Ymmoto et l. Journl of Medicl Cse Reports (2018) 12:370 https://doi.org/10.1186/s13256-018-1931-5 CASE REPORT Hereditry crdic myloidosis ssocited with Pro24Ser trnsthyretin muttion: cse report Hiroyuki Ymmoto 1* Tomoki Yokochi 6 Open Access, Toru Hshimoto 2, Shunji Kwmur 3, Michiki Hiroe 4, Tro Ymshit 5, Yukio Ando 5 nd Astrct Bckground: Trnsthyretin myloidosis is systemic disorder cused y extrcellulr deposition of insolule myloid firils in peripherl nd utonomic nerves, hert, kidney, gstrointestinl trct, nd other orgns. Hereditry trnsthyretin myloidosis is n utosoml dominnt disese. More thn 120 muttions hve een reported in the trnsthyretin gene with considerle phenotypic heterogeneity nd geogrphic diversity. Among them, spordic cse of hereditry trnsthyretin myloidosis with crdic-predominnt phenotype is very rre, progressive, nd potentilly ftl if left undignosed. However, clinicl dignosis of crdic myloidosis still remins chllenging due to non-specific symptoms, nd less sensitivity nd specificity of medicl exmintions. Cse presenttion: A 60-yer-old Jpnese mn with history of emolic stroke nd hypertrophic crdiomyopthy visited our deprtment for hert filure. The present cse exhiited only crdiomyopthy without ny clinicl signs of systemic myloidosis mnifested s crpl tunnel syndrome, polyneuropthy, or utonomic dysfunction. An echocrdiogrm reveled severe symmetric left ventriculr hypertrophy, itril dilttion, pericrdil effusion, nd preserved left ventriculr ejection frction of 50% with severe distolic dysfunction. Technetium pyrophosphte scintigrphy indicted mrked diffuse myocrdil uptke of technetium pyrophosphte, strongly suggesting trnsthyretin crdic myloidosis, which ws firmly confirmed y left ventriculr endomyocrdil iopsy. Genetic nlysis demonstrted trnsthyretin C70T (Pro24Ser) heterozygous muttion. Tfmidis, trnsthyretin stilizer, ws strted. His crdic symptoms remined unchnged for 12 months. Conclusions: Here we report the cse of ptient with hereditry crdic myloidosis ssocited with Pro24Ser muttion in trnsthyretin, which is the first cse reported in Jpn. Technetium pyrophosphte scintigrphy ws extremely useful for definitive dignosis. Thus, we propose tht the nucler imging technique should e tken into ccount even for n explortory dignosis of trnsthyretin crdic myloidosis. Keywords: Trnsthyretin, Crdic myloidosis, Hereditry ATTR myloidosis Bckground Trnsthyretin (TTR) myloidosis is systemic disorder cused y extrcellulr deposition of insolule myloid firils in peripherl nd utonomic nerves, hert, kidney, gstrointestinl trct, nd other orgns. A TTR gene product is one of the components of myloid, which is plsm protein predominntly produced in the liver, * Correspondence: hymmoto19700908@gmil.com 1 Deprtment of Crdiology, Crdiovsculr Center, Show Generl Hospitl, 8-1-1 Hnkognei, Kodir City, Tokyo 187-8510, Jpn Full list of uthor informtion is ville t the end of the rticle cting s trnsporter of thyroxine nd retinol-inding protein. Hereditry myloid TTR (ATTR) myloidosis is n utosoml dominnt disese in which gene muttions led to chnges in the protein TTR [1]. More thn 120 muttions hve een reported in the TTR gene with considerle phenotypic heterogeneity nd geogrphic diversity. A sustitution of 30th vline y methionine (Vl30Met) is the most common genetic vrint found in endemic res in Portugl, Sweden, nd Jpn [2]. The Vl30Met vrint induces progressive neurologicl symptoms, such s xonl sensory utonomic nd motor The Author(s). 2018 Open Access This rticle is distriuted under the terms of the Cretive Commons Attriution 4.0 Interntionl License (http://cretivecommons.org/licenses/y/4.0/), which permits unrestricted use, distriution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde. The Cretive Commons Pulic Domin Dediction wiver (http://cretivecommons.org/pulicdomin/zero/1.0/) pplies to the dt mde ville in this rticle, unless otherwise stted.
Ymmoto et l. Journl of Medicl Cse Reports (2018) 12:370 Pge 2 of 5 neuropthy, wheres other muttions (Vl122Ile, Thr60Al, Leu111Met, nd Ile68Leu) predominntly show infiltrtive crdiomyopthy [3]. A spordic cse of hereditry ATTR crdic myloidosis is very rre, progressive, nd potentilly ftl if left undignosed; thus, erly dignosis is criticl. However, the clinicl dignosis of crdic myloidosis remins chllenging ecuse neurologicl symptoms re less recognized in spordic cse [4]. Therefore, development of n pproprite strtegy to rech correct dignosis of crdic myloidosis hs een long overdue. Here we report the cse of ptient with crdic myloidosis ssocited with single muttion in TTR, which is the first cse in Jpn. In ddition, we propose new dignostic strtegy of crdic myloidosis, which my contriute to estlishing n erly nd differentil dignosis of this rre crdic disese. Cse presenttion A 60-yer-old Jpnese mn visited our deprtment for hert filure. He did not smoke tocco; he hd two histories of crdioemolic cererl infrction t ges 47 nd 59. Also, he hd hypertrophic crdiomyopthy t ge 58, ut hd no coronry risk fctors including hypertension. His lood pressure ws 107/72 mmhg with hert rte of 60 ets per minute. He hd grde 2/6 systolic murmur nd mild pretiil edem. Crpl tunnel syndrome, polyneuropthy, nd utonomic dysfunction were unremrkle. An electrocrdiogrm showed norml sinus rhythm with QS wves in inferior leds, nd with low QRS voltges in leds V1 to V4 (Fig. 1). A chest X-ry showed crdiomegly (Fig. 1). An echocrdiogrm demonstrted severe symmetric left ventriculr hypertrophy (LVH; the interventriculr septum nd the posterior wll were 13 mm nd 16 mm, respectively), itril dilttion, pericrdil effusion, nd preserved left ventriculr ejection frction of 50% (Fig. 2). Incresed right ventriculr wll thickness ws lso seen. There ws grde III distolic dysfunction (Fig. 2). The unexplined LVH led us to suspect crdic myloidosis. Technetium pyrophosphte ( 99m Tc-PYP) scintigrphy indicted mrked diffuse myocrdil uptke of 99m Tc-PYP (Fig. 3), which strongly suggested TTR crdic myloidosis. In ddition, crdic mgnetic resonnce imging reveled wide-spreding trnsmurl lte gdolinium enhncement t the ventriculr nd tril wlls, lso supporting this notion (Fig. 3). A left ventriculr endomyocrdil iopsy confirmed TTR-relted myloid deposits (Fig. 4). DNA sequence nlysis demonstrted TTR C70T (Pro24Ser) heterozygous muttion (Fig. 5). Therefore, we ssume tht the Pro24Ser muttion is responsile for crdic myloidosis. Further genotyping of TTR of the fmily memers of our ptient reveled tht his third son hs the identicl muttion (Fig. 5), while he showed no clinicl signs. Our ptient ws ineligile for hert trnsplnttion due to his ge (over 60) nd renl dysfunction; thus, comined usge of diuretics nd tfmidis, TTR stilizer, ws dministered. His crdic symptoms remined unchnged for 12 months. Discussion In this report, we descried the first cse of hereditry crdic myloidosis ssocited with Pro24Ser TTR muttion in Jpn. Also, we demonstrted tht nucler imging is effectively useful for definitive dignosis of crdic myloidosis. A rre cse of hereditry myloidosis ssocited with the TTR muttion (Pro24Ser) hs een reported previously [5]. All silings of the single fmily hd similr, lte-onset symptoms of systemic myloidosis mnifested s crpl tunnel syndrome, polyneuropthy, utonomic dysfunction, nd crdiomyopthy. Note tht these phenotypes were locted t oth the nervous system nd crdic muscle. On the other hnd, the ptient descried in this report exhiited n isolted crdic-predominnt phenotype despite hving the sme muttion. In generl, muttions tht cuse genetic disese strongly correlte with mny spects of phenotype, including onset, loction, nd the degree of progression. It hs een reported, however, tht there re severl cses exhiiting inconsistency in terms of genotype-phenotype Fig. 1 A 12-led electrocrdiogrm. Chest X-ry
Ymmoto et l. Journl of Medicl Cse Reports (2018) 12:370 Pge 3 of 5 RV LV RV LV PE RA LA Fig. 2 Trnsthorcic echocrdiogrphy in picl four chmer (, left pnel) nd short xis view (right). Trnsmitrl flow reveled n erly mitrl inflow to lte filling velocity rtio of 2.6 (, left pnel). Tissue Doppler imging of the mitrl nnulus (right). LA left trium, LV left ventricle, PE pericrdil effusion, RA right trium, RV right ventricle (201) Tl-Cl (99m) Tc-PYP merge Fig. 3 Horizontl long-xis imges of crdic dul-isotope technique (thllium chloride nd technetium pyrophosphte). thllium chloride ws used for myocrdil perfusion s control. The lte gdolinium enhncement imges in the horizontl long-xis (upper pnels) nd short-xis views (lower pnels). 99mTc-PYP technetium pyrophosphte, 201Tl-Cl thllium chloride
Ymmoto et l. Journl of Medicl Cse Reports (2018) 12:370 Pge 4 of 5 Fig. 4 Endomyocrdil iopsy imges. Congo red stining showed myloid deposits within the tissue (left), with pple-green irefringence under polrized light (center). Immunostining ginst trnsthyretin ws positive (right). Brs, 100 μm correltion. For instnce, TTR Vl30Met yields vriety of phenotypes including ge of onset, severity, genetic penetrnce, nd regionl specificity [1]. In Jpn nd Portugl, the TTR Vl30Met muttion is frequently found in endemic fmilil history, presenting neurologicl-predominnt phenotypes tht egin t n erly ge. In contrst, the muttion found in Sweden is rther spordic, nd is ssocited with lte onset nd crdic-predominnt phenotypes [6]. This heterogeneity my e explined y severl possiilities, such s epigenetic configurtion round TTR gene, dditionl muttion in nother gene not yet identified, or trnscriptionl regultion medited y non-coding RNA [7, 8]. A definitive dignosis of crdic myloidosis is significntly difficult ecuse LVH is common symptom in hypertension, ortic stenosis, nd hypertrophic I 1 2 II III 1 2 3 4 5 6 7 1 2 3 IV 1 2 3 Fig. 5 DNA sequencing of trnsthyretin indictes muttion in exon2 with nucleotide sustitution t 70th (C70T), resulting in Pro24Ser vrint of the trnsthyretin protein. Genotyping of trnsthyretin in fmily memers of the ptient. Arrow indictes the prond. Individuls with heterozygous Pro24Ser muttion (filled symols); wild-type (shded); not tested (open)
Ymmoto et l. Journl of Medicl Cse Reports (2018) 12:370 Pge 5 of 5 crdiomyopthy [9]. This cse hd een considered to hve hypertrophic crdiomyopthy ecuse of symmetric hypertrophy. He hd severl episodes of crdioemolic infrction despite norml sinus rhythm, followed y hert filure. Intrinsic tril dysfunction induced y myloid deposition to the hert muscle my result in tril thromi [10, 11]. These clinicl signs my provide criticl clue to erly dignosis of crdic myloidosis. Therefore, crdic myloidosis should e tken into ccount when LVH is ccompnied y emolic stroke or hert filure. Infiltrtion of the hert y myloidogenic proteins induces severl types of crdic myloidosis, including myloid immunogloulin light-chin (AL) myloidosis, hereditry ATTR myloidosis, nd wild-type ATTR myloidosis. Limited specificity in dignostic techniques nd poor sensitivity of noncrdic iopsy or dominl ft spirtion my result in delyed dignosis [12]. Recently, nucler imging technique employing 99m Tc-PYP hs een descried s relile dignostic tool for ATTR crdic myloidosis, which is distinguished from AL myloidosis with high specificity, nd crdic TTR deposition cn e detected t n erly symptomtic stge [13, 14]. In fct, we demonstrted in this report tht crdic rdioisotope exmintion ws very effective in the dignosis of hereditry ATTR crdic myloidosis. This is the first cse of hereditry crdic myloidosis ssocited with TTR muttion (Pro24Ser) in Jpn. We propose tht n explortory dignosis utilizing nucler imging is highly relile to identify ATTR crdic myloidosis. Conclusions We report cse of isolted crdic myloidosis ssocited with Pro24Ser muttion in TTR, which is the first cse reported in Jpn. We demonstrted tht 99m Tc-PYP scintigrphy is extremely useful for definitive dignosis of this rre disese. Arevitions 99m Tc-PYP: Technetium pyrophosphte; AL: Amyloid immunogloulin lightchin; ATTR: Amyloid trnsthyretin; LVH: Left ventriculr hypertrophy; TTR: Trnsthyretin Acknowledgements Not pplicle. Funding No source of funding ws declred for this study. Authors contriutions HY prepred clinicl design nd concept. HY, TH, SK, TY, YA, nd ToY were involved in cquisition of clinicl dt. HY, MH, YA, nd ToY nlyzed nd interpreted the dt, nd HY nd ToY wrote the mnuscript. All uthors discussed, red, nd pproved the sumission of this mnuscript to the journl. Ethics pprovl nd consent to prticipte The uthoriztion for the use of cse informtion nd mterils ws otined from the Institutionl Review Bord of Nrit-Tomisto Tokushuki Hospitl. We lso otined n informed consent from the ptient. Consent for puliction Written informed consent ws otined from the ptient for puliction of this cse report nd ny ccompnying imges. A copy of the written consent is ville for review y the Editor-in-Chief of this journl. Competing interests The uthors declre tht they hve no competing interests. Pulisher s Note Springer Nture remins neutrl with regrd to jurisdictionl clims in pulished mps nd institutionl ffilitions. Author detils 1 Deprtment of Crdiology, Crdiovsculr Center, Show Generl Hospitl, 8-1-1 Hnkognei, Kodir City, Tokyo 187-8510, Jpn. 2 Deprtment of Crdiovsculr Medicine, Nrit-Tomisto Tokushuki Hospitl, Chi, Jpn. 3 Deprtment of Pthology, Tokyo Women s Medicl University, Tokyo, Jpn. 4 Deprtment of Crdiology, Center Hospitl of the Ntionl Center for Glol Helth nd Medicine, Tokyo, Jpn. 5 Deprtment of Neurology, Grdute School of Medicl Sciences, Kummoto University, Kummoto, Jpn. 6 Deprtment of Clinicl Reserch, Chi Tokushuki Hospitl, Chi, Jpn. Received: 27 August 2018 Accepted: 21 Novemer 2018 References 1. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Iked S, et l. Guideline of trnsthyretin-relted hereditry myloidosis for clinicins. Orphnet J Rre Dis. 2013;8:31. 2. Plnte-Bordeneuve V, Sid G. 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