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      Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder

      letter
      1 , 1 , , 2 , 3 , 1 , 4 , 5 , 6 , 7 , 1 , 1 , 1 , 1 , 8 , 1 , 9 , 1 , 10 , 11 , 12 , 13 , 10 , 14 , 15 , 16 , 6 , 17 , 18 , 19 , 13 , 20 , 21 , 22 , 23 , 24 , 14 , 25 , 26 , 27 , on behalf of the Japan TGCV study group
      Orphanet Journal of Rare Diseases
      BioMed Central
      Adipose triglyceride lipase, Atherosclerosis, Rare disease, Triglyceride-deposit cardiomyovasculopathy, Triglyceride metabolism

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          Abstract

          Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies . We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder.

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          Most cited references50

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          Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.

          Mobilization of fatty acids from triglyceride stores in adipose tissue requires lipolytic enzymes. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Until now, hormone-sensitive lipase (HSL) was the only enzyme known to hydrolyze triglycerides in mammalian adipose tissue. Here, we report that a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis. It is interesting that ATGL contains a "patatin domain" common to plant acyl-hydrolases. ATGL is highly expressed in adipose tissue of mice and humans. It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. Inhibition of ATGL markedly decreases total adipose acyl-hydrolase activity. Thus, ATGL and HSL coordinately catabolize stored triglycerides in adipose tissue of mammals.
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            The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy.

            Neutral lipid storage disease comprises a heterogeneous group of autosomal recessive disorders characterized by systemic accumulation of triglycerides in cytoplasmic droplets. Here we report a neutral lipid storage disease subgroup characterized by mild myopathy, absence of ichthyosis and mutations in both alleles of adipose triglyceride lipase (PNPLA2, also known as ATGL). Three of these mutations are predicted to lead to a truncated ATGL protein with an intact patatin domain containing the active site, but with defects in the hydrophobic domain. The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. NLSDM is distinct from Chanarin-Dorfman syndrome, which is characterized by neutral lipid storage disease with ichthyosis, mild myopathy and hepatomegaly due to mutations in ABHD5 (also known as CGI-58).
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              Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome.

              Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive form of nonbullous congenital ichthyosiform erythroderma (NCIE) that is characterized by the presence of intracellular lipid droplets in most tissues. We previously localized a gene for a subset of NCIE to chromosome 3 (designated "the NCIE2 locus"), in six families. Lipid droplets were found in five of these six families, suggesting a diagnosis of CDS. Four additional families selected on the basis of a confirmed diagnosis of CDS also showed linkage to the NCIE2 locus. Linkage-disequilibrium analysis of these families, all from the Mediterranean basin, allowed us to refine the NCIE2 locus to an approximately 1.3-Mb region. Candidate genes from the interval were screened, and eight distinct mutations in the recently identified CGI-58 gene were found in 13 patients from these nine families. The spectrum of gene variants included insertion, deletion, splice-site, and point mutations. The CGI-58 protein belongs to a large family of proteins characterized by an alpha/beta hydrolase fold. CGI-58 contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. Interestingly, CGI-58 differs from other members of the esterase/lipase/thioesterase subfamily in that its putative catalytic triad contains an asparagine in place of the usual serine residue.
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                Author and article information

                Contributors
                liming@cnt-osaka.com
                +81-6-6872-8215 , khirano@cnt-osaka.com
                yikeda@ncvc.go.jp
                xhigashi@onh.go.jp
                hashimoto@cnt-osaka.com
                bozhang@fukuoka-u.ac.jp
                kjunji@endmet.med.osaka-u.ac.jp
                ksugimura@cardio.med.tohoku.ac.jp
                hmiyauchi_circ@yahoo.co.jp
                suzukia@cnt-osaka.com
                y-hara@cnt-osaka.com
                atakagi@cnt-osaka.com
                yasuikeda@cnt-osaka.com
                kazukob@med.kobe-u.ac.jp
                hommefrancophile1950@yahoo.co.jp
                zaimanobuhiro@gmail.com
                y-satoshi@cnt-osaka.com
                cl.biochem@gmail.com
                nakamurah@kure-nh.go.jp
                kawa@komakihp.gr.jp
                eiryu@juntendo.ac.jp
                keino@hs.hokudai.ac.jp
                ysk3ta55@yahoo.co.jp
                a-sawamu@med.nagoya-u.ac.jp
                inaba178@koto.kpu-m.ac.jp
                sakatayk@cardio.med.tohoku.ac.jp
                yasui@life.osaka-cu.ac.jp
                nagasawa@hyo-med.ac.jp
                tuckahoe@med.hokudai.ac.jp
                shimakaz@juntendo.ac.jp
                sohsuke@kanazawa-med.ac.jp
                hao.hiroyuki@nihon-u.ac.jp
                nakatani@cardiology.med.osaka-u.ac.jp
                tomomi_i@cardiol.med.kyushu-u.ac.jp
                amanot@aichi-med-u.ac.jp
                naito.hiroaki@k.nissay-hp.or.jp
                nagasaka@cnt-osaka.com
                nihisak@fukuoka-u.ac.jp
                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                1750-1172
                11 June 2019
                11 June 2019
                2019
                : 14
                : 134
                Affiliations
                [1 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Laboratory of Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics and Triglyceride Research Center (TGRC), Graduate School of Medicine, , Osaka University, ; 6–2-4, Furuedai, Suita, Osaka, 565-0874 Japan
                [2 ]ISNI 0000 0004 0378 8307, GRID grid.410796.d, Department of Pathology, , National Cerebral and Cardiovascular Center, ; 5–7-1, Fujishirodai, Suita, Osaka, 565-8565 Japan
                [3 ]ISNI 0000 0004 0377 7966, GRID grid.416803.8, Department of Radiology, , National Hospital Organization Osaka National Hospital, ; 2–1-14, Hoenzaka, Chuo-ku, Osaka, 540-0006 Japan
                [4 ]ISNI 0000 0001 0672 2176, GRID grid.411497.e, Department of Biochemistry, , Fukuoka University Medical School, ; 7–45–1, Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
                [5 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Metabolic Medicine, Graduate School of Medicine, , Osaka University, ; 2–2, Yamadaoka, Suita, Osaka, 565-0871 Japan
                [6 ]ISNI 0000 0001 2248 6943, GRID grid.69566.3a, Department of Cardiovascular Medicine, , Tohoku University Graduate School of Medicine, ; 1–1, Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8574 Japan
                [7 ]ISNI 0000 0004 0370 1101, GRID grid.136304.3, Department of Cardiovascular Medicine, , Chiba University Graduate School of Medicine, ; 1–8-1, Inohara, Chuo-ku, Chiba, 260-8670 Japan
                [8 ]ISNI 0000 0001 1092 3077, GRID grid.31432.37, Division of Molecular Brain Science, , Kobe University Graduate School of Medicine, ; 7–5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
                [9 ]ISNI 0000 0004 1936 9967, GRID grid.258622.9, Department of Applied Biological Chemistry, Graduate School of Agriculture, , Kindai University, ; 3327–204, Nakamachi, Nara, 631-8505 Japan
                [10 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Faculty of Health Sciences, , Hokkaido University, ; Kita-12, Nishi-5, Sapporo, 060-0812 Japan
                [11 ]GRID grid.416698.4, Kure Medical Center and Chugoku Cancer Center, , National Hospital Organization, ; 3–1, Aoyama-cho, Kure, Hiroshima, 737-0023 Japan
                [12 ]ISNI 0000 0004 1763 8254, GRID grid.415442.2, Department of Cardiovascular Medicine, , Komaki City Hospital, ; 1–20, Jobushi, Komaki, Aichi 485-8520 Japan
                [13 ]ISNI 0000 0004 1762 2738, GRID grid.258269.2, Department of Cardiovascular Medicine, , Juntendo University Graduate School of Medicine, ; 2–1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
                [14 ]ISNI 0000 0001 0727 1557, GRID grid.411234.1, Department of Cardiology, , Aichi Medical University, ; 1–1 Yazakokarimata, Nagakute, Aichi 480-1195 Japan
                [15 ]ISNI 0000 0001 0943 978X, GRID grid.27476.30, Department of Cardiovascular Medicine, Graduate School of Medicine, , Nagoya University, ; 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8560 Japan
                [16 ]ISNI 0000 0001 0667 4960, GRID grid.272458.e, Department of Infection Control and Laboratory Medicine, , Kyoto Prefectural University of Medicine, ; 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566 Japan
                [17 ]ISNI 0000 0001 1009 6411, GRID grid.261445.0, Faculty of Human Life Science, , Osaka City University, ; 3–3-138, Sugimoto, Sumiyoshi-ku, Osaka, 558-8585 Japan
                [18 ]ISNI 0000 0000 9142 153X, GRID grid.272264.7, Department of Internal Medicine, Division of Kidney and Dialysis, , Hyogo College of Medicine, ; 1–1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 Japan
                [19 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Department of Cardiovascular Medicine, , Hokkaido University Graduate School of Medicine, ; Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638 Japan
                [20 ]ISNI 0000 0001 0265 5359, GRID grid.411998.c, Department of Pathology and Laboratory Medicine, , Kanazawa Medical University, ; 1–1 Daigaku, Uchinada, Ishikawa 920-0293 Japan
                [21 ]ISNI 0000 0001 2149 8846, GRID grid.260969.2, Department of Pathology, , Nihon University School of Medicine, ; 30–1 Ohyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610 Japan
                [22 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Center for Global Health, Department of Medical Innovation, , Osaka University Hospital.4F Center of Medical Innovation and Translational Research, ; 2–2 Yamadaoka, Suita, Osaka, 565-0871 Japan
                [23 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Cardiovascular Medicine, , Osaka University Graduate School of Medicine, ; 2–2 (A8) Yamadaoka Suita, Osaka, 565-0871 Japan
                [24 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Cardiovascular Medicine, Graduate School of Medicine, , Kyushu University, ; 3–1–1, Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
                [25 ]Department of Radiology, Nippon Life Hospital, 2–1-54, Enokojima, Nishi-ku, Osaka, 550-0006 Japan
                [26 ]ISNI 0000 0004 0590 7891, GRID grid.416860.d, Department of Pediatrics, , Takarazuka City Hospital, ; 4–5-1, Obama, Takarazuka, Hyogo 665-0827 Japan
                [27 ]GRID grid.413918.6, Department of Endocrinology and Diabetes Mellitus, , Fukuoka University Chikushi Hospital, ; 1–1-1, Zokumyoin, Chikushino, Fukuoka, 818-8502 Japan
                Article
                1087
                10.1186/s13023-019-1087-4
                6560904
                31186072
                ae08cc3c-d628-4367-ac3f-fe6501875117
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 January 2019
                : 1 May 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: 17ek0109092h0003
                Award Recipient :
                Categories
                Letter to the Editor
                Custom metadata
                © The Author(s) 2019

                Infectious disease & Microbiology
                adipose triglyceride lipase,atherosclerosis,rare disease,triglyceride-deposit cardiomyovasculopathy,triglyceride metabolism

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