Transthyretin-related Amyloidosis Research Articles

Glu89Gln transthyretin-related amyloidosis in Italy and Bulgaria: does geographic area influence phenotype beyond the shared mutation?

Background Glu89Gln transthyretin (TTR) variant is a well-known cause of systemic amyloidosis with a cardiologic, neurologic or mixed phenotype. Even though Glu89Gln transthyretin (TTR) variant has been described worldwide, it remains unknown whether geographical area influences the phenotypic expression of the disease (as happens with the Val30Met mutation, which is known to manifest with different phenotypes in different geographical contexts). We hypothesized that significant phenotypic differences exist between patients with Glu89Gln-related amyloidosis according to the specific geographic origin.

Cardiologic Phenotypes and Natural History of FAC

Fifty years ago, the focus on the Val30Met type of the disease, in which neurologic manifestations predominate, led to the widespread notion that hereditary transthyretin-related amyloidosis (ATTR) was essentially a neurologic disease. It is now clear that ATTR is extremely heterogeneous on both genotypic and phenotypic grounds. The clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to strictly cardiac manifestations. This heterogeneity is linked to several factors including specific transthyretin mutations, geographic distribution and endemic vs. non-endemic aggregation type. The existence of exclusively or predominantly cardiac phenotypes makes the recognition of the disease very challenging since it can mimic other more common causes of left ventricular “hypertrophy”. Assessment of such patients should include an active search for possible red flags that can indicate the correct final diagnosis. More in general the clinician must be aware that: • Cardiac amyloidosis (CA) should be suspected in any patient with heart failure, unexplained increased LV wall thickness and non-increased end systolic left ventricular volume • In a patient with an initial diagnosis of hypertrophic cardiomyopathy (HCM), look for the infiltrative phenotype hidden beneath the hypertrophic one! • A distinctive sign of CA is the abnormal ratio between left ventricular thickness and QRS voltages rather than low QRS voltages, alone. The absence of low QRS voltages doesn’t rule out a CA if the context is otherwise fitting and up to 20% of subjects with CA can have electrocardiographic evidence of left ventricular hypertrophy. • In an elderly man with unexplained concentric left ventricular hypertrophy, especially in the absence of hypertension, always consider the possibility of wtTTR CA! • Amyloidotic cardiomyopathy in an elderly patient with monoclonal gammopathy is not necessarily related to AL: consider the possibility of wTTR + MGUS • Longitudinal LV function can be severely depressed despite a normal LVEF and the myocardial contraction fraction is often low suggesting reduced global myocardial shortening. • Myocardial deformation is reduced in amyloidotic cardiomiopathy but the apex is generally spared • In CA, Gadolinium distribution at MRI is heterogeneous: subendocardial late gadolinium enhancement (LGE) is not the only diagnostic pattern and the absence of LGE does not exclude CA. • Bilateral carpal tunnel syndrome in a man with HCM-like phenotype on echo is highly suggestive of TTR-related CA The natural history of ATTR is only partially known, due to the rarity of the disease and its high genotypic heterogeneity. Patients with ATTR cardiomyopathy have a much more indolent course than those with AL etiology. Progression of neurological disease and heart failure are the leading causes of death. As in AL amyloidosis, in ATTR the presence of cardiac involvement is an incremental risk factor for overall and cardiovascular events. Consequently, non-Val30Met mutations, in which cardiac involvement is more frequent and severe, appear to be associated with a particularly poor prognosis, even after successful OLT . Very little is known about the underlying cause and the incidence of sudden death, which has been reported to be associated with the occurrence of advanced atrioventricular blocks, ventricular tachycardia/fibrillation, or, probably more frequently, electromechanical dissociation.

Rapid detection of wild-type and mutated transthyretins.

Familial amyloid polyneuropathy is caused by a variant transthyretin, which is a serum protein secreted by the liver. We previously reported that mutated transthyretins were detected in serum samples by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). The aim of this study was to evaluate the clinical usefulness of SELDI-TOF MS for diagnosis of transthyretin-related amyloidosis. We used 106 serum samples obtained from patients who were clinically suspected of having amyloidosis between February 2011 and April 2014. SELDI-TOF MS allowed analysis for transthyretin via a 3-h one-step procedure. Of the 106 patients, 51 are transthyretin amyloidosis. Mutated transthyretins were detected in serum samples from 30 of 51 patients with transthyretin amyloidosis. The results of genetic analysis showed that all of those patients had mutations in the transthyretin gene. For all 18 patients with senile systemic amyloidosis of 51 patients with transthyretin amyloidosis, SELDI-TOF MS detected only wild-type transthyretin peaks, not mutated transthyretin peaks. SELDI-TOF MS is a clinically useful tool for diagnosis of transthyretin-related amyloidosis.

A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis.

The mechanisms underlying transthyretin-related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non-amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano-enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis-mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.

A Review of Tafamidis for the Treatment of Transthyretin-Related Amyloidosis.

Transthyretin (TTR)-related amyloidosis (ATTR) is a devastating disease which affects a combination of organs including the heart and the peripheral nerves, and which has a fatal outcome if not treated within a average of 10 years. Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR; tafamidis therefore has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation. The first tafamidis trial, Fx-005, evaluated the effect of 18 months of tafamidis treatment (20 mg once daily) on disease progression, as well as assessing its safety in TTR-FAP Val30Met patients. The secondary objective of this trial was to study the pharmacodynamic stabilization of mutated TTR. Tafamidis proved effective in reducing the progress of neuropathy, and in maintaining the nutritional status and quality of life of stage 1 (able to walk without support) Val3OMet TTR-FAP patients. Furthermore, TTR stabilization was achieved in more than 90% of patients. An extension study, Fx-006, was conducted to determine the long-term safety and tolerability of tafamidis and to assess the efficacy of the drug on slowing disease progression. No significant safety or tolerability issues were noticed. Taken together, the results from both trials indicated that the beneficial effects of tafamidis were sustained over a 30-month period and that starting treatment early is desirable. Results are expected from an extended open-label study but data that have already been presented show that long-term use of tafamidis in Val30Met patients is associated with reduced progression in polyneuropathy. Tafamidis was initially approved for commercial use in Europe in 2011 and has since been approved for use in Japan, Mexico, and Argentina where it is used as a first-line treatment option for patients with early-stage TTR-FAP. Patients should be carefully followed at referral centers to ascertain the individual response to treatment. In cases of discontinuation, liver transplantation and enrollment in clinical trials of novel drugs aimed mostly toward suppression of TTR production are options.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-015-0031-3) contains supplementary material, which is available to authorized users.

Autonomic neurophysiological evaluation in Transthyretin-related amyloidosis: heart rate variability is impaired mostly in patients with absent sympathetic skin response (P1.288)

Autonomic neurophysiological evaluation in Transthyretin-related amyloidosis: heart rate variability is impaired mostly in patients with absent sympathetic skin response (P1.288)

Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases

Purpose: Assessment of ocular involvement in transthyretin-related familial amyloidosis with polyneuropathy (FAP) in a large cohort of Portuguese patients.Methods: We reviewed the medical records of 513 Portuguese FAP mutation carriers, at the Ophthalmology Service, Centro Hospitalar do Porto, between 1 January 2008 and 31 January 2013. Abnormal conjunctiva vessels (ACV), Schirmer test, tear break-up time (TBUT), amyloid deposition on the iris (DAI), scalloped iris, amyloid deposition on the anterior capsule of the lens (DAL), vitreous amyloidosis, retinal amyloid angiopathy and glaucoma were evaluated and registered.Results: Of the 513 carriers, 477 (93%) had clinical systemic disease with a median duration of 9.3 (5.1–13.7) years and 247 were men. Of these, 343 (72%) had been liver transplanted, on median of 6.6 (3.3–10.8) years before inclusion in this study. No ocular abnormalities were identified in the asymptomatic carriers (7%). The abnormalities observed with decreasing frequency were abnormal TBUT (379 patients, 79.5%, 751 eyes), abnormal Schirmer test (320 patients, 67%, 635 eyes), DAI (183 patients, 38.4%, 350 eyes), DAL (157 patients, 32.9%, 308 eyes), scalloped iris (133 patients, 27.9%, 238 eyes), glaucoma (97 patients, 20%, 165 eyes), vitreous amyloidosis (83 patients, 17.4%, 139 eyes), ACV (68 patients, 14%, 136 eyes) and amyloidotic retinal angiopathy (21 patients, 4%, 32 eyes).Patients with abnormal Schirmer test (p < 0.001), scalloped iris (p = 0.006) and vitreous amyloidosis (p = 0.007) were significantly older than the others. According to their age of onset of systemic disease, the patients have been split into early-onset (<40 years old), intermediate-onset (40–50 years old), late onset (>50 years old) and asymptomatic carriers. We observed a statistically significant difference in the prevalence of ACV (p = 0.045) and of an abnormal Schirmer test (p = 0.004) between groups. Transplanted patients have a significantly higher prevalence of DAI (p = 0.001), DAL (p = 0.009) and vitreous amyloidosis (p = 0.025) than non-transplanted patients. Of the 165 eyes with glaucoma, 92.1% had scalloped iris (p < 0.001) and of 32 eyes with retinal amyloidotic angiopathy, 68.8% had vitreous amyloidosis (p < 0.001). All prevalences increased with time of disease. The earliest ocular manifestations were abnormal Schirmer test and abnormal TBUT (12% and 17% at 5 years of clinical disease) and the least prevalent was retinal amyloid angiopathy (8% at 15 years of clinical disease).Conclusion: Ocular disorders in FAP patients are common, and their prevalence increases with disease duration. Prevalence is influenced by several factors, such as the age at onset of FAP and liver transplantation.

MODIFIED BMI DOES NOT PREDICT ADVERSE OUTCOMES IN PATIENTS WITH CARDIAC AMYLOID UNDERGOING HEART TRANSPLANTATION: A REPORT FROM ICCAT (INTERNATIONAL CONSORTIUM FOR CARDIAC AMYLOID TRANSPLANTATION)

Modified body mass index (mBMI), (BMI × serum albumin) predicts clinical outcomes after liver-transplant for transthyretin-related amyloidosis (ATTR). We sought to evaluate the utility of mBMI to predict outcomes in patients with cardiac amyloidosis undergoing orthotopic heart transplantation (OHT

Clinical features and outcomes of systemic amyloidosis with gastrointestinal involvement: a single-center experience

Background/AimsThe gastrointestinal (GI) tract often becomes involved in patients with systemic amyloidosis. As few GI amyloidosis data have been reported, we describe the clinical features and outcomes of patients with pathologically proven GI amyloidosis.MethodsWe identified 155 patients diagnosed with systemic amyloidosis between April 1995 and April 2013. Twenty-four patients (15.5%) were diagnosed with GI amyloidosis using associated symptoms, and the diagnoses were confirmed by direct biopsy.ResultsAmong the 24 patients, 20 (83.3%) had amyloidosis light chain (AL), three (12.5%) had amyloid A, and one (4.2%) had transthyretin-related type amyloidosis. Their median age was 57 years (range, 37 to 72), and 10 patients were female (41.7%). The most common symptoms of GI amyloidosis were diarrhea (11 patients, 45.8%), followed by anorexia (nine patients, 37.5%), weight loss, and nausea and/or vomiting (seven patients, 29.2%). The histologically confirmed GI tract site in AL amyloidosis was the stomach in 11 patients (55.0%), the colon in nine (45.0%), the rectum in seven (35.0%), and the small bowel in one (5.0%). Patients with GI involvement had a greater frequency of organ involvement (p = 0.014). Median overall survival (OS) in patients with GI involvement was shorter (7.95 months; range, 0.3 to 40.54) than in those without GI involvement (15.84 months; range, 0.0 to 114.53; p = 0.069) in a univariate analysis. A multivariate analysis of prognostic factors for AL amyloidosis revealed that GI involvement was not a significant predictor of OS (p = 0.447).ConclusionsThe prognosis of patients with AL amyloidosis and GI involvement was poorer than those without GI involvement, and they presented with more organ involvement and more advanced disease than those without organ involvement.

Coexistence of degenerative aortic stenosis and wild type transthyretin-related cardiac amyloidosis: a potentially dangerous association that can be non-invasively identified

Background Degenerative aortic stenosis (AS) and wild type transthyretin (TTR)-related cardiac amyloidosis (wt-ATTR) share a common demographic and clinical profile. It has been recently suggested that the coexistence of wt-ATTR could negatively influence the outcome of elderly patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). TTR-related cardiac amyloidosis can be accurately identified by technetium-99m-3, 3-diphosphono-1, 2 propanodicarboxylic acid (99mTc-DPD) scintigraphy. We decided to investigate the coexistence of cardiac amyloidosis in elderly patients with aortic stenosis referred for aortic valve replacement (TAVR or surgery).

Cardiac involvement and clinical follow up of patients with hereditary transthyretin related amyloidosis associated with Glu89Gln mutation

Cardiac involvement and clinical follow up of patients with hereditary transthyretin related amyloidosis associated with Glu89Gln mutation

Cardiac amyloidosis detected on tc-99m bone scan.

Cardiac amyloidosis is an important cause of restrictive cardiomyopathy and congestive heart failure. There are two major types of cardiac amyloidosis: cardiac amyloid light-chain (AL) and transthyretin-related cardiac amyloidosis (ATTR) [1, 2]. The treatment options and prognosis for these two subtypes are different. The AL subtype cardiac amyloidosis is associated with greater than 50 % mortality within 6 months after the diagnosis, while the ATTR subtype has a more favorable prognosis of 98–100 % 2-year survival [3, 4]. Therefore, differentiating the type of cardiac amyloidosis (AL vs. ATTR) is crucial in guiding patient care. Due to its variable clinical symptoms, as well as the nonspecific ECG and echocardiographic presentations, cardiac amyloidosis is a diagnostic challenge and usually underdiagnosed [5, 6]. Endomyocardial biopsy remains the gold standard for diagnosis (Fig. 1). Fig. 1 A 68-year-old male with prostate cancer underwent a bone scan for disease staging. Diffuse cardiac uptake of the bone-seeking radiotracer, Tc-99m MDP (methylene diphosphonate), was incidentally found (arrow, a: bone scan). Given the patient’s ... Perugini et al. [7] demonstrated Tc-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-99m DPD) bone scan findings among patients with cardiac amyloidosis of ATTR (n = 15) and AL (n = 10) subtypes in which cardiac Tc-99m DPD uptake was present in all ATTR patients and absent in all AL patients at visual assessment. Rapezzi et al. [8] evaluated myocardial uptake of Tc-99m DPD in patients with ATTR-related (n = 45, 28 mutant and 17 wild-type) and AL-related (n = 34) cardiac amyloidosis as well as 15 nonaffected controls. On semiquatitative analysis, patients with ATTR had higher visual scoring of cardiac retention (range: score 0, absent cardiac uptake and normal bone uptake; score 1, mild cardiac uptake, inferior to bone uptake; score 2, moderate cardiac uptake accompanied by attenuated bone uptake; score 3, strong cardiac uptake with attenuated bone uptake), with positive and negative predictive values of 88 and 100 % (visual score ≥2). On quantitative analyses, compared to AL and unaffected controls, ATTR patients also had significantly higher (p < 0.0001) heart retention (HR, 7.8 %) and heart-to-whole-body retention ratios (H/WB 10.4), while both unaffected controls (HR 3.5 %; H/WB 5.7) and AL subtypes (HR 4.0 %; H/WB 6.1) were similarly low. Another bone scintigraphic tracer, Tc-99m hydroxymethylene diphosphonate (Tc-99m HDP), has shown high cardiac retention and H/WB ratios in 19 of 30 patients with ATTR cardiac amyloidosis [9]. Bokhari et al. [10] reported that 45 subjects (12 AL, 16 ATTR wild type and 17 ATTR mutants) underwent Tc-99m pyrophosphate (Tc-99m PYP) cardiac imaging. Subjects with ATTR cardiac amyloid had a significantly higher semiquantitative cardiac visual score (range, 0; no uptake to 3, diffuse uptake) than the AL cohort (2.9 ± 0.06 versus 0.8 ± 0.27; P < 0.0001) as well as a higher quantitative score (1.80 ± 0.04 versus 1.21 ± 0.04; P < 0.0001). Using a heart-to-contralateral-lung ratio of 1.5 on Tc-99m PYP cardiac imaging distinguished ATTR amyloidosis (≥1.5) from AL amyloidosis (<1.5), with 97 % sensitivity and 100 % specificity. Sporadic case reports [11, 12] have shown that Tc-99m MDP radiotracers can accumulate in the heart in patients with cardiac amyloidosis; however, there were no corresponding myocardium tissue biopsy results. Our case demonstrated that intense cardiac uptake of Tc-99m MDP correlates with biopsy-proven ATTR cardiac amyloidosis. We think that the preferential binding of Tc-99m MDP to ATTR is similar to those of Tc-99m PYP, Tc-99m DPD (not available in the USA) and Tc-99m HDP, which may be due to the fact that transthyretin amyloid fibrils have higher calcium contents. Given its universal availability, Tc-99m MDP imaging may serve as a noninvasive adjunct in the differential diagnosis of cardiac amyloid.

Contemporary treatment of amyloid heart disease.

The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied.

Pathophysiology and treatment of cardiac amyloidosis.

Amyloid cardiomyopathy should be suspected in any patient who presents with heart failure and preserved ejection fraction. In patients with echocardiographic evidence of ventricular thickening and without a clear history of hypertension, infiltrative cardiomyopathy should be considered. If imaging suggests the presence of amyloid deposits, confirmation by biopsy is required, although endomyocardial biopsy is generally not necessary. Assessment of aspirated subcutaneous fat and bone-marrow biopsy samples verifies the diagnosis in 40-80% of patients, dependent on the type of amyloidosis. Mass spectroscopy can be used to determine the protein subunit and classify the disease as immunoglobulin light-chain amyloidosis or transthyretin-related amyloidosis associated with mutant or wild-type TTR (formerly known as familial amyloid cardiomyopathy and senile cardiac amyloidosis, respectively). In this Review, we discuss the characteristics of cardiac amyloidosis, and present a structured approach to both the assessment of patients and treatment with emerging therapies and organ transplantation.

The “Wagshurst study”: p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy

Background: Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant.Methods and results: This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and 99mTc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by 99mTc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade (n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0–108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%.Conclusions: This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long-term survival rates.

CARDIAC AND EXTRACARDIAC AMYLOIDOSIS IN V122I ATTR

IntroductionHereditary transthyretin-related amyloidosis (ATTR) is a genetically heterogenous disease which may present with a predominant peripheral and autonomic neuropathy, a cardiac myopathy, or with both neurological and cardiac involvement. The...

Familial amyloid polyneuropathy: elaboration of a therapeutic patient education programme, “EdAmyl”

Background: Transthyretin-related amyloidosis (ATTR) is an autosomal dominant disease affecting the peripheral and autonomic nervous system, heart, eyes and kidneys. It is the most disabling hereditary polyneuropathy in adults. The French National Reference centre for this disease was accredited in 2005 with 10 lines of action. One of them is to inform and educate patients about their disease to improve their care and reduce morbidities. We thus decided to elaborate a therapeutic patient education (TPE) programme, starting with patients’ needs assessment.Methods: A qualitative research study was conducted with one-to-one semi-structured interviews of selected individuals. Recorded interviews were analysed to identify the skills that patients need to acquire. A TPE programme was elaborated on the basis of these findings.Results: Seven patients, one asymptomatic carrier and two healthy spouses were interviewed. Analysis of the interviews showed that interviewees had a good knowledge of the disease and its symptoms but they had difficulties explaining the disease mechanism and did not have an adequate knowledge of the available treatment options, although they knew that liver transplant might halt progression of the disease. ATTR amyloidosis appeared to have a major negative impact on the patient’s physical and mental well-being. Patients feared loss of autonomy and having to require assistance from their relatives and spouses. All interviewees were keen to participate in a TPE programme. Based on this needs assessment, we identified seven skills that patients need to acquire and several pedagogical goals to be achieved during the education programme. An interdisciplinary team then elaborated a complete TPE programme.Conclusion: Elaboration of a TPE programme for ATTR amyloidosis required to obtain useful information from the patients themselves, and their relatives, concerning their perception of their disease. This needs’ assessment constituted the basis for designing the first TPE programme, to our knowledge, for ATTR amyloidosis. After translation, this programme could be applied in other EU countries and worldwide for this rare disease.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

In silico analysis of TTR gene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis

Introduction: Transthyretin (TTR)-related amyloidosis is a life-threatening disease. Currently, several questions about the pathogenic mechanisms of TTR-related amyloidosis remain unanswered.Methods: We have investigated various TTR-related issues using different in silico approaches.Results: Using an amino acid similarity-based analysis, we have indicated the most relevant TTR secondary structures in determining mutation impact. Our amyloidogenic propensity analysis of TTR missense substitutions has highlighted a similar pattern for wild-type and mutated TTR amino β acid sequences. However, some mutations present differences with respect to the general distribution. We have identified non-coding variants in cis-regulatory elements of the TTR gene, and our analysis on V122I-related haplotypes has indicated differences in non-coding regulatory variants, suggesting differences among V122I carriers. The analysis of methylation status indicated CpG sites that may affect TTR expression. Finally, our interactive network analysis revealed functional partners of TTR that may play a modifier role in the pathogenesis of TTR-related amyloidosis.Discussion and conclusion: Our data provided new insights into the pathogenesis of TTR-related amyloidosis that, if they were to be confirmed through experimental investigations, could significantly improve our understanding of the disease.

Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators

To attain functionality, proteins must fold into their three-dimensional native state. The intracellular balance between protein synthesis, folding, and degradation is constantly challenged by genetic or environmental stress factors. In the last ten years, protein misfolding induced by missense mutations was demonstrated to be the seminal molecular mechanism in a constantly growing number of inborn errors of metabolism. In these cases, loss of protein function results from early degradation of missense-induced misfolded proteins. Increasing knowledge on the proteostasis network and the protein quality control system with distinct mechanisms in different compartments of the cell paved the way for the development of new treatment strategies for conformational diseases using small molecules. These comprise proteostasis regulators that enhance the capacity of the proteostasis network and pharmacological chaperones that specifically bind and rescue misfolded proteins by conformational stabilization. They can be used either alone or in combination, the latter to exploit synergistic effects. Many of these small molecule compounds currently undergo preclinical and clinical pharmaceutical development and two have been approved: saproterin dihydrochloride for the treatment of phenylketonuria and tafamidis for the treatment of transthyretin-related hereditary amyloidosis. Different technologies are exploited for the discovery of new small molecule compounds that belong to the still young class of pharmaceutical products discussed here. These compounds may in the near future improve existing treatment strategies or even offer a first-time treatment to patients suffering from nowadays-untreatable inborn errors of metabolism.