Case Reports Transthyretin lie 122 and Cardiac in African-Americans 2 Case Reports

Daniel R. Jacobson, MD Two cases of resulting from deposition of the lie 122 variant of Michael Ittmann, MD, PhD transthyretin in African-Americans are presented. These cases illustrate several typical Joel N. Buxbaum, MD abnormalities and digoxin toxic- Rosemary Wieczorek, MD features of this disorder, including electrocardiographic Peter D. Gorevic, MD ity. Transthyretin lIe 122 is a common amyloidogenic variant in African-Americans (present as a heterozygous variant in 4 % of this population); therefore, the diagnosis of trans- thyretin lIe 122 cardiac amyloidosis should be considered in African-Americans with un- explained restrictive or . (Tex Heart Inst J 1997;24:45-52)

Crardiac amyloidosis results from deposition of insoluble protein fibrils in the cardiac interstitium, along the conduction system, and in the vascular subendothelium, leading to restrictive cardiomyopathy, arrhythmias, pos- tural hypotension, and occasionally .' Fifteen different proteins that form amyloid in humans have been described, each of which tends to form deposits in different organs, resulting in different clinical disease patterns.23 The 2 proteins Key words: African- Americans/genetics; that most often form deposits in the cardiac ventricles and conduction system, amyloidosis/diagnosis; compromising cardiac function, are immunoglobulin light chains (AL amyloid), amyloidosis/ethnology; and transthyretin (TTR), a serum transport protein of 4 identical 127-amino acid amyloidosis/genetics; heart conduction system! subunits. Normal-sequence TTR has an inherent tendency to form amyloid in the physiopathology; heart cardiac ventricles of people over age 60; this condition is termed senile cardiac diseases/etiology; heart amyloidosis (SCA). Because many individuals with SCA also have small deposits failure, congestive; isoleu- cine/genetics; prealbuminl of TTR amyloid in the lungs and elsewhere, the alternative name senile systemic transthyretin; variation amyloidosis (SSA) is also used.4 (genetics) Many mutations in the TTR molecule affect its conformation, increasing its ten- dency to form amyloid; variant-sequence TTR-amyloidosis develops primarily in From: The Department of the heart and along the peripheral nerves, as well as in the gastrointestinal tract, Medicine (Drs. Buxbaum vitreous, and elsewhere.2 Depending on the primary site of deposition, the dis- and Jacobson), New York University Medical Center ease has been termed familial amyloid cardiomyopathy or familial amyloid poly- and Medical Service, neuropathy. This distinction is not always clear cut, however, because some TTR and the Department of variants lead to extensive amyloid deposits in both sites. Of the more than 50 Pathology (Drs. Ittmann and Wieczorek), New York known amyloidogenic TTR point mutations, most have been described in a single University Medical Center kindred, and each has a characteristic disease pattern and typical age of onset.2'5 and Laboratory Service, New One variant, containing a substitution of isoleucine (Ile) for valine (Val) at amino York Department of Veterans Affairs Medical Center, New acid 122, causes late-onset cardiac amyloidosis, and has been reported only in York, New York 10010; and patients of African descent.6 We now report the clinicopathologic data on 2 Afri- the Department of Medicine, can-American patients with late-onset cardiac amyloidosis resulting from deposi- State University of New York, Stony Brook, New tion of TTR Ile 122. Genetic analysis on the 2nd patient is also presented (the York 1 1794, and Northport genetic analysis, but not the clinical information, on patient 1 has been reported Department of Veterans previously).7'8 Affairs Medical Center (Dr. Gorevic), Northport, New York 11768 Case Reports

Address for reprints: Patient 1 Daniel R. Jacobson, MD, A 68-year-old African-American man from West Virginia was admitted to a hospi- Research Service 151, tal in 1979 with a 3-week history of progressive shortness of breath, orthopnea, New York VA. Medical Center, 423 E. 23 St., paroxysmal nocturnal dyspnea, and 1 brief episode of "passing out." There was a New York, NY 10010 12-year history of hypertension, and a 7-year history of congestive ,

Texas Heart InstituteJournal Transthyretin lie 122 45 treated with digoxin and diuretics, following a myo- closed pleural biopsies and an open pleural biopsy cardial infarction. The patient had been hospitalized revealed only chronic pleuritis, without evidence of on several occasions in the preceding 5 years for de- granulomas or malignancy. On the 27th day of hos- compensated congestive heart failure. The patient pitalization, the patient underwent bronchoscopy had a brother with a history of ; with a transbronchial biopsy, which revealed am- 4 other siblings were reportedly in good health. The yloidosis, as determined by Congo red positivity. patient's father had died at a young age as a result of Serum protein electrophoresis and immunoelectro- trauma, and his mother had died at age 45. The pa- phoresis, serum immunoglobulin levels, and urine tient's 3 children were in good health. Upon review protein electrophoresis results were all normal, with of systems, numbness and tingling were noted in the no evidence of a monoclonal protein. Bone marrow fingers of both hands of the patient (Table I7-10). aspiration and biopsy were normal, without an in- Physical examination revealed a well-developed crease in plasma cells. Results of upper-extremity male in moderate respiratory distress. The pulse rate nerve conduction studies were consistent with a di- was 86 beats/min and regular, the blood pressure agnosis of bilateral carpal tunnel syndrome. The was 160/i 10 mmHg, and the respiratory rate was 32/ patient was discharged on digoxin (0.25 mg/day), min. Cardiac examination was notable for S3 and quinidine, furosemide, theophylline, prazosin, trans- S4 summation gallops. No murmur was heard. Pul- dermal nitrate, and potassium chloride. monary examination revealed diffuse expiratory During the next 21/2 years, the patient was hospi- wheezes, bibasilar rales, and diminished breath talized 6 times for increased shortness of breath and sounds at the left base. The liver was palpable 2 cm peripheral edema. His exacerbations of congestive below the right costal margin. Hepatojugular reflux heart failure were attributed to noncompliance with was noted. There was 1+ pitting edema of the low- his prescribed medications and diet. During this time er extremities. Upper-extremity sensation was de- his ECG did not change. Chest radiography often re- creased bilaterally, in the distribution of the median vealed pleural effusions. He was treated with diuret- nerve. ics, digoxin, and salt restriction. The electrocardiogram (ECG) revealed normal At age 71 the patient was 1st admitted to the sinus rhythm at 80 beats/min, with frequent atrial Northport (New York) Veterans Administration Medi- premature contractions and occasional ventricu- cal Center with another exacerbation of congestive lar premature contractions. There were Q waves heart failure. Chest radiography revealed a pleural in leads III and aVF and nonspecific ST- effusion, which was found on thoracentesis to be a changes in leads I, aVL, V5, and V6. The voltage was transudate. The ECG was unchanged (Fig. 1A). Ra- normal. Chest radiography revealed dionuclide imaging of the heart with 99technetium and a left pleural effusion. Thoracentesis yielded pyrophosphate revealed diffuse uptake throughout bloody, exudative pleural fluid, which was negative the left ventricle, consistent with cardiac amyloid- cytologically and negative for acid-fast bacilli. A ven- osis. Cardiac catheterization revealed a pulmonary tilation-perfusion lung scan was nondiagnostic. The artery pressure of 60/40 mmHg, right ventricular patient was treated with digoxin, diuretics, prazo- pressure of 60/20 mmHg, mean right atrial pressure sin, and nitrates, and his symptoms improved. Two of 17 mmHg, and left ventricular end-diastolic pres-

TABLE 1. Patients with Cardiac Amyloid Deposition of TTR lie 122 Whose Clinical Histories Have Been Reported

Case Age at Neurop- TTR lie 122 Number Death Sex athy CTS ECG Findings Genotype References

1 71 M - + Nonspecific ST-T Homozygote 7, 8, and wave changes this report (Fig. 1) 2 82 M - - Low voltage, Heterozygote This report others (Fig. 1) 3 72 M +* + Not reported Homozygote 9 4 64 M - - Atrial Heterozygote 10

CTS = carpal tunnel syndrome; ECG = electrocardiographic *No symptoms, but abnormal extremity nerve conduction studies.

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Fig. 1 Electrocardiograms on the 2 patients. Low limb lead voltage, defined as a ORS complex of< 15 mm in leads I + I/ + 111I11 is seen in patient 2, where the summed I + II + Ill ORS voltage = 8 mm. -t---._.+_...+. sure of 25 mmHg. The left ventricular ejection frac- greater than 2.0 ng/dL. One week after a hospital tion was 25%. No valvular disease was noted. The discharge, the patient presented with increasing right coronary artery had several areas of 30% to shortness of breath to a different hospital, where his 70% stenosis. Endomyocardial biopsy was not per- diagnosis of amyloidosis was not known. He was formed. Results of repeat serum protein immuno- diagnosed with an exacerbation of congestive heart electrophoresis and bone marrow examination were failure and treated with digoxin and diuretics. He again normal. When the patient was discharged from was transferred to the Northport V.A. Medical Cen- the hospital, he was taking furosemide, spironolac- ter, in hemodynamically stable condition, with a tone, nifedipine, and 0.25 mg/day of digoxin. regular pulse of 120 beats/min and blood pressure During the next 4 months, the patient was hospi- of 100/60 mmHg, without postural changes. The talized twice more for increases in the severity of digoxin level was 5.7 ng/mL. The initial ECG dem- congestive heart failure. He was treated with digox- onstrated an accelerated atrioventricular (AV) nodal in, diuretics, and nifedipine. The serum digoxin rhythm. The next day the patient's ECG demon- level, measured on multiple occasions, was never strated normal sinus rhythm with 1st degree AV

Texas Heart InstituteJournal Transthyretin lie 122 47 block, frequent ventricular premature contractions, on the right lateral pleura. Arterial blood gas on episodes of atrioventricular dissociation, and epi- room air revealed a pH of 7.39, pCO2 of 52, and pO2 sodes of up to 40 beats of ventricular . of 36, with 68% oxygen saturation. Hemogram and The patient underwent right heart catheterization, liver function studies were normal. Pulmonary func- which revealed a pulmonary capillary wedge pres- tion studies revealed combined obstructive and re- sure of 20 mmHg and a cardiac output of 2.6 L/min. strictive disease, and the patient's symptoms were He was treated with diuretics, hydralazine, nifedi- attributed to combined chronic obstructive pulmo- pine, and lidocaine. Three days after admission he nary disease and probable asbestosis. The patient developed increasing shortness of breath and a re- was treated with oxygen, bronchodilators, and di- fractory idioventricular rhythm. He went into car- uretics. diac arrest and could not be resuscitated. The ECG revealed a normal sinus rhythm at 97 On autopsy, the heart was globular and weighed beats/min and low limb lead voltage. First-degree AV 700 grams. The left ventricular wall was 2.1 cm thick block, evidence of left , Q waves and the right ventricular wall was 0.9 cm thick. The in leads VI and V2, and right axis deviation were also coronary arteries were patent, with moderate ath- observed (Fig. 1B). A rhythm strip revealed occa- erosclerosis. Microscopic examination revealed scat- sional supraventricular premature contractions. A tered areas of loss of myocardial fibers interspersed gallium scan revealed normal pulmonary uptake and with hypertrophied myocardial fibers. The endocar- increased cardiac uptake, consistent with cardiomy- dium was thickened, and the subendocardial space opathy; however, in view of the patient's lung dis- showed irregular hyaline deposits. On Congo red ease, the increased cardiac uptake was interpreted staining, amyloid deposits were seen throughout the as being relative to poor uptake by the lungs, rather myocardium. Congo red staining was also positive than arising from intrinsic cardiac disease. for amyloid in the blood vessel walls of the lungs, The patient was clinically stable. A repeat arterial spleen, liver, and pancreas; in the splenic trabeculae blood gas, with the patient receiving 0.5 L/min 02, and intersinusoidal spaces; and in the pancreatic revealed a pH of 7.35, pCO2 of 55, and pO2 of 53, ductal walls. Results were negative in the stomach, with 85% oxygen saturation. One month after admis- small bowel, gall bladder, adrenals, kidneys, urinary sion, the patient was found semicomatose, with dif- bladder, testes, prostate, skin, lymph nodes, thyroid, fuse involuntary myoclonic movements. He regained and bone marrow. Immunohistochemistry was posi- consciousness, but 2 days later he was found unre- tive with an anti-TTR antibody. As previously re- sponsive and could not be resuscitated. ported, biochemical analysis of the amyloid fibrils On autopsy, the heart weighed 467 grams. The left revealed TTR, with an Ile substitution at codon 122,7 ventricular wall was 2.0 cm thick and the right ven- and genetic analysis revealed that the patient was tricular wall was 0.8 cm thick. The lungs weighed homozygous for the variant allele.8 1,670 grams. The pleural surfaces were covered with gray plaques and adhesions, and the parenchyma Patient 2 showed severe emphysema and fibrosis. The other An 82-year-old African-American man presented in internal organs were grossly normal. Microscopic 1992 to the New York Veterans Administration hos- examination of the heart revealed extensive eosino- pital with a history of many years of generalized philic deposits of amyloid, confirmed by Congo red weakness and shortness of breath and a 1-week his- staining. To determine the type of amyloidosis, im- tory of frequent falling. The patient was a retired munohistochemical stains were performed: the amy- plumbing supply worker with a history of asbestos loid deposits were reactive with antibody to TTR exposure. He had smoked 1 to 2 packs of cigarettes and nonreactive with antibody to Kc and x light per day for 70 years. There was no known personal chains (Fig. 2). A small amount of amyloid was seen or family history of heart disease or amyloidosis. The also in the portal zones of the liver, but none was blood pressure was 130/60 mmHg; the pulse was 92 found elsewhere. Microscopic examination of the beats/min and regular, with occasional premature lungs revealed extensive fibrosis, severe emphy- beats; and the respiratory rate was 26/min. Cardiac sema, and numerous asbestos bodies. Genetic analy- examination revealed normal heart sounds, with no sis revealed that the patient was heterozygous for murmur or gallop. Pulmonary examination revealed TTR Ile 122 (Fig. 3). bilateral rales over the lower lung fields and diffuse expiratory wheezes. Results of the neurologic exami- Discussion nation were normal. There was 1+ bilateral ankle edema. No hepatosplenomegaly was noted. This report brings to 4 the number of African-Ameri- Chest radiography revealed minimal cardiac en- cans whose clinical disease courses have been de- largement and increased interstitial markings, with scribed in detail with extensive amyloidosis consist- bilateral pleural effusions and a soft tissue density ing of the TTR Ile 122 variant (Table I). None of the

48 Transthyretin lie 122 Volume 24, Number 1, 1997 383-

121-

Fig. 3 Genetic analysis of DNA isolated from patient 2. The patient's DNA was amplified by the polymerase chain reaction (PCR) using upstream primer 5'-cgggctctggtggaaatggatc and a downstream primer that introduces a Fok/ restriction site into PCR products derived from the allele encoding TTR lIe 122, as described.8 Following treatment with Fok/, the normal allele is identified as a digestion-resistant band of 151 base pairs, while the mutant allele is identified as a digested band of 124 base pairs. Lane 1: Marker DNA. Lane 2: Normal control DNA. Lane 3: DNA from patient 2, where the presence of both bands indicates TTR lIe 122 heterozygosity.

T i W p3 -* I I... . . C' .1 findings on each, prior to the genetic analyses, sug- t; * ~9 gested the diagnosis of SCA/SSA, which was the la- bel originally applied to cases 1 and 3 in Table I.'9 9 ; Genetic analysis on all 4 patients revealed the TTR Ie * A, Ile 122 variant; therefore, each patient's disease is more accurately labeled familial amyloid cardiomy- 'a opathy despite the absence of a known family his- tory of amyloidosis. *% The allele encoding TTR Ile 122 is carried by 4% of African-Americans: in a recent study, 66 TTR Ile ,v 122 alleles were identified in DNA samples from

I t 1,688 African-Americans without a known personal * . . or family history of amyloidosis. The calculated al- '-p. lele frequency of 0.020 was similar for all geograph- ic areas, that about 1.2 million African- Fig. 2 Immunohistochemical staining of amyloid from patient indicating 2 (A and B) and control tissue from a patient with immuno- Americans carry the TTR Ile 122 allele, and 12,000 globulin light (AL) amyloid (C). Antigen retrieval12 was followed are homozygous for the variant allele.6 This variant by immunohistochemical studies performed with anti-TTR has been described only in individuals with African antibody (A and C) or with control serum (B). The anti-TTR ancestry. The risk to TTR Ile 122 gene carriers (both antibody was used at 1:300 with an overnight incubation. homozygotes and heterozygotes) of developing Cardiac tissue in from patient 2 shows a strongly positive reaction with the anti-TTR antibody and no reaction with the symptomatic cardiac amyloidosis is not yet known. control serum. The AL amyloid control is negative, demon- From the measured allele frequency of 0.020, we es- strating antibody specificity for TTR. timated that heterozygotes outnumber homozygotes in the African-American population by 100:1. That 2 of the first 4 reported patients have been homo- 4 patients was known to have a family history of zygotes strongly suggests that homozygotes are at amyloidosis, and all presented with their 1st cardiac greater risk for disease than are heterozygotes. It is symptoms after age 60. Thus the clinicopathologic perhaps surprising that in the 4 cases in Table I, the

Texas Heart InstituteJournal Transthyretin lie 122 49 clinical disease in the homozygotes appears to have amyloid deposition at that site, as the carpal ligament been neither more severe nor of earlier onset than is now known to be a common site of amyloid depo- that occurring in the heterozygotes; however, this sition, including TTR amyloid.9'25'26 In patient 2, the disease pattern is similar to that seen in the 1 other low-voltage ECG could have suggested the diagno- amyloidogenic TTR variant that has been described sis, but the chronic obstructive pulrnonary disease in several homozygotes, TTR Met 30.13,14 and asbestosis were thought to explain his symp- The patients presented here illustrate several typi- toms and test findings. Although it is not known cal features of cardiac amyloidosis. As illustrated by whether his death was directly caused by asbestosis, patient 1, patients with TTR cardiac amyloidosis may amyloidosis, or both, the repeated, sudden loss of live for several years after diagnosis; the prognosis consciousness when his respiratory status appeared is much better for TTR than for AL cardiac amyloid- stable suggests an , which is the apparent osis.15"6 Both patients had congestive heart failure, mechanism of death in many patients with cardiac and on autopsy, the patients' hearts were increased amyloidosis. both in weight and in biventricular wall thickness. Cardiac amyloidosis is definitively diagnosed an- An abnormal ECG is a common finding on nonin- temortem by endomyocardial biopsy followed by vasive evaluation; the most common ECG changes special staining (e.g., with Congo red) for amyloid. are low voltage, various arrhythmias, and a pseudo- Alternatively, in a patient in whom the diagnosis is infarct pattern.111"17-18 No ECG change is specific for clinically suspected, tissue from a different organ can amyloidosis, however, and in some cases the ECG be biopsied; if amyloid is present, the diagnosis of shows none of the typical diagnostic features. Low cardiac amyloidosis is presumed. Traditionally, rec- voltage may be less likely to occur in patients with a tal biopsies have been performed, but the gastro- history of hypertension, in whom left ventricular intestinal tract may be uninvolved. In recent years, hypertrophy may ensue, as in patient 1. (Of note: more useful (and less invasive) than rectal biopsy on autopsy of this patient, hypertrophic myocytes, has been subcutaneous fat aspiration, which is usu- which are not ordinarily associated with amyloid- ally diagnostic if endothelial cells are obtained in the osis, were present.) The most useful noninvasive test aspirated sample.27'28 is echocardiography, which can strongly suggest the After amyloid material is identified, immunohis- diagnosis of cardiac amyloidosis, particularly when tochemical analysis should be performed to deter- a "sparkling" pattern is seen, although the sensitiv- mine the specific type of amyloid present (TTR, AL, ity of this sign is low.'7'19 Results of other noninvasive or rarely, other types). Before the widespread avail- tests, including 99technetium pyrophosphate scan- ability of immunohistochemical reagents that react ning, may be consistent with the diagnosis, but their with the various amyloid proteins, hematologic stud- low sensitivity limits their use in evaluating patients ies to attempt to identify a monoclonal protein in the with suspected cardiac amyloidosis.'7 serum or urine were the diagnostic tests of choice The history of patient 1 illustrates the high toxic- (as in patient 1); if a monoclonal immunoglobulin ity risk of digitalis compounds in cases of amyloid- light chain was found, the diagnosis was presumed osis.11'20'21 This patient had been given digoxin to be AL amyloid.'5 The difficulties with this ap- intermittently during the 3 years following his origi- proach are that some patients with AL amyloid do nal diagnosis of amyloidosis. Digoxin toxicity was not have a demonstrable serum or urine monoclonal not apparent during this time, but the patient may protein, and even if these tests are positive, they do have been protected by his apparent noncompliance not prove that the monoclonal protein (a common with his prescribed medications. The digoxin may incidental finding in elderly populations) is con- have contributed to his arrhythmias. The measured tained in the amyloid material. digoxin level was not in the toxic range until the Patients with AL amyloidosis should receive che- patient's final hospitalization. However, digitalis motherapy, directed at controlling growth of the compounds bind to amyloid fibrils;20 therefore, the clone of plasma cells producing the amyloidogenic measured serum level may not accurately reflect the immunoglobulin light chain; such therapy has re- risk of toxicity. Nifedipine, too, binds to amyloid fi- cently been shown to prolong patient survival.16 In brils,22 is also contraindicated in amyloidosis,23'24 and contrast, chemotherapy is of no benefit in patients may have contributed to the patient's death. with TTR amyloid. Following the determination that Both cases illustrate the difficulty often encoun- the amyloid fibrils consist of TTR, genetic analysis tered in making a definitive diagnosis of cardiac should be considered in order to discover whether amyloidosis. Patient 1 underwent a lengthy evalua- the patient has a TTR variant. Patients under 60 years tion prior to establishment of the diagnosis. In pa- of age with clinically significant cardiac amyloidosis tient 2, amyloidosis was not suspected before death. probably carry a TTR variant: symptomatic deposi- In patient 1, the carpal tunnel syndrome, confirmed tion of normal-sequence TTR has not been described by nerve conduction studies, may have reflected in this age group. Younger patients with familial

50 Transthyretin lie 122 Volume 24, Number 1, 1997 TTR-amyloidosis have been successfully treated with 9. Nichols WC, Liepnieks JJ, Snyder EL, Benson MD. Senile liver transplantation, which removes the source of cardiac amyloidosis associated with homozygosity for a variant TTR synthesis, permitting the gradual resorp- transthyretin variant (ILE-122).J Lab Clin Med 1991;117:175- tion of amyloid fibrils and resolution of end-organ 80. 10. Saraiva MJM, Sherman W, Marboe C, Figueira A, Costa P, de damage.29 The 2 cases presented here and the oth- Freitas AF, et al. Cardiac amyloidosis: report of a patient ers in Table I indicate that patients with hereditary heterozygous for the transthyretin isoleucine 122 variant. TTR-amyloidosis can experience their 1st symptoms Scand J Immunol 1990:32:341-6. over age 65; therefore, genetic analysis is also war- 11. Buja LM, Khoi NB, Roberts WC. Clinically significant cardiac ranted in older patients. amyloidosis. Clinicopathologic findings in 15 patients. Am J Although older patients may Cardiol 1970;26:394-405. be deemed ineligible for liver transplantation, ge- 12. Cattoretti G, Becker MHG, Key G, Duchrow M, Schluter C, netic information may be of use in evaluating other Galle J, et al. Monoclonal antibodies against recombinant family members; in addition, the earliest age at which parts of the Ki-67 antigen (MIB 1 and MIB 3) detect prolifer- TTR Ile 122 amyloidosis can cause clinical disease is ating cells in microwave-processed formalin-fixed paraffin not known. Patients with TTR-amyloidosis may also sections. J Pathol 1992; 168:357-63. 13. SkareJ, Yazici H, Erken E, Dede H, Cohen A, Milunsky A, et be candidates for experimental protocols aimed at al. Homozygosity for the met30 transthyretin gene in a Turk- reducing the concentration of circulating TTR. With ish kindred with familial amyloidotic polyneuropathy. Hum an estimated 1.2 million African-Americans carrying Genet 1990;86:89-90. the TTR Ile 122 gene (including 12,000 homozy- 14. Holmgren G, Bergstrom S, Drugge U, Lundgren E, Nording- gotes), this diagnosis should be considered in Afri- Sikstrom C, Sandgren 0, et al. Homozygosity for the trans- thyretin-Met30-gene in seven individuals with familial amy- can-Americans with restrictive cardiomyopathy or loidosis with polyneuropathy detected by restriction enzyme unexplained arrhythmias. analysis of amplified genomic DNA sequences. Clin Genet 1992;41:39-41. 15. Olson LJ, Gertz MA, Edwards WD, Li CY, Pellika PA, Holmes Addendum DRJr, et al. Senile cardiac amyloidosis with myocardial dys- function. Diagnosis by endomyocardial biopsy and immu- Several additional African-American patients have re- nohistochemistry. N Engl J Med 1987;317:738-42. cently been described30 who were found on autopsy 16. Skinner M, AndersonJJ, Simms R, Falk R, Wang M, Libbey C, to have cardiac amyloidosis resulting from deposi- et al. Treatment of 100 patients with primary amyloidosis: a tion of TTR Ile 122, further supporting the causal randomized trial of melphalan, prednisone, and colchicine relationship between this variant allele and the de- versus colchicine only. Am J Med 1996;100:290-8. 17. Simons M, Isner JM. Assessment of relative sensitivities of velopment of late-onset cardiac amyloidosis. noninvasive tests for cardiac amyloidosis in documented car- diac amyloidosis. Am J Cardiol 1992;69:425-7. Acknowledgments 18. Beckman A, Bjerle P, Olofsson B-O. Electrocardiographic findings in familial amyloidotic polyneuropathy. Am J Non- We thank Connie Kane for technical assistance, and invas Cardiol 1992;6:192-6. Dr. 19. Hartmann A, Frenkel J, Hopf R, Baum RP, Hor G, Schneider Eric Steinberg for his review of the manuscript. M, et al. Is technetium-99 m-pyrophosphate scintigraphy valuable in the diagnosis of cardiac amyloidosis? Int J Card References Imaging 1990;5:227-31. 20. Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in 1. Roberts WC, Waller BF. Cardiac amyloidosis causing cardiac amyloid cardiomyopathy. Circulation 1981;63: 1285-8. dysfunction: analysis of 54 necropsy patients. Am J Cardiol 21. Brandt K, Cathcart ES, Cohen AS. A clinical analysis of the 1983;52:137-46. course and prognosis of forty-two patients with amyloidosis. 2. Jacobson DR, Buxbaum JN. Genetic aspects of amyloidosis. Am J Med 1968;44:955-69. Adv Hum Genet 1991;20:69-123. 22. Gertz MA, Skinner M, Connors LH, Falk RH, Cohen AS, Kyle 3. Husby G. Nomenclature and classification of amyloid and RA. Selective binding of nifedipine to amyloid fibrils. Am J amyloidoses. J Intern Med 1992;232:511-2. Cardiol 1985;55(13 Pt 1):1646. 4. Pitkanen P, Westermark P, Cornwell GG III. Senile systemic 23. Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA. Worsen- amyloidosis. AmJ Pathol 1984;117:391-9. ing of congestive heart failure in amyloid heart disease 5. Saraiva MJM. Transthyretin mutations in health and disease. treated by calcium channel-blocking agents. Am J Cardiol Hum Mutat 1995;5:191-6. 1985;55(13 Pt 1):1645. 6. Jacobson DR, Pastore R, Poos S, Malendowicz S, Kane I, 24. Griffiths BE, Hughes P, Dowdle R, Stephens MR. Cardiac Shivji A, et al. Revised transthyretin Ile 122 allele frequency amyloidosis with asymmetrical septal hypertrophy and de- in African-Americans. Hum Genet 1996;98:236-8. terioration after nifedipine. Thorax 1982;37:711-2. 7. Gorevic PD, Prelli FC, Wright J, Pras M, Frangione B. Sys- 25. Kyle RA, Gertz MA, Linke RP. Amyloid localized to tenosyn- temic senile amyloidosis. Identification of a new prealbumin ovium at carpal tunnel release. Immunohistochemical iden- (transthyretin) variant in cardiac tissue: immunologic and tification of amyloid type. Am J Clin Pathol 1992;97:250-3. biochemical similarity to one form of familial amyloidotic 26. Skinner M, Harding J, Skare I, Jones LA, Cohen AS, Milunsky polyneuropathy. J Clin Invest 1989;83:836-43. A, et al. A new transthyretin mutation associated with amy- 8. Jacobson DR. A specific test for transthyretin 122 (Val --Ile), loidotic vitreous opacities. Asparagine for isoleucine at po- based on PCR-primer-introduced restriction analysis (PCR- sition 84. Ophthalmology 1992;99:503-8. PIRA): confirmation of the gene frequency in blacks. Am J 27. Gertz MA, Li CY, Shirahama T, Kyle RA. Utility of subcuta- Hum Genet 1992;50:195-8. neous fat aspiration for the diagnosis of systemic amyloidosis

Texas Heart Institute Journal Transthyretin Ile 122 51 (immunoglobulin light chain). Arch Intern Med 1988;148: 30. Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, 929-33. Buck FS, Buxbaum JN. Variant-sequence transthyretin (iso- 28. Maruyama K, Ikeda S, Yanagisawa N, Nakazato M. Diagnos- leucine 122) in late-onset cardiac amyloidosis in black Amer- tic value of abdominal fat tissue aspirate in familial amyloid icans. N Engl J Med 1997;336:466-73. polyneuropathy. J Neurol Sci 1987;81:11-8. 29. Skinner M, Lewis WD, Jones LA, KasirskyJ, Kane K, Ju ST, et al. Liver transplantation as a treatment for familial amyloid- otic polyneuropathy. Ann Intern Med 1994;120:133-4.

52 Transthyretin lie 122 Volume 24, Number 1, 1997