Conjunctival lymphangiectasia and retinal angiopathy in hereditary transthyretin amyloidosis

Background Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare condition where a mutation in the transthyretin gene leads to systemic deposition of amyloid. The manifestations and prognosis of ATTR amyloidosis depends on the specific ATTR mutation, with over 100 mutations reported in the literature. The manifestations of many rare forms of ATTR amyloidosis have not been well described, particularly the late-onset ophthalmic findings. Case presentation We present the case of a 43-year-old Caucasian male with a diagnosis of ATTRD18E amyloidosis confirmed by fat pad biopsy. He had diffuse systemic involvement, including cardiovascular, pulmonary, and gastrointestinal symptoms. He also had significant ocular involvement including vitreous opacities, retinal angiopathy, and conjunctival lymphangiectasia. These ocular findings modestly progressed at 2-year follow-up. Discussion The ATTRD18E mutation is a rare variant, with few described cases. To our knowledge, this is the first documented case of ATTRD18E amyloidosis with significant ocular involvement. These ocular findings may serve as a relevant biomarker for severe disease prognosis in ATTRD18E amyloidosis. With improving treatments addressing the systemic symptoms of ATTR amyloidosis, a better understanding of the late-onset ocular symptoms is becoming increasingly relevant.

Molecular Mechanisms of Cardiac Amyloidosis

Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, a method for removing deposited amyloid has not been established. Methods for reducing cytotoxicity caused by amyloid deposition and amyloid precursor protein to protect cardiovascular cells are also needed. In this review, we outline the molecular mechanisms and treatments of cardiac amyloidosis.

Phenotypic heterogeneity and diagnostic features of transthyretin amyloidosis with polyneuropathy

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic progressive fatal disease, for which a modifying therapy has recently been proposed that delays the progression of the disease and improves the patient’s quality of life. The delay in the diagnosis of ATTR-amyloidosis is associated with the heterogeneity of the manifestations of the disease, as well as insufficient awareness of doctors of different specialties about the disease. A review of recent studies on the symptomatology, diagnosis, molecular genetic characteristics of ATTR-amyloidosis and the most common forms of the disease with the predominant involvement of peripheral nerves and the heart, as well as the kidneys, gastrointestinal tract, and eyes is presented. The international consensus recommendations for the diagnosis of suspected ATTR-amyloidosis using modern methods that facilitate early and accurate diagnosis are discussed. The reasons and the most frequent misdiagnoses of ATTR-amyloidosis, which also lead to a delay in the timely appointment of therapy, are considered. Molecular genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy and cardiomyopathy. A diagnostic algorithm based on the initial symptoms and manifestations of the cardiovascular and nervous systems facilitates the identification of a patient with clinical suspicion of ATTR-amyloidosis by the general practitioner. Early diagnosis is critically important for patients with ATTR polyneuropathy, since the early prescription of Vindakel (tafamidis), registered in the Russian Federation in 2017, allows a significant clinical effect to be obtained. Timely administration of Vindakel significantly slows down the progression of the disease, improves the prognosis and quali ty of life in patients with ATTR polyneuropathy.

Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTRS52P. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α2-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.

Two-Year Evaluation of the German Clinical Amyloidosis Registry

Introduction Currently there are no sufficient epidemiology data on systemic amyloidosis in Germany. Our aim was to collect epidemiological data on amyloidosis diseases to determine incidence and distribution of amyloidosis types in Germany. In addition, data on diagnosic pathways, demographic, clinical and biological factors, quality of life (Qol) and overall survival (OS) have been collected. Methods: The actual registry population consists of the first n=1000 reported cases of newly diagnosed amyloidosis patients between 4.1.18 - 21.11.19. Data cutoff of the analysis was June 30, 2021. Patients were included in the registry by two main ways: personal presentation at the amyloidosis outpatient clinic or phone contact of the attending physician to the Amyloidosis Center. Inclusion criteria were either a Congo Red positive tissue sample or unequivocal findings in bone scintigraphy (ATTR amyloidosis). Patients were contacted every 6 months to obtain QoL data using EORTC QLQ-C30, EQ-5D-5L and SF36-v2 questionnaires. This registry was financially supported by Prothena. Results: During this time period 963 of the first 1000 reported newly diagnosed patients (37 pts. did not fulfil inclusion criteria and were excluded) were evaluated mainly through the amyloidosis outpatient clinic (n=581, 60.3%). Seventy-three percent of cases were male (n=706). The median age at diagnosis was 71 years and differed between the AL pts.(65,5 years) and ATTRwt (78 years) patients. The subgroup distribution was as follows: 438 (45,5%) AL pts., 318 (33%) ATTRwt pts., 35 (3,6%) ATTRv pts, 60 (6,2%) ATTR of unknwon subtype, 66 (6,8%) local amyloidosis, 30 (3,1%) AA amyloidosis, 12 (1,2%) others and 4 (0,4%) not typed. Diagnosis was confirmed by biopsy in 88% and in 12% by bone scintigraphy. The most commonly involved organs were heart (n=733, 76,1%) and kidney (n=305, 31,7%). Cardiac staging systems were used for systemic AL (Kumar et al., 2014) with heart involvement and ATTR amyloidosis (Gillmore et al., 2018). Data on survival were available in all cases (median follow-up 27 months). During the observation time 249 patients died (60 ATTRwt and 153 AL pts., 36 other, figure). The most frequent cause of death was amyloidosis itself (n=191, 76,7%). Seven (2,8%) patients died due to therapeutic complications. Compared to ATTRwt patients with cardiac AL amyloidosis had a higher hazard to die, 1 year survival was 78.96% (95% CI 75.23% - 82.88%) compared to 94.30% (95% CI 91.80% - 96.90%), respectively. In multivariate analysis (including age, cardiac staging systems and time from symptoms to diagnosis) factors associated with worse OS were increasing age for AL pts. (HR 1.04, p<0,001 for AL, and highest cardiac stage (HR 2.33, p=0,001 for AL and 5.69, p<0,001 for ATTRwt). Conclusion: The first 2 years of the German clinical amyloidosis registry have been successful to generate valuable clinial data for all types of amyloidosis from newly diagnosed patients. Subtyping the amyloid precursor protein was successful in nearly all patients. The most common form is AL followed by ATTRwt amyloidosis. Heart involvment was very common and pts. were mostly in advanced cardiac stage. Main cause of death was amyloidosis related. In 2020 we have started an extended registry (financially supported by Janssen) including anonymized biopsy reports from reference pathologists. With this approach we will probably obtain more precise data on incidence in Germany. Figure 1 Figure 1. Disclosures Hegenbart: Alnylam: Honoraria; Akcea: Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding. Carpinteiro: Janssen: Honoraria; BMS: Honoraria; GSK: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Müller-Tidow: Pfizer: Research Funding; Bioline: Research Funding; Janssen: Consultancy, Research Funding. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding.