Early onset of Chanarin-Dorfman syndrome with severe liver involvement in a patient with a complex rearrangement of ABHD5 promoter

BMC Medical Genetics

Daniela Tavian⁶  Bruno Giardina³  Raquel quintão Roque⁷  Eleonora Druve Tavares Faguntes⁵  Laura Moro⁴  Eugenia Ribeiro Valadares²  Sara Missaglia¹ 

[1] CRIBENS-Laboratory of Cellular Biochemistry and Molecular Biology, Catholic University of the Sacred Heart, Milan, Italy;Department of Propedêutica Complementar, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;Laboratory of Clinical Molecular Diagnostics, Institute of Biochemistry and Clinical Biochemistry, Catholic University, School of Medicine, Rome, Italy;Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy;Department of Pediatrics, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;Psychology Department, Catholic University of the Sacred Heart, Milan, Italy;Ambulatório de Erros Inatos do Metabolismo, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

关键词: Ichthyosis;    Liver involvement;    Lipid disorder;    ABHD5;    Chanarin-Dorfman syndrome;   

Others  :  1092260
DOI  :  10.1186/1471-2350-15-32

 received in 2013-07-11, accepted in 2014-03-11,  发布年份 2014

【 摘 要 】

Background

α/β-hydrolase domain-containing protein 5 (ABHD5) plays an important role in the triacylglycerols (TAG) hydrolysis. Indeed, ABHD5 is the co-activator of adipose triglyceride lipase (ATGL), that catalyses the initial step of TAG hydrolysis. Mutations in ABHD5 gene are associated with the onset of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive lipid storage disorder, characterized by non-bullous congenital ichthyosiform erythroderma (NCIE), hepatomegaly and liver steatosis.

Case presentation

We describe here a 5-years-old Brazilian child who presented with NCIE at birth and diffuse micro and macro-vesicular steatosis on liver biopsy since she was 2 years old. Molecular analysis of coding sequence and putative 5′ regulatory region of ABHD5 gene was performed. A homozygous novel deletion, affecting the promoter region and the exon 1, was identified, confirming the suspected diagnosis of CDS for this patient. RT-PCR analysis showed that the genomic rearrangement completely abolished the ABHD5 gene expression in the patient, while only a partial loss of expression was detected in her parents. This is the first report describing the identification of a large deletion encompassing the promoter region of ABHD5 gene. The total loss of ABHD5 expression may explain the early onset of CDS and the severe liver involvement. After molecular diagnosis, the patient started a special diet, poor in fatty acids with medium chain triglycerides (MCT), and showed hepatic and dermatologic improvement in spite of severe molecular defect.

Conclusions

This case report extends the spectrum of disease-causing ABHD5 mutations in CDS providing evidence for a novel pathogenic mechanism for this rare disorder. Moreover, our preliminary data show that early diagnosis and prompt treatment of neutral lipid accumulation might be useful for CD patients.

【 授权许可】

   
2014 Missaglia et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Lefevre C, Jobard F, Caux F, Bouadjar B, Karaduman A, Heilig R, Lakhdar H, Wollenberg A, Verret JL, Weissenbach J, Ozgüc M, Lathrop M, Prud’homme JF, Fischer J: Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Genet 2001, 69:1002-1012.
• [2]Fischer J, Lefèvre C, Morava E, Mussini JM, Laforêt P, Negre-Salvayre A, Lathrop M, Salvayre R: The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 2007, 39:28-30.
• [3]Tavian D, Missaglia S, Redaelli C, Pennisi EM, Invernici G, Wessalowski R, Maiwald R, Arca M, Coleman RA: Contribution of novel ATGL missense mutations to the clinical phenotype of NLSD-M: a strikingly low amount of lipase activity may preserve cardiac function. Hum Mol Genet 2012, 21:5318-5328.
• [4]Dorfman ML, Hershko C, Eisenberg S, Sagher F: Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 1974, 110:2661-2666.
• [5]Chanarin I, Pate A, Slavin G, Wills EJ, Andrews TM, Stewart G: Neutral-lipid storage disease: a new disorder of lipid metabolism. Br Med J 1975, 1:553-555.
• [6]Ujihara M, Nakajima K, Yamamoto M, Teraishi M, Uchida Y, Akiyama M, Shimizu H, Sano S: Epidermal triglyceride levels are correlated with severity of ichthyosis in Dorfman-Chanarin syndrome. J Dermatol Sci 2010, 57:102-107.
• [7]Ronchetti N, Prati D, Pezzotta MG, Tavian D, Colombo R, Callea F, Colli A: Severe steatohepatitis in a patient with a rare neutral lipid storage disorder due to ABHD5 mutation. J Hepatol 2008, 49:474-477.
• [8]Bruno C, Bertini E, Di Rocco M, Cassandrini D, Ruffa G, De Toni T, Seri M, Spada M, Li Volti G, D’Amico A, Trucco F, Arca M, Casali C, Angelini C, Dimauro S, Minetti C: Clinical and genetic characterization of Chanarin-Dorfman syndrome. Biochem Biophys Res Commun 2008, 369:1125-1128.
• [9]Redaelli C, Coleman RA, Moro L, Sertedaki A, Kakourou T, Elsayed SM, Prati D, Colli A, Mela D, Colombo R, Tavian D: Clinical and genetic characterization of ChanarineDorfman syndrome patients: first report of large deletions in the ABHD5 gene. Orphanet J Rare Dis 2010, 5:33. BioMed Central Full Text
• [10]Aggarwal S, Maras JS, Alam S, Khanna R, Gupta SK, Ahuja A: Novel nonsense mutation of ABHD5 in Dorfman-Chanarin syndrome with unusual findings: a challenge for genotype-phenotype correlation. Eur J Med Genet 2012, 55:173-177.
• [11]Tavian D, Colombo R: Improved cytochemical method for detecting Jordans’ bodies in neutral-lipid storage diseases. J Clin Pathol 2007, 60:956-958.
• [12]Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R: Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ ABHD5. Am J Physiol Endocrinol Metab 2009, 297:289-296.
• [13]Lord CC, Brown JM: Distinct roles for a-b hydrolase domain 5 (ABHD5/CGI-58) and adipose triglyceride lipase (ATGL/PNPLA2) in lipid metabolism and signaling. Adipocyte 2012, 1:1-9.
• [14]Lord CC, Bettero JL, Ivanova PT, Milne SB, Myers DS, Madenspacher J, Thomas G, Chung S, Liu M, Davis MA, Lee RG, Crooke RM, Graham MJ, Parks JS, Brasaemle DL, Fessler MB, Brown HA, Brown JM: CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action. Diabetes 2012, 61:355-363.
• [15]Emre S, Ünver N, Evans SE, Yüzbaşioğlu A, Gürakan F, Gümrük F, Karaduman A: Molecular analysis of Chanarin-Dorfman syndrome (CDS) patients: identification of novel mutations in the ABHD5 gene. Eur J Med Genet 2010, 53:141-144.
• [16]Cakir M, Bruno C, Cansu A, Cobanoglu U, Erduran E: Liver cirrhosis in an infant with Chanarin–Dorfman syndrome caused by a novel splice-site mutation in ABHD5. Acta Paediatr 2010, 99:1592-1594.
• [17]Pujol RM, Gilaberte M, Toll A, Florensa L, Lloreta J, González-Enseñat MA, Fischer J, Azon A: Erythrokeratoderma variabilis-like ichthyosis in Chanarin-Dorfman syndrome. Br J Dermatol 2005, 153:838-841.
• [18]Samuelov L, Fuchs-Telem D, Sarig O, Sprecher E: An exceptional mutational event leading to Chanarin-Dorfman syndrome in a large consanguineous family. Br J Dermatol 2011, 164:1390-1392.
• [19]Angelini C, Philippart M, Borrone C, Bresolin N, Cantini M, Lucke S: Multisystem triglyceride storage disorder with impaired long-chain fatty acid oxidation. Ann Neurol 1980, 7:5-10.
• [20]Kakourou T, Drogari E, Christomanou H, Giannoulia A, Dacou-Voutetakis C: Neutral lipid storage disease-response to dietary intervention. Arch Dis Child 1997, 77:184.
• [21]Mitra S, Samanta M, Sarkar M, Chatterjee S: Dorfman-Chanarin syndrome: a rare neutral lipid storage disease. Indian J Pathol Microbiol 2010, 53:799-801.