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A 33-year-old man with nephrotic syndrome and lecithin-cholesterol acyltransferase (LCAT) deficiency. Description of two new mutations in the LCAT gene

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A 33-year-old man with nephrotic syndrome and lecithin-cholesterol acyltransferase (LCAT) deficiency. Description of two new mutations in the LCAT gene
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  Nephrol Dial Transplant (2004) 19: 1622–1624DOI: 10.1093/ndt/gfh179 Case Report A 33-year-old man with nephrotic syndrome and lecithin–cholesterolacyltransferase (LCAT) deficiency. Description of two new mutationsin the  LCAT   gene Giovanni M. Frasca ` 1 , Letizia Soverini 1 , Elena Tampieri 1 , Guido Franceschini 2 , Laura Calabresi 2 ,Livia Pisciotta 4 , Paola Preda 3 , Alba Vangelista 1 , Sergio Stefoni 1 and Stefano Bertolini 4 1 Nephrology, Dialysis and Renal Transplantation Unit and  3 Electron Microscopy Unit, Pathology Department, St OrsolaUniversity Hospital, Bologna,  2 Centro E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milanoand  4 Internal Medicine Department, Genova, Italy Keywords:  chronic renal failure; focal segmental glo-merulosclerosis; genetic diseases; hereditary nephrop-athies; lecithin–cholesterol acyltransferase (LCAT)deficiency; nephrotic syndrome Introduction Familial lecithin–cholesterol acyltransferase (LCAT)deficiency is a rare autosomal recessive disease causedby mutation in the  LCAT   gene, located on chromo-some 16q22 (GenBank accession nos: genomic DNAX04981, cDNA NM_000229). LCAT catalyses theformation of cholesteryl esters via the hydrolysis andtransfer of sn-2 fatty acid from phosphatidylcholineto the 3-hydroxyl group of cholesterol. A deficiency of this enzyme leads to increased levels of phosphatidyl-choline and unesterified cholesterol in the blood andto the formation of an abnormal lipoprotein (called‘lipoprotein-X’) rich in both phosphatidylcholine andunesterified cholesterol. As a consequence, progressivelipid deposition occurs in various tissues, including thekidney [1], resulting in progressive glomerular sclerosiswhich becomes clinically manifest in the third to fourthdecade of life and eventually leads to end-stage renaldisease [2].To date, 13 affected families have been found inItaly (including the one here described), but the diseasemay have been underdiagnosed.We here report on a 33-year-old man investigatedfor steroid-resistant nephrotic syndrome and progres-sive deterioration of renal function where clinical,morphological and biochemical data led to the diag-nosis of familial LCAT deficiency, confirmed by theidentification of two new mutations in the  LCAT   gene. Case A 33-year-old man was admitted to our hospital fornephrotic proteinuria (4–6g/day) and reduced renalfunction (serum creatinine 2.3mg/dl; creatinine clear-ance 45ml/min/1.73m 2 ). Proteinuria had occasionallybeen found 4 years earlier, when the glomerularfiltration rate was within the normal range (serumcreatinine 1mg/dl), and was associated with an increasein total serum cholesterol (302mg/dl) and tryglicerides(455mg/dl); serum complement was within the normalrange and the search for non-organ-specific autoanti-bodies was negative; a renal biopsy was carried out inanother hospital which produced a diagnosis of ‘focalsegmental glomerulosclerosis’. The patient was treatedwith a combination of gemfibrozil, simvastatin, enala-pril and low dose acetylsalicyclic acid without anysignificantimprovementinproteinuria.Twoyearslater,owingtothepersistence ofnephroticproteinuriaandanincrease in serum creatinine (1.5mg/dl), he underwenta second renal biopsy in a different hospital wherethe diagnosis of ‘focal segmental glomerulosclerosis’was confirmed and a short course of steroids wasundertaken without any improvement in urinaryfindings.In 2001, the patient was admitted to our hospitalafter a further increase in serum creatinine, which hadnow risen above 2mg/dl.On admission, physical examination showed mod-erate pedal oedema and normal blood pressure(120/80mmHg). Corneal greyish opacities wereobserved. Correspondence and offprint requests to : Giovanni M. Frasca, MD,Nephrology, Dialysis and Renal Transplantation Unit, St OrsolaUniversity Hospital, Via Massarenti 9, 40137 Bologna, Italy. Email:frasca@orsola-malpighi.med.unibo.itNephrol Dial Transplant Vol. 19 No. 6    ERA–EDTA 2004; all rights reserved   b  y g u e  s  t   onA pr i  l  2  3  ,2  0 1  6 h  t   t   p :  /   /  n d  t   . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   The family history revealed dyslipidaemia in thefather, who had died at the age of 69 of myocardialinfarction, and in a brother; a second brother and asister had no sign of renal disease or lipid abnor-malities. The family pedigree is reported in Figure 1.Laboratory investigations showed: haemoglobin10g/dl, MCV 88 m m 3 , WBC 4100/mm 3 with a normaldifferential count, poikilocytosis and ‘target’ erythro-cytes in peripheral blood film examination; haptoglo-bin 52mg/dl (normal range 70–200mg/dl); total serumproteins 5g/dl with increased  a 2 fraction at pro-tidogram, erythrocyte sedimentation rate 99; serumcomplement fractions were within the normal range.Coomb’s test and autoantibodies were negative. Totalcholesterol was 306mg/dl (while assuming fluvastatin40mg/day), high-density lipoprotein (HDL) choles-terol 16mg/dl, triglycerides 587mg/dl, apolipoproteinA-I 35mg/dl (normal range 115–180), apolipoproteinA-II5mg/dl(normalrange26–51)andapolipoproteinB51mg/dl (normal range 70–160). LCAT activitywas absent in the patient and in the brother withdyslipidaemia (reported as II2 in Figure 1) who had noproteinuria at urinalysis. Table 1 reports the lipidprofiles of the family members investigated.A renal biopsy was carried out percutaneously.Immunofluorescence examination of renal tissuerevealed diffuse granular C3 deposits in the mesangialarea and on several glomerular capillary walls; focaland segmental granular deposits of IgM and fibrinogenwere observed on the capillary walls.Light microscopy showed global sclerosis involvingseven out of 11 glomeruli; in the remainder, focalsegmental glomerular sclerosis was observed alongwith mesangial expansion, a mild increase in mesangialcellularity and irregular thickening of the glomerularcapillary walls, with vacuolization of the glomerularbasement membrane due to intramembranous lipiddeposits, resulting in a typical ‘foamy’ appearance.Diffuse tubular atrophy with thickening of the tubularbasement membranes, along with focal interstitialfibrosis and mononuclear cells infiltrates, were alsofound.Electron microscopy examination showed lipiddeposits with both a vacuolar lucent appearance andelectron-dense lamellar structures in the mesangialmatrix, in the glomerular and tubular basementmembranes, as well as in the Bowman’s capsule andendothelial cells.Genetic analysis showed that the proband wascompound heterozygous for two novel mutations,which were designated according to the recommendednomenclature [3]. (i) A deletion of five nucleotidesGCCCG (g.977–981del, c.141–145del) in exon 1. Themutation caused a frameshift after Arg23 withthe introduction of 52 novel amino acids and theoccurrence of a termination codon at position 76. (ii) Anucleotide transition in exon 5 (g.2439, c.614 G>A),which converted the codon 181 (AGC) for serine into acodon (AAC) for asparagine. The Ser181 residue is oneof the components of the catalytic triad, which isconserved in all the animal species examined [4].The proband’s brother carried both mutations; theother brother and the sister were heterozygous for the Table 1.  Lipid profiles of the familyNormal Subjects II2 (brother) II3 (sister) II4 (brother) I2 (mother)values II1 (proband)Total cholesterol <200 185 124 133 131 215(mg/dl)Free cholesterol <55 165 113 42 43 76(mg/dl)FC/TC (%) <28 89 91 32 33 35HDL-cholesterol >40 16 15 33 40 36(mg/dl)Triglycerides <150 587 409 144 115 217(mg/dl)ApoA-I 115–180 35 42 84 107 107(mg/dl)ApoA-II 26–51 5 5 22 29 28(mg/dl)ApoB 70–160 51 27 71 72 136(mg/dl)LCAT activity 25–55 0 0 23 14 8(nmol/ml/h)FC/TC, free cholesterol/total cholesterol. III 1 2 34 1 2 m1/m2 m1/m2 m1/+ m1/ m1/+ +/m2 Fig. 1.  Pedigree of the family investigated. The arrow shows theproband. m1/ þ  denotes subjects heterozygous for mutation in exon1;  þ /m2 denotes subjects heterozygous for mutation in exon 5;m1/m2 denotes compound heterozygous for both mutations (see textfor details).Nephrotic syndrome due to LCAT deficiency 1623   b  y g u e  s  t   onA pr i  l  2  3  ,2  0 1  6 h  t   t   p :  /   /  n d  t   . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   deletion in exon 1, and the mother was heterozygousfor the missense mutation in exon 5. Discussion Clinical manifestations of familial LCAT deficiencyinclude corneal opacities, haemolytic anaemia andrenal involvement, initially characterized by protein-uria, with progressive deterioration of renal function[1]. End-stage renal disease, which generally occursin the fourth decade of life, is the major cause of morbidity and mortality in these patients.In the case reported here, corneal opacity along witha previous histological diagnosis of focal segmentalglomerulosclerosis led us to consider the possibility of an LCAT deficiency. The presence of mild haemolyticanaemia (due to phospholipid abnormalities in theerythrocyte membrane), low HDL cholesterol and afamily history of dyslipidaemia supported this hypoth-esis. The diagnosis was suggested further by the‘foamy’ appearance of the glomerular basementmembrane on light microscopy examination of silver-stained renal biopsy specimens and by the presence of typical lipid deposits within the glomerular basementmembrane and podocytes at electron microscopicexamination of renal tissue. The lipid profile andgenetic analysis of the patient and his family membersdefinitively confirmed the diagnosis by identifyingmutations of the  LCAT   gene.It is of interest that the brother (II2) does not showany urinary abnormality although he lacks LCATactivity and carries the same genetic mutationsdetected in the patient with renal failure. Obviously,we did not carry out a renal biopsy in this subject so wedo not know whether some lipid deposition hasoccurred in his kidney, despite the absence of urinaryabnormalities. It has already been observed thatclinical manifestations of patients with  LCAT   genemutations may vary even among members of the samefamily carrying identical mutations [5], so it is stillunclear whether other factors besides lipid depositionin tissues may affect the clinical picture and, particu-larly, lead to the development of renal lesions.Immunohistochemical investigations, carried out onrenal tissue obtained from LCAT-deficient subjects,has shown that oxidized phosphatidylcholine accumu-lates in the glomeruli of these patients, as a result of reduced or absent LCAT activity which is also able toremove oxidized lipids [6], and suggested that oxidizedphosphatidylcholine may play an important role ininducing renal lesions [2]. More recently, it has beendemonstrated that lipoprotein-X, which accumulatesin subjects with LCAT deficiency, can stimulatemonocyte chemoattractant protein-1 (MCP-1) expres-sion in mesangial cells via nuclear factor- k B (NF- k B).This finding suggests that infiltrating monocytes cansignificantly contribute to renal damage by taking uplarge amounts of lipoprotein-derived lipids whichresults in foam cell formation and, on the otherhand, by secreting a wide variety of cytokines andgrowth factors which can lead to development of glomerular sclerosis [7]. Whatever the mechanism(s)superimposed on lipid deposition leading to progres-sive renal damage, it is important to form a correctdiagnosis not only to treat patients appropriately (andavoid useless and potentially dangerous drugs), butalso to identify other affected family members andprovide genetic counselling.In conclusion, this case underlines once more theneed for a careful physical examination of patientswith otherwise unexplained renal disease, focusingattention on whether other organ systems are involved,and may suggest the correct diagnosis. It also stressesthe importance of accurate family investigation when-ever possible. Acknowledgements.  This work was supported in part by a grant fromTelethon-Italy (no. GGP02264) to L.C. and in part by a grant fromthe Italian Ministry of Education and Research (MM06178194_006)to S.B. Conflict of interest statement . None declared. References 1. Bernstein J, Churg J. Heritable metabolic diseases. In: JennetteJCOJ, Schwartz MM, Silva FG, eds.  Heptinstall’s Pathology of the Kidney . Lippincott-Raven, Philadelphia PA; 1998: 1287–13202. Jimi S, Uesugi N, Saku K  et al.  Possible induction of renaldysfunction in patients with lecithin:cholesterol acyltransferasedeficiency by oxidized phosphatidylcholine in glomeruli. Arteriosler Thromb Vasc Biol   1999; 19: 794–8013. Dunnen JT and Antonarakis AE. Mutation nomenclatureextension and suggestions to describe complex mutations: adiscussion.  Hum Mutat  2000; 15: 7–124. Peelman F, Verschelde J-L, Vanloo B  et al.  Effects of naturalmutations in lecithin:cholesterol acyltransferase on the enzymestructure and activity.  J Lipid Res  1999; 40: 59–695. Funke H, Eckardstein AV, Pritchard P  et al.  Geneticand phenotypic heterogeneity in familial lecithin–cholesterolacyltransferase (LCAT) deficiency.  J Clin Invest  1993; 91:677–6836. Subbaiah PV, Liu M. Disparate effects of oxidation on plasmaacyltransferase activities: inhibition of cholesterol esterificationbut stimulation of transesterification of oxidized phospholipids. Biochim Biophys Acta  1996; 1301: 115–1267. Lynn EG, Siow YL, Frohlich J, Cheung GTY, Karmin O.Lipoprotein-X stimulates monocyte chemoattractant protein-1expression in mesangial cells via nuclear factor- k B.  Kidney Int 2001; 60: 520–532 Received for publication: 22.9.03Accepted in revised form: 28.1.04 1624 G. M. Frasca `  et al  .   b  y g u e  s  t   onA pr i  l  2  3  ,2  0 1  6 h  t   t   p :  /   /  n d  t   . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om 
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