Transthyretin-Related Familial Amyloidotic Polyneuropathy

NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD Transthyretin-Related Familial Amyloidotic Polyneuropathy

Yukio Ando, MD; Masaaki Nakamura, MD; Shukuro Araki, MD

ransthyretin-related familial amyloidotic polyneuropathy (FAP) is a fatal hereditary amyloidosis. Until 20 years ago, FAP was thought to be restricted to endemic occurrence in certain areas. However, owing to progress in biochemical and molecular genetic analyses, FAP is now believed to occur worldwide. As of today, reports of about T100 different points of single or double mutations, or a deletion in the transthyretin gene, have been published, and several different phenotypes of FAP have been documented, even for the same mutation in the transthyretin gene. We present herein the current clinicopathological, biochemical, molecular genetic, and epidemiological aspects of transthyretin-related FAP, and we introduce a new diagnostic procedure for the disease. Arch Neurol. 2005;62:1057-1062

Familial amyloidotic polyneuropathy is found in large foci of FAP patients, al- (FAP) is a fatal hereditary amyloidosis in though the reason for this characteristic which amyloidogenic mutated transthy- remains to be elucidated. Recently, sev- retin (ATTR), apolipoprotein A-I, and gel- eral phenotypes of FAP, including the solin have been identified as FAP-related polyneuropathic, oculoleptomeningeal, amyloidogenic proteins.1-5 Of these pro- and cardiac types, have been reported, and teins, ATTR is the most common through- heterogeneity of clinical symptoms is rec- out the world.2,4 Andrade1 first described ognized even for the same mutation of the a large group of patients with FAP (here- TTR gene. Tashima et al7 described the after referred to as FAP patients) and the phenotypes of FAP patients with ATTR ATTR Val30Met mutation in Portugal in Val30Met, which could be classified into 1952, and other large foci have been dis- the following 4 types with different domi- covered in Japan4 and Sweden.2 Until 20 nant impairments: sensory, motor, auto- years ago, FAP was thought to be re- nomic, and visceral organ. stricted to endemic occurrence in those In Japan, Araki et al4 first reported a fo- areas.1,2,4 However, owing to progress in cus of FAP patients with ATTR Val30Met biochemical and molecular genetic analy- in the Arao district, Kumamoto, and Kito ses, this disease is now believed to occur et al8 reported another focus in Nagano on worldwide.4,6 Honshu Island. More than 20 points of As of today, reports of about 100 dif- mutation in the TTR gene have now been ferent points of single or double muta- reported from the long islands of Japan.9 tions or of a deletion in the TTR gene have In this review, we present the current clini- appeared; most of these cases involve small copathological, biochemical, molecular ge- kindreds or no family history.6 Of TTR- netic, and epidemiological aspects of TTR- related FAP types, ATTR Val30Met is the related FAP and introduce a simple new most common3 and only ATTR Val30Met diagnostic procedure.

Author Affiliations: Department of Diagnostic Medicine, Graduate School of CLINICAL FEATURES Medical Sciences, Kumamoto University, Kumamoto, Japan (Drs Ando and Nakamura); and Department of Neurology, Ohmuta Tenryo Hospital, Ohmuta Among the confirmed 100 points of Fukuoka, Japan (Dr Araki). mutation or deletion in the TTR gene, 13

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table. Initial Clinical Symptoms in Patients Peripheral Nerve With FAP ATTR Val30Met Cardiac Dysfunction

Autonomic System Symptom* No. of Patients Carpal Tunnel Sensory disturbances in lower limbs 52 Eye Gastrointestinal symptoms 38 Leptomeninges and/or Erectile dysfunction 5 Central Nervous System Faintness or syncope 5 Kidney Muscle weakness in lower limbs 3

Liver Abnormal laboratory data for urine 5 Decrease in visual acuity 4 Skin Arrhythmias 5 Nonpathologic

0 10 20 30 40 50 60 70 Abbreviations: ATTR, amyloidogenic mutated transthyretin; FAP, familial Total No. of Affected Organs of TTR-Related FAP amyloidotic polyneuropathy. *Indicates the initial symptoms of 117 patients from among the 169 patients with FAP ATTR Val30Met registered from 1968 to 2003 in the Arao Figure 1. Clinical symptoms in patients with transthyretin (TTR)-related district, Kumamoto, Japan. familial amyloidotic polyneuropathy (FAP), shown as the total numbers of amyloid-associated tissues, from previous reports. The polyneuropathic form is often accompanied by cardiac amyloid deposition. Neuropathic Form of Fap

Most TTR-related FAP cases are classified as the neuro- Dysfunction of Peripheral Nerves pathic type. Among these neuropathic FAP forms, ATTR Dissociated Anesthesia Val30Met is the most common; its characteristics in- Muscle Weakness and Atrophy clude an autonomic, sensory dominant polyneuropathy Dysesthesia (Figure 2). Many clinicopathological studies of this FAP Dyscoria type have been performed. From our data on 169 FAP Decrease of Skin Temperature patients with ATTR Val30Met, the inheritance pattern is Sensory Disturbance autosomal dominant with a high penetrance rate and an Coldness equal sex ratio. The symptoms are first recognized when Hoarseness a patient is 18 to 83 years of age, with a mean age at onset of 35.3 years.5 The disease is slowly progressive and Autonomic Dysfunction reaches the terminal stage in 10.8 years. The age at on- 10 Dysuria set in this type of FAP was found to show anticipation, Diarrhea as seen in FAP patients in other endemic areas. Constipation Evidence of a sensorimotor peripheral neuropathy is Orthostatic Hypotension usually found in the lower limbs. Dissociation of sen- Erectile Dysfunction sory impairment is common, with pain and tempera- Dyshidrosis ture sensation being the most severely affected. Auto- Nausea nomic nervous system involvement, such as dyshidrosis, sexual impotence, disturbances of gastrointestinal tract Constitutional Conditions motility (diarrhea alternating with constipation), ortho- Anemia static hypotension, and urinary disturbances, is fre- Weight Loss quent (Figure 2). Cardiac and renal dysfunction are also 4,5 Arrhythmia commonly recognized during the course of the illness Edema and anemia is observed. Ocular involvements such as vit- Burning reous opacity, keratoconjunctivitis sicca, glaucoma, and 11 0 20 40 60 80 100 papillary disorders are commonly seen. The initial symp- Incidence, % toms of 117 FAP patients with ATTR Val30Met are presented in the Table and include the clinical manifesta- Figure 2. Clinical manifestations in patients with familial amyloidotic tions of an autonomic sensorimotor polyneuropathy. polyneuropathy (FAP) with amyloidogenic mutated transthyretin (ATTR) Significant numbers of FAP patients also often com- Val30Met. One hundred sixty-nine patients with FAP ATTR Val30Met were registered from 1968 to 2003 in the Arao district, Kumamoto, Japan. plain of diarrhea, constipation, hematuria, proteinuria, decrease in visual acuity, and cardiac arrhythmias as initial symptoms.5,12 To diagnose ATTR Val30Met–type FAP, cooperation among gastroenterologists, nephrologists, mutations are nonpathological forms.6 Other abnormal ophthalmologists, and cardiologists is essential. TTR mutations induce FAP, which can be classified into several phenotypes such as neuropathic, oculolepto- Leptomeningeal Type of FAP meningeal, and cardiac (Figure 1). Several types of ATTR mutations do not cause neuropathy, although they in- Attention has recently focused on the oculoleptomenin- duce other symptoms of the FAP disorder. geal form of FAP (induced by several point mutations

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 in the TTR gene), as well as on the advanced stages of and variant TTR. Alves et al18 reported that subjects pos- ATTR Val30Met–type FAP.13,14 Cerebral amyloid angi- sessing the TTR Thr119Met gene are asymptomatic car- opathy and ocular amyloidosis are common characteris- riers and that compound heterozygotes with ATTR tic clinical features in those types of FAP.13,14 Cerebral Val30Met and TTR Thr119Met genes show very mild FAP amyloid angiopathy is characterized by amyloid deposi- symptoms or have no symptoms. These authors also tion in the media and adventitia of medium and small showed, by means of semidenaturing isoelectric focus- arteries, arterioles, and occasionally veins of the cortex ing, marked TTR tetrameric structural stability in pa- and leptomeninges.14 Typical clinical central nervous tients with TTR Thr119Met or ATTR Val30Met/TTR system manifestations include cerebral infarction and Thr119Met genes.18 Various studies confirmed these find- hemorrhage, hydrocephalus, ataxia, spastic paralysis, ings, and TTR tetrameric structural stability in com- convulsion, and dementia.13,14 These symptoms are pound heterozygotes has now been widely accepted. In often found in several types of TTR-related FAP and addition, Terazaki et al19 described an interesting com- lead to classification into (oculo)leptomeningeal amy- pound heterozygote patient with late-onset FAP with loidosis, in which amyloid deposition is also found in ATTR Val30Met/TTR Arg104His mutation who had very vitreous bodies and other tissues of the eye.13,14 mild and slowly progressive clinical symptoms, and whose Although amyloid deposits in the meningocerebrovas- tetrameric TTR stability was greater than that of the TTR cular system were thought to be the cause of those cen- from a compound heterozygote patient with ATTR tral nervous system symptoms, the precise mechanism Val30Met/TTR Thr119Met mutation. of amyloid formation remains to be elucidated. These reports suggest the therapeutic possibility of stabilization of the tetrameric form of TTR. Because thy- NEUROPATHOLOGICAL FEATURES roxine is one of the most important molecules for stabilizing tetrameric TTR, thyroxine-based therapeutic drugs Although various pathological reports of amyloid depo- have been proposed. Baures et al20 also tested various non- sition in systemic organs have been published, the scale steroidal anti-inflammatory drugs for stabilization of the of the studies was small. A clinicopathological, histo- tetrameric form of TTR because the nonsteroidal anti- chemical, immunohistochemical, and ultrastructural study inflammatory drug structures resemble the structure of of materials obtained by autopsy or biopsy in 17 pa- thyroxine and these drugs bind to TTR via a thyroxine tients was performed by Takahashi et al.15 In the au- binding site. These authors reported that flufenamic acid, topsy cases, amyloid deposits were predominant in the a nonsteroidal anti-inflammatory drug, showed prom- peripheral nerve tissues, autonomic nervous system, cho- ise for tetrameric TTR stabilization. However, most non- roid plexus, cardiovascular system, and kidneys. Amy- steroidal anti-inflammatory drugs bind to albumin in loid involvement in the anterior and posterior roots of plasma, so the bioavailability of these drugs for TTR sta- the spinal cord, spinal ganglia, thyroid, and gastrointes- bilization may be insufficient. tinal tract was also frequent. In the cardiac conduction Recent studies have suggested that certain metal ions system, amyloid deposition was prominent in the sino- affect amyloidogenesis in several types of amyloidosis. atrial node and in the limbs of the intraventricular bundle. In FAP, metal ions may influence the stability of the te- In sural nerve biopsy specimens from patients with early- trameric form of TTR. Ando21 therefore investigated stage FAP, amyloid deposits were observed in the small whether various metal ions (eg, Zn2ϩ,Cu2ϩ,Ca2ϩ,Fe3ϩ, vessel walls and the surrounding tissues. In the ad- Al3ϩ, and Cr3ϩ) affect amyloidogenesis of wild-type TTR vanced cases, amyloid deposits were found in the sub- and ATTR. Among the metal ions, Cr3ϩ increased the te- perineural and/or epineural regions. The numbers of my- trameric stability of both wild-type TTR and ATTR elinated and unmyelinated nerve fibers decreased Val30Met purified from healthy subjects and homozy- markedly, which indicated degenerative changes in gote FAP patients, respectively, and suppressed TTR amy- Schwann cells. Degenerative changes in the axon, my- loidogenesis induced by low pH levels in a concentration- elin sheath, and Schwann cells and the decrease in col- dependent manner. In contrast, Al3ϩ decreased TTR lagen fibers paralleled the severity of the peripheral nerve tetrameric stability and induced TTR amyloidogenesis in disturbances. a concentration-dependent manner. These findings in- Morphometric data on the number and caliber of my- dicate that Cr3ϩ and Al3ϩ may act as a suppressor and an elinated fibers in the sural nerve biopsy specimen from inducer, respectively, of TTR amyloidogenesis, al- patients with early-stage FAP showed a greater reduc- though in vivo evaluation of the effects is needed. An in- tion of small-caliber fibers than of large-caliber fibers. In gredient in health foods, Cr3ϩ is widely used through- patients with more advanced FAP, the numbers of my- out the world, so administration of this metal ion to elinated fibers were decreased.15 patients with FAP would present no problems.

BIOCHEMICAL ASPECTS MOLECULAR GENETICS OF AMYLOIDOGENESIS The human TTR gene was localized at 18p11.1-q12.3, and It is widely believed that stabilizing tetrameric TTR, as a its structure was first determined by Tsuzuki et al.22 potential therapeutic strategy, is a prerequisite for pre- Complementary DNA coding for the human TTR gene was vention of amyloid formation, especially in ATTR cloned from a complementary DNA library prepared from Val30Met–type FAP.16 McCutchen et al17 first demon- human liver; genetic analysis used the restriction enzyme strated this concept by using recombinant wild-type TTR NsiI. In 100 abnormal TTR genes, 0, 36, 40, and 24 points

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Healthy Subject Screening by Mass Spectrometry Healthy Subject FAP ATTR Val30Met Homozygote FAP ATTR Tyr114Cys Heterozygote FAP ATTR Val30Met Heterozygote Family History (+) Atypical Cases

Typical Clinical Symptoms (+) Examination of a Known Mutation Examination of an Unknown Mutation A B Non-RI SSCP 0.04 3500 Exon 4

3000 0.03 2500

0.02 2000

Intensity 1500 0.01

1000 Fluorescence –d(F2/F1)/dT 0 500

–0.01 0 50.59 56.28 61.84 67.44 354 370 386 Temperature, °C Seconds

DNA Sequencing

Figure 3. A diagnostic screening method for transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP). A, Detection of amyloidogenic mutated TTR (ATTR) Val30Met by the LightCycler system (Roche Diagnostics, Basel, Switzerland). B, Nonradioisotopic single-strand conformational polymorphism (non-RI SSCP) analysis in an FAP ATTR Tyr114Cys heterozygote. The arrow points to an additional peak.

of mutation were detected in exons 1, 2, 3, and 4, respec- ATGACACCTGGGAGCCATTTGCCTCTGGG-3Ј-OH) tively; a deletion in the TTR gene also occurred. were used to detect ATTR Val30Met. Because a single mis- The main sites of production of TTR confirmed by in match can significantly reduce the melting temperature situ hybridization methods are the liver, retinal pig- of the oligonucleotide, the melting temperature is re- ment epithelium, choroid plexus of the brain, and vis- duced when the amplified gene encodes ATTR Val30Met. ceral yolk sac endoderm.23 Therefore, it is possible with the use of melting curve analysis to discriminate among a healthy subject, an FAP Clinical Genetic Testing ATTR Val30Met homozygote, and an FAP ATTR Val30Met heterozygote (Figure 3A). For the screening of FAP, we first performed mass spec- trometric analysis (Figure 3) with a system for serum Nonisotopic Single-Strand Conformational and cerebrospinal fluid that uses methods such as elec- Polymorphism. Single-strand conformational polymor- tron spray ionization–mass spectrometry and matrix- phism (SSCP) was applied with samples with molecular assisted laser desorption ionization/time-of-flight mass mass shift in TTR to determine the exon in which a mu- spectrometry. With this system, the presence or ab- tation was present.26 However, a conventional type of SSCP sence of mutations in the TTR gene can be determined. requires a radioisotope to perform the procedure. There- A shift in the molecular mass caused by substitution of fore, to avoid the need for a radioisotope, we recently de- amino acids can be detected as a peak that differs from veloped SSCP analysis with capillary electrophoresis27 in those identifying the wild-type TTR gene. which a forward primer labeled with Cy5 and a micro- Another method, in addition to polymerase chain re- chip (iChip 12; Hitachi Chemical Co, Ltd, Tokyo, Ja- action and restriction endonuclease analysis, has recently pan) filled with a separation gel for SSCP (i-S gel 3; Hi- been used for screening in patients who have a family his- tachi Chemical Co, Ltd) are used. An example of SSCP tory or typical clinical manifestations or who come from a analysis with capillary electrophoresis of an FAP ATTR area where FAP is prevalent. By means of the LightCycler Tyr114Cys heterozygote is presented herein. As shown method (Roche Diagnostics, Basel, Switzerland),24 we can in Figure 3B, an additional peak is observed when the detect the presence or absence of a TTR mutation in 1 hour. amplified gene encodes for ATTR Tyr114Cys.

Detection of ATTR Val30Met via the LightCycler. Light- Other Diagnostic Methods Cycler technology can detect mutations quickly and accu- rately by using fluorescent hybridization probes and melting Ando et al28 presented a histochemical method of diag- curves.25 For example, an anchor probe (5Ј-TGTGGCC- nosis of ATTR Val30Met by using the hair of FAP pa- GTGCATGTGT-3Ј-fluorescein isothiocyanate, in which the tients and monoclonal antibody supplied by Paulo M. P. underlined nucleotide is the normal nucleotide) and a sen- Costa, PhD, Centro de Estudos de Paramiloidose, Porto, sor probe (LC Red 640-5Ј-CAGAAAGGCTGCTG Portugal. Also, Ando et al28 demonstrated abundant ab-

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Portugal Japan

Figure 4. Distribution of familial amyloidotic polyneuropathy (FAP) in the world. Locations of foci of patients with FAP amyloidogenic mutated transthyretin Val30Met described in previous reports and obtained from personal communications are presented. The size of the circles is related to the number of patients at each location.

normal ocular vessels in FAP patients with ATTR identified. The issue of whether there is a common ori- Val30Met, a finding that has diagnostic value. gin in the foci for a mutant allele has not been resolved. Furthermore, Continho31 hypothesized that a mutant al- EPIDEMIOLOGY lele in the Portuguese kindred could be a single origin of the mutation for FAP foci throughout the world, in- The presence of patients with TTR-related FAP has been cluding Japan, Europe, North and South America, and confirmed in more than 30 countries, with ATTR Africa. This hypothesis was based only on well-known Val30Met verified in patients in more than 15 coun- historical relations and has not been scientifically tested. tries6 (Figure 4). Only ATTR Val30Met–type FAP has Ohmori et al32 compared haplotypes in several foci of pa- large foci in the world, although the reason for this is not tients with FAP and discovered that a common founder known. Holmgren et al29 performed an epidemiological could be conceivable for Japanese and Portuguese pa- study in the northern part of Sweden and estimated that tients and for Portuguese and Spanish patients but not the number of ATTR Val30Met gene carriers in a total for Swedish and other patients. Additional studies of geno- population of 500 000 in the area was approximately 7500, types and phenotypes are needed. although the penetrance of the mutation was as low as about 2%. By 1994, 1233 FAP patients with ATTR LIVER TRANSPLANTATION Val30Met from 489 pedigrees had received a diagnosis at Centro de Estudos de Paramidoidose in Porto, Portu- For treatment of FAP, liver transplantation has been re- gual.30 So far, more than 1500 FAP patients have been ported to halt the progression of clinical manifesta- registered in Portugal (M. J. M. Saraiva, PhD, oral com- tions.33 According to data in the Familial Amyloidotic munication, September 2003). In Japan, more than 350 Polyneuropathy World Transplant Registry, 54 centers FAP patients were found in the following 2 endemic foci: in 16 countries have performed orthotopic liver trans- Arao city in the Kumamoto prefecture and Ogawa vil- plantation (OLT) for FAP. During 2003, approximately lage in the Nagano prefecture. In addition, 44 FAP kin- 60 OLTs were performed worldwide. During the past de- dreds with ATTR Val30Met were traced. They were ge- cade, 539 patients have undergone 579 OLTs. Survival nealogically independent and were geographically of the patients has been excellent (overall 5-year sur- scattered throughout Japan. vival of 77%) and comparable to the survival for OLT performed for other chronic liver disorders, but a longer fol- ORIGIN OF FAP ATTR Val30Met low-up is needed to compare the outcome after OLT with the natural course of the disease. The main cause of death As already described, in the 1960s, large foci of patients was related to cardiac difficulties (39%).34 were found in Japan and Sweden,3,6 in addition to Por- The use of sequential liver transplantation with re- tugal. These 3 countries are geographically distant, and sected livers from patients with FAP started in Portugal; a consanguineous relationship between foci has not been more than 50 patients have received livers from FAP pa-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tients.34 Although no patients have started to show the patients with familial amyloidotic polyneuropathy type I. Intern Med. 1995; clinical symptoms of FAP, careful neurological fol- 34:748-750. 11. Ando E, Ando Y, Okamura R, Ando M, Negi A. Ocular manifestations of familial low-up examinations should be continued. amyloidotic polyneuropathy type I: long-term follow-up. Br J Ophthalmol. 1997; In conclusion, TTR-related amyloidosis is not an in- 81:295-298. significant disease, and many more affected patients would 12. Ando Y, Suhr O. Autonomic dysfunction in familial amyloidotic polyneuropathy likely be found if more careful and precise investiga- (FAP). Amyloid. 1998;5:288-300. tions were performed. The collaboration of neurolo- 13. Goren H, Steinberg MC, Farboody GH. Familial oculoleptomeningeal amyloidosis. Brain. 1980;103:473-495. gists, gastroenterologists, ophthalmologists, and cardi- 14. Ushiyama M, Ikeda S, Yanagihara N. Transthyretin-type cerebral amyloid angi- ologists is needed to make a definitive diagnosis. opathy in type I familial amyloid polyneuropathy. Acta Neuropathol (Berl). 1991; 81:524-528. Accepted for Publication: June 27, 2004. 15. Takahashi K, Yi S, Kimura Y, Araki S. Familial amyloidotic polyneuropathy type Correspondence: Yukio Ando, MD, Department of Diag- 1 in Kumamoto, Japan: a clinicopathologic, histochemical, immunohistochemical, and ultrastructural study. Hum Pathol. 1991;22:519-527. nostic Medicine, Graduate School of Medical Sciences, Ku- 16. Kelly JW, Lansbury PT Jr. A chemical approach to elucidate the mechanism of mamoto University, 1-1-1 Honjo, Kumamoto 860-0811, transthyretin and ␤-protein amyloid formation. Amyloid. 1994;1:186-205. Japan ([email protected]). 17. McCutchen SL, Colon W, Kelley JW. Transthyretin mutation Leu-55-Pro signifi- Author Contributions: Study concept and design: Ando. cantly alters tetramer stability and increases amyloidogenicity. Biochemistry. 1993; Acquisition of data: Ando and Nakamura. Analysis and in- 32:12119-12127. 18. Alves IL, Divino CM, Schussler GC, et al. Thyroxine binding in a TTR Met 119 terpretation of data: Ando, Nakamura, and Araki. Draft- kindred. J Clin Endocrinol Metab. 1993;77:484-488. ing of the manuscript: Ando and Nakamura. Critical re- 19. Terazaki H, Ando Y, Misumi S, et al. A novel compound heterozygote (FAP ATTR vision of the manuscript for important intellectual content: Arg104His/ATTR Val30Met) with high serum transthyretin (TTR) and retinol bind- Araki. Statistical analysis: Nakamura. Obtained funding: ing protein (RBP) levels. Biochem Biophys Res Commun. 1999;264:365-370. Ando. Administrative, technical, and material support: Ando 20. Baures PW, Oza VB, Peterson SA, Kelly JW. Synthesis and evaluation of inhibi- and Nakamura. Study supervision: Araki. tors of transthyretin amyloid formation based on the non-steroidal anti- inflammatory drug, flufenamic acid. Bioorg Med Chem. 1999;7:1339-1347. Funding/Support: This study was supported by grants from 21. Ando Y. New therapeutic approaches for familial amyloidotic polyneuropathy (FAP). the Amyloidosis Research Committee, the Pathogenesis Amyloid. 2003;10(suppl 1):55-66. and Therapy of Hereditary Neuropathy Research Com- 22. Tsuzuki T, Mita S, Maeda S, Araki S, Shimada K. Structure of the human preal- mittee for Surveys and Research on Specific Diseases from bumin gene. J Biol Chem. 1985;260:12224-12227. the Ministry of Health and Welfare of Japan, Charitable 23. Herbert J, Wilcox JN, Pham KT, et al. Transthyretin: a choroid plexus–specific transport protein in human brain: the 1986 S. Weir Mitchell Award. Neurology. 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