1. Introduction
Amyloidosis is a rare multisystemic disorder characterized by the extracellular accumulation of insoluble fibrils formed from misfolded protein subunits (from 10 to 15 kD). These fibrils (around 10 nm in diameter) are constituted of peptides arranged in an antiparallel β-sheet structure, conferring insolubility, resistance to proteolysis, and specific dyeing properties, such as Congo red affinity and apple-green birefringence under polarized light microscopy, in addition to a distinctive fibrillar appearance under electron microscopy [ 1 , 2 , 3 ].
Amyloid fibrils are made up of additional components, including serum amyloid P (SAP), a calcium-dependent glycoprotein that improves fibril stability, glycosaminoglycans (GAGs) that promote nucleation, and apolipoprotein E (APOE) [ 2 ].
Amyloidosis can be classified as localized or systemic. Localized amyloidosis is confined to a single organ or tissue, as may be seen in Alzheimer’s disease and type II diabetes, while systemic amyloidosis involves a lot of organs and tissues. Systemic amyloidosis is categorized into four main types: AL, AA, ATTR, and Aβ2M, with additional rare variants [ 2 ].
The most common type in adults is light-chain amyloidosis (AL), often associated with low-grade clonal proliferations, multiple myeloma, or, less frequently, non-Hodgkin lymphomas or Waldenström’s disease. In this kind of amyloidosis, the precursor proteins are immunoglobulin light chains (κ o λ), leading to a wide range of clinical manifestations [ 2 ].
The predominant form in children and the second most common type in adults is systemic AA amyloidosis [ 3 ]. It derives from the acute-phase protein Serum Amyloid A (SAA), associated with Apolipoprotein HDL3, and is frequently related to chronic inflammatory conditions. Hereditary periodic fever syndromes, such as familial Mediterranean fever (FMF) and other autoinflammatory disorders, are the most common causes of amyloidosis in pediatric patients. Other pediatric causes include systemic juvenile idiopathic arthritis (JIA) [ 4 ] and various chronic inflammatory conditions. In contrast, AA amyloidosis does develop very rarely as a complication of other chronic inflammatory diseases in adults and almost never in children, such as Sjogren’s syndrome [ 5 ]. Currently, the prevalence of secondary amyloidosis is significantly reduced for advances in biological therapies [ 2 , 3 , 6 ].
The list of conditions associated with AA amyloidosis is continually expanding; a significant susceptibility factor for idiopathic form is obesity, as suggested by recent evidence [ 7 ].
The third most common type is transthyretin amyloidosis (ATTR). This form is primarily hereditary, resulting from point mutations in transthyretin (TTR) protein, leading to peripheral and autonomic neuropathy. Senile systemic amyloidosis represents an acquired form and usually presents in elderly men with slowly progressive cardiomyopathy. Finally, most frequently associated with long-term dialysis in end-stage renal disease is β2-microglobulin amyloidosis (Aβ2M), though a hereditary form has also been identified, characterized by autonomic neuropathy and gastrointestinal involvement [ 2 ].
2. Epidemiology
A recent Swedish study estimated the incidence of AL amyloidosis at around 3.2 cases per million people per year, while the reported incidence of AA amyloidosis was 2.0 cases per million annually [ 2 ]. AL amyloidosis is more frequently observed in men, while AA amyloidosis is more common in women, largely due to the higher prevalence of rheumatoid arthritis in the female population. The median age of presentation for both types of amyloidosis is typically between 55 and 60 years. Both forms of amyloidosis are characterized by a poor prognosis, with median survival ranging from 6 to 12 months for AL amyloidosis and 3 to 4 years for the AA variant [ 2 ].
Amyloidosis is extremely rare in children [ 8 ], with its incidence largely reflecting the frequency of predisposing conditions. FMF primarily affects populations in the Mediterranean region, including Turkey, Arabia, Armenia, and non-Ashkenazi Jewish communities [ 9 ]. Before the large use of colchicine in therapy, amyloidosis was a frequent complication of FMF, affecting 60–75% of patients over the age of 40. Many studies have demonstrated variations in FMF severity based on geographic region, with a significantly higher incidence of amyloidosis observed among Turkish and Armenian individuals residing in their countries of origin compared to those who have emigrated to Northern Europe or the United States, suggesting the importance of environmental factors in the exacerbation of the inflammatory response [ 9 ].
The incidence of reactive amyloidosis for Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is reported to range from 14% to 25%, while it is approximately 3% in Mevalonate kinase deficiency (MKD) [ 3 ]. The most common rheumatic disease in childhood is JIA, and the historical incidence of AA amyloidosis in JIA patients, which varied from 1% to 10%, has substantially reduced due to earlier diagnosis and improved treatment strategies [ 3 ].
3. Classification and Immunopathophysiology
In accordance with guidelines established by the International Society of Amyloidosis (ISA), amyloid is identified as an extracellular aggregation of fibrillary proteins, that shows a Congo red affinity and apple-green birefringence under polarized light microscopy [ 10 ]. Amyloid formation arises from several factors: increased concentration of proteins with acquired or hereditary mutations [ 11 ], wild-type proteins with an intrinsic propensity for misfolding [ 12 ], or proteolytic remodeling of wild-type proteins.
Normally, a robust quality control system guarantees correct protein folding and eliminates misfolded proteins at both intracellular and extracellular levels. Amyloidogenesis occurs when this system is overwhelmed or compromised, particularly with aging [ 13 , 14 , 15 ]. During amyloid fibril formation, the amyloid P component, apolipoprotein E (APOE), and glycosaminoglycans (GAGs) contribute to the formation and persistence of amyloid deposits. These components are consistent across all amyloid types, regardless of the specific protein involved, making them true markers of amyloidosis. The current classification of amyloidosis is based on type of amyloid protein, using the standard nomenclature “AX”, where “A” stands for amyloidosis and “X” represents the protein in the fibrils [ 10 ] ( Figure 1 ).
To date, 36 amyloidogenic proteins have been identified in humans. Amyloidosis can be classified into localized and systemic forms, depending on the degree of fiber deposition. Localized amyloidosis is associated with at least 19 proteins, while systemic amyloidosis involves 14 proteins, with some variants [ 10 ].
Amyloidosis may be classified as hereditary or acquired. The ISA recommends the term “hereditary” over “familial” for amyloidosis involving mutated proteins. “ATTRv” (variant) is preferred over “ATTRm” (mutant) to describe hereditary transthyretin amyloidosis, while “ATTRwt” refers to wild-type transthyretin amyloidosis [ 10 ]. Although some phenotypes are associated with specific amyloid types, classification based on clinical presentation alone is not recommended due to heterogeneity influenced by genetic and environmental factors [ 10 ]. The “amyloid hypothesis” postulates that amyloid fibril formation involves multiple steps: unfolding and misfolding of precursor proteins, nucleation, polymerization, fibril elongation, and tissue deposition. Normally, protein folding is mediated by chaperones in the endoplasmic reticulum, but extracellular factors such as low pH, oxidative stress, and elevated temperature can induce protein unfolding. For amyloidogenesis, precursor proteins must adopt a partially unfolded conformation. Misfolded proteins that escape degradation can aggregate into amyloid fibrils.
Amyloid fibril formation occurs in two phases: nucleation and elongation. During the nucleation phase, misfolded protein monomers form insoluble oligomers, which are the core of fiber formation. This step is energy-intensive and rate-limiting. Intermediate oligomers are highly toxic, generating reactive oxygen species and inducing cellular stress Once the nucleus is formed, fibrils grow by nucleation-dependent polymerization, adding more monomers [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ].
Regardless of the precursor protein, amyloid fibrils share structural characteristics: nonbranching, insoluble fibrils with a diameter of 7.5–10 nm, low molecular weight (5–25 kDa), and a cross-β-sheet secondary structure [ 22 ]. Intermolecular hydrogen bonds between the amide and carbonyl groups of the main chain monomers stabilize the β-sheet structure. Protofibrils stack perpendicularly to the fiber axis to form amyloid fibrils [ 23 ]. Organ tropism in amyloidosis is influenced by the type and sequence of the precursor protein, but the exact mechanism is still unknown. Fibril formation requires specific tissue conditions, including adequate local amyloid concentration and a conducive environment, such as low pH. Factors like the extracellular matrix, proteases, shear forces, and metals also promote aggregation and fibril formation [ 24 ].
3.1. Forms of Amyloidosis
Table 1 encompasses the main forms of amyloidosis currently recognized. The following discussion will focus on the most frequently documented phenotypes in the literature.
3.1.1. AL Amyloidosis
AL amyloidosis is the most prevalent form of systemic amyloidosis in developed countries [ 25 , 26 , 27 ], primarily caused by clonal proliferation of bone marrow plasma cells that secrete a monoclonal immunoglobulin light chain, which deposits as amyloid fibrils in tissues. Misfolding may result from primary sequence of monoclonal light chain or from genetic and epigenetic factors. AL amyloidosis is often associated with multiple myeloma and other B-cell lymphoproliferative disorders, such as non-Hodgkin lymphoma and Waldenström macroglobulinemia. Hereditary AL amyloidosis is extremely rare, particularly in children [ 11 , 28 , 29 ].
3.1.2. AA Amyloidosis
AA amyloidosis arises from serum amyloid A (SAA) protein, an acute-phase reactant produced by the liver [ 30 ], typically associated with chronic inflammatory conditions. It is the leading cause of systemic amyloidosis in developing countries due to high prevalence of infections like subacute bacterial endocarditis and tuberculosis [ 31 , 32 , 33 , 34 , 35 ]. Other causes are JIA, IBD, tumor, and vasculitis. AA amyloidosis is also the most common form in pediatric populations, frequently associated with hereditary autoinflammatory diseases. Hereditary AA amyloidosis is linked to autoinflammatory diseases, while hereditary amyloidoses involve mutations in amyloidogenic protein itself. Specific risk factors have been identified in AA amyloidosis development in autoinflammatory disease, and these are explained in Table 2 [ 36 ].
However, high levels of SAA resulting from continuous subclinical or clinical inflammation are the leading cause of AA amyloidosis development [ 36 ]. Indeed, chronic inflammation may be observed in up to one-third of children with FMF during intercritical times, causing an elevated risk of renal AA amyloidosis over time. Recently, obesity has emerged as a significant risk factor for idiopathic AA amyloidosis [ 37 ]. Notably, 19% of AA amyloidosis cases lack an identifiable underlying condition [ 2 , 3 , 6 , 7 ]. Although chronic inflammation is a key factor in the development of AA amyloidosis, it does not affect all patients with chronic diseases. Serum amyloid A, the precursor protein, is produced by the liver in response to proinflammatory cytokines such as IL-6, IL-1, and TNF-α, and plays a role in lipid metabolism. Under normal conditions, SAA is fully degraded by macrophages through lysosomes. In amyloidosis, however, incomplete degradation and the accumulation of intermediate products occur, leading to amyloid deposition in tissues [ 38 , 39 ]. Moreover, there is growing evidence that genetic predisposition may lead to higher susceptibility to accumulation and deposition of SAA, leading to extracellular accumulation and damage.
3.1.3. ALECT2 Amyloidosis
ALECT2 amyloidosis, the third most common renal amyloidosis after AL and AA [ 40 ], involves amyloid fibrils derived from leukocyte chemotactic factor 2 (LECT2) [ 41 ] Although no genetic component has been identified, there is a strong association with Mexican–American ethnicity, as well as among Native Americans, Punjabis, Egyptians, and First Nations peoples of British Columbia [ 33 , 40 , 42 , 43 , 44 ]. ALECT2 primarily affects older patients.
3.1.4. Hereditary Amyloidosis
Hereditary amyloidoses are autosomal dominant diseases with variable penetrance and onset, often lacking a family history. These conditions involve variant plasma proteins forming amyloid deposits, typically beginning in mid-life. Collectively, they account for about 10% of all systemic amyloidosis cases [ 45 , 46 , 47 ]. In isolated areas of Portugal, Sweden, and Japan, a founder effect has led to higher incidences [ 48 ]. ATTRv is the most common hereditary amyloidosis globally, caused by mutations in the TTR protein. TTR, primarily produced by the liver, transports thyroxine and retinol. Mutations in the TTR gene weaken monomeric interactions, leading to tetramer dissociation and amyloid fibril accumulation. The Val122Ile mutation, prevalent in 3–4% of African Americans, leads to a cardiac phenotype, whereas Val30Met [ 27 , 49 ], common in Sweden, Portugal, and Japan, is associated with polyneuropathy [ 50 , 51 ].
3.1.5. Iatrogenic Amyloidosis
Aβ2M amyloidosis results from the accumulation of β2-microglobulin, associated with rheumatological manifestations in long-term hemodialysis patients. β2-microglobulin is normally excreted by kidneys, and its levels increase in end-stage renal disease, as it is above the filtration threshold of some dialysis membranes [ 11 , 52 ].
4. Clinical Manifestations
Amyloidosis is a multisystemic disorder with various clinical manifestations that depend on the precursor protein, the extent of amyloid deposition, and organs involved ( Table 3 and Table 4 ) [ 46 ].
Like the adult population, in pediatric patients, symptoms due to amyloid deposition may also present with clinical manifestations of an underlying disease, which is often different to that in adults. Commonly affected organs include heart, kidneys, nervous system, liver, and gastrointestinal tract ( Figure 2 ). Nonspecific symptoms such as fatigue and weight loss may develop gradually and often go unnoticed until appearance of more specific and alarming symptoms [ 1 , 2 ].
In a study of 459 adult patients with amyloidosis, only 26% received a diagnosis within one year of symptom onset, and 49% saw four or more physicians before a definitive diagnosis was made [ 53 ]. Although analogous data for pediatric population are not available, it is reasonable to assume that diagnostic delays may largely overlap. Specific signs of AL amyloidosis, such as tongue enlargement and periorbital purpura, occur in only 15% of patients [ 26 ]. Cardiac and renal involvement are the most important predictors influencing survival [ 54 ]. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy; and monoclonal gammopathy of undetermined significance (MGUS) with atypical clinical features [ 55 ]. In AL amyloidosis, the heart is involved in about 75% of cases, the kidneys in 57%, the nerves in 22%, and the liver in 20% [ 56 ].
4.1. Kidney
Renal parenchyma is one of the most frequently involved sites in systemic and hereditary amyloidosis [ 40 ]. In adults, renal amyloidosis typically presents with nonselective proteinuria and/or renal insufficiency [ 46 ], commonly involving glomeruli and requiring renal biopsy [ 7 ]. Amyloid is suspected through the presence of amorphous “hyaline” deposits, which are weakly periodic acid–Schiff (PAS)-positive and exhibit argyrophilic loss [ 40 , 57 , 58 ]. There are, on the other hand, cases in which patients have only mild proteinuria and normal renal function [ 59 ]. In children, renal amyloidosis can present with proteinuria or nephrotic syndrome, which may be followed by chronic renal insufficiency. As in the adult population, even in children the type of proteinuria is not specified. Asymptomatic proteinuria is the most common initial presentation of kidney disease; therefore, urine examination should be performed in all patients with disease associated with a risk of secondary amyloidosis [ 1 ]. Unlike in adults, hematuria and hypertension rarely occur in children [ 54 ]. Since primary amyloidosis is extremely rare in children, secondary amyloidosis is the most common pattern of renal amyloidosis in pediatric patients [ 6 ]; in adults, however, the renal pattern may result from either primary or secondary amyloidosis.
4.2. Heart
Cardiac amyloidosis is a rare cause of cardiomyopathy, reported exclusively in adults. Main systemic amyloidosis with clinically significant cardiac involvement includes AL and ATTR [ 50 ], while AA amyloidosis rarely affects heart clinically [ 7 , 60 , 61 ]. Cardiac presentation in AL amyloidosis in adults usually includes heart failure with preserved ejection fraction [ 62 , 63 ]. Early symptoms may include dyspnea, edema, hypotension, arrhythmias, and atypical angina due to amyloid deposits in coronary arteries [ 2 ]. Ventricular wall thickening with preserved ejection fraction and absence of left ventricular dilation may suggest amyloidosis [ 64 ]. In childhood, we find only a case report about a 12-year-old boy presented with a single syncopal event, intermittent and nonspecific chest pain, and fatigue and shortness of breath, which was diagnosed with ventricular noncompaction by echocardiography, and he has preserved ejection fraction. Eventual genetic testing confirmed a TTR gene mutation associated with hereditary transthyretin amyloidosis [ 65 ]. This case report could provide a basis for understanding the early symptomatology of cardiac amyloidosis in pediatrics, which may present with early, nonspecific symptoms such as syncope, intermittent and nonspecific chest pain, fatigue, and shortness of breath. However, further studies are needed for a complete understanding.
4.3. Gastrointestinal System
The gastrointestinal tract is frequently involved in systemic amyloidosis, most commonly AL, followed by AA and hereditary types [ 7 ]. Gastrointestinal involvement occurs in about 17% of AL amyloidosis patients [ 55 ] and 20% of those with reactive amyloidosis [ 66 ]. Clinical presentations in adults can range from vague symptoms such as epigastric pain, diarrhea, malabsorption, hematochezia, hematemesis, and constipation to obstruction, gastrointestinal bleeding, and perforation [ 67 ]. In children, we found that early symptoms include epigastric pain, abdominal pain, and gastrointestinal bleeding, together with symptoms of the underlying condition, as described by Kamei et al. in a case report of a 16-year-old Japanese girl who died from secondary AA amyloidosis associated with juvenile rheumatoid arthritis; the patient presented with amyloid deposits in various sites, including the kidneys, vascular walls, spleen, and gastrointestinal tract, particularly in the ileum. This led to peritonitis and hemorrhagic necrosis of the terminal ileum, ultimately resulting in her death [ 8 ]. From this, we can deduce that symptoms of gastrointestinal amyloidosis are similar in adults and children. Additionally, in children, symptoms of an underlying condition will also be present. Deposition of amyloid in the liver and spleen in adult causes hepatomegaly and splenomegaly, with elevation of liver enzymes, which can complicate drug management; furthermore, splenomegaly can lead to splenic rupture [ 68 , 69 ]. In children, however, the presence of hepatomegaly is not necessarily associated with elevated liver enzymes, which may sometimes remain within normal ranges [ 70 ].
4.4. Lungs
In lungs, amyloid deposits can be localized or associated with systemic disease [ 71 , 72 ]. Lung biopsy is rarely performed. Localized disease like nodular amyloidosis carries a better prognosis compared to diffuse alveolar amyloidosis [ 73 ]. Pulmonary amyloidosis may present radiologically with multiple pulmonary nodules, a solitary nodular mass, or ground-glass opacities, and symptoms such as dyspnea, physical decline, cough, hemoptysis, and bronchitis [ 71 ]. There are no reported cases in the literature regarding amyloid deposition in the lungs of children.
4.5. Nervous System
Sensory and motor peripheral neuropathy and autonomic neuropathy can occur in amyloidosis, although they are rare in secondary forms [ 1 ]. Amyloidosis is a relatively rare cause of peripheral neuropathy, accounting for approximately 3% of cases in the Mayo Clinic laboratory [ 74 , 75 ]. Diagnosis is often delayed because clinical features can mimic many other neuropathies [ 7 ]. No cases were found in children, but it could plausibly occur in children as well.
5. Diagnosis
Amyloidosis should be considered in the differential diagnosis of patients with nephrotic proteinuria, heart failure with preserved ejection fraction, neuropathy, hepatomegaly, and unexplained gastrointestinal symptoms [ 25 , 26 , 76 ]. The diagnostic approach begins with routine tests to assess organ involvement, including renal and liver function tests, chest X-rays, spirometry, ECG, BNP, and troponin. A definitive diagnosis is confirmed through biopsy of affected tissues and amyloid typing. The gold standard for diagnosis involves detecting amyloid deposits in tissue samples [ 57 , 77 , 78 ]. Under optical microscopy, these deposits appear extracellular, eosinophilic, and metachromatic. Congo red staining, viewed under polarized light, is a reference standard, revealing characteristic apple-green birefringence due to alternating hydrophobic and hydrophilic regions along the fiber axis [ 57 , 79 ]. Identifying a specific amyloid protein type is crucial, as it impacts treatment decisions [ 11 , 57 ]. While biopsies of target organs such as the kidney or heart are the most sensitive, less invasive options like abdominal fat or bone marrow biopsies are often recommended [ 57 , 79 , 80 , 81 , 82 , 83 ]. Sensitivity of fat biopsies for amyloid detection varies by amyloid type, ranging from 70 to 90% for AL amyloidosis and 67% for hereditary ATTR amyloidosis to only 14% for wild-type ATTR amyloidosis [ 57 , 80 , 83 , 84 ]. Sensitivity for bone marrow biopsies is approximately 60% [ 25 , 79 , 85 ].
Recently, pyrophosphate scintigraphy has been proposed for the radiological detection of ATTR cardiomyopathy [ 77 ]. Confirming the presence of amyloid is just the beginning; determining a specific type of amyloid is essential for appropriate treatment planning.
Immunofluorescence and immunohistochemistry characterization use antibodies against various amyloidogenic proteins. Immunohistochemistry employs antibodies conjugated with enzymes (such as horseradish peroxidase) to visualize the presence of target antigens in tissues. Enzymatic reaction products result in colorimetric changes, facilitating observation of structures under an optical microscope [ 86 ]. Immunofluorescence identifies the same antigens through antibodies conjugated to fluorochromes that emit light when exposed to ultraviolet light, enabling their observation under a fluorescence microscope [ 87 ]. A panel of antibodies directed against precursor fibrils should be ensured to facilitate the identification of the main forms of amyloidosis. For instance, antibodies such as anti-AA, anti-ALλ, anti-ALκ, anti-ATTR, anti-AHγ, anti-Aβ2M, anti-AFib, anti-ALECT2, anti-AApoAI, anti-ALys, anti-ACys, and anti-AGel should be included. Currently, the literature remains uncertain about which of the two techniques offers superior sensitivity and specificity for diagnostic purposes [ 40 , 88 , 89 , 90 , 91 , 92 ]. In challenging cases where immunofluorescence or immunohistochemistry are inconclusive, or if less common types are detected [ 40 ], proteomic techniques allow for unequivocal identification of protein-forming amyloid deposits, particularly utilizing mass spectrometry [ 25 , 26 , 27 , 50 , 88 , 89 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ]. Molecular and genetic testing can be performed in cases of hereditary amyloidosis (e.g., TTR, fibrinogen, lysozyme, apolipoproteins AI and AII, and gelsolin) [ 27 , 76 , 101 , 102 , 103 , 104 ].
6. Treatment and Prognosis
Amyloidosis has a poor prognosis if untreated and undiagnosed. Therefore, early diagnosis and starting treatment as early as possible are necessary to stabilize disease and prevent ongoing progression. The primary strategy is to reduce inflammatory activity of underlying condition, and it is important to stop the growth of amyloid deposits by eliminating the precursors necessary for their formation. Although there is a lack of longitudinal studies regarding pediatric population, it can be assumed that, compared to the adult/elderly population, which is generally burdened by greater comorbidities, treating the underlying condition may ensure a better prognosis and a lower risk of disease development. Treatment of amyloidosis includes treatment of the underlying cause, symptom management, chemotherapy, peripheral blood stem cell transplant, organ transplant, physiotherapy, and psychosocial support.
6.1. AA Amyloidosis
For AA amyloidosis, treatment aims to reduce inflammation, thus maintaining serum amyloid A levels to baseline values (below 3 mg/L) [ 105 ]. Keeping SAA levels below 10 mg/L can increase the 10-year survival rate to 90%, while levels above 10 mg/L are associated with a survival rate of less than 40% [ 106 ]. These are data concerning adults; for the pediatric population, there are no data. To achieve normal SAA values there must be complete suppression or eradication of the underlying chronic inflammatory disease. Improvement in treatments for chronic inflammatory diseases with the introduction of anti-inflammatory drugs like methotrexate and biologics targeting TNF and IL-1 have made the suppression of SAA at low or even normal serum concentrations a realistic goal [ 107 ]. In addition to colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and IL-6 inhibitor tocilizumab, may optimize the treatment of FMF and the prevention or control of AA amyloidosis [ 108 ]. It should be noted that even heterozygous FMF genotypes have an increased risk of AA amyloidosis, and treatment should also be administered in paucisymptomatic patients to prevent complications [ 109 ]. Moreover, no agreement has been established on the discontinuation time for colchicine in asymptomatic FMF patients, with most patients subjected to lifelong prophylaxis [ 109 ]. The previously mentioned drugs, such as methotrexate, colchicine, anakinra, canakinumab, and tocilizumab, are used in pediatrics as therapies for various conditions, including mevalonate kinase deficiency, juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, tumor necrosis factor receptor-associated periodic syndrome, and familial Mediterranean fever, which we previously noted increases the risk of pediatric amyloidosis.
6.2. AL Amyloidosis
AL amyloidosis is most frequently encountered in the elderly population, with a mean age of diagnosis of approximately 60 years and an incidence that increases with age [ 110 ]. In AL amyloidosis, the goal is to treat underlying plasma cell dyscrasia with chemotherapy and normalize kappa or lambda light chain levels [ 111 ]. High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) in eligible patients has shown significant benefits [ 112 ]. However, recent studies suggest that this approach may not be superior to standard-dose melphalan plus dexamethasone [ 113 ]. Meanwhile, numerous studies on new drugs such as thalidomide, bortezomib, lenalidomide, and pomalidomide have shown promising effects, often with the best results in combination with dexamethasone [ 114 ]. It has been found that in the first 6 months after diagnosis, 25% of AL amyloidosis patients die due to end-stage organ failure [ 56 ]. Several risk models are used for AL amyloidosis [ 115 ]. The Mayo Clinic 2004 model classifies patients into three stages based on cardiac troponin T below 0.035 μg/L and N-terminal probrain natriuretic peptide (NT-proBNP) below 332 ng/L. Patients are considered stage I if both markers are below thresholds, stage II if only one marker is below threshold, and stage III if both are at or above thresholds. The 2012 Mayo model classifies patients based on cardiac troponin T or high-sensitivity troponin T, NT-proBNP, and difference between involved and uninvolved free light chains. All models have similar predictive value for survival [ 116 , 117 , 118 ]. The 2004 model better predicts early mortality, while the 2012 model has a better prediction for long-term survival. AL amyloidosis prognosis can be determined by two or three blood tests [ 119 ]. AL amyloidosis is extremely rare in children [ 11 , 28 , 29 ] and we did not find data in the literature about treatment except for a case report concerning a 13-year-old girl with primary localized nasopharyngeal AL amyloidosis where the main treatment was surgical [ 120 ].
6.3. TTR Amyloidosis
Hereditary ATTR amyloidosis treatment has traditionally involved liver transplantation to remove source of circulating mutant TTR [ 121 ]. However, this approach may not be effective in some cases, particularly with late-onset disease or non-TTR-Met30 mutations. Wild-type ATTR amyloidosis has a median overall survival of 3.6 years, with survival rates varying by stage [ 121 , 122 , 123 ]. Treatment now available includes TTR stabilizers, such as Tafamidis, and TTR amyloid removal, as well as gene silencing, while gene editing therapies are on the way. Since TTR amyloidosis is hereditary, early diagnosis is important for improving prognosis. In endemic countries where ATTRv is often familial, family members are offered genetic testing, and presymptomatic carriers are regularly seen in clinic. Symptomatic carriers often undergo biopsy to confirm tissue deposition of TTR. In nonendemic countries, both genetic testing and testing for amyloidosis are indicated in suspected cases [ 124 ]. The only case of TTR amyloidosis we found in the literature in the pediatric field is that of cardiac TTR amyloidosis, which was primarily treated with implantation of a defibrillator and will be followed up every 3–5 years to determine when to start therapy with Tafamidis [ 65 ]. Currently, there are no studies on Tafamidis in pediatrics.
6.4. Ab2M Amyloidosis
In Ab2M amyloidosis, kidney transplantation is the treatment of choice. After transplantation, amyloidosis appears to stabilize, with serum β2-microglobulin levels dropping to normal, but there have been no reported decreases in amyloid deposits [ 125 ]. No data were found regarding children.
6.5. Other Variants
For other variants of amyloidosis, the current basis for treatment is the so-called precursor–product concept. The central idea of this concept, as described above, is that further growth of amyloid deposits will stop when the supply of the necessary precursors is interrupted [ 2 ].
7. Discussion
In adults, amyloidosis is most associated with conditions like multiple myeloma or chronic inflammatory diseases, where overproduction of certain proteins leads to their misfolding and deposition as amyloid. The most common form in adults is AL amyloidosis, resulting from clonal proliferation of plasma cells. This form typically affects older individuals and is associated with organ involvement, such as kidneys, heart, liver, and the nervous system. Symptoms can include fatigue, edema, weight loss, and organ-specific dysfunctions like nephrotic syndrome, cardiomyopathy, or neuropathy.
In contrast, pediatric amyloidosis is much rarer and often has a genetic basis. The most common forms in children are AA amyloidoses, such as those caused by mutations in genes associated with autoinflammatory syndromes, like FMF. These genetic mutations lead to abnormal production of amyloidogenic proteins that deposit in various tissues. Clinical presentation in children may include recurrent fevers, abdominal pain, arthritis, and, in the case of FMF, a high risk of developing renal amyloidosis. Pediatric patients may also present with systemic involvement, but progression can vary significantly depending on underlying genetic disorder.
In adults, diagnosis often involves a combination of clinical evaluation, laboratory tests, imaging studies, and tissue biopsy to confirm amyloid deposition and to determine amyloid type. In children, diagnosis is often guided by the identification of underlying genetic mutations through genetic testing, especially in cases of hereditary amyloidosis. Tissue biopsy is less commonly performed in children unless absolutely necessary.
In adults with AL amyloidosis, the primary treatment focuses on targeting underlying plasma cell disorder with chemotherapy, including drugs like bortezomib, lenalidomide, and dexamethasone, which aim to reduce the production of amyloidogenic light chains. In cases of familial amyloidosis in adults, liver transplantation may be considered to prevent further production of the abnormal protein.
In pediatric amyloidosis, treatment often focuses on managing underlying genetic conditions. For example, in FMF, colchicine is a standard treatment to prevent attacks and reduce the risk of amyloid deposition. In hereditary forms linked to other genetic mutations, emerging therapies targeting specific molecular pathways or gene therapy may offer future potential, though these treatments are still under investigation.
In conclusion, while amyloidosis shares common pathological features across age groups, differences in etiology, clinical presentation, and treatment between adults and children necessitate tailored approaches to management. Early diagnosis is crucial for initiating specific treatment for the type of amyloidosis, especially in the pediatric population, which has a longer life expectancy and fewer comorbidities, allowing for better tolerability of the various therapeutic approaches. Understanding this issue is crucial for improving outcomes and quality of life for patients.
Acknowledgments
Chat-GPT-4.0 was used for minor grammar and spelling.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Conceptualization, methodology, writing—original draft preparation and editing, figures: G.B.Z., M.S., J.C., N.C., G.D.P., A.D.B., V.C., A.D.L., S.L.B., F.C. and G.D.D. Supervision, revision, and approval of the final version of the paper: G.D.D. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Bilginer Y. Akpolat T. Ozen S. Renal Amyloidosis in Children Pediatr. Nephrol. 2011 26 1215 1227 10.1007/s00467-011-1797-x 21360109 PMC3119800
2. Hazenberg B.P.C. Amyloidosis. A Clinical Overview Rheum. Dis. Clin. N. Am. 2013 39 323 345 10.1016/j.rdc.2013.02.012 23597967
3. Sözeri B. Dincel N. Mir S. An Overview of the Amyloidosis in Children with Rheumatic Disease Amyloidosis—An Insight to Disease of Systems and Novel Therapies Guvenc I.A. IntechOpen London, UK 2011
4. La Bella S. Rinaldi M. Di Ludovico A. Di Donato G. Di Donato G. Salpietro V. Chiarelli F. Breda L. Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis Int. J. Mol. Sci. 2023 24 1846 10.3390/ijms24031846 36768167 PMC9916312
5. La Bella S. Vivarelli M. Di Ludovico A. Di Donato G. Chiarelli F. Breda L. Kidney Manifestations of Pediatric Sjögren’s Syndrome Pediatr. Nephrol. 2024 39 711 721 10.1007/s00467-023-06135-1 37638982
6. Woo P. Amyloidosis in Children Baillieres Clin. Rheumatol. 1994 8 691 697 10.1016/S0950-3579(05)80122-0 7954869
7. Picken M.M. The Pathology of Amyloidosis in Classification: A Review Acta Haematol. 2020 143 322 334 10.1159/000506696 32392555
8. Kamei T. Ishihara T. Fujihara S. Nakamura H. Yokota T. Imada N. Akizuki S. Iwata T. Uchino F. Amyloidosis Associated with Juvenile Rheumatoid Arthritis Acta Pathol. Jpn. 1982 32 123 133 10.1111/j.1440-1827.1982.tb02033.x 7072494
9. Lancieri M. Bustaffa M. Palmeri S. Prigione I. Penco F. Papa R. Volpi S. Caorsi R. Gattorno M. An Update on Familial Mediterranean Fever Int. J. Mol. Sci. 2023 24 9584 10.3390/ijms24119584 37298536 PMC10253709
10. Buxbaum J.N. Dispenzieri A. Eisenberg D.S. Fändrich M. Merlini G. Saraiva M.J.M. Sekijima Y. Westermark P. Amyloid Nomenclature 2022: Update, Novel Proteins, and Recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee Amyloid 2022 29 213 219 10.1080/13506129.2022.2147636 36420821
11. Benson M.D. Buxbaum J.N. Eisenberg D.S. Merlini G. Saraiva M.J.M. Sekijima Y. Sipe J.D. Westermark P. Amyloid Nomenclature 2018: Recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee Amyloid 2018 25 215 219 10.1080/13506129.2018.1549825 30614283
12. Picken M.M. Diagnosis of Amyloid beyond Congo Red Curr. Opin. Nephrol. Hypertens. 2021 30 303 309 10.1097/MNH.0000000000000695 33395039
13. Chiti F. Dobson C.M. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress over the Last Decade Annu. Rev. Biochem. 2017 86 27 68 10.1146/annurev-biochem-061516-045115 28498720
14. Nuvolone M. Merlini G. Systemic Amyloidosis: Novel Therapies and Role of Biomarkers Nephrol. Dial. Transpl. 2016 32 770 780 10.1093/ndt/gfw305 27540044
15. Misra P. Blancas-Mejia L.M. Ramirez-Alvarado M. Mechanistic Insights into the Early Events in the Aggregation of Immunoglobulin Light Chains Biochemistry 2019 58 3155 3168 10.1021/acs.biochem.9b00311 31287666 PMC6650354
16. Dobson C.M. Protein Folding and Misfolding Nature 2003 426 884 890 10.1038/nature02261 14685248
17. Khurana R. Gillespie J.R. Talapatra A. Minert L.J. Ionescu-Zanetti C. Millett I. Fink A.L. Partially Folded Intermediates as Critical Precursors of Light Chain Amyloid Fibrils and Amorphous Aggregates Biochemistry 2001 40 3525 3535 10.1021/bi001782b 11297418
18. Wickner S. Maurizi M.R. Gottesman S. Posttranslational Quality Control: Folding, Refolding, and Degrading Proteins Science 1999 286 1888 1893 10.1126/science.286.5446.1888 10583944
19. Merlini G. Bellotti V. Molecular Mechanisms of Amyloidosis N. Engl. J. Med. 2003 349 583 596 10.1056/NEJMra023144 12904524
20. Ramirez-Alvarado M. Principles of Protein Misfolding Molecular Biology of Protein Folding, Part B Elsevier Amsterdam, The Netherlands 2008 115 160 10.1016/S0079-6603(08)00404-2 19121701
21. Koike H. Iguchi Y. Sahashi K. Katsuno M. Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment Molecules 2021 26 5091 10.3390/molecules26165091 34443678 PMC8401015
22. Naiki H. Gejyo F. [20] Kinetic Analysis of Amyloid Fibril Formation Methods in Enzymology Elsevier Amsterdam, The Netherlands 1999 305 318 10.1016/s0076-6879(99)09022-9 10507032
23. Chiti F. Dobson C.M. Protein Misfolding, Functional Amyloid, and Human Disease Annu. Rev. Biochem. 2006 75 333 366 10.1146/annurev.biochem.75.101304.123901 16756495
24. Stevens F.J. Kisilevsky R. Immunoglobulin Light Chains, Glycosaminoglycans, and Amyloid Cell. Mol. Life Sci. 2000 57 441 449 10.1007/PL00000706 10823245 PMC11146913
25. Gertz M.A. Immunoglobulin Light Chain Amyloidosis: 2018 Update on Diagnosis, Prognosis, and Treatment Am. J. Hematol. 2018 93 1169 1180 10.1002/ajh.25149 30040145
26. Merlini G. Dispenzieri A. Sanchorawala V. Schönland S.O. Palladini G. Hawkins P.N. Gertz M.A. Systemic Immunoglobulin Light Chain Amyloidosis Nat. Rev. Dis. Primers 2018 4 38 10.1038/s41572-018-0034-3 30361521
27. Naiki H. Sekijima Y. Ueda M. Ohashi K. Hoshii Y. Shimoda M. Ando Y. Human Amyloidosis, Still Intractable but Becoming Curable: The Essential Role of Pathological Diagnosis in the Selection of Type-specific Therapeutics Pathol. Int. 2020 70 191 198 10.1111/pin.12902 31961039
28. Al Hamed R. Bazarbachi A.H. Bazarbachi A. Malard F. Harousseau J.-L. Mohty M. Comprehensive Review of AL Amyloidosis: Some Practical Recommendations Blood Cancer J. 2021 11 97 10.1038/s41408-021-00486-4 34006856 PMC8130794
29. Ikura H. Endo J. Kitakata H. Moriyama H. Sano M. Fukuda K. Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis Int. J. Mol. Sci. 2022 23 6336 10.3390/ijms23116336 35683015 PMC9181426
30. Westermark G.T. Fändrich M. Westermark P. AA Amyloidosis: Pathogenesis and Targeted Therapy Annu. Rev. Pathol. Mech. Dis. 2015 10 321 344 10.1146/annurev-pathol-020712-163913 25387054
31. Lane T. Pinney J.H. Gilbertson J.A. Hutt D.F. Rowczenio D.M. Mahmood S. Sachchithanantham S. Fontana M. Youngstein T. Quarta C.C. Changing Epidemiology of AA Amyloidosis: Clinical Observations over 25 Years at a Single National Referral Centre Amyloid 2017 24 162 166 10.1080/13506129.2017.1342235 28686088
32. Papa R. Lachmann H.J. Secondary, AA, Amyloidosis Rheum. Dis. Clin. N. Am. 2018 44 585 603 10.1016/j.rdc.2018.06.004 30274625
33. Larsen C.P. Ismail W. Kurtin P.J. Vrana J.A. Dasari S. Nasr S.H. Leukocyte Chemotactic Factor 2 Amyloidosis (ALECT2) Is a Common Form of Renal Amyloidosis among Egyptians Mod. Pathol. 2016 29 416 420 10.1038/modpathol.2016.29 26867784 PMC5411489
34. Deshayes S. Aouba A. Grateau G. Georgin-Lavialle S. Infections and AA Amyloidosis: An Overview Int. J. Clin. Pract. 2021 75 e13966 10.1111/ijcp.13966 33368925
35. Brunger A.F. Nienhuis H.L.A. Bijzet J. Hazenberg B.P.C. Causes of AA Amyloidosis: A Systematic Review Amyloid 2020 27 1 12 10.1080/13506129.2019.1693359 31766892
36. La Bella S. Di Ludovico A. Di Donato G. Scorrano G. Chiarelli F. Vivarelli M. Breda L. Renal Involvement in Monogenic Autoinflammatory Diseases: A Narrative Review Nephrology 2023 28 363 371 10.1111/nep.14166 37142240
37. Blank N. Hegenbart U. Dietrich S. Brune M. Beimler J. Röcken C. Müller-Tidow C. Lorenz H.-M. Schönland S.O. Obesity Is a Significant Susceptibility Factor for Idiopathic AA Amyloidosis Amyloid 2018 25 37 45 10.1080/13506129.2018.1429391 29364741
38. Okuda Y. AA Amyloidosis—Benefits and Prospects of IL-6 Inhibitors Mod. Rheumatol. 2019 29 268 274 10.1080/14397595.2018.1515145 30132351
39. Ozdogan H. Ugurlu S. Familial Mediterranean Fever Presse Med. 2019 48 e61 e76 10.1016/j.lpm.2018.08.014 30686512
40. Said S.M. Sethi S. Valeri A.M. Leung N. Cornell L.D. Fidler M.E. Herrera Hernandez L. Vrana J.A. Theis J.D. Quint P.S. Renal Amyloidosis Clin. J. Am. Soc. Nephrol. 2013 8 1515 1523 10.2215/CJN.10491012 23704299 PMC3805078
41. Benson M.D. James S. Scott K. Liepnieks J.J. Kluve-Beckerman B. Leukocyte Chemotactic Factor 2: A Novel Renal Amyloid Protein Kidney Int. 2008 74 218 222 10.1038/ki.2008.152 18449172
42. Larsen C.P. Beggs M.L. Wilson J.D. Lathrop S.L. Prevalence and Organ Distribution of Leukocyte Chemotactic Factor 2 Amyloidosis (ALECT2) among Decedents in New Mexico Amyloid 2016 23 119 123 10.3109/13506129.2016.1145110 26912093 PMC4898138
43. Hutton H.L. DeMarco M.L. Magil A.B. Taylor P. Renal Leukocyte Chemotactic Factor 2 (LECT2) Amyloidosis in First Nations People in Northern British Columbia, Canada: A Report of 4 Cases Am. J. Kidney Dis. 2014 64 790 792 10.1053/j.ajkd.2014.06.017 25064673
44. Rezk T. Gilbertson J.A. Rowczenio D. Bass P. Lachmann H.J. Wechalekar A.D. Fontana M. Mahmood S. Sachchithanantham S. Whelan C.J. Diagnosis, Pathogenesis and Outcome in Leucocyte Chemotactic Factor 2 (ALECT2) Amyloidosis Nephrol. Dial. Transplant. 2016 33 241 247 10.1093/ndt/gfw375 29401357
45. Álvarez Rubio J. Manovel Sánchez A.J. González-Costello J. García-Pavía P. Limeres Freire J. García-Pinilla J.M. Zorio Grima E. García-Álvarez A. Valverde Gómez M. Espinosa Castro M.Á. Characterization of Hereditary Transthyretin Cardiac Amyloidosis in Spain Rev. Española Cardiol. 2022 75 488 495 10.1016/j.recesp.2021.07.007 34711514
46. Muchtar E. Dispenzieri A. Magen H. Grogan M. Mauermann M. McPhail E.D. Kurtin P.J. Leung N. Buadi F.K. Dingli D. Systemic Amyloidosis from A (AA) to T (ATTR): A Review J. Intern. Med. 2021 289 268 292 10.1111/joim.13169 32929754
47. Sekijima Y. Transthyretin (ATTR) Amyloidosis: Clinical Spectrum, Molecular Pathogenesis and Disease-Modifying Treatments J. Neurol. Neurosurg. Psychiatry 2015 86 1036 1043 10.1136/jnnp-2014-308724 25604431
48. Obi C.A. Mostertz W.C. Griffin J.M. Judge D.P. ATTR Epidemiology, Genetics, and Prognostic Factors Methodist Debakey Cardiovasc. J. 2022 18 17 26 10.14797/mdcvj.1066 PMC8932385 35414855
49. Jacobson D.R. Alexander A.A. Tagoe C. Buxbaum J.N. Prevalence of the Amyloidogenic Transthyretin (TTR) V122I Allele in 14 333 African–Americans Amyloid 2015 22 171 174 10.3109/13506129.2015.1051219 26123279
50. Maurer M.S. Bokhari S. Damy T. Dorbala S. Drachman B.M. Fontana M. Grogan M. Kristen A.V. Lousada I. Nativi-Nicolau J. Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis Circ. Heart Fail. 2019 12 e006075 10.1161/CIRCHEARTFAILURE.119.006075 31480867 PMC6736650
51. Suhr O.B. Lundgren E. Westermark P. One Mutation, Two Distinct Disease Variants: Unravelling the Impact of Transthyretin Amyloid Fibril Composition J. Intern. Med. 2017 281 337 347 10.1111/joim.12585 28093848
52. Reese W. Hopkovitz A. Lifschitz M.D. B2-Microglobulin and Associated Amyloidosis Presenting as Bilateral Popliteal Tumors Am. J. Kidney Dis. 1988 12 323 325 10.1016/S0272-6386(88)80228-2 3052048
53. Lousada I. Comenzo R.L. Landau H. Guthrie S. Merlini G. Light Chain Amyloidosis: Patient Experience Survey from the Amyloidosis Research Consortium Adv. Ther. 2015 32 920 928 10.1007/s12325-015-0250-0 26498944 PMC4635176
54. Ozen S. Renal Amyloidosis in Familial Mediterranean Fever Kidney Int. 2004 65 1118 1127 10.1111/j.1523-1755.2004.00485.x 14871446
55. Gertz M.A. Dispenzieri A. Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review JAMA J. Am. Med. Assoc. 2020 324 79 89 10.1001/jama.2020.5493 32633805
56. Muchtar E. Gertz M.A. Kyle R.A. Lacy M.Q. Dingli D. Leung N. Buadi F.K. Hayman S.R. Kapoor P. Hwa Y.L. A Modern Primer on Light Chain Amyloidosis in 592 Patients with Mass Spectrometry–Verified Typing Mayo Clin. Proc. 2019 94 472 483 10.1016/j.mayocp.2018.08.006 30770096
57. Picken M.M. Modern Approaches to the Treatment of Amyloidosis Adv. Anat. Pathol. 2013 20 424 439 10.1097/PAP.0b013e3182a92dc3 24113313
58. Sethi S. Theis J.D. Pathology and Diagnosis of Renal Non-AL Amyloidosis J. Nephrol. 2018 31 343 350 10.1007/s40620-017-0426-6 28828707
59. Nishi S. Alchi B. Imai N. Gejyo F. New Advances in Renal Amyloidosis Clin. Exp. Nephrol. 2008 12 93 101 10.1007/s10157-007-0008-3 18175051
60. Dubrey S. The Clinical Features of Immunoglobulin Light-Chain (AL) Amyloidosis with Heart Involvement QJM Int. J. Med. 1998 91 141 157 10.1093/qjmed/91.2.141 9578896
61. Dubrey S.W. Cha K. Simms R.W. Skinner M. Falk R.H. Electrocardiography and Doppler Echocardiography in Secondary (AA) Amyloidosis Am. J. Cardiol. 1996 77 313 315 10.1016/S0002-9149(97)89403-9 8607418
62. Mohammed S.F. Mirzoyev S.A. Edwards W.D. Dogan A. Grogan D.R. Dunlay S.M. Roger V.L. Gertz M.A. Dispenzieri A. Zeldenrust S.R. Left Ventricular Amyloid Deposition in Patients with Heart Failure and Preserved Ejection Fraction JACC Heart Fail. 2014 2 113 122 10.1016/j.jchf.2013.11.004 24720917 PMC3984539
63. Ritts A.J. Cornell R.F. Swiger K. Singh J. Goodman S. Lenihan D.J. Current Concepts of Cardiac Amyloidosis Heart Fail. Clin. 2017 13 409 416 10.1016/j.hfc.2016.12.003 28279425
64. Damy T. Costes B. Hagège A.A. Donal E. Eicher J.-C. Slama M. Guellich A. Rappeneau S. Gueffet J.-P. Logeart D. Prevalence and Clinical Phenotype of Hereditary Transthyretin Amyloid Cardiomyopathy in Patients with Increased Left Ventricular Wall Thickness Eur. Heart J. 2016 37 1826 1834 10.1093/eurheartj/ehv583 26537620
65. Torpoco Rivera D.M. Williams C.T. Karpawich P.P. Cardiac Amyloidosis in a Child Presenting with Syncope: The First Reported Case and a Diagnostic Dilemma Pediatr. Cardiol. 2022 43 700 703 10.1007/s00246-021-02778-9 34783874
66. van der Hilst J.C.H. Simon A. Drenth J.P.H. Hereditary Periodic Fever and Reactive Amyloidosis Clin. Exp. Med. 2005 5 87 98 10.1007/s10238-005-0071-6 16284730
67. Ebert E.C. Nagar M. Gastrointestinal Manifestations of Amyloidosis Am. J. Gastroenterol. 2008 103 776 787 10.1111/j.1572-0241.2007.01669.x 18076735
68. Looi L.-M. Sumithran E. Morphologic Differences in the Pattern of Liver Infiltration between Systemic AL and AA Amyloidosis Hum. Pathol. 1988 19 732 735 10.1016/S0046-8177(88)80181-3 2454214
69. Renzulli P. Schoepfer A. Mueller E. Candinas D. Atraumatic Splenic Rupture in Amyloidosis Amyloid 2009 16 47 53 10.1080/13506120802676922 19291515
70. Strauss R.G. Schubert W.K. James MeAdams A. Amyloidosis in Childhood J. Pediatr. 1969 74 272 282 5762889 10.1016/s0022-3476(69)80076-4
71. Baumgart J.-V. Stuhlmann-Laeisz C. Hegenbart U. Nattenmüller J. Schönland S. Krüger S. Behrens H.-M. Röcken C. Local vs. Systemic Pulmonary Amyloidosis—Impact on Diagnostics and Clinical Management Virchows Arch. 2018 473 627 637 10.1007/s00428-018-2442-x 30136180
72. Grogg K.L. Aubry M.-C. Vrana J.A. Theis J.D. Dogan A. Nodular Pulmonary Amyloidosis Is Characterized by Localized Immunoglobulin Deposition and Is Frequently Associated with an Indolent B-Cell Lymphoproliferative Disorder Am. J. Surg. Pathol. 2013 37 406 412 10.1097/PAS.0b013e318272fe19 23282974
73. Riehani A. Soubani A.O. The Spectrum of Pulmonary Amyloidosis Respir. Med. 2023 218 107407 10.1016/j.rmed.2023.107407 37696313
74. Prada V. Massucco S. Venturi C. Geroldi A. Bellone E. Mandich P. Minuto M. Varaldo E. Mancardi G. Grandis M. Diagnostic Value of Sural Nerve Biopsy: Retrospective Analysis of Clinical Cases from 1981 to 2017 Front. Neurol. 2019 10 1218 10.3389/fneur.2019.01218 31824401 PMC6884026
75. Loavenbruck A.J. Singer W. Mauermann M.L. Sandroni P. Dyck P.J.B. Gertz M. Klein C.J. Low P.A. Transthyretin Amyloid Neuropathy Has Earlier Neural Involvement but Better Prognosis than Primary Amyloid Counterpart: An Answer to the Paradox? Ann. Neurol. 2016 80 401 411 10.1002/ana.24725 27422051 PMC5016242
76. Wechalekar A.D. Gillmore J.D. Hawkins P.N. Systemic Amyloidosis Lancet 2016 387 2641 2654 10.1016/S0140-6736(15)01274-X 26719234
77. Flaherty K.R. Morgenstern R. Pozniakoff T. DeLuca A. Castano A. Maurer M.S. Bokhari S. 99mTechnetium Pyrophosphate Scintigraphy with Cadmium Zinc Telluride Cameras Is a Highly Sensitive and Specific Imaging Modality to Diagnose Transthyretin Cardiac Amyloidosis J. Nucl. Cardiol. 2020 27 371 380 10.1007/s12350-019-01831-8 31463816
78. Maurer M.S. Hanna M. Grogan M. Dispenzieri A. Witteles R. Drachman B. Judge D.P. Lenihan D.J. Gottlieb S.S. Shah S.J. Genotype and Phenotype of Transthyretin Cardiac Amyloidosis J. Am. Coll. Cardiol. 2016 68 161 172 10.1016/j.jacc.2016.03.596 27386769 PMC4940135
79. Javidiparsijani S. Picken M.M. Should the Reporting of Bone Marrow Positivity for Amyloid Be Revised?: A Critical Assessment Based on 66 Biopsies From a Single Institution Arch. Pathol. Lab. Med. 2020 144 967 973 10.5858/arpa.2019-0324-OA 31944863
80. Fine N.M. Arruda-Olson A.M. Dispenzieri A. Zeldenrust S.R. Gertz M.A. Kyle R.A. Swiecicki P.L. Scott C.G. Grogan M. Yield of Noncardiac Biopsy for the Diagnosis of Transthyretin Cardiac Amyloidosis Am. J. Cardiol. 2014 113 1723 1727 10.1016/j.amjcard.2014.02.030 24698461
81. Quarta C.C. Gonzalez-Lopez E. Gilbertson J.A. Botcher N. Rowczenio D. Petrie A. Rezk T. Youngstein T. Mahmood S. Sachchithanantham S. Diagnostic Sensitivity of Abdominal Fat Aspiration in Cardiac Amyloidosis Eur. Heart J. 2017 38 1905 1908 10.1093/eurheartj/ehx047 28605421 PMC5837229
82. Van Gameren I.I. Hazenberg B.P.C. Bijzet J. Van Rijswijk M.H. Diagnostic Accuracy of Subcutaneous Abdominal Fat Tissue Aspiration for Detecting Systemic Amyloidosis and Its Utility in Clinical Practice Arthritis Rheum. 2006 54 2015 2021 10.1002/art.21902 16732553
83. Garcia Y. Collins A.B. Stone J.R. Abdominal Fat Pad Excisional Biopsy for the Diagnosis and Typing of Systemic Amyloidosis Hum. Pathol. 2018 72 71 79 10.1016/j.humpath.2017.11.001 29133141
84. Vrana J.A. Theis J.D. Dasari S. Mereuta O.M. Dispenzieri A. Zeldenrust S.R. Gertz M.A. Kurtin P.J. Grogg K.L. Dogan A. Clinical Diagnosis and Typing of Systemic Amyloidosis in Subcutaneous Fat Aspirates by Mass Spectrometry-Based Proteomics Haematologica 2014 99 1239 1247 10.3324/haematol.2013.102764 24747948 PMC4077087
85. Hasserjian R.P. Goodman H.J.B. Lachmann H.J. Muzikansky A. Hawkins P.N. Bone Marrow Findings Correlate with Clinical Outcome in Systemic AL Amyloidosis Patients Histopathology 2007 50 567 573 10.1111/j.1365-2559.2007.02658.x 17394492
86. Magaki S. Hojat S.A. Wei B. So A. Yong W.H. An Introduction to the Performance of Immunohistochemistry Methods Mol. Biol. 2019 1897 289 298 30539453 10.1007/978-1-4939-8935-5_25 PMC6749998
87. Im K. Mareninov S. Diaz M.F.P. Yong W.H. An Introduction to Performing Immunofluorescence Staining Methods Mol. Biol. 2019 1897 299 311 30539454 10.1007/978-1-4939-8935-5_26 PMC6918834
88. Messias N.C. Walker P.D. Larsen C.P. Paraffin Immunofluorescence in the Renal Pathology Laboratory: More than a Salvage Technique Mod. Pathol. 2015 28 854 860 10.1038/modpathol.2015.1 25676556
89. Gonzalez Suarez M.L. Zhang P. Nasr S.H. Sathick I.J. Kittanamongkolchai W. Kurtin P.J. Alexander M.P. Cornell L.D. Fidler M.E. Grande J.P. The Sensitivity and Specificity of the Routine Kidney Biopsy Immunofluorescence Panel Are Inferior to Diagnosing Renal Immunoglobulin-Derived Amyloidosis by Mass Spectrometry Kidney Int. 2019 96 1005 1009 10.1016/j.kint.2019.05.027 31447055
90. Owen-Casey M.P. Sim R. Cook H.T. Roufosse C.A. Gillmore J.D. Gilbertson J.A. Hutchison C.A. Howie A.J. Value of Antibodies to Free Light Chains in Immunoperoxidase Studies of Renal Biopsies J. Clin. Pathol. 2014 67 661 666 10.1136/jclinpath-2014-202231 24817705 PMC4112424
91. Abildgaard N. Rojek A.M. Møller H.E. Palstrøm N.B. Nyvold C.G. Rasmussen L.M. Hansen C.T. Beck H.C. Marcussen N. Immunoelectron Microscopy and Mass Spectrometry for Classification of Amyloid Deposits Amyloid 2020 27 59 66 10.1080/13506129.2019.1688289 31752543
92. Barreca A. Bottasso E. Veneziano F. Giarin M. Nocifora A. Martinetti N. Attanasio A. Biancone L. Benevolo G. Roccatello D. Immunohistochemical Typing of Amyloid in Fixed Paraffin-Embedded Samples by an Automatic Procedure: Comparison with Immunofluorescence Data on Fresh-Frozen Tissue PLoS ONE 2021 16 e0256306 10.1371/journal.pone.0256306 34428239 PMC8384180
93. Adams D. Ando Y. Beirão J.M. Coelho T. Gertz M.A. Gillmore J.D. Hawkins P.N. Lousada I. Suhr O.B. Merlini G. Expert Consensus Recommendations to Improve Diagnosis of ATTR Amyloidosis with Polyneuropathy J. Neurol. 2021 268 2109 2122 10.1007/s00415-019-09688-0 31907599 PMC8179912
94. Linke R.P. Meinel A. Chalcroft J.P. Sensitive and Reliable Immunohistochemical Typing of 21 Different Amyloid Classes in 782 Patients Using Amyloid-Type Specific Antibodies Directed against the Amyloidotic Conformation. With Comments on the Gold Standard Debate Amyloid 2017 24 157 158 10.1080/13506129.2017.1292905 28434338
95. Freudenthaler S. Hegenbart U. Schönland S. Behrens H.-M. Krüger S. Röcken C. Amyloid in Biopsies of the Gastrointestinal Tract—A Retrospective Observational Study on 542 Patients Virchows Arch. 2016 468 569 577 10.1007/s00428-016-1916-y 26915034 PMC4856726
96. Dogan A. Amyloidosis: Insights from Proteomics Annu. Rev. Pathol. Mech. Dis. 2017 12 277 304 10.1146/annurev-pathol-052016-100200 27959636
97. Lavatelli F. di Fonzo A. Palladini G. Merlini G. Systemic Amyloidoses and Proteomics: The State of the Art EuPA Open Proteom. 2016 11 4 10 10.1016/j.euprot.2016.02.003 29900105 PMC5988550
98. Picken M.M. Proteomics and Mass Spectrometry in the Diagnosis of Renal Amyloidosis Clin. Kidney J. 2015 8 665 672 10.1093/ckj/sfv087 26613021 PMC4655794
99. Gilbertson J.A. Theis J.D. Vrana J.A. Lachmann H. Wechalekar A. Whelan C. Hawkins P.N. Dogan A. Gillmore J.D. A Comparison of Immunohistochemistry and Mass Spectrometry for Determining the Amyloid Fibril Protein from Formalin-Fixed Biopsy Tissue J. Clin. Pathol. 2015 68 314 317 10.1136/jclinpath-2014-202722 25637636
100. Rezk T. Gilbertson J.A. Mangione P.P. Rowczenio D. Rendell N.B. Canetti D. Lachmann H.J. Wechalekar A.D. Bass P. Hawkins P.N. The Complementary Role of Histology and Proteomics for Diagnosis and Typing of Systemic Amyloidosis J. Pathol. Clin. Res. 2019 5 145 153 10.1002/cjp2.126 30740936 PMC6648380
101. Parman Y. Adams D. Obici L. Galán L. Guergueltcheva V. Suhr O.B. Coelho T. Sixty Years of Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) in Europe Curr. Opin. Neurol. 2016 29 S3 S13 10.1097/WCO.0000000000000288 26734951 PMC4739317
102. Rubin J. Maurer M.S. Cardiac Amyloidosis: Overlooked, Underappreciated, and Treatable Annu. Rev. Med. 2020 71 203 219 10.1146/annurev-med-052918-020140 31986086
103. Gillmore J.D. Lachmann H.J. Rowczenio D. Gilbertson J.A. Zeng C.-H. Liu Z.-H. Li L.-S. Wechalekar A. Hawkins P.N. Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis J. Am. Soc. Nephrol. 2009 20 444 451 10.1681/ASN.2008060614 19073821 PMC2637055
104. Stangou A.J. Banner N.R. Hendry B.M. Rela M. Portmann B. Wendon J. Monaghan M. MacCarthy P. Buxton-Thomas M. Mathias C.J. Hereditary Fibrinogen A α-Chain Amyloidosis: Phenotypic Characterization of a Systemic Disease and the Role of Liver Transplantation Blood 2010 115 2998 3007 10.1182/blood-2009-06-223792 19633201
105. Lachmann H.J. Goodman H.J.B. Gilbertson J.A. Gallimore J.R. Sabin C.A. Gillmore J.D. Hawkins P.N. Natural History and Outcome in Systemic AA Amyloidosis N. Engl. J. Med. 2007 356 2361 2371 10.1056/NEJMoa070265 17554117
106. Gillmore J.D. Lovat L.B. Persey M.R. Pepys M.B. Hawkins P.N. Amyloid Load and Clinical Outcome in AA Amyloidosis in Relation to Circulating Concentration of Serum Amyloid A Protein Lancet 2001 358 24 29 10.1016/S0140-6736(00)05252-1 11454373
107. Caorsi R. Federici S. Gattorno M. Biologic Drugs in Autoinflammatory Syndromes Autoimmun. Rev. 2012 12 81 86 10.1016/j.autrev.2012.07.027 22884553
108. Siligato R. Gembillo G. Calabrese V. Conti G. Santoro D. Amyloidosis and Glomerular Diseases in Familial Mediterranean Fever Medicina 2021 57 1049 10.3390/medicina57101049 34684086 PMC8541210
109. La Bella S. Di Ludovico A. Di Donato G. Basaran O. Ozen S. Gattorno M. Chiarelli F. Breda L. The Pyrin Inflammasome, a Leading Actor in Pediatric Autoinflammatory Diseases Front. Immunol. 2024 14 1341680 10.3389/fimmu.2023.1341680 38250061 PMC10796709
110. Dima D. Mazzoni S. Anwer F. Khouri J. Samaras C. Valent J. Williams L. Diagnostic and Treatment Strategies for AL Amyloidosis in an Era of Therapeutic Innovation JCO Oncol. Pract. 2023 19 265 275 10.1200/OP.22.00396 36854070
111. Gertz M.A. Lacy M.Q. Dispenzieri A. Hayman S.R. Kumar S.K. Leung N. Gastineau D.A. Effect of Hematologic Response on Outcome of Patients Undergoing Transplantation for Primary Amyloidosis: Importance of Achieving a Complete Response Haematologica 2007 92 1415 1418 10.3324/haematol.11413 17768110
112. Skinner M. Sanchorawala V. Seldin D.C. Dember L.M. Falk R.H. Berk J.L. Anderson J.J. O’Hara C. Finn K.T. Libbey C.A. High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study Ann. Intern. Med. 2004 140 85 10.7326/0003-4819-140-2-200401200-00008 14734330
113. Jaccard A. Moreau P. Leblond V. Leleu X. Benboubker L. Hermine O. Recher C. Asli B. Lioure B. Royer B. High-Dose Melphalan versus Melphalan plus Dexamethasone for AL Amyloidosis N. Engl. J. Med. 2007 357 1083 1093 10.1056/NEJMoa070484 17855669
114. Gatt M.E. Palladini G. Light Chain Amyloidosis 2012: A New Era Br. J. Haematol. 2013 160 582 598 10.1111/bjh.12191 23294331
115. Dittrich T. Benner A. Kimmich C. aus dem Siepen F. Veelken K. Kristen A.V. Bochtler T. Katus H.A. Müller-Tidow C. Hegenbart U. Performance Analysis of AL Amyloidosis Cardiac Biomarker Staging Systems with Special Focus on Renal Failure and Atrial Arrhythmia Haematologica 2019 104 1451 1459 10.3324/haematol.2018.205336 30655373 PMC6601086
116. Suzuki K. Wechalekar A.D. Kim K. Shimazaki C. Kim J.S. Ikezoe T. Min C.K. Zhou F. Cai Z. Chen X. Daratumumab plus Bortezomib, Cyclophosphamide, and Dexamethasone in Asian Patients with Newly Diagnosed AL Amyloidosis: Subgroup Analysis of ANDROMEDA Ann. Hematol. 2023 102 863 876 10.1007/s00277-023-05090-z 36862168 PMC9998577
117. Kumar S. Dispenzieri A. Lacy M.Q. Hayman S.R. Buadi F.K. Colby C. Laumann K. Zeldenrust S.R. Leung N. Dingli D. Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements J. Clin. Oncol. 2012 30 989 995 10.1200/JCO.2011.38.5724 22331953 PMC3675680
118. Dispenzieri A. Gertz M.A. Kyle R.A. Lacy M.Q. Burritt M.F. Therneau T.M. Greipp P.R. Witzig T.E. Lust J.A. Rajkumar S.V. Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis J. Clin. Oncol. 2004 22 3751 3757 10.1200/JCO.2004.03.029 15365071
119. Kyriakou P. Mouselimis D. Tsarouchas A. Rigopoulos A. Bakogiannis C. Noutsias M. Vassilikos V. Diagnosis of Cardiac Amyloidosis: A Systematic Review on the Role of Imaging and Biomarkers BMC Cardiovasc. Disord. 2018 18 221 10.1186/s12872-018-0952-8 30509186 PMC6278059
120. Domínguez S. Wienberg P. Clarós P. Clarós A. Vila J. Primary Localized Nasopharyngeal Amyloidosis. A Case Report Int. J. Pediatr. Otorhinolaryngol. 1996 36 61 67 10.1016/0165-5876(96)01330-4 8803693
121. Wilczek H.E. Larsson M. Ericzon B.-G. Long-Term Data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) Amyloid 2011 18 193 195 10.3109/13506129.2011.574354072 21838484
122. Okamoto S. Zhao Y. Lindqvist P. Backman C. Ericzon B.-G. Wijayatunga P. Henein M.Y. Suhr O.B. Development of Cardiomyopathy after Liver Transplantation in Swedish Hereditary Transthyretin Amyloidosis (ATTR) Patients Amyloid 2011 18 200 205 10.3109/13506129.2011.615872 22080763
123. Grogan M. Scott C.G. Kyle R.A. Zeldenrust S.R. Gertz M.A. Lin G. Klarich K.W. Miller W.L. Maleszewski J.J. Dispenzieri A. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System J. Am. Coll. Cardiol. 2016 68 1014 1020 10.1016/j.jacc.2016.06.033 27585505
124. Dardiotis E. Kyriakides T. Drug and Gene Therapy for Treating Variant Transthyretin Amyloidosis (ATTRv) Neuropathy Curr. Neuropharmacol. 2023 21 471 481 10.2174/1570159X21666221108094736 36366846 PMC10207904
125. Yamamoto S. Gejyo F. Historical Background and Clinical Treatment of Dialysis-Related Amyloidosis Biochim. Biophys. Acta Proteins Proteom. 2005 1753 4 10 10.1016/j.bbapap.2005.09.006 16226497