Frequencies and geographic distributions of genetic mutations in transthyretinand non-transthyretin-related familial amyloidosis

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1 Clin Genet 2015: 88: Printed in Singapore. All rights reserved Short Report Frequencies and geographic distributions of genetic mutations in transthyretinand non-transthyretin-related familial amyloidosis 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: /cge Zhen D.B., Swiecicki P.L., Zeldenrust S.R., Dispenzieri A., Mauermann M.L., Gertz M.A. Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis. Clin Genet 2015: 88: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Inherited forms of amyloidosis are rare; of these, transthyretin-related (ATTR) is the most common, but non-attr has been described as well. We studied a large case series of ATTR and a small series of non-attr to better determine the mutation frequencies and geographic distributions of these inherited forms of amyloidosis in the United States. We performed a retrospective cross-sectional study of 284 ATTR and non-attr patients seen at Mayo Clinic in Rochester, Minnesota, from 1 January 1970 through 29 January Mutations were identified by DNA sequencing, restriction fragment length polymorphism, or mass spectroscopy. The genetic testing method was unknown for several patients, but a small proportion were identified by family history or by classical clinical presentation associated with a specific mutation. The most common ATTR mutations were Thr60Ala (24%), Val30Met (15%), Val122Ile (10%), and Ser77Tyr (5%). Non-ATTR mutations included gelsolin (n = 3), apolipoprotein A-I (n = 6), apolipoprotein A-II (n = 1), fibrinogen A-α (n = 9), and lysozyme (n = 1). Although rare, ATTR and, to a lesser extent, non-attr are prevalent in the United States and should be considered for patients presenting in the appropriate clinical context. Conflict of interest None of the authors have relevant financial disclosures. Dr M. A. G. is an investigator on a trial of a drug to treat transthyretin amyloidosis sponsored by ISIS. No honoraria received. D.B. Zhen a, P.L. Swiecicki a, S.R. Zeldenrust b, A. Dispenzieri b, M.L. Mauermann c and M.A. Gertz b a Department of Internal Medicine, b Division of Hematology, and c Department of Neurology, Mayo Clinic, Rochester, MN, USA Key words: amyloidosis apolipoprotein fibrinogen gelsolin hereditary lysozyme mutation transthyretin Corresponding author: Morie A. Gertz, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Tel.: ; fax: ; gertz.morie@mayo.edu Received 9 June 2014, revised and accepted for publication 9 September 2014 The amyloidoses are a group of acquired or inherited diseases involving systemic tissue deposition of misfolded proteins. Mutations in transthyretin (TTR) (MIM ) leading to TTR-related amyloidosis (ATTR) (MIM ) characterize the most common form of inherited amyloidosis, but non-attr has been described as well (1). TTR is primarily synthesized in the liver and serves as an important plasma transport protein for thyroxine and retinol (2). TTR is a tetramer consisting of 127 amino acid monomers that assemble into β-pleated sheets (3). Single base substitutions resulting in missense mutations make up the majority of the genetic alterations in ATTR (4). Translation of these changes results in the misfolding of individual subunits and destabilization of the tetrameric structure (2). Subsequent deposition of abnormally folded TTR in nerves leads to the development of length-dependent sensorimotor polyneuropathy as well as autonomic neuropathy that is characteristically seen in ATTR (1); however, TTR can be deposited in other organs as well, particularly the heart (5) and kidney (6). Over 100 unique mutations of 396

2 Familial amyloidosis genetic mutations TTR have been identified (2). The most prevalent mutation worldwide is the substitution of valine by methionine at position 30 of the TTR molecule (Val30Met) (MIM ). The majority of case series on ATTR have been conducted in Europe and Asia. The mutation composition of a large sample of ATTR patients in the United States still needs to be elucidated. We conducted a retrospective analysis of a large case series of ATTR patients seen at Mayo Clinic in Rochester, Minnesota, to better determine the mutation frequencies and geographic distributions of ATTR in the United States. Materials and methods A retrospective chart review was conducted of all patients with a diagnosis of ATTR seen at Mayo Clinic in Rochester, Minnesota, from 1 January 1970 through 29 January This study was approved by the Mayo Clinic Institutional Review Board, and all patients provided written, informed consent to permit use of their medical records in our amyloidosis database for minimal-risk retrospective studies. Amyloidosis was confirmed from tissue biopsies showing green birefringence with Congo red staining. During the 43-year period in which patients were seen, the diagnostic methods varied. Mutations in TTR were identified in peripheral blood by restriction fragment length polymorphism (RFLP) ( ) or by direct Sanger sequencing (primarily after 2001). When it was available, immunohistochemistry of amyloid tissue helped direct the diagnosis in several cases. Starting in 2002, laser capture mass spectrometry of the amyloid from tissues aided in typing the amyloid, and germline mutations were verified by Sanger sequencing of DNA from peripheral blood mononuclear cells (7). When mutation information was unavailable or could not be ascertained, patients were determined to have ATTR on the basis of typical clinical presentation or positive family history (or both). Patients excluded from this series, as they presumably had senile systemic amyloidosis (MIM ), were those who had primary cardiac involvement, were older than 65, had no family history, had TTR but no mutational analysis performed, or had no identified mutation. In addition, patients were excluded if no mutation testing results were available and if they had a syndrome consistent with primary (AL) amyloidosis (MIM ), secondary (AA) amyloidosis (MIM ), or familial Mediterranean fever (MIM ). Results Our retrospective review identified 284 patients who had confirmed inherited forms of amyloidosis. For 224 of those patients (all symptomatic), specific mutations were identified. Fig. 1 shows the distributions of the age at diagnosis of these patients grouped by mutation and sex. The majority of the patients in the study population were male (218 patients, 77%). The median age at diagnosis overall was 63 years. The method of mutation identification was known for 181 patients: DNA sequencing (97 patients, 34%); RFLP analysis (67 patients, 24%); mass spectrometry (9 patients, 3%); and family history (7 patients, 2%); a non-attr (gelsolin) mutation was identified in one patient solely on the presence of the typical clinical presentation without any formal mutation testing. For 43 patients (15%), the method of mutation identification was unknown as it had been performed at another center before the patient was evaluated at our facility. For 60 patients (21%), the pathogenic mutation was unknown as testing either was not performed or was performed before the availability of mass spectrometry and DNA sequencing. Table 1 lists genetic mutations identified in the population of this study. Of these mutations, each of the four most common [Thr60Ala (MIM ), Val30Met, Val122Ile (MIM ), and Ser77Tyr (MIM )] was identified in more than 10 patients. Several other TTR mutations were also identified (Table S1, Supporting Information). Twenty patients (7%) were identified as having non-attr mutations (three gelsolin, nine fibrinogen A-α, six apolipoprotein A-I, one apolipoprotein A-II, and one lysozyme; specific mutations are listed in the Table S1). The geographic distributions of the identified mutations are shown in Fig. 2. As we wanted to focus on the geographic distributions of the mutations in the United States, we excluded the 32 international patients (11%) from this analysis. Discussion ATTR is a heterogeneous multisystem disease that carries considerable morbidity and mortality. This investigation is the largest single-center experience to date describing the genetic mutations of ATTR patients in the United States. The male to female ratio was 3:1. Patient age at symptom onset was normally distributed. This differs from the bimodal distribution described in a recent study (8). We also detected a later age at onset than described for patients in Japan (9), Portugal (10), and Sweden (11). While our institution evaluates a diverse population, thus implicating the potential for varying penetrance leading to these age and sex differences, referral bias could also contribute to these findings as families with certain mutations may be seen at other amyloid centers aside from ours. The four most common mutations identified in this study group, in order of decreasing frequency, were Thr60Ala, Val30Met, Val122Ile, and Ser77Tyr. Val30Met is the most prevalent mutation overall worldwide (1). In the United States, Val122Ile is the most prevalent TTR-associated mutation (12); it is seen in % of African Americans (13, 14). However, Thr60Ala was the most frequently identified mutation in this study population and likely reflects the fact that most of the patients of this study were white. Ser77Tyr has been described in only a few case reports and is thought to be especially prevalent among Jewish Yemenites (15). 397

3 Zhen et al. Fig. 1. Age of patients at diagnosis of transthyretin (TTR)- and non-ttr-related amyloidosis (ATTR). Patients are grouped by mutation. (a) Male patients (n = 218). (b) Female patients (n = 66). Table 1. Mutation frequencies among 284 patients with confirmed inherited forms of amyloidosis Mutation Patients, No. Thr60Ala 68 Val30Met 42 Val122Ile 28 Ser77Tyr 15 Leu58His 8 Asp38Ala 4 Ala45Asp 3 Glu54Gly 3 Gly47Glu 3 Phe33Leu 3 Other ATTR a 51 Other non-attr a 20 Unknown 60 ATTR, transthyretin-related amyloidosis. a See Table S1 for a complete listing of mutations carried by fewer than three patients. We also identified patients affected with non-attr disease, specifically mutations in the proteins of gelsolin, apolipoprotein A-I, fibrinogen A-α, apolipoprotein A-II, and lysozyme. Gelsolin-related amyloidosis arises from the misfolding of an important calcium-dependent regulator of actin filaments and subsequent deposition in the eyes, skin, and peripheral nerves (16). The predominant mutation in the Finnish population involves amino acid substitution of aspartic acid by asparagine at residue 187 of the gelsolin protein (Asp187Asn) (MIM ) (17). We identified this mutation in only one of the three gelsolin-associated amyloidosis patients in this study. The mutation status of the other two patients was unknown. In apolipoprotein A-I-associated amyloidosis, the N-terminal fragments of the variant protein lead to extracellular deposition in various organs, particularly the liver, kidney, stomach, and intestines (18). Among our patients whose apolipoprotein mutations could be identified, Arg173Pro (MIM ) and Leu75Pro (MIM ) were the most common. Arg173Pro was 398

4 Familial amyloidosis genetic mutations Fig. 2. Geographic distributions of mutations in 252 US patients with transthyretin (TTR)- and non-ttr-related amyloidosis (ATTR). Values inside each symbol indicate the number of patients with a particular mutation in that state. originally identified by Hamidi Asl et al. (19) and is clinically characterized by predominantly dermatologic manifestations, dysphonia, and cardiomyopathy; it has been identified in both American and British populations. Leu75Pro was originally identified in Italy in patients with predominantly hepatic and renal involvement (20). In addition to gelsolin and apolipoprotein A-I non-attr mutations, we incidentally identified several patients with abnormal deposition of fibrinogen A-α, apolipoprotein A-II, and lysozyme, all of which are associated with hereditary renal amyloidosis (21). The Arg554Leu (MIM ) mutation was the first fibrinogen A-α mutant variant identified in a Peruvian kindred (22). Glu526Val (MIM ) was subsequently identified in an American kindred of Irish descent populations (23) and is considered the most common mutant variant of fibrinogen A-α. While the majority of fibrinogen mutations involve primarily single base substitutions, several frameshift mutations have been identified as well (24, 25). Several of our patients with fibrinogen-associated hereditary renal amyloidosis also carried these mutations. Interestingly, we identified two mutations with unknown clinical relevance, Thr536Val (MIM ) and Ser553Leu (MIM ), for which we could not find any published studies. The specific mutations could not be ascertained from the available medical records for one patient with apoliprotein A-II and the other with lysozyme-associated disease. This study of ATTR and non-attr mutations in the United States had several limitations. First, for a large group of patients, the mutations were unknown. If the pathogenic mutation had been identified and the patients had been assigned a mutation group, our analysis would have been altered. However, this limitation is inherent in a retrospective study. Second, the RFLP assays, which were used before sequencing was available, tested only for the most common mutations. Third, the lack of other identifiable pedigrees and demographic information (i.e. race and place of birth) for some of our patients limited our ability to determine whether these factors had a role in the geographic distributions of mutations. Although inherited forms of amyloidosis are rare, ATTR and, to a lesser extent, non-attr are prevalent in the United States and should be considered if patients present with a progressive course of multisystem disease, including sensorimotor polyneuropathy, cardiomyopathy, or nephropathy. Future studies should focus on identifying the initial presenting symptoms, appropriate diagnostic methods, and clinical predictors of survival among ATTR patients. Supporting Information Additional supporting information may be found in the online version of this article at the publisher s web-site. References 1. Plante-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol 2011: 10 (12):

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