ATTR V30M Research Articles

Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis

Background: Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls.Methods: Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee.Results: The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively).Conclusions: A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.

Allele specific expression of the transthyretin gene in swedish patients with hereditary transthyretin amyloidosis (ATTR V30M) is similar between the two alleles.

BackgroundHereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3′ UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3′ UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C>T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR’s mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression.Methodology/Principal FindingsAllele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3′ UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3′ UTR SNP regardless of added miRNA.Conclusions/SignificanceThe SNP found in the 3′ UTR of the TTR gene has no effect on degrading the variant allele’s expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3′ UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.

Vitreous surgery impact in glaucoma development in liver transplanted familial amyloidosis ATTR V30M Portuguese patients

Purpose: Familial amyloidosis with polyneuropathy (FAP) sometimes courses with vitreous amyloid. The aim of this study was to evaluate the incidence of glaucoma after vitrectomy in FAP patients. Methods: A total of 79 eyes of 42 liver transplanted FAP patients and 16 eyes of 16 non-FAP patients with rhegmatogenous retina detachment were collected. The patients were divided in to three groups: Group I – FAP patients with vitreous opacities submitted to vitrectomy, Group II – FAP patients without vitreous opacities and not submitted to vitrectomy and, Group III – non-FAP patients with rhegmatogenous retinal detachment submitted to vitrectomy. The Group I was subdivided into: Ia – “complete” vitrectomy; Ib – “incomplete” vitrectomy. The onset of glaucoma was considered when the intraocular pressure level was higher than 21 mmHg, with concomitant visual field abnormalities and optic nerve cupping. Results: Post vitrectomy glaucoma was more frequent in Group I (56.1%) than in Group III (12.5%) and in Group II (10.5%). We observed a higher incidence of glaucoma in the Ia than in the Ib subgroup (86.4 vs. 21.1%) and earlier appearance in subgroup Ia (7.9 ± 3.6 vs. 39.5 ± 6.6 months). Conclusion: Vitrectomy induced the development of glaucoma in FAP patients.

Potential use of glucuronylglucosyl-β-cyclodextrin as a novel therapeutic tool for familial amyloidotic polyneuropathy

Transthyretin (TTR)-related familial amyloidotic polyneuropathy, which is induced by amyloidogenic transthyretin (ATTR), is characterized by systemic accumulation of amyloid fibrils. Although it is believed that protein misfolding of monomeric form of TTR is a rate-limiting step for TTR amyloid formation, no effective therapy targeting this misfolding step is available. Our recent studies revealed that cyclodextrins (CyDs), cyclic oligosaccharides composed of glucose units, might interact with TTR and prevent the protein misfolding. In this study, we focused on and elucidated the inhibitory effect of 6-O-α-(4-O-α-d-Glucuronyl)-d-glucosyl-β-CyD (GUG-β-CyD) on TTR amyloid formation. Tryptophan (Trp) fluorescence and 1H-NMR spectroscopy analyses indicated that GUG-β-CyD stabilized TTR conformation via interaction with the hydrophobic amino acids of TTR. Moreover, GUG-β-CyD suppressed TTR deposition in transgenic rats possessing a human ATTR V30M gene in vivo. Collectively, these data indicate that GUG-β-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation.

Antibody therapy for familial amyloidotic polyneuropathy

Although it is believed that altered conformations exposing cryptic regions are intermediary and critical steps in the mechanism of transthyretin (TTR) amyloid formation, no effective therapy targeting this step is available. In this study, to establish the antibody therapy for familial amyloidotic polyneuropathy (FAP), we generated a monoclonal anti-TTR antibody, which specifically reacts with surface epitopes of TTR (MAb ATTR) and evaluated its binding affinity and specificity for TTR amyloid fibrils. MAb ATTR showed specific binding affinity for TTR amyloid fibrils, but not for native form of TTR. Moreover, MAb ATTR indeed showed the high consistency with Congo red positive areas in tissue specimens from FAP ATTR V30M patients, indicating that MAb ATTR showed binding affinity and specificity for TTR amyloid fibrils in vitro and in vivo. MAb ATTR may have a potential to suppress TTR amyloid deposition and become a candidate for the antibody therapy for FAP.

No ocular involvement in familial amyloidotic polyneuropathy ATTR V30M domino liver recipients

In many transplantation centers domino liver transplantation is an established procedure, increasing the number of available liver grafts. Increasingly, grafts from familial amyloidotic polyneuropathy (FAP) patients are used. Ocular involvement is a well known manifestation of FAP, and can be vision-threatening. The aim of this study was to evaluate the risk of development of familial amyloidotic polyneuropathy ocular manifestations in domino liver recipients. Forty-four cirrhotic patients submitted to liver transplantation were studied, with an average of 6 years of follow up after the procedure. Twenty two patients had received a liver from a FAP donor (Group 1) and 22 had received a liver from a non-FAP cadaveric donor (Group 2). Both groups were similar for mean age and gender. Routine ophthalmological examinations with particular attention to amyloid deposition in the anterior segment and vitreous, peripheral retina state, lacrimal functions tests (Schirmer and tear break-up time) and pupillometry (dynamic and static) were performed. No statistically significant differences were observed in all studied ophthalmic parameters between the two groups. No FAP related ophthalmic manifestations were detected after 6 years of domino liver transplantation, but further prospective regular ophthalmological examinations are necessary to detect the eventual development of late ocular manifestations.

RECURRENCE OF VITREOUS AMYLOIDOSIS AND NEED OF SURGICAL REINTERVENTION IN PORTUGUESE PATIENTS WITH FAMILIAL AMYLOIDOSIS ATTR V30M

Vitreous amyloid deposits are one of the most common ocular manifestations of familial amyloidosis ATTR V30M (FAP-I), which can be the only manifestation of the disease and can appear even after liver transplantation. Removal by vitrectomy is usually performed, but vitreous amyloid recurrence has been frequently reported. This study was undertaken to evaluate the recurrence of vitreous amyloidosis and its relationship with the degree of previous vitreous removal. Fifty-four vitrectomized eyes from 32 patients with FAP-I were evaluated in the course of a follow-up period of 30.7 ± 17.2 months (range, 8-78; median = 30 months). An extensive, as possible, vitrectomy with indentation was performed in 41 eyes (complete), and in the others 13 eyes only a vitrectomy without indentation (incomplete) was performed. The parameters evaluated were the incidence of amyloid deposits and visual outcomes. A noteworthy visual acuity gain was observed, although a few patients had a subsequent decrease of visual acuity related to new vitreous amyloid deposition in the visual axis. These new amyloid deposits did not occur in eyes that had undergone extensive vitreous removal, but only in nonextensive vitrectomized eyes (P < 0.001). Recurrence of amyloid deposition only occurred in nonextensive vitrectomized eyes and represents a false recurrence associated with incomplete vitrectomy.

Familial amyloidotic polyneuropathy (Portuguese type variant I) and female pelvic floor dysfunction: a tribute to Magellan

Familial amyloidotic polyneuropathy, Portuguese type variant I (FAP-1) is an inherited autosomal dominant disorder caused by disturbance in protein metabolism that was first described by Corino de Andrade in 1939 [1]. The disease originated in Northern Portugal but is found all over the world as a result of the Portuguese navigating expeditions of the fifteenth century, pioneered by Magellan. Most patient clusters are now observed in Portugal, Sweden, and Japan [2]. In Portugal, according to population data from 2008, 3,525 patients with FAP-1 were enrolled in the Portuguese Amyloidosis Centre of Studies. In Sweden, there are 7,500 carriers of the genetic mutation, whereas in Japan, over 350 patients with FAP-1 have been identified. Majorca, Spain, is the area with the highest prevalence in the Mediterranean region and the fourth in the world after Portugal, Sweden, and Japan with 44 patients described. There are also isolated case reports from France, Netherlands, Greece, Italy, USA, and Australia. The exact prevalence of FAP-1 in Brazil which is considered the hub of historical Portuguese colonies, however, remains unknown (Fig. 1). The principal pathology is a mutation on chromosome number 18 of the transthyretin protein where the amino acid methionine replaced valine at position 30 (ATTR V30M) leading to the production of an abnormal amyloid protein by the liver [3]. Systemic deposition of this amyloid in various tissues particularly the axons of peripheral neurons leads to progressive peripheral neuropathy of the sensory, motor, and autonomic nerves. Neurogenic digestive disturbances (44.2%) and neurological symptoms of the lower extremities (43.7%) are the most common primary clinical manifestations of FAP-1 [2, 3]. The early clinical features of FAP-1 are summarized in Table 1. FAP type 1 manifests itself during adulthood. The Portuguese variant of the disease has an early age of onset, an average of 33.5±9 years. Late age of onset (above 50 years of age) tends to occur in non-Portuguese disease clusters. When patients show these suspicious clinical features, FAP-1 is diagnosed by confirming the presence of amyloid deposits in tissue biopsies obtained from the subcutaneous tissues of the abdominal wall, skin, gastric or rectal mucosa, peri-tendinous fat, or sural nerve and further gene sequencing studies to identify the mutation ATTR V30M [2]. The only curative treatment option available for patients with FAP-1 is liver transplantation in order to eliminate abnormal hepatic synthesis of the ATTR V30M amyloid protein [3]. A brief urogynecologic review of FAP1 is important because of the potential for causing pelvic floor dysfunction associated with variable nonurogynecologic clinical presentations in mutation women carriers, the multi-disciplinary approach needed for management of this unusual condition and the wide geographical distribution of the disease. Our data are supported by M. J. Gomes Urodynamics, Neuro-Urology and Female Urology Unit, Department of Urology, Centro Hospitalar Porto ICBAS, Porto University, 4000 Porto, Portugal

Anticipation of presbyopia in Portuguese familial amyloidosis ATTR V30M

The aim of this study was to evaluate if Portuguese patients with familial amyloidosis, liver transplanted and not, have an earlier development of presbyopia compared with a normal population and its relation with the presence or the absence of anterior capsule opacification of the lens. This study was performed to evaluate if Portuguese patients with familial amyloidosis and in a blood donors population (control group). Three hundred and fifty-six subjects, 144 amyloidotic patients and 212 healthy individuals, were evaluated for the need of plus lenses for normal near reading (Jaeger chart 1 at 33 cm). In familial amyloidosis patients, the value of the add-power was related to age, liver transplantation status, and presence of visible anterior capsule opacification of the lens. In both groups, the value of add-power was positively correlated with age (r = 0.91; P < 0.005). Familial amyloidosis patients require more add-power than control individuals of similar age, and need to use reading glasses at earlier ages. The age of onset of presbyopia in familial amyloidosis patients was significantly lower than in control individuals (32 years vs. 42 years). Adjusting for age, no significant difference was observed in add-power values between liver transplanted and not transplanted amyloidotic patients, suggesting that liver transplantation has no influence on presbyopia evolution in these patients. Familial amyloidosis patients had an earlier onset of presbyopia, probably related to amyloid deposition on the anterior capsule of the lens, which is not halted by liver transplantation.

Characterization of End-Stage Renal Disease After Liver Transplantation in Transthyretin Amyloidosis (ATTR V30M)

Transthyretin (TTR) amyloidosis, an autosomal-dominant disease, is characterized by peripheral and autonomic neuropathy—familial amyloidotic polyneuropathy (FAP). End-stage renal disease (ESRD) occurs at 10 years after the onset of neuropathy. Orthotopic liver transplantation (OLT) is the usual treatment of choice. We evaluated FAP patients, ATTR V30M, before and after OLT who started dialysis within 3 months after surgery. The 11 patients had an age at the onset of neuropathy of 31.9 ± 6.3 years with a mean evolution of disease to OLT of 4.54 ± 2.5 years. The glomerular filtration rate was <60 mL/min in 2 patients, 2 displayed nephrotic range proteinuria, and 3 had microalbuminuria. Elective pacemaker implantation was necessary in 8 subjects. Post-OLT 3 patients developed proteinuria, 2 of whom showed increasing nephrotic syndrome. Dysautonomia worsened leading to bladder catheterization in 6. In patients with previous normal renal function and proteinuria <3 g/d, the evolution of neuropathy to the first dialysis was 14.6 ± 4.2 years versus 7.5 ± 1.1 among the other subjects. Overall, dialysis was implemented at 7.4 ± 4.9 years after surgery. There was no liver graft dysfunction. The heart evaluation post-OLT showed the following: 3 patients with de novo dysrhythmias requiring pacemaker implantation and 3 with N-terminal pro-natriuretic peptide levels >10,000 pg/mL. Death occurred in 4 subjects at an average of 26 months after initiation of dialysis. Concerning ESRD, there was no clear benefit of transplantation in the early stages. Patients with normal renal function and lower levels of proteinuria showed slower progression to ESRD, irrespective of their duration of neuropathy.

Erythropoietin production by distal nephron in normal and familial amyloidotic adult human kidneys

the kidney is the major site of erythropoietin production. Many efforts have been made to identify renal erythropoietin-producing cells. Previous studies showed conflicting results, but the predominant localization reported was the peritubular interstitial and tubular epithelial cells. This study was conducted to identify the erythropoietin-producing cells in renal biopsies from 10 cadaveric donors and 45 patients with familial amyloidosis ATTR V30M, thirteen of them with anemia. Familial amyloidosis Type I (FAP-I) is a genetic disorder caused by a transthyretin (TTR) protein variant presenting a single amino acid substitution of methionine for valine at position 30 of the polypeptide chain (TTR V30M). Anemia in FAP-I is associated with inappropriately low serum erythropoietin levels. erythropoietin expression was detected by in situ hybridization (ISH) and confirmed by laser capture microdissection followed by PCR. Renal segments were identified by immunohistochemistry. erythropoietin was mainly expressed by epithelial distal tubular cells and collecting tubules and additionally, in a few biopsies, by glomerular cells. A similar expression pattern was observed in donors and FAP-I patients. No increased mRNA erythropoietin expression was found in anemic patients, all of them presenting only a slight expression in medulla and cortex. these results suggest the distal nephron as the major site of erythropoietin production, and support the notion that an inappropriate erythropoietin production is the cause of anemia in familial amyloidosis ATTR V30M.

Death Anxiety and Symbolic Immortality in Relatives at Risk for Familial Amyloid Polyneuropathy Type I (FAP I, ATTR V30M)

This study is an investigation of the impact of familial amyloid polyneuropathy type I (FAP I, ATTR V30M) on death anxiety and symbolic immortality. Templer and Drolet's scales were administered to 524 individuals: (1) 84 relatives at risk, (2) 92 relatives not at risk for FAP I; and (3) a control group (n = 348) with no known hereditary disease in their families. At-risk relatives had, on average, a higher score for death anxiety and a lower score for symbolic immortality, than either those not-at-risk or controls. There were no significant differences in scores on either measure for those not-at-risk versus controls. Being at risk increases death anxiety and threatens the sense of symbolic immortality and psychosocial wellbeing. This may be true for other serious hereditary disorders as well. Genetic counsellors should become familiar with these concepts, feel comfortable initiating discussions about death with their patients, and be able to identify and reinforce their patients' and family members' sense of symbolic immortality.

SELDI-TOF Mass Spectrometry Evaluation of Variant Transthyretins for Diagnosis and Pathogenesis of Familial Amyloidotic Polyneuropathy

Mass spectrometric analyses are valuable for detection of transthyretin (TTR) variants, which cause familial amyloidotic polyneuropathy (FAP). However, those methods require an immunoprecipitation step with an anti-TTR antibody and are not suitable for quantitative detection. We investigated the usefulness of SELDI-TOF mass spectrometry (MS) without an immunoprecipitation step. We used ProteinChips with chromatographic capture formats to detect TTRs. We attempted to correlate the intensity of mixed samples of amyloidogenic TTR (ATTR) V30M to wild-type (WT) TTR. We analyzed the proportion of ATTR V30M in amyloid-laden cardiac tissues from FAP patients, and also evaluated samples from FAP patients with 16 other TTR mutations. Detection of ATTR required only 3 h of SELDI-TOF MS analysis. We determined that SELDI-TOF MS was suitable for quantitative detection of ATTR V30M and demonstrated that the proportion of ATTR V30M to WT TTR was 46.6% in amyloid-laden cardiac tissue from an FAP patient who died 10 years after liver transplantation. With this method, we identified 12 of 17 TTR variants. Small mass shifts and low concentrations of variants prevented ATTR detection. By changing the analytical conditions, we achieved detection of low concentrations of ATTR Y114C in serum. SELDI-TOF MS is a reliable tool for quantitative evaluation of TTR variants, in both tissue amyloid deposits and body fluids. This method is useful for the diagnosis and investigation of the pathogenesis of FAP.

A transgenic rat with the human ATTR V30M: A novel tool for analyses of ATTR metabolisms

Amyloidogenic transthyretin (ATTR) is the pathogenic protein of familial amyloidotic polyneuropathy (FAP). To establish a tool for analyses of ATTR metabolisms including after liver transplantations, we developed a transgenic rat model expressing human ATTR V30M and confirmed expressions of human ATTR V30M in various tissues. Mass spectrometry for purified TTR revealed that rat intrinsic TTR and human ATTR V30M formed tetramers. Congo red staining and immunohistochemistry revealed that nonfibrillar deposits of human ATTR V30M, but not amyloid deposits, were detected in the gastrointestinal tracts of the transgenic rats. At 24h after liver transplantation, serum human ATTR V30M levels in transgenic rats that received livers from normal rats became lower than detectable levels. These results thus suggest that this transgenic rat may be a useful animal model which analyzes the metabolism of human ATTR V30M including liver transplantation studies.

Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils

We have investigated the structure of in vivo formed transthyretin (TTR) amyloid deposits by using antisera raised against short linear sequences of the TTR molecule. In immunohistochemistry, antisera anti-TTR41-50 and anti-TTR115-124-a reacted specifically with both wildtype ATTR and ATTR V30M material, whereas only anti-TTR41-50 recognized ATTR Y114C material. Similar results were obtained by ELISA analysis of ATTR V30M and ATTR Y114C vitreous amyloid, where the anti-TTR115-124-a antiserum failed to react with ATTR Y114C material. Moreover, neither of the antisera recognized natively structured TTR present in pancreatic alpha cells. Our results strongly indicate that the TTR molecule undergoes structural changes during fibrillogenesis in vivo. The finding of a structural difference between wildtype ATTR and ATTR V30M material on one hand and ATTR Y114C material on the other suggests that the fibril formation pathway of these ATTR variants may differ in vivo.

Psychological aspects of pre‐symptomatic testing for Machado–Joseph disease and familial amyloid polyneuropathy type I

Machado-Joseph disease [MJD, also spinocerebellar ataxia type 3 (SCA3)] and familial amyloid polyneuropathy type I (FAP-I or ATTR V30M) are neurodegenerative disorders, inherited in an autosomal dominant fashion, which have a high prevalence in Portugal, probably due to a founder effect. MJD and FAP-I are late-onset diseases, with symptoms emerging usually during adulthood. CGPP, which is the national reference centre for these disorders, has a genetic lab that offers diagnostic, pre-symptomatic and prenatal testing and an outpatient clinic to counsel and follow relatives at risk for hereditary ataxias, FAP-I and Huntington disease (HD). The present work is a review of our 10-year experience with psychological counselling of individuals at risk for MJD and FAP-I. Persons at risk for FAP-I may show a better response to pre-symptomatic testing than those who are at risk for MJD and HD because of the availability of liver transplantation, which may improve their health and life expectancy. Psychological well-being and specific distress of MJD and FAP-I test applicants, before undergoing genetic testing (baseline level) and 3 to 6 months after disclosure of test results, have shown a low level of change, both in identified carriers and non-carriers. A major goal of psychological characterization of at-risk individuals for MJD and FAP-I is to determine the factors that influence the uptake of genetic testing.

Aging and transthyretin-related amyloidosis: Pathologic examinations in pulmonary amyloidosis

Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 ± 8.75 vs. 39.75 ± 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M.

Liver transplantation and new therapeutic approaches for familial amyloidotic polyneuropathy (FAP)

Liver transplantation has been considered as a promising therapy to halt the progression of clinical symptoms in familial amyloidotic polyneuropathy (FAP) because most transthyretin (TTR) is produced by the liver. In addition, domino liver transplantation using an FAP patient's liver has been performed because of a shortage of donor livers. However, because the use of liver transplantation as therapy for FAP has given rise to several problems, an alternative treatment is needed. We have tried several other approaches. Recent studies suggested that certain metal ions affect amyloidogenesis. Among metal ions tested in an in vitro amyloid formation study, Cr3+ increased stability of both normal and mutant TTR tetramers and suppressed TTR amyloidogenesis induced by low pH. Our findings indicate that Cr3+ acts to suppress TTR amyloidogenesis. BSB, a Congo red derivative that binds to amyloid fibrils in FAP as well as to those in senile plaques in Alzheimer's disease, effectively suppressed TTR amyloid formation in vitro. BSB may thus be useful for preventing amyloid formation. Free radical scavenger therapy was also tried in FAP patients but yielded no conclusive results. Immunization for transgenic mice having the ATTR V30M gene using ATTR Y78P resulted in suppression of amyloid deposits. Finally, an RNA/DNA chimera and single-stranded oligonucleotides (SSOs) were tested in vitro and in vivo in an attempt to repair the amyloidogenic TTR gene in the liver and retina. On the basis of results achieved so far, SSO is a promising tool for gene therapy.

Amyloid deposition in ocular tissues of patients with familial amyloidotic polyneuropathy (FAP)

It is known that the severity of ocular symptoms does not always correlate with the systemic symptoms inpatients with familial amyloidotic polyneuropathy (FAP ATTR V30M). The ocular tissues may have their own TTR metabolic system. The aim of this study is to clarify the distribution of amyloid deposition in the ocular tissues and to investigate the relationship between ocular symptoms and histopathological changes. We analyzed histopathologically 9 autopsied eyes taken from 3 Japanese and 6 Swedish patients with FAP ATTR V30M. Localization of amyloid deposition varied among the different cases, but there were some tendencies in the distribution. The degree of amyloid deposition in the ocular tissues was not always correlated with the duration of the disease. The frequency of amyloid deposition in the conjunctiva, iris, trabecular meshwork and vitreous body were 88.9%, 44.4%, 11.1% and 11.1% respectively in the 9 patients. These frequencies in the histopathological changes correlated with the frequencies in the clinical ocular manifestations as previously reported.