Transthyretin-related vitreous amyloidosis in different endemic areas.

BACKGROUND: to investigate the vitreous opacity in patients with familial amyloidotic polyneuropathy (FAP) in two major endemic areas, Japan and Sweden. METHODS: we obtained clinical data for 90 patients with vitreous opacity that was associated with FAP amyloidogenic transthyretin (ATTR) Val30Met; 18 Japanese patients and 72 Swedish patients. We reviewed medical records at Kumamoto University Hospital in Japan and Umeå University Hospital in Sweden. We evaluated the characteristics of the patients, systemic and ocular histories, clinical findings and treatment. RESULTS: swedish patients were significantly older at the onset of vitreous opacity (mean age 67.8 years) than were Japanese patients (47.6 years). A similar age difference was found for the onset of polyneuropathy. In addition, Swedish patients without polyneuropathy were significantly older (74.1 years) at the onset of vitreous opacity than those with polyneuropathy (64.6 years). A significant difference in the occurrence of vitreous opacity as the only manifestation of FAP was seen for Swedish patients (35%) compared with Japanese patients (6%). CONCLUSIONS: swedish FAP ATTR Val30Met patients appeared to develop vitreous opacity later and more frequently compared with Japanese patients.

Impact of liver transplantation on transthyretin-related ocular amyloidosis in Japanese patients.

OBJECTIVE: To evaluate the long-term impact of liver transplantation on ocular manifestations of familial amyloid polyneuropathy (FAP) in Japanese patients. METHODS: Medical records were retrospectively reviewed in a long-term follow-up study. Of 52 patients with FAP amyloidogenic transthyretin Val30Met, 22 patients underwent liver transplantation. We assessed ocular manifestations, including amyloid deposition at the pupillary border, pupillary border with irregularity, vitreous opacities, and glaucoma, in patients who underwent liver transplantation. In addition, we compared the clinical characteristics of vitreous opacities-the most common ocular manifestation of FAP-in patients who underwent liver transplantation and those who did not to determine the effect of transplantation on the progression of ocular amyloidosis. RESULTS: Mean time after FAP onset was 10 years and after liver transplantation was 7 years in patients who underwent liver transplantation. All ocular manifestations increased with time after transplantation. Eight patients (36%) developed vitreous opacities and 4 patients (18%) developed glaucoma during follow-up. Mean time from FAP onset to vitreous opacities onset was significantly shorter in patients with early-onset disease who underwent liver transplantation than in those who did not. CONCLUSIONS: Patients with FAP who undergo liver transplantation continue to have a long-term risk of severe ocular manifestations, especially vitreous opacities and glaucoma, which can restrict their daily lives, even after liver transplantation.

Ocular amyloid angiopathy associated with familial amyloidotic polyneuropathy caused by amyloidogenic transthyretin Y114C.

PURPOSE: To report the clinicopathological findings for a unique ocular amyloid angiopathy in patients with familial amyloidotic polyneuropathy (FAP) caused by amyloidogenic transthyretin Y114C. DESIGN: Three case reports. METHODS: Retrospective review of clinicopathological findings, course, and treatment of the 3 patients. MAIN OUTCOME MEASURES: Visual acuity, intraocular pressure, fundus photography, fluorescein angiography (FA), indocyanine green angiography, and histopathological analysis. RESULTS: In the 32-year-old patient, in the early stage of FAP, indocyanine green angiography demonstrated multiple sites of hyperfluorescence, with staining along major choroidal veins. Retinal vessels appeared normal clinically and on FA. In the 48-year-old patient, who had late-stage FAP, examination of the fundus revealed pinpoint white amyloid opacities over the retinal surface, sheathing of retinal vessels, and scattered retinal hemorrhages. Fluorescein angiography showed vascular closure, focal staining, and microaneurysms. Indocyanine green angiography revealed multiple sites of hyperfluorescence, with staining along retinal and choroidal vessels. Examination during follow-up revealed that these vascular changes continued to progress. Histopathological study of an eye obtained at autopsy from the 49-year-old patient revealed marked intravascular and extravascular amyloid deposition. CONCLUSIONS: Severe and progressive amyloid angiopathy causing visual disturbance was seen in patients with FAP caused by amyloidogenic transthyretin Y114C.

Transthyretin synthesis in rabbit ciliary pigment epithelium.

Ocular symptoms of transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) suggest that ciliary pigment epithelium (CPE) may synthesize TTR and its TTR may lead to amyloid formation in addition to TTR from vessels and retinal pigment epithelium (RPE). To clarify sites of TTR synthesis in ocular tissues, we performed in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) for qualitative detection of TTR mRNA. In addition, we quantified levels of TTR mRNA expression by means of real-time quantitative RT-PCR. Furthermore, although TTR is an anti-acute phase protein in serum level, no reports on changes in TTR expression in ocular tissues during acute inflammation exist. To investigate changes in TTR expression in ocular tissues during inflammation, we induced uveitis by endotoxin challenge in rabbits and used real-time quantitative RT-PCR to examine changes in TTR mRNA expression in ocular tissues. In situ hybridization and RT-PCR qualitatively demonstrated TTR mRNA not only in RPE but also in CPE. Real-time quantitative RT-PCR showed that the level of TTR mRNA expression in the CPE was about one-third of that in the RPE. TTR mRNA expression in ocular tissues decreased as the degree of inflammation increased. These results suggest that TTR synthesized in the CPE may lead to ocular manifestations, especially glaucoma, in FAP. TTR mRNA also acts as an anti-acute phase reactant in ocular tissues.

A different amyloid formation mechanism: de novo oculoleptomeningeal amyloid deposits after liver transplantation.

BACKGROUND: Liver transplantation has served as a treatment for patients with familial amyloidotic polyneuropathy (FAP) because variant transthyretin (TTR), the pathogenic protein of FAP, is predominantly produced by the liver. However, the effect on amyloid formation of TTR that is synthesised by the retina and the choroid plexus remains to be elucidated in FAP patients with liver transplants. OBJECTIVE: To investigate changes in ocular tissues and the central nervous system (CNS) of FAP patients after liver transplantation. DESIGN: Clinical study. SETTING: Graduate School of Medical Sciences, Kumamoto University, Japan. INTERVENTION: Transplantation of livers from cadaveric or living donors. MEASUREMENTS: Preoperative measures and postoperative (16-108 months) follow-up of clinical data, including routine ophthalmologic, neurologic, and laboratory evaluations. RESULTS: In 22 patients with FAP related to the amyloidogenic TTR (ATTR) Val30Met and 3 patients with FAP ATTR Tyr114Cys, after liver transplantation, 3 patients began to show evidence of de novo glaucoma, and 1 had vitreous opacity that was caused by the variant TTR. Another three patients showed new amyloid deposits in the pupillary margin, which could lead to glaucoma and vitreous opacity. As for changes in the CNS and levels of total protein and TTR in cerebrospinal fluid (CSF), after liver transplantation, two FAP ATTR Tyr114Cys patients exhibited de novo amyloid deposition in the leptomeninges, and total protein and TTR levels in CSF were significantly increased. CONCLUSIONS: Oculoleptomeningeal involvement in FAP was not prevented by liver transplantation because variant TTR produced by the retina and the choroid plexus forms amyloid fibrils in situ.

A case of vitreous amyloidosis without systemic symptoms in familial amyloidotic polyneuropathy.

We describe a case of vitreous amyloidosis without systemic symptoms in familial amyloidotic polyneuropathy (FAP) associated with Val30Met transthyretin mutation. A healthy 74-year-old woman noticed left blurred vision and floaters in 1992. Severe vitreous opacities were identified in the left eye. The patient displayed no systemic symptoms, and Congo red staining of the biopsy samples of the stomach and duodenum revealed no amyloid deposition. A diagnosis of FAP was confirmed following genetic investigation. Vitrectomy and cataract surgery was performed with intraocular lens implantation in April 1998. Histopathological examination of the vitreous material revealed amyloid fibrils. Intraocular pressure (IOP) gradually elevated and cupping of the optic disc enlarged. Trabeculectomy was performed in February 2000, but postoperative IOP was again elevated and a needling procedure was performed in March 2000. No postoperative recurrence of vitreous opacity has been reported and IOP has remained well controlled. In the present case, ocular manifestations were the only symptoms of FAP and systemic symptoms have not developed, after more than 12 years. FAP should be suspected as the cause in cases of vitreous opacities in patients from areas with endemic foci of FAP.

Secondary glaucoma in patients with familial amyloidotic polyneuropathy.

OBJECTIVE: To elucidate the clinical features and surgical outcomes of the treatment of secondary glaucoma associated with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP). DESIGN: Retrospective case study. PARTICIPANTS: Forty-nine Japanese patients with FAP. METHODS: For all patients, measurement of best-corrected visual acuity, intraocular pressure, and visual fields as well as slitlamp and ocular fundus examinations were conducted and compared. In addition, the exact mutation of the amyloidogenic TTR variants was analyzed for all 49 patients with FAP. The TTR mutations included amyloidogenic TTR (ATTR) Val30Met in 41 patients, ATTR Tyr114Cys in 6, ATTR Ser50Ile in 1, and a compound heterozygous mutation of ATTR Val30Met + Arg104His in 1. RESULTS: The onset of secondary glaucoma was defined as elevation of intraocular pressure and glaucomatous changes in visual field defects. Secondary glaucoma was detected in 12 (24%) of the 49 patients. The incidence of secondary glaucoma in patients with the Val30Met mutation (17%) was lower than for the other FAP genotypes (P =.02 using the chi(2) test). Of 20 glaucomatous eyes, amyloid deposition on the pupil and anterior surface of the lens was found in 18 eyes. Amyloid deposition was found prior to glaucoma in 11 eyes and at the first visit to our clinic in another 7 eyes. In the 11 eyes in which the onset of glaucoma occurred following amyloid deposition along the pupil, the mean +/- SD period between the onsets of pupillary amyloid deposition and glaucoma was 2.55 +/- 1.43 years (range, 0.2-4.0 years). Further statistical analyses revealed significant relationships between the onset of secondary glaucoma and both amyloid deposition (P<.001) and vitreous opacity (P<.001). Surgical treatment was required in 15 (75%) of the 20 glaucomatous eyes. In 9 (81%) of the 11 eyes that underwent trabeculectomy, the intraocular pressure was well controlled at or lower than 20 mm Hg during the follow-up period. In the eyes that underwent combined trabeculotomy and sinusotomy (2 eyes), nonpenetrating trabeculectomy (1 eye), or a cyclodestructive procedure (1 eye), the intraocular pressure was poorly controlled. CONCLUSIONS: Glaucoma is not a rare condition in patients with FAP, especially because liver transplantation now enables patients with FAP to live longer. Careful observation of amyloid deposition along the pupil allows the prediction of glaucoma onset.

Vitreous opacities and outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy.

PURPOSE: To report the prevalence of vitreous opacities and the outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy (FAP). DESIGN: Observational case series. METHODS: In 37 patients with FAP and the ATTR Val30 Met mutation, vitreous opacities were present in 14 eyes of 9 patients and vitrectomy combined with phacoemulsification and intraocular lens implantation was performed in five eyes of three patients. In six patients with the ATTR Tyr114Cys mutation, vitreous opacities were present in both eyes of all six patients and vitrectomy combined with phacoemulsification and intraocular lens implantation was performed in nine eyes of six patients. The mean follow-up period after vitreous surgery was 20.9 +/- 16.8 months (range, 3 to 52 months). RESULTS: The prevalence of vitreous opacities is much higher in patients with ATTR Tyr114Cys (100%) than in those with ATTR Val30 Met (24%). The mean age at the onset of vitreous opacities was significantly lower in the patients with ATTR Tyr114Cys (37.0 +/- 5.3 years) than in the nine patients with ATTR Val30 Met (52.8 +/- 9.1 years; P <.005). Visual acuity improved in all 14 eyes after vitreous surgery; however, final visual acuity decreased in one eye owing to the occurrence of a central retinal vein occlusion. Vitreous opacities mildly increased in two eyes. CONCLUSIONS: Our data suggest that the ATTR Val30 Met and ATTR Tyr114Cys mutations induce different clinical features of vitreous opacities. Vitreous surgery combined with phacoemulsification and implantation of an intraocular lens is a safe and useful treatment. Careful long-term follow-up should be performed.

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 in patients 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.

Type I (transthyretin Met30) familial amyloid polyneuropathy in Japan: early- vs late-onset form.

BACKGROUND: Type I (transthyretin Met30) familial amyloid polyneuropathy (FAP TTR Met30) occurs in 2 endemic foci in Japan. We have also reported late-onset Japanese cases unrelated to an endemic focus and showing distinctive clinicopathologic features. OBJECTIVE: To compare clinical and geographic features of FAP TTR Met30 between patients with onset before and after 50 years of age. DESIGN AND SETTING: Clinical information was obtained through a nationwide survey by the Study Group for Hereditary Neuropathy in Japan. RESULTS: Families with early-onset disease in this study numbered 82, and those with late onset, 59. In families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. Families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. CONCLUSIONS: This study confirmed differences in clinical and geographic features between early- and late-onset FAP TTR Met30. Late-onset cases may be more prevalent and widespread than previously believed.

Presence of variant transthyretin in aqueous humor of a patient with familial amyloidotic polyneuropathy after liver transplantation.

To determine the origin of transthyretin (TTR) in the aqueous humor of patients with familial amyloidotic polyneuropathy (FAP), we measured TTR levels and analyzed the TTR forms in the aqueous humor of three FAP patients (one patient; liver transplanted, and two patients; non-transplanted). The total TTR levels were almost the same as reported previously in non-transplanted patients and slightly increased in a transplanted patient. Analyses with mass spectrometry in the two non-transplanted FAP ATTR V30M patients revealed that both wild type and variant TTR forms were detected in their aqueous humor samples. Moreover, variant TTR forms could be detected in the aqueous humor of the transplanted patient while the liver produced no variant TTR. These results suggest that variant TTR in aqueous humor may be derived from retina where TTR was produced. In conclusion, TTR metabolism may occur in its own ocular cycle and variant TTR produced by the retina may play an important role in amyloid formation in the ocular tissues of FAP patients.