LE IPERCHILOMICRONEMIE FAMILIARI
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1 LE IPERCHILOMICRONEMIE FAMILIARI Livia Pisciotta Di.M.I.-Università di Genova
2 HYPERCHYLOMICRONEMIA SYNDROME Ø Hypertriglyceridemia (>10 mmol/l, >877 mg/dl) Ø Fasting chylomicronemia Ø Recurrent abdominal pain Ø Recurrent acute pancreatitis Ø Ø Ø Ø Ø Eruptive xanthomas Lipemia retinalis Hepato-splenomegaly Failure to thrive Clinical diagnosis 1-20 years Albumin Chylomicrons Milk
3 Figure 1. ERUPTIVE XANTHOMAS
4 LIPEMIA RETINALIS salmon-coloured retina
5 Apo C-III Chylomicron Apo B-48 Remnant Apo B-48 HDL TG CE Apo E, Apo C-II, Apo A-V Apo C-II TG CE Apo A-V Apo E LPL Apo E LPL GPI-HBP1 GPI-HBP1 Endothelial Cell LPL LMF-1 ER Adipocyte
6 HYPERTRIGLYCERIDEMIAS
7 The distribution of genetic variants in candidate genes for severe HTG type 1 and type 5 Sunderan et al. Journal of Internal Medicine 2012
8 Severe Hypertriglyceridemia and Hyperchylomicronemia GENE LPL APOC2 APOA5 GPI-HBP1 LMF1 CREB3L3 GCKR APOB Disease HCHYL HCHYL HTG/HCHYL HCHYL HCHYL HTG/HCHYL HTG HTG
9 Prevalence of LPL gene mutations in the general population Homozygotes or compound heterozygotes 1: Heterozygotes 1:500
10 Rabacchi C., Pisciotta L.,Cefalù B. et al. Atherosclerosis 241 (2015)
11 LPL gene sequencing of 149 patients with severe HTG (TG >10 mmol/l) referred to tertiary Lipid Clinics in Italy severe HTG: - 26 patients (17.4%) were homozygotes, 9 patients (6%) were compound heterozygotes patients (10%) were simple heterozygotes for rare LPL gene variants. Rabacchi C., Pisciotta L.,Cefalù B. et al. Atherosclerosis 241 (2015)
12 LPL gene sequencing of 149 patients with severe HTG (TG >10 mmol/l) referred to tertiary Lipid Clinics in Italy - 24 patients (48%) suffered from pancreatitis Rabacchi C., Pisciotta L.,Cefalù B. et al. Atherosclerosis 241 (2015)
13 APOC2 gene (19q13.2) Del 241 bp (Fs>X52) * Exon A>G (-189 from ATG) -87 T>A (-190 from ATG) IVS2-30 G>A IVS2 +1 G>C c.1 A>G (M-22V) c.10 C>T (R-19X) c.70 del C (Fs>X18) c.118 del G (V18X) c.122 A>C (K19T) c.142 T>C (W26R) c.177 C>A (Y37X)* c.177 C>G (Y37X) * c.178 G>A (E38K) * Italian mutations c del GC (A44C>Fs>X46) c.229 A>C (K55Q) c.255 C>A (Y63X)* c.270 del T (Fs>X75) c.273 ins C (Fs>X96) c.281 T>C (L72P) *
14 Heparan sulfate proteoglycans and GPIHBP1 HDL Apo C-II LPL Endothelial wall TG-rich Lipoproteins Remnants Apo A-V Apo A-V Receptors
15 ?? I 1 2 II III IV TC 300 mg/dl Tg 4400 mg/dl Abdominal pain Planar and eruptive xanthomas Hepatosplenomegaly Priore Oliva C et al. Arterioscler Thromb Vasc Biol 2005; 25:
16 APOA5 gene Exon Promote r 5 UTR ATG 3 UTR TGA c.442 C>T (Q148X) NH COOH NH COOH Priore Oliva C et al. Arterioscler Thromb Vasc Biol 2005; 25:
17 ?? SS SW SW SS CC CT CT CC SW SW SW SS SS SW SW SW SW CT CT CT CC CC CT CT CT CT SW WW LPL activity 40% APOA5 c.56 C>G (S19W) APOC3 482 C>T No Apo AV in plasma CT TT
18 APOA5 gene Exon Promote r 5 UTR ATG 3 UTR TGA IVS3 +3 g>c (Fs16X19) c.289 C>T (Q97X) c.415 C>T (Q139X) c.442 C>T (Q148X) NH COOH NH COOH NH COOH NH COOH NH COOH
19 Pancreatitis at 56 y 44 y 64 y TG mg/dl HDL-C mg/dl c del GAG (p.e99 del) Pisciotta L. et al. Clin Chim Acta. 2011; 20:
20 59 y BMI 29.3 Tc 246 HDLc 45 Tg y BMI 26.5 Tc 235 HDLc 48 Tg y BMI 28.7 Tc 248 HDLc 42 Tg y BMI 30.2 Tc 225 HDLc 28 Tg 988 Pisciotta L. et al. Clin Chim Acta. 2011; 20: c.758 T>C (L253P) c.56 C>G (S19W)
21 APOA5 gene (exon 4) TGA 3 UTR c.283 C>T Q95X c.289 C>T Q97X c del GAG E99 del c.415 C>T Q139X c.427 del C R143AfsX199 c.442 C>T Q148X c.494 G>A G165D c.553 G>T G185C c.724 del C L242CfsX297 c.725 T>C L242P c.756 G>C Q252H c.758 T>C L253P c.764 A>G E255G c.811 G>T G271C c.880 C>T Q295X c.902 G>C R301P c.913 C>T Q305X c del GAG E309 del c.941 T>G L314R c.944 C>T A315V c.962 A>T H321L c del AG E327CfsX345 c del ACAG D332VfsX336 c ins 28 nt S333RfsX337
22 LMF1 NH 2 49 aa Cytoplasm ER membrane CNX chaperone Calnexin Lipase interaction domain (LPL, HL, EL) 187 aa GS Y439X Y464X Lipase maturation domain ER lumen COOH Partial folding monomer N-term LMF1 C-term LPL monomer inactive Maturation LPL head-to-tail homodimer active ER
23 LMF-1 DEFICIENCY IN HUMANS F 48 years TG 2800 mg/dl LPL Deficiency HL Deficiency Recurrent pancreatitis Tuberous xanthomas Lipodystrophy Exon 9 c.1317 C>G, TAC > TAG (Y439X)
24 Mutation of LMF-1 gene found in Italy? M 42 years Recurrent pancreatitis since 32 years CT 374 mg/dl HDL 44 mg/dl TG 2400 mg/dl LPL activity 50% HL activity 75% Homozygote c.1391 G >A (W464X) Heterozygote c.1391 G > A (W464X)
25 CHYOS Capillary lumen CHYOS CHYOS Mutant GPIHBP1 CHYOS Endothelial cells GPIHBP1 Subendothelial space LPL Parenchymal cells
26 GPI-HBP1: c.166 G>C (G56R), normal LPL binding Age TC TG HDL-C Apo A-I Apo B Pancreatiti s CHD GPI-HBP1 APOE V-CAD, BP RR ε2ε GR ε3ε RR ε2ε3 - GR ε2ε2 - GG ε2ε3 - GR ε2ε3 Wang J, Hegele R Lipids Health Dis 2007; 6: 23
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28 Buonuomo et al. J of Clinical lipidology 2015 GPI-HBP1 mutations
29 Patiens with familial hyperchylomicronemia from mutations of GPI-HBP1 Buonuomo et al. J of Clinical lipidology 2015
30 CREB3L3 gene (19p13.3) Exon PPARα mrna 2586 nt (expressed in the liver and small intestine) CREB-H (461 aa) camp responsive element binding protein 3-like 3 (endoplasmic reticulum-bound transcription factor)
31 ER bzip TM GOLGI bzip S2 P TM S1 P NUCLEUS bzip Transcriptional activation APOC2, APOA4, APOA5 APOC3 LPL
32 12/449 HTG patients (2.7%): Lee JH et al. Nature Medicine 2011; 17: W46X (1) G105R (2) P166L (2) V180M (1) D182N (1) E240K (2) 245fs (3) Mature CREB-H bzip Plasma TG: 18.14±5.48 mmol/l; 1605±485 mg/dl (mean±sem) Range mmol/l; mg/dl Wild 245fs CTG AAA AAA ATC CGC L 244 K K I R 248 CTG GAA AAA TAT CCG TGA L 244 E K Y P X 347
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36 Hyperchylomicronemia and pancreatitis due to LPL autoantibody Ø 5 patients described Ø 1 male and 4 females Ø age 29.4±14.9 years (range 9-50) Ø TG 3866±1433 mg/dl (range )
37 CASE REPORT A 20-yr-old girl from Albania presented acute pancreatitis and serum TG>8000 mg/dl. After only 3 weeks of treatment with plasma exchange, strict restriction of dietary fat and fenofibrate 145 mg, she continued to experience pancreatitis and TG >4000 mg/ dl. Pisciotta L. et al. Unpublished data
38 No mutations of candidate genes were found Auutoimmunity screening ANA, ENA, ANCA, SSA» ANA positive: > 1:160 pattern speckled, (VN <1:80) Antibodies anti SS-A (Ro) 1.0 TPO, TGA, TSH, ft4 Anti-TPO 848 U/ml Anti-TGA 460 U/ml ft4 11,2 ng/l TSH: 11,59 miu/l Pisciotta L. et al. Unpublished data
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40 Triglycerides during plasma exchanges 4000 TG(mg/dl) ABDOMINAL PAIN P.EX P.EX. P.EX gg +9gg +14gg +24gg +31gg +37gg +45gg +50gg +52gg +56gg +63gg +70gg +78gg +87gg +94gg Pisciotta L. et al. Unpublished data
41 Immunosoppressive therapy: AZA100 mg/die + CS 50 mg/die Pisciotta L. et al. Unpublished data
42 Triglycerides during immunosoppressive therapy 4000 TG(mg/dl) CS 50 mg+aza 100 mg CS 25 mg CS 10 mg CS 5 mg gg +14gg +16gg +26gg +35gg +42gg +72gg Pisciotta L. et al. Unpublished data
43 Detection of LPL autoantibody in patient serum 0,3 0,25 0,2 IgG 0,15 0,1 0,05 0 High TG serum IgA and IgM undetectable levels Serum after treatment Serum from Control subjects Pisciotta L. et al. Unpublished data
44 Thank you to my professor Stefano Bertolini for some of these slides THANK YOU FOR YOUR ATTENTION
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