publications

(5 citation statements)

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“…Consistent with this notion, it has recently been reported that NPC2 deficiency in human fibroblasts confers their activation [36]. Intriguingly, autopsy has revealed that NPC2 deficiency is associated with pronounced pulmonary fibrosis [37], known to be primarily mediated by activated fibroblasts [38]. Because normalization of cholesterol in the NPC2 −/− fibroblasts failed to correct their activated phenotype [36], it is possible that the ameliorating effect experienced by NPC2 therapy is independent of its function in intracellular cholesterol trafficking.…”

Section: Discussionmentioning

confidence: 85%

Protein Replacement Therapy Partially Corrects the Cholesterol-Storage Phenotype in a Mouse Model of Niemann-Pick Type C2 Disease

et al. 2011

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Niemann-Pick type C2 (NPC2) disease is a fatal autosomal recessive neurovisceral degenerative disorder characterized by late endosomal-lysosomal sequestration of low-density lipoprotein derived cholesterol. The breach in intracellular cholesterol homeostasis is caused by deficiency of functional NPC2, a soluble sterol binding protein targeted to the lysosomes by binding the mannose-6-phosphate receptor. As currently there is no effective treatment for the disorder, we have investigated the efficacy of NPC2 replacement therapy in a murine gene-trap model of NPC2-disease generated on the 129P2/OlaHsd genetic background. NPC2 was purified from bovine milk and its functional competence assured in NPC2-deficient fibroblasts using the specific cholesterol fluorescent probe filipin. For evaluation of phenotype correction in vivo, three-week-old NPC2 −/− mice received two weekly intravenous injections of 5 mg/kg NPC2 until trial termination 66 days later. Whereas the saline treated NPC2 −/− mice exhibited massive visceral cholesterol storage as compared to their wild-type littermates, administration of NPC2 caused a marked reduction in cholesterol build up. The histological findings, indicating an amelioration of the disease pathology in liver, spleen, and lungs, corroborated the biochemical results. Little or no difference in the overall cholesterol levels was observed in the kidneys, blood, cerebral cortex and hippocampus when comparing NPC2 −/− and wild type mice. However, cerebellum cholesterol was increased about two fold in NPC2 −/− mice compared with wild-type littermates. Weight gain performance was slightly improved as a result of the NPC2 treatment but significant motor coordination deficits were still observed. Accordingly, ultrastructural cerebellar abnormalities were detected in both saline treated and NPC2 treated NPC2 −/− animals 87 days post partum. Our data indicate that protein replacement may be a beneficial therapeutic approach in the treatment of the visceral manifestations in NPC2 disease and further suggest that neurodegeneration is not secondary to visceral dysfunction.

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Section: Discussionmentioning

confidence: 85%

Protein Replacement Therapy Partially Corrects the Cholesterol-Storage Phenotype in a Mouse Model of Niemann-Pick Type C2 Disease

et al. 2011

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“…Lung involvement is a prominent feature of the NPC2 disease. It is thought to be caused by the lung infiltration by foamy macrophages and is associated with pulmonary alveolar proteinosis, unlike NPC1 patients in whom respiratory complications are typically due to recurrent aspirations and infections [ 47 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Yılmaz

Baruteau

Rahim

et al. 2020

IJMS

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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.

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“…Liu et al have provided insights into the impact of impaired NPC1 function. Mice lacking functional NPC1 genes showed significant macrophage infiltration and cholesterol accumulation in their lungs, providing insight into the potential effects of disrupted cholesterol trafficking in the respiratory system [77][78][79][80].…”

Section: The Lung Involvement In Niemann-pick Disease Type Cmentioning

confidence: 99%

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

Tirelli,

Rondinone,

Italia

et al. 2024

Biomolecules

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Niemann–Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase α is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies.

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Forme respiratoire néonatale létale de la maladie de Niemann-Pick C2 et diagnostic anténatal par l'étude des mutations du gène HE1/NPC2

Cited by 12 publications

References 12 publications

Protein Replacement Therapy Partially Corrects the Cholesterol-Storage Phenotype in a Mouse Model of Niemann-Pick Type C2 Disease

Protein Replacement Therapy Partially Corrects the Cholesterol-Storage Phenotype in a Mouse Model of Niemann-Pick Type C2 Disease

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

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