Effects of miglustat treatment in a patient affected by an atypical form of Tangier disease
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RESEARCH
Open Access
Effects of miglustat treatment in a patient affected by an atypical form of Tangier disease Annalisa Sechi1, Andrea Dardis1, Stefania Zampieri1, Claudio Rabacchi2, Paolo Zanoni2, Sebastiano Calandra2, Giovanna De Maglio3, Stefano Pizzolitto3, Valerio Maruotti4, Antonio Di Muzio4, Frances Platt5 and Bruno Bembi1*
Abstract Background: Tangier disease (TD) is a rare autosomal recessive disorder, resulting from mutations in the ATP binding cassette transporter (ABCA1) gene. The deficiency of ABCA1 protein impairs high density lipoprotein (HDL) synthesis and cholesterol esters trafficking. Case Report: A 58 year-old female, presenting with complex clinical signs (splenomegaly, dysarthria, dysphagia, ataxia, tongue enlargement, prurigo nodularis, legs lymphedema, pancytopenia and bone marrow foam cells), was misdiagnosed as Niemann-Pick C (NPC) and treated with miglustat (300 mg/day), normalizing neurological symptoms and improving skin lesions and legs lymphedema. Subsequently filipin-staining and molecular analysis for NPC genes were negative. Lipid profiling showed severe deficiency of HDL, 2 mg/dl (n.v. 45-65) and apoAI, 5.19 mg/dl (n.v. 110-170), suggesting TD as a probable diagnosis. Molecular analysis of ABCA1 gene showed the presence of a novel homozygous deletion (c.4464-486_4698 + 382 Del). Miglustat treatment was then interrupted with worsening of some neurological signs (memory defects, slowing of thought processes) and skin lesions. Treatment was restarted after 7 months with neurological normalization and improvement of skin involvement. Conclusions: These results suggest miglustat as a possible therapeutic approach in this untreatable disease. The mechanisms by which miglustat ameliorates at least some clinical manifestations of TD needs to be further investigated. Keywords: Tangier Disease, Niemann Pick type C, Miglustat, Glycosphingolipids
Introduction Tangier disease (TD) (OMIM #205400) is a rare autosomal recessive disorder, resulting from mutations in the ATP binding cassette transporter (ABCA1) gene, mapped to chromosome 9q22-q31. The ABCA1 gene encodes a multiple trans-membrane domain protein (ABCA1) involved in the efflux of free cholesterol from peripheral cells to Apolipoprotein A-I (ApoAI) generating nascent high-density lipoprotein (HDL). As a result of the ABCA1 defect, patients present with a characteristic severe deficiency or absence of HDL in the plasma, rapid catabolism of ApoAI and an accumulation of cholesterol esters in macrophages and other reticuloendothelial cells in multiple tissues [1,2]. Biochemically, the disease is therefore characterized by very low plasma levels of HDL * Correspondence: [email protected] 1 Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy Full list of author information is available at the end of the article
and ApoAI, low total cholesterol and normal or high levels of triglycerides. Classical clinical symptoms include hyperplastic orange tonsils, polyneuropat
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