IGVL gene region usage correlates with distinct clinical presentation in IgM vs non-IgM light chain amyloidosis.
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ABSTRACT:
SUBMITTER: Sidana S
PROVIDER: S-EPMC8095150 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: This study aimed to better understand the clinical, electrophysiological, pathological features and prognosis of peripheral nerve involvements in primary immunoglobulin light-chain (AL) amyloidosis. Methods: We retrospectively reviewed the clinical data of eight AL amyloidosis patients with peripheral neuropathy as the initial presentation including clinical features, histopathological findings and treatment. Results: There were seven males and one female aged from 52 to 66 years. Initial symptoms included symmetrical lower extremity numbness, lower extremity pain and carpal tunnel syndrome. Seven patients suffered from severe pain and required pain management. Six patients had predominant autonomic dysfunction. Six patients had cardiac involvement, and one patient had renal involvement. Monoclonal proteins were found in all patients, with IgA λ in one, IgG λ in two, λ alone in three, κ alone in one and IgM κ in one. Sural nerve biopsies were performed in 7 cases, all of which showed amyloid deposition in the endoneurium (in the perivascular region in some cases), in addition to moderate to severe myelinated fiber loss with axonal degeneration. Six patients were treated with combined chemotherapy. In three patients who began chemotherapy earlier (6-10 months after onset), two achieved a hematological complete response, and one achieved a partial response. three patients who had delayed chemotherapy (36 months after onset) died between 5 and 12 months after diagnosis. Conclusion: Early recognition of AL amyloidosis with peripheral neuropathy as the initial symptom is very important. Nerve biopsy can help to make the diagnosis. Early diagnosis and chemotherapy are critical to achieve better outcomes.
| S-EPMC8505956 | biostudies-literature
Project description:Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic light chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by the response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. It needs to be risk-adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.
| S-EPMC5841939 | biostudies-literature
Project description:Light chain (AL) amyloidosis is the most common form of amyloidosis involving the kidney. It is characterized by albuminuria, progressing to overt nephrotic syndrome and eventually end-stage renal failure if diagnosed late or ineffectively treated, and in most cases by concomitant heart involvement. Cardiac amyloidosis is the main determinant of survival, whereas the risk of dialysis is predicted by baseline proteinuria and glomerular filtration rate, and by response to therapy. The backbone of treatment is chemotherapy targeting the underlying plasma cell clone, that needs to be risk-adapted due to the frailty of patients with AL amyloidosis who have cardiac and/or multiorgan involvement. Low-risk patients (?20%) can be considered for autologous stem cell transplantation that can be preceded by induction and/or followed by consolidation with bortezomib-based regimens. Bortezomib combined with alkylators, such as melphalan, preferred in patients harboring t(11;14), or cyclophosphamide, is used in most intermediate-risk patients, and with cautious dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents, such as pomalidomide, ixazomib, and daratumumab, prove effective in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. Novel approaches based on small molecules interfering with the amyloidogenic process and on antibodies targeting the amyloid deposits gave promising results in preliminary uncontrolled studies, are being tested in controlled trials, and will likely prove powerful complements to chemotherapy. Finally, improvements in the understanding of the molecular mechanisms of organ damage are unveiling novel potential treatment targets, moving toward a cure for this dreadful disease.
| S-EPMC5976806 | biostudies-literature
Project description: Not available
| S-EPMC7364018 | biostudies-literature
Project description: Not available
| S-EPMC8083944 | biostudies-literature
Project description:BackgroundAmyloid light-chain (AL) amyloidosis is an ultra-rare disease associated with significant morbidity and mortality. Few studies have examined the global epidemiology of this condition.MethodsThis study estimated the diagnosed incidence and 1-year, 5-year, 10-year, and 20-year period prevalence of AL amyloidosis in 2018 for countries in and near Europe, and in the United States (US), Canada, Brazil, Japan, South Korea, Taiwan, and Russia. A systematic literature review (SLR) was conducted to identify country-specific, age- and gender-specific diagnosed incidence of AL amyloidosis and observed survival data-point inputs for an incidence-to-prevalence model. Extrapolations were used to estimate incidence and prevalence for countries without registry or published epidemiological data.ResultsOf 171 publications identified in the SLR, 10 records met the criteria for data extraction, and two records were included in the final incidence-to-prevalence model. In 2018, an estimated 74,000 AL amyloidosis cases worldwide were diagnosed during the preceding 20 years. The estimated incidence and 20-year prevalence rates were 10 and 51 cases per million population, respectively.ConclusionsOrphan medicinal product designation criteria of the European Medicines Agency or Electronic Code of Federal Regulations indicate that a disease must not affect > 5 in 10,000 people across the European Union or affect < 200,000 people in the US. This study provides up-to-date epidemiological patterns of AL amyloidosis, which is vital for understanding the burden of the disease, increasing awareness, and to further research and treatment options.
| S-EPMC9295439 | biostudies-literature
Project description:IntroductionInformation detailing the experience of patients with light chain (AL) amyloidosis is lacking. The primary aim of this study was to gather data on the patient experience to understand the challenges in diagnosis and to gain insight into barriers to accessing appropriate care.MethodsPatients with amyloidosis, family members, and caregivers were invited to participate in an online 16-question survey (available from January 29 to February 5, 2015). Participants with AL amyloidosis were sent an eight-question follow-up survey.ResultsThe initial survey was completed by 533 participants (follow-up survey completed by 201 participants). AL amyloidosis was the most common diagnosis. For 37.1% of respondents, the diagnosis of amyloidosis was not established until ≥ 1 year after the onset of initial symptoms. Diagnosis was received after visits to 1, 2, 3, 4, or ≥ 5 physicians by 7.6%, 23.5%, 20.3%, 16.8%, and 31.8% of respondents, respectively. Correct diagnosis was most often made by hematologists/oncologists (34.1%). Treatments included chemotherapy (63.1%) and stem cell transplantation (38.9%) and were difficult to tolerate for 54.1% of respondents. A significant number of respondents felt uninformed about clinical trials. Nevertheless, approximately half (46.1%) believed that enrolling in a trial would enhance their care.ConclusionsEstablishing a diagnosis of amyloidosis is difficult. Current treatments are difficult to tolerate and do not substantially improve quality of life for most patients. There is an urgent need for well-tolerated therapies with clear treatment benefit. Patient awareness of clinical trials can be improved, especially given that respondents indicated high willingness to participate.
| S-EPMC4635176 | biostudies-literature
Project description:BackgroundCardiac involvement in amyloid light-chain (AL) amyloidosis usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is an uncommon scenario characterized by a challenging diagnostic and therapeutic workup.Case summaryA 57-year-old asymptomatic man was presented for an incidental finding of myocardial necrosis at the electrocardiogram (ECG) performed for newly diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinaesia with normal LV systolic function with 'apical sparing' pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischaemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic workup was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow, and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed, and the patients was timely started on chemotherapy.DiscussionThe diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flowchart has to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management.
| S-EPMC9998033 | biostudies-literature
Project description:Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the ? light-chain is dominant (?/?=1:2) in healthy individuals, ? is highly overrepresented (?/?=3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We examined the correlation between sequence and structural stability of dimeric variable domains of immunoglobulin light chains using molecular dynamics simulations of 24 representative dimer interfaces, followed by energy evaluation of conformational ensembles for 20 AL patients' light chain sequences. We identified a stable interface with displaced N-terminal residues, provides the structural basis for AL protein fibrils formation. Proline isomerization may cause the N-terminus to adopt amyloid-prone conformations. We found that ? light-chains prefer misfolded dimer conformation, while ? chain structures are stabilized by a natively folded dimer. Our study may facilitate structure-based small molecule and antibody design to inhibit AL. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang.
| S-EPMC5927852 | biostudies-literature
Project description:BACKGROUND:Light chain (AL) amyloidosis is a rare, complex disease associated with significant morbidity and mortality. Delays in diagnosis are common and may have detrimental consequences on patients' prognosis. Too little is known regarding the patient journey to diagnosis. OBJECTIVE:The objective of this study was to describe the patient-reported journey to a correct diagnosis for AL amyloidosis. METHODS:Using a mixed-methods approach, data were collected from clinician (n = 4) and patient (n = 10) interviews and a survey of community-based patients with AL amyloidosis (n = 341). Data were used to document the patient experience between the onset of symptoms and the receipt of a diagnosis. RESULTS:Delays in diagnosis were common. Qualitative and quantitative data indicated that initial symptoms were varied and similar to other more prevalent diseases. Two themes regarding the journey to diagnosis emerged: (1) barriers to an early diagnosis; and (2) the emotional toll of the journey. Time to diagnosis was heavily influenced by how patients interpreted their initial symptoms, whether they sought early medical help, and challenges associated with making differential diagnoses. Survey results indicate that patients with primary cardiac involvement were more likely to receive a delayed diagnosis than those with primary kidney involvement. Patients described mixed emotions associated with the eventual diagnosis of AL amyloidosis. CONCLUSIONS:These data support a need for better early identification and support for patients seeking a diagnosis. Increasing clinician awareness may reduce the time to diagnosis. Additional research is needed to identify optimal diagnostic testing to reduce delays in treatment initiation and subsequent severe impacts on health.
| S-EPMC5845075 | biostudies-literature