Mutations In Transthyretin Gene Research Articles

Epidemiology, diagnosis, and management of cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium. It manifests in two primary subtypes: transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further classified into wild-type and hereditary based on transthyretin gene mutation. Advances in diagnostics and therapeutics have transformed CA from a rare and untreatable condition to a more prevalent and manageable disease. Noninvasive diagnostic tools such as electrocardiography, echocardiography, and cardiac magnetic resonance can raise suspicion for CA; bone scintigraphy can non-invasively confirm ATTR, while AL necessitates histological confirmation. The severity of ATTR and AL can be assessed through serum biomarker-based staging. Treatment approaches differ, ranging from silencing or stabilizing transthyretin and degrading amyloid fibrils in ATTR to employing anti-plasma cell therapies and autologous stem cell transplantation in AL.

Palinacousis in amyloidosis: exploring the hallucinatory phenomenon in brain pathology—a case report

BackgroundHereditary transthyretin amyloidosis, caused by transthyretin gene mutations, progresses with systemic impact and often presents peripheral neuropathy. Recent research reveals central nervous system involvement, marked by leptomeningeal amyloid accumulation and transient focal neurological episodes displaying cortical dysfunction.Case presentationA 47-year-old Caucasian man with hereditary transthyretin amyloidosis presented with motor aphasia, right hemiparesis, fever, and an altered state of consciousness. Tests ruled out stroke or infection. While improving, the patient reported an ongoing auditory repetition phenomenon for 48 hours despite efforts to shift focus or introduce new stimuli.ConclusionThis represents the first known case report documenting palinacousis in hereditary transthyretin amyloidosis attributed to central nervous system involvement. This case highlights the complexities in assessment and management of patients when neurological and psychiatric symptoms overlap.

DON’T FORGET ABOUT CARDIAC AMYLOIDOSIS: WHEN RED FLAGS MATTER

Abstract Case Report A 78–year–old man came to our attention for worsening dyspnea, asthenia and frequent lipothymic episodes in the last few weeks. Nothing remarkable was reported in anamnesis except for periodic cardiological check–ups ascribed to hypertensive heart disease and moderate aortic stenosis. Other cardiovascular risk factors were obesity, previous smoking habits and dyslipidemia. A recent 24–hours ECG monitoring revealed slow permanent atrial fibrillation (AF) with 3–seconds pauses, frequent premature ventricular complexes (PVCs) and some PVCs couplets. On arrival, NT–proBNP was elevated (2952 pg/mL), while ECG showed AF with a heart rate of 50/m and low voltages in peripheral leads. Transthoracic echocardiogram revealed a biatrial dilatation, a severe left ventricular (LV) concentric hypertrophy with a preserved LV ejection fraction (EF) and a moderate aortic stenosis. In addition, a restrictive LV filling pattern, a decreased longitudinal myocardial contraction and an apical sparing of longitudinal strain were reported. Invasive coronary angiography was performed with evidence of normal coronary arteries. Given the echocardiographic suspicion of amyloidosis, a 99mTc–Hydroxymethylene diphosphonate (HMDP) scintigraphy was performed, showing a moderate cardiac uptake and an attenuated bone uptake (Perugini Score 2). Serum and urine immunofixation resulted negative. Genetic testing did not find any mutations in Transthyretin (TTR) gene. Therefore, the diagnosis of TTR wild–type amyloidosis was made. Before discharge, putting it all together, we opted to implant a leadless pacemaker in order to protect the patient from life–threatening bradyarrhythmias. Discussion Although it is currently considered rare, there is growing evidence that cardiac amyloidosis may be more common than once thought. First of all, it should be investigated in HFpEF–patients (heart failure with preserved EF) with LV hypertrophy. Despite several red flags (low QRS voltages, conduction disorders, elevated NT–proBNP, severe LV hypertrophy and aortic stenosis) and various medical consultations, our patient had to wait 4 years or more to be diagnosed with cardiac amyloidosis. Inevitably, a diagnostic delay means loss of time in treatment initiation. Earlier diagnosis would enable us to improve our patients’ survival and heart failure hospitalization. Awareness alone is not enough, we must be right on target too.

Hereditary Transthyretin Amyloidosis: How to Differentiate Carriers and Patients Using Speckle-Tracking Echocardiography.

Hereditary transthyretin amyloidosis is a rare disease caused by transthyretin (TTR) gene mutations. The aim of our study was to identify early signs of cardiac involvement in patients with a TTR gene mutation in order to differentiate carriers from patients with neurological or cardiac disease. A case-control study was carried out on 31 subjects with the TTR mutation. Patients were divided into three groups: 23% with cardiac amyloidosis and polyneuropathy (group A), 42% with only polyneuropathy (group B) and 35% carriers (group C). Speckle-tracking echocardiography (left-ventricular global longitudinal strain-GLS, atrial stiffness) was performed in all patients. The apical/basal longitudinal strain ratio (SAB) and relative apical sparing (RAS) were assessed in all subjects. Analyzing groups C and B, we only found a significant difference in the SAB (p-value 0.001) and RAS (p-value 0.039). These parameters were significantly more impaired in group A compared to group B (SAB p-value 0.008; RAS p-value 0.002). Also, atrial stiffness was significantly impaired in groups A and B compared to group C. Our study suggests the diagnostic role of the SAB and RAS in cardiac amyloidosis. The SAB and RAS showed a gradual increase from carriers to patients with neurological and cardiac diseases. Thus, these parameters, in addition to atrial stiffness, could be used to monitor carriers. More extensive data are needed.

Effect of patisiran on myocardial deformation parameters in patients with hereditary transthyretin amyloidosis

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Hereditary transthyretin amyloidosis (ATTRh) is a rare autosomal dominant disease caused by transthyretin (TTR) gene mutations. It can involve several systems on the basis of ATTR gene variant, age, duration of symptoms before diagnosis. Some TTR gene variants have a predominant cardiological or neurologic or mixed phenotype, therefore patients can have only cardiac amyloidosis or only polyneuropathy or both. Recently several advances have been performed in the diagnosis and treatment of cardiac amyloidosis, especially ATTRh amyloidosis using RNA-targeting and gene editing therapies. Particularly, patisiran is a small interfering RNAs that can be used only in patients with ATTRh polyneuropathy with or without concomitant cardiac amyloidosis (stage 1 or 2). Apollo A trial sub analysis demonstrated protective effects of patisiran on the heart. Purpose To assess the effects of patisiran on cardiac function in patients with ATTRh amyloidosis treated with patisiran. Methods a prospective study was carried out enrolling 31 subjects with ATTRh (20 men, 11 women, median age 61,7 ± 10,45 years old). 7 patients (22,6%) had cardiac amyloidosis plus polyneuropathy; 13 patients (41,9%) had only polyneuropathy without cardiac involvement; 11 patients were carriers without clinical manifestations. All patients except carriers were treated with patisiran. Cardiological evaluation including electrocardiogram and echocardiogram was performed in all patients at the time of enrollment and after an average period of 20 months of patisiran therapy. Comprehensive echocardiographic evaluation included the measurement of left ventricular global longitudinal strain (GLS), relative apical sparing, apical/basal strain ratio, myocardial work index expressed as global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE), left atrial reservoir strain (PALS) and atrial stiffness (LASi). Results the group of patients with only polyneuropathy remained clinically stable over time and all echocardiographic parameters didn’t change significantly. In patients with cardiac amyloidosis, we found a significant improvement in GLS (−12,39±3,31% at baseline vs − 16,32 ± 2,84%, p value 0,03) and in LASI (1,6±0,30 vs 1±0,5, p value 0,01). GWI, GWE and GCW increased during follow-up, GWW reduced but not significantly. Also a reduction in the relative apical sparing (1,08±0,36 vs 1,05±0,25, p value 0,85) and in apical/basal strain ratio (2,5±1,4 vs 2,37±1,59, p value 0,87) was observed. No other significant changes in echocardiographic parameters were found. Conclusion Patisiran seems to be effective in stabilizing cardiac disease in ATTRh, significantly improving GLS and LASI. These new echocardiographic parameters should be used to monitor response to therapy in cardiac amyloidosis. The main limitation of our study is represented by the small sample size and to confirm our results wider studies are awaited.

Right ventricular-dominant transthyretin deposition: an early stage or a rare phenotype of wild-type transthyretin amyloid cardiomyopathy?

An 86-year-old Japanese man was referred to our hospital because of leg oedema. Electrocardiography revealed a right bundle branch block, and transthoracic echocardiography showed a left ventricular septal wall thickness of 15 mm. On cardiovascular magnetic resonance imaging (CMR), late gadolinium enhancement areas and high native T1 value areas extended in the basal region of the left ventricular lateral wall (Panels A and C), the right ventricular (RV) side of the septum, and the RV free wall (Panels B and D). Abnormal accumulation of 99mTc-labelled pyrophosphate (99mTc-PYP) in the myocardium was visualized in concordance with the abnormal areas on CMR (Panels E and F). The patient was diagnosed with wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) due to the histological evidence of transthyretin deposition in the myocardium and no transthyretin gene mutation. In this case, both CMR and 99mTc-PYP scintigraphy, which are reliable imaging tools for transthyretin deposition in the myocardium, revealed RV-dominant transthyretin deposition. Based on the UK ATTR-CM staging system, this case was classified as Stage 1. Since no cases of RV-dominant transthyretin deposition have been reported in the literature, it is unclear whether RV-dominant transthyretin deposition is an early stage or a very rare clinical phenotype of wild-type ATTR-CM. Nonetheless, clinicians should be aware of an RV-dominant transthyretin deposition pattern in wild-type ATTR-CM.

Neuropathic pain experience in symptomatic and presymptomatic subjects carrying a transthyretin gene mutation.

Pain is a common symptom of hereditary transthyretin amyloidosis (ATTRv), however, its occurrence in late-onset ATTRv has not been investigated thoroughly. Our aim was to describe the pain experience and its impact on quality of life (QoL) in symptomatic patients and presymptomatic carriers harboring a transthyretin (TTR) gene mutation with a late-onset phenotype. Study participants (aged ≥18 years) were consecutively recruited from four Italian centers. Clinical disability was assessed using the Familial Amyloid Polyneuropathy (FAP) stage and Neuropathy Impairment Score (NIS). The Norfolk questionnaire evaluated QoL and the Compound Autonomic Dysfunction Test assessed autonomic involvement. Neuropathic pain was screened using the Douleur Neuropathique 4 (DN4) questionnaire, and pain intensity and its impact on daily activity were assessed using the Brief Pain Inventory severity and interference subscores. Data on the type of TTR mutation, presence of cardiomyopathy, treatment, and Body Mass Index (BMI) were collected. Overall, 102 subjects with TTR mutations (mean age ± SD 63.6 ± 13.5 years) were recruited, including 78 symptomatic patients (68.1 ± 10.9 years) and 24 presymptomatic carriers (49 ± 10.3 years). Pain was reported by 75.5% of all subjects, but was more frequent in symptomatic patients than in presymptomatic carriers (85.9 vs. 41.6%, respectively). Pain exhibited neuropathic features (DN4≥4) in 69.2% of symptomatic patients and in 8.3% of presymptomatic carriers. Subjects with neuropathic pain were older (p = 0.015) had worse FAP stage (p < 0.001), higher NIS scores (p < 0.001), greater autonomic involvement (p = 0.003), and a lower QoL (p < 0.001) than those without neuropathic pain. Neuropathic pain was associated with higher pain severity (p < 0.001) and had a significant negative impact on daily activities (p < 0.001) Neuropathic pain was not associated with gender, mutation type, TTR therapy, or BMI. Approximately 70% of late-onset ATTRv patients complained of neuropathic pain (DN4≥4) that worsened as peripheral neuropathy progressed and increasingly interfered with daily activities and QoL. Notably, 8% of presymptomatic carriers complained of neuropathic pain. These results suggest that assessment of neuropathic pain may be useful to monitor disease progression and identify early manifestations of ATTRv.

Leptomeningeal amyloidosis: features of the clinical picture (clinical observation)

Hereditary transthyretin amyloidosis belongs to a group of diseases with an autosomal dominant type of transmission and a heterogeneous clinical picture, which depends on the type of transthyretin gene mutation. The leptomeningeal form is a rare phenotypic variant of amyloidosis with a predominant involvement of brain and spinal cord meninges, as well as cortical meningeal vessels. The main manifestations of this phenotype include cephalalgic syndrome, episodes of acute cerebrovascular accident, hearing impairment, epileptic seizures, progressive cognitive impairment reaching the degree of dementia, impaired consciousness, etc. The article describes a clinical case of revealing of amyloidogenic mutation Ala45Thr with a hereditary family history and typical manifestations of leptomeningeal amyloidosis at the onset of the disease, as well as impaired renal function. Neuroimaging with contrast enhancement revealed a characteristic thickening of the meninges of the spinal cord due to the deposition of amyloid masses.

Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis.

Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland. Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed. In 2017-2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased left ventricular ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke. According to available data, this is the first time that the types of TTR mutations and the clinical characteristics of Polish patients with cardiac hereditary ATTR have been described. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population.

Abstract 14210: Heart Failure Hospitalizations and Mortality Outcomes in PV142I Transthyretin Cardiomyopathy Patients Treated With Tafamidis

Introduction: TTR amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in the geriatric population. The pV142I (V122I) transthyretin gene mutation is carried in 3.4% of African Americans. It is the most common cause of hereditary ATTR-CM (hATTR-CM) in the United States with a median survival of 2.5 years from diagnosis. Tafamidis is a selective transthyretin stabilizer approved in 2019 that has been shown to improve survival in wild type and hereditary ATTR-CM with New York Heart Association class I to III symptoms. The impact of tafamidis treatment on heart failure hospitalization (HFH) and mortality outcomes in pV142I hATTR-CM requires further investigation. Hypothesis: Tafamidis decreases HFH and mortality in pV142I ATTR-CM. Methods: We conducted a retrospective chart review of patients diagnosed with ATTR-CM with pV142I mutations enrolled in Emory University's Cardiac Amyloidosis Clinic between January 2014 and February 2022. Kaplan-Meier (KM) curves stratified by tafamidis use were generated for mortality and first HFH within 2 years of initial diagnosis. Log-rank test was used to compare KM curves. A p-value &lt; 0.05 was considered significant. Results: 111 patients in our study have pV142I hATTR-CM, including 47 (42%) prescribed tafamidis and 64 (58%) who were not prescribed. The median survival was 616 [interquartile range 277-731] days for patients treated with tafamidis and 595 [216, 731] days for untreated patients. The median time to HFH with tafamidis was 464 [167, 685] days and 233 [41, 613] days for untreated patients. Patients with tafamidis use had both lower rate of mortality (p = 0.005) and HFH (p = 0.035) than those who did not. Conclusion: In patients with pV142I hATTR-CM within our cohort, tafamidis use was associated with lower rates of mortality and heart failure hospitalization. These findings are consistent with previously described benefits in a generalized ATTR-CM population.

Analysis of myocardial function by deformation imaging in patients with transthyretin gene mutation

Abstract Introduction Hereditary transthyretin (TTR) amyloidosis is a rare disease that can affect various organs. The early identification of cardiac involvement through echocardiography allows to corroborate the diagnosis and to start therapy at an early stage. Purpose The aim of our study was to detect early signs of cardiac involvement in patients with TTR gene mutation and neurological phenotype or absence of any organ disease (carriers) compared to patients with TTR gene mutation and cardiac amyloidosis (CA). Material and methods An observational study was conducted on a sample of 31 patients with TTR gene mutation. Patients were divided into 3 groups (23% CA, 42% amyloid neuropathy and 35% carriers). All patients underwent echocardiography with evaluation of left ventricular myocardial deformation indices (apical/basal strain ratio and relative apical sparing). Results Carriers and patients with amyloid neuropathy had normal left ventricular systolic and diastolic function. Analyzing left ventricular longitudinal global strain (GLS) we didn't find significant differences between carriers and neuropathy, but we found a significant difference about apical/basal strain ratio and relative apical sparing (respectively 1.33±0.20 vs 1.58±0.25, p value 0.001 and 0.62±0.07 vs 0.72±0.08, p value 0.039). Conclusion Relative apical sparing is specific to identify CA; the apical/basal ratio seems to gradually increase from carriers to patients with cardiac amyloidosis and it could be used to monitor patients with TTR mutation, before developing CA. Funding Acknowledgement Type of funding sources: None.

A multi-modality, multi-parametric phenotyping study of transthyretin amyloid cardiomyopathy associated with the p.V142I TTR variant

Abstract Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3–4% of individuals of African descent carry a transthyretin gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM. This equates to 1.6 million potential carriers in the USA alone. We report findings from a multi-parametric, multi-modality phenotyping study of p.V142I ATTR-CM. Hypothesis The phenotype of p.V142I variant ATTR-CM is an aggressive form of ATTR CM. Methods A retrospective phenotyping study of 395 patients with p.V142I-ATTR-CM at our national referral centre was conducted. Patients underwent evaluation at the centre at time of diagnosis, including clinical and functional assessment, echocardiography, biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of first presentation) were used as a comparator group. Results Average age of pV142I ATTR-CM patients was 75.8 years. There was significant functional impairment (38.2% of cases NHYA ≥ III, mean 6 minute walk test distance 272m). Significant impairment of echocardiographic parameters was seen; mean LVEF 43%, global longitudinal strain −9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid regurgitation (51%). Median NT-proBNP was 3165 ng/L (IQR 4224). Arrhythmias were common with 17.4% of patients having a bradyarrhythmia, 26.1% having atrial fibrillation/flutter, and 5.6% having a pacemaker at presentation. Uni and multivariate cox regression analysis identified serum troponin, tricuspid regurgitation, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters were statistically significantly worse and five year survival by Kaplan Meier analysis was significantly reduced when compared to matched WT ATTR-CM patients (p&amp;lt;0.05) (Figure 1). Mean serum high sensitivity troponin T and extracellular volume (ECV) by cardiac magnetic resonance (CMR) was higher in p.V142I ATTR-CM than WT ATTR-CM cases (94 ng/L vs 74.2 ng/L, p&amp;lt;0.05, 58% vs 55%, p&amp;lt;0.05). Interventricular wall thickness however was lower in p.V142I ATTR-CM than matched WT cases (17.2 mm vs 16.8 mm). Conclusion p.V142I ATTR-CM is an aggressive phenotype, with significant functional impairment, burden of regurgitant valvular disease and systolic impairment resulting in poor survival. Patients with p.V142I ATTR-CM had a higher burden of amyloid infiltration as measured as shown by ECV measurements on CMR, higher serum troponin and lower wall thickness when compared to a matched cohort of WT ATTR-CM patients. This novel observation suggests a unique disease mechanism that is more cardiotoxic which results in myocyte loss and myocardial thinning as opposed to myocyte hypertrophy. Funding Acknowledgement Type of funding sources: None.

A CHANGE OF HEART: A CASE OF CARDIAC AMYLOIDOSIS

A CHANGE OF HEART: A CASE OF CARDIAC AMYLOIDOSIS

Familial Amyloidotic Polyneuropathy with Leptomeningeal and Cardiac Involvement in a Patient with Gly73Glu Transthyretin Gene Mutation — Non-invasive Diagnostic Approach with Multimodality Imaging Findings: a Case Report

Familial Amyloidotic Polyneuropathy with Leptomeningeal and Cardiac Involvement in a Patient with Gly73Glu Transthyretin Gene Mutation — Non-invasive Diagnostic Approach with Multimodality Imaging Findings: a Case Report

A pilot study of nailfold capillaroscopy in hereditary transthyretin amyloidosis

Nailfold capillaroscopy (NFC) is a safe and non-invasive imaging tool for evaluating microvascular abnormalities. This retrospective cross-sectional study aimed to analyze the NFC outcomes and clinical characteristics in patients and an asymptomatic carrier with transthyretin (TTR) gene mutation. The participants consist of eight patients with genetically and clinically confirmed hereditary amyloidogenic transthyretin (ATTRv) amyloidosis and one asymptomatic carrier. The TTR gene mutant forms of six male and three female participants from six families were Asp38Ala (five patients), Lys35Asn (three patients), and Ala36Pro (one patient). All participants showed decreased capillary density, dilatated capillaries, and destructed architecture in NFC. Early progression identification of a carrier to patients with symptoms is a major concern from a therapeutic viewpoint in ATTRv amyloidosis. Therefore, further studies with a larger number of subjects will be needed to determine the use of NFC as an early detection tool.

P319 SOMETHING MORE OF SIMPLE CARDIAC CONDUCTION DISORDERS

Abstract Background Cardiac amyloidosis (CA) is an infiltrative disease caused by extracellular deposition of amyloid fibrils. Possible cardiac manifestations include heart failure with preserved ejection fraction (EF), aortic valve stenosis, microvascular coronary artery disease, atrial fibrillation (AF), ventricular arrhythmias, and cardiac conduction disorders (CCD). We report a case of advanced CCD in a patient first diagnosed with wild–type transthyretin amyloidosis (ATTRwt). Case Report An 88–year–old man went to Emergency Room for chest pain with minimal elevation of troponin I and increase in NTproBNP. The patient reported a recent syncope with ribs fractures. The medical history showed hypertension, paroxysmal AF, carotid atherosclerosis, vascular encephalopathy and prostate cancer. Troponin I monitoring showed plateau values and there were no clinical signs of heart failure. ECG showed regular sinus rhythm with marked first degree atrioventricular block, right bundle branch block and left anterior fascicular block (Fig. 1A). Cardiac telemetry recorded brief phases of atrioventricular dissociation (AVD). Transthoracic echocardiography showed severe left ventricular concentric hypertrophy (LVCH) with granular–sparkling appearance and preserved EF, reduced global longitudinal strain with apical sparing (Fig. 1B), mitral–aortic valve degeneration and dilation of the ascending aorta. Given the advanced CCD with AVD and the recent syncope, the patient underwent a dual–chamber pacemaker implantation. In consideration of the echocardiographic suspicion of CA, following Gillmore’s diagnostic algorithm (GDA), serum electrophoresis and assay of serum free light chains were performed and resulted normal, while 99mTc–DPD bone scintigraphy was positive for significant radiotracer cardiac uptake (Perugini grade 3) (Fig. 1C). Based on this result, we carried out the search for transthyretin gene mutations which resulted negative, and therefore the diagnosis of ATTRwt was made. Discussion Advanced CCD in patients with transthyretin CA are present in about 9.5% of cases at the time of diagnosis, especially in older patients. It is therefore essential, in case of concomitant LVCH, to suspect the presence of CA as the cause of CCD by searching for the disease red flags and following the GDA to non–invasively confirm or exclude the diagnosis of CA. A correct and timely diagnosis of CA makes it possible to treat the disease and its complications, improving the prognosis.

AUTOSOMAL DOMINANT MÜLLER CELL SHEEN DYSTROPHY: Clinical, Histopathologic, and Genetic Assessment in an Extended Family With Long Follow-Up.

Autosomal dominant Müller cell dystrophy is a rare condition we described in 1991. It is characterized by a striking sheen appearance on the retinal surface with progressive retinal changes leading to disorganization and atrophy with a decreased b-wave electroretinograms. We examined 45 members of a 4-generation family. Fifteen subjects from three generations were found with the disease, without gender predilection. Seven patients underwent ophthalmic examination including fundus examination, intravenous fluorescein angiogram, spectral-domain optical coherence tomography, and electroretinogram. Six patients have a 30-year follow-up. Histopathology examination was performed on eyes of the eldest patient. Whole exome sequencing was done in four affected subjects. Findings include a decreased visual acuity, abnormal cellophane-like sheen of the vitreoretinal interface, a "plush" nerve fiber layer, and characteristic macular changes. Electroretinogram showed a selective b-wave diminution. Intravenous fluorescein angiogram presented perifoveal hyperfluorescence and capillary leakage. Spectral-domain optical coherence tomography revealed cavitations involving inner and later outer retinal layers with later disorganization. Histopathologic findings included Müller cell abnormalities with cystic disruption of inner retinal layers, pseudoexfoliation in anterior segment, and amyloidosis of extraocular vessels. Pedigree analysis suggests an autosomal dominant inheritance with late onset. DNA analysis demonstrated a previously undescribed heterozygous missense p.Glu109Val mutation in transthyretin. To the best of our knowledge, this is the first family reported with this disorder. Our data support the hypothesis that autosomal dominant Müller cell dystrophy is a distinct retinal dystrophy affecting Müller cells. Mutations in transthyretin gene may manifest as a predominantly retinal disorder.

Heart Failure Due to Cardiac Transthyretin Amyloidosis

A 90-year-old male patient presented with complaints and physical examination compatible with decompensated heart failure. Electrocardiogram showed atrial fibrillation and low voltage in limb leads, and echocardiogram identified biatrial dilatation, in addition to mild increases in ventricular wall thickness and diameter. Magnetic resonance imaging confirmed suspicion of cardiac amyloidosis. With negative serum and urinary protein electrophoresis and positive pyrophosphate cardiac scintigraphy, diagnosis of transthyretin cardiac amyloidosis was confirmed. Transthyretin gene mutations were not identified on sequencing, characterizing wild-type transthyretin [...]

172 Two mutations, one patient: which phenotype?

Abstract Methods and results Woman, 55 years old, she has as comorbidity high blood pressure and mild obesity. She came at our attention to perform screening cardiological exams after her brother, who was affected by amyloidotic TTR-related cardiomyopathy with Val30Met mutation, died for sudden cardiac death. At the first evaluation the patient is completely asymptomatic, she has not angor, dyspnoea and heartbeat. The ECG and echocardiography were negative for amyloidotic signs of heart involvement. The Tc-99-DPD scintigraphy showed no cardiac uptake (visual score = 0). To complete the diagnostic path the patient had been evaluated by a neurologist with electromyography, which was negative, and genetic test, which confirmed the presence of Val30Met mutation of TTR-gene. For this last outcome we decided to follow the patient at our clinics. In the following years the patient developed a progressive reduction of exercise tolerance and symmetric negative T waves in anterolateral and inferior lead at ECG. The echocardiogram showed a progressive medio-apical septal hypertrophy. To exclude an ischaemic cause the patient made a stress myocardial scintigraphy, which was negative for ischaemic signs, and she underwent to cardiac MRI which showed a septal thickness of 16 mm without amyloidotic radiological signs in T1-weighted and LGE sequences. For this reason, we suspected that the patient had a hypertrophic cardiomyopathy and she had been undergone another time to genetic test which confirmed the Val30Met TTR-mutation and MYBPC3 mutation. Usually, this last gene mutation for myosin binding protein C is associated with late-onset hypertrophic cardiomyopathy. Into account the new diagnosis and her sudden cardiac death family history we calculated the patient’s HCM-risk score which was under 4%, so that we did not undergo the patient to ICD implantation. Conclusions The case report is a rare example of coexistence of the transthyretin gene mutation and myosin binding protein C in the same patient. In this case to perform a correct diagnosis, it is crucial use an integrated multimodal approach including ECG, echocardiography and cardiac MRI.

Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation

BackgroundTo determine the capability of 99mTc-DPD scintigraphy to detect early cardiac involvement and predict clinical worsening in transthyretin (TTR) gene mutation patients. MethodsEleven mutated subjects with normal interventricular septum (IVS) thickness, NT-proBNP level and no cardiac symptoms underwent three seriate 99mTc-DPD scans (visually and semiquantitatively analyzed), and was followed-up for 5-8-years. ResultsSix patients showed no myocardial accumulation in all scans. Increased IVS thickness occurring in one patient 4 years after the last scan was the only abnormal finding in these patients; no cardiac symptoms developed during the follow-up. In three patients, cardiac radiotracer uptake was found at enrollment; other laboratory/instrumental abnormal findings occurred later and cardiac symptoms developed during the follow-up period. Two patients had a negative 99mTc-DPD scan at enrollment and showed cardiac uptake in the following scans. Increased mean left-ventricular (LV) wall thickness was found 3 years after positive scintigraphy; NT-proBNP increased later in one patient. These patients developed cardiac symptoms during the follow-up period. Conclusions99mTc-DPD scan detects cardiac involvement in subjects with TTR gene mutation earlier than ECG, echocardiography and biochemical markers, occurring some years before the fulfillment of current diagnostic criteria for cardiac amyloidosis. A positive 99mTc-DPD scan predicts cardiac symptoms onset.