Clinical characterization of patients with cardiac amyloidosis in a referral center of Colombia.

Objective: The objective of the study is to describe the characteristics of our first cohort of amyloidosis in a Latin America cardiovascular reference center in Colombia. Methods: This is a historic cohort study and data were taken from the electronic records of the Fundación Cardioinfantil-Instituto de cardiología; adult patients with a diagnosis of cardiac amyloidosis were included and a descriptive analysis was presented. Results: A total of 31 patients with amyloidosis were included. 17 were Transthyretin Amyloidosis (ATTR) subtype and 14 were AL subtype. An overall mortality of 25% was found. The mean age at diagnosis was 74 years, male sex predominant. More frequent comorbidities were hypertension and atrial fibrillation. The most frequent clinical presentation was congestive heart failure (75%), with mildly reduced ejection fraction (41.94%), followed by reduced ejection fraction (32.26%), and preserved ejection fraction (25.81%). In the ATTR subtype, a reduced ejection fraction was found at 41.18% and a mildly reduced ejection fraction at 35.29%. Conclusion: These results provide information on the most frequent type of amyloidosis and the late timing to diagnose in our historic cohort study, we present some of the baseline characteristics and most frequent approaches to diagnose Cardiac Amyloidosis that represents all challenges in clinical practice. Improvements are needed in the diagnosis and early treatment of these patients.

Objetivo: Describir las características de nuestra primera cohorte de amiloidosis en un centro de referencia cardiovascular de Latinoamérica en Colombia. Métodos: Los datos fueron tomados de los registros electrónicos de la Fundación Cardioinfantil- Instituto de cardiología; Se incluyeron pacientes adultos con diagnóstico de amiloidosis cardíaca y se presenta un análisis descriptivo. Resultados: Se incluyeron un total de 31 pacientes con amiloidosis. 17 eran ATTR y 14 eran AL. Se encontró una mortalidad global del 25%. La edad media al diagnóstico fue de 74 años, predominando el sexo masculino. Las comorbilidades más frecuentes fueron Hipertensión y Fibrilación auricular. La presentación clínica más frecuente fue insuficiencia cardíaca congestiva (75%), con fracción de eyección levemente reducida (41.94%), seguida de fracción de eyección reducida (32.26%) y fracción de eyección preservada (25.81%). En el subtipo ATTR, la fracción de eyección reducida se encontró en el 41.18% y la fracción de eyección levemente reducida en el 35.29%. Conclusión: Estos resultados brindan información sobre el tipo de amiloidosis más frecuente y el momento del diagnóstico, el cual fue tardío en nuestra cohorte, su prevalencia en el sexo masculino (61.29%), edad promedio al diagnóstico de 74 años, principal presentación clínica y abordaje más frecuente, mostrando el desafío que representa en la práctica clínica llegar al diagnóstico. Se necesitan mejoras en el diagnóstico y tratamiento precoz de estos pacientes.

Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil (REACT-SP).

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil. RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Ultrasonographic nerve enlargement in post-transplanted patient with hereditary transthyretin amyloidosis.

A 43-year-old male patient with a 7-year history of liver transplantation due to p.Val50Met hereditary transthyretin amyloidosis (ATTRv) persisted with refractory neuropathic pain, distal weakness, and progressive worsening of dysautonomia. Nerve ultrasound was performed showing increased nerve cross-sectional area and enlarged fascicles in proximal sites in both arms, suggestive of amyloidosis. Nerve enlargement is commonly reported in inflammatory and hereditary demyelinating hypertrophic neuropathies but can also be present in deposition diseases. Neuromuscular ultrasound is a tool for the bed-side assessment of peripheral neuropathies and it is useful for early diagnosis of ATTRv.

TRANSTHYRETIN AMYLOIDOSIS THERAPIES: GUIDING THE FUTURE.

Transthyretin (TTR) amyloidosis (ATTR) is a progressive condition characterized by multiorgan accumulation of amyloid deposits composed of transthyretin (TTR) fibrils. Over the past decades, despite being a rare disease, ATTR amyloidosis has enabled top-tier therapeutics. In the 90s, organ transplantation was the mainstream therapeutic option and fostered distinct approaches, such as combined liver-heart transplant and domino (sequential) liver transplantation. Likewise, several TTR molecule stabilizers were developed successfully. Over the past decade, oriented genetic therapies emerged to prevent, control, and, surprisingly, reverse amyloid deposition. Silencing the TTR gene using different strategies is flourishing, and ongoing trials continue to evaluate diverse approaches to optimize their application. The following perspective describes the currently available treatments for ATTR amyloidosis and the prospects on the potential application of these strategies in other medical fields.

Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy.

Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

Excisional goniotomy with Kahook Dual Blade in a patient with glaucoma secondary to Transthyretin Amyloidosis.

PURPOSE: To report for the first time the successful use of the Kahook Dual Blade excisional goniotomy technique in a patient with Transthyretin Amyloidosis. PATIENT AND METHODS: The Kahook Dual Blade is a single use ab interno trabeculectomy device that removes the trabecular meshwork reducing aqueous humor outflow resistance. A patient with Transthyretin Amyloidosis underwent this procedure. RESULTS: Ab interno goniotomy with Kahook Dual Blade was a successful surgical solution to reduce intraocular pressure in a patient with Transthyretin Amyloidosis secondary glaucoma controlling IOP in association with topical hypotensors for at least 6 months. CONCLUSIONS: Ab interno goniotomy with Kahook Dual Blade is a surgical option for this type of glaucoma, that treats the main site of aqueous outflow resistance in this pathology with the advantage of being minimally invasive.

Late-onset hereditary ATTR V30M amyloidosis with polyneuropathy: Characterization of Brazilian subjects from the THAOS registry.

BACKGROUND: Despite growing numbers of patients diagnosed with late-onset hereditary ATTR V30M amyloidosis with polyneuropathy (ATTRv-PN), this condition remains poorly characterized in Brazil. OBJECTIVE: Characterize late-onset V30M ATTRv-PN in Brazil. MATERIAL AND METHODS: Demographic and clinical data at the time of enrolment for Brazilian subjects with symptomatic V30M ATTRv-PN were extracted from the ongoing, multinational, longitudinal, observational Transthyretin Amyloidosis Outcomes Survey (THAOS; cut-off date: January 30, 2017). Subjects were divided into those with symptom onset at age <50 years (EO-V30M), and at age ≥50 years (LO-V30M). RESULTS: A total of 96 Val30Met patients were symptomatic. LO-V30M (n = 25, 26.0%) had a longer time to diagnosis (mean 5.1 vs. 2.8 yrs.; p = 0.006) and less frequently positive family history (40% vs. 95.8%; p < 0.0001) than EO-V30M. Clinically, subjects with LO-V30M had more imbalance (92% vs. 54.9%; p = 0.006), deep sensory loss (100% vs. 80%; p = 0.0178), electrocardiogram abnormalities (88.9% vs. 59.4; p = 0.0241), and interventricular septum hypertrophy (69.2% vs. 0%; p < 0001) and less frequently sensory dissociation (12% vs. 74%; p < 0.0001). Also, LO-V30M tended to have more severe mean Neurologic Composite Score (101 vs. 70 pts.; p = 0.1136). CONCLUSIONS: LO-V30M ATTRv-PN is not unusual in Brazil, tending to be more difficult to diagnose and present with a more severe phenotype, with more large nerve fibers and cardiac involvement than EO-V30M. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745.

Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series.

We describe 542 cases of symptomatic hereditary transthyretin amyloid polyneuropathy (ATTR-PN) identified through a review of the literature published between 2005 and 2016. Approximately 18% of the cases were from countries where ATTR-PN is traditionally considered to be endemic (i.e., Portugal, Japan, and Sweden). East Asia (Japan, China, Taiwan, and South Korea) contributed a sizeable combined proportion (37.0%, n = 200) with Japan (n = 92) and China (n = 71) being the primary contributors. The most common genotypes among the 65 genotypes represented in the sample were Val30Met (47.6%), Ser77Tyr (10%), Ala97Ser (6.5%), and Phe64Leu (4.4%). Cases with genotypes other than the aforementioned four had the lowest ages at onset (mean 49.2 [standard deviation {SD} 21.0; inter-quartile range {IQR}14.7]) and diagnosis (mean 53.4 [SD 21.0; IQR 14.7]). Conversely, Phe64Leu mean age of onset was 67.5 (SD 8.8; IQR 5.2) and mean age of diagnosis was 71.3 (SD 8.8; IQR 5.4). The prevalence of upper and lower limb involvement at the time of diagnosis (67 and 41%) observed across all cases is consistent with the typical presentation of ATTR-PN. Other notable findings at the time of diagnosis included a high rate of impotence among the Ala97Ser cases versus all others (67% vs. 21%) and a high rate of non-motor visual symptoms (i.e., visual opacities and glaucoma) in the Ser77Tyr cases versus all others (93% vs. 16%). Though comparisons were made descriptively and were hindered by inconsistency of reporting across the cases, these findings support the notion that ATTR-PN is a more phenotypically and geographically variable disease than is typically considered.

The genetic heterogeneity of hereditary transthyretin amyloidosis in a sample of the Brazilian population.

To present the genetic heterogeneity of a sample of the Brazilian population with transthyretin (TTR) mutations. This cohort study was descriptive and retrospective, and enrolled patients with peripheral neuropathy of unknown cause that were found to have a mutation in the TTR gene during the process of etiological investigation, between July 1997 to January 2016. Over the study period, 129 point mutations were identified in 448 tested patients, of whom 128 were of Brazilian origin. The TTR Val30Met mutation was identified in 116 patients (90.6%); while 7 (4.7%) patients had a pathogenic non-TTR mutation and 7 (4.7%) carried non-pathogenic mutations (4.7%). The four non-TTRMet30 pathogenic mutations were TTR Aps38Tyr; TTR Ile107Val; TTR Val71Ala; and TTR Val122Ile. In the non-pathogenic group, we only found two mutations, including TTR Gly6Ser and TTR Thr119Thr. Our study depicts a scenario of greater genetic heterogeneity among Brazilian hereditary transthyretin amyloidosis (hATTR) patients with familial amyloidotic polyneuropathy (FAP). We expect that this number will grow fast over a short period of time, due to increasing availability of genetic tests, increasing knowledge of the disease and the multivariate origin of our population.

Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy.

Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and -7.8 (-44.3, 28.8) kg/m2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. TRIAL REGISTRATION: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.

Amiloidose familiar por transtirretina TTR Val30Met e os primórdios do Centro de Estudos de Paramiloidose Antonio Rodrigues de Mello / Principles of the Familial transthyretin amyloidosis TTR Val30Met and the beginning of the Paramyloidosis Center of Antonio Rodrigues de Mello

Objetivos: considerar as etapas de desenvolvimento do conhecimento sobre a Polineuropatia amiloidótica familiar de Corino Andrade, atualmente conhecida como Amiloidose familiar por transtirretina (TTR) TTR Val30Met - AFTTTRVal30Met; registrar os primórdios e os princípios fundamentais do Centro de Estudos de Paramiloidose Antonio Rodrigues de Mello (CEPARM) de atendimento aos sofredores de doença de herança autossômica dominante sistêmica e com polineuropatia de predomínio sensitivo-motora-autonômica; rever aspectos atuais sobre a doença, etiológicos, epidemiológicos, clínicos, diagnósticos e terapêuticos. Método: Revisão narrativa sobre a AFTTTRVal30Met baseada em: documentos da época da fundação do CEPARM e de seis casos iniciais (além de outros 23 arrolados pelo Centro Português); artigos recentes. Resultados: Três momentos básicos são registrados no desenvolvimento do conhecimento sobre os doentes: 1-o inicial, clínico-patológico (1939-52); 2-da abordagem multiprofissional (1952-80); 3-de melhor conhecimento da sua fisiopatogenia e tentativa de debelá-la ou abrandá-la, aí mencionadas as revelações genômicas e o papel da TTR mutante (TTRm) (1980-91); 4-a partir do transplante hepático e evolução do conhecimento sobre a TTRm (1991-). A criação do CEPARM surgiu na confluência dos momentos dois e três: necessidade de contemplar o atendimento integral aos sofredores da doença ultrapassando a etapa diagnóstica, e início da definição da pré-albumina anômala (TTRm). Conclusão: a abordagem multidisciplinar continua a ser a meta de atendimento aos pacientes com PAF, além das iniciativas ao aprimoramento terapêutico, diagnóstico e profilático da doença, dependentes da aliança com áreas de pesquisa das ciências biológicas.

Objective: to consider the development stages of the knowledge about the Familial amyloid neuropathy of Corino Andrade, currently known as Familial transthyretin (TTR) amyloidosis TTR Val30Met - FTATTR Val30Met; to register the beginnings and the basic principles of the Center of Studies of Paramyloidosis Antonio Rodrigues de Mello (CEPARM) of the disease sufferers consultations: systemic disease, autosomal dominant inheritance, sensorial-motor and autonomic polyneuropathy; to review the current state of knowledge on the illness, etiologic, clinical, epidemiologic, diagnostic and therapeutic. Method: Narrative review about FTAVal30Met based on: documents at the time of CEPARM foundation and the initial cases (beyond 24 others enrolled by the Portuguese Center); recent articles. Results: in the development of the knowledge on the mentioned patients: 1-initial, medical-pathological one (1939-52); 2-of multiprofessional approach (1952-80); 3 of better knowledge of its physiopathogeny and attempt to reduce or eradicate it, the genomics revelations and the paper of the mutant TTR (TTRm) (1980-91); 4-from the first liver transplant and the increasing knowledge about the TTRm (1991-). The creation of the CEPARM appeared in the confluence of moments two and three: necessity to contemplate the integrated management of the patients exceeding the diagnostic stage, and the beginning of the definition of the anomalous pre-albumin (TTRm). Conclusion: the patients' multidisciplinary approach continues to be the main goal of their management, besides the initiatives to improve therapeutic, diagnostic and prophylactics goals, based on the alliance between basic and clinical sciences.