Amyloid Neuropathies
Amyloid Neuropathies, Familial
Prealbumin
Amyloidosis
Amyloid
Diabetic Neuropathies
Amyloid beta-Peptides
Serum Amyloid A Protein
Peripheral Nervous System Diseases
Amyloid beta-Protein Precursor
Hereditary Sensory and Motor Neuropathy
Islet Amyloid Polypeptide
Cerebral Amyloid Angiopathy
Hereditary Sensory and Autonomic Neuropathies
Optic Neuropathy, Ischemic
Serum Amyloid P-Component
Polyneuropathies
Sural Nerve
Amyloid Precursor Protein Secretases
Alzheimer Disease
Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. (1/76)
We report a middle-aged woman with a novel transthyretin (TTR) variant, Leu12Pro. She had extensive amyloid deposition in the leptomeninges and liver as well as the involvement of the heart and peripheral nervous system which characterizes familial amyloid polyneuropathy caused by variant TTR. Clinical features attributed to her leptomeningeal amyloid included radiculopathy, central hypoventilation, recurrent subarachnoid haemorrhage, depression, seizures and periods of decreased consciousness. MRI showed a marked enhancement throughout her meninges and ependyma, and TTR amyloid deposition was confirmed by meningeal biopsy. The simultaneous presence of extensive visceral amyloid and clinically significant deposits affecting both the peripheral and central nervous system extends the spectrum of amyloid-related disease associated with TTR mutations. The unusual association of severe peripheral neuropathy with symptoms of leptomeningeal amyloid indicates that leptomeningeal amyloidosis should be considered part of the syndrome of TTR-related familial amyloid polyneuropathy. (+info)Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. (2/76)
Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens). (+info)1H-NMR structural studies of a cystine-linked peptide containing residues 71-93 of transthyretin and effects of a Ser84 substitution implicated in familial amyloidotic polyneuropathy. (3/76)
The Ile-->Ser84 substitution in the thyroid hormone transport protein transthyretin is one of over 50 variations found to be associated with familial amyloid polyneuropathy, a hereditary type of lethal amyloidosis. Using a peptide analogue of the loop containing residue 84 in transthyretin, we have examined the putative local structural effects of this substitution using 1H-NMR spectroscopy. The peptide, containing residues 71-93 of transthyretin with its termini linked via a disulfide bond, was found to possess the same helix-turn motif as in the corresponding region of the crystallographically derived structure of transthyretin in 20% trifluoroethanol (TFE) solution. It therefore, represents a useful model with which to examine the effects of amyloidogenic substitutions. In a peptide analogue containing the Ile84-->Ser substitution it was found that the substitution does not greatly disrupt the overall three-dimensional structure, but leads to minor local differences at the turn in which residue 84 is involved. Coupling constant and NOE measurements indicate that the helix-turn motif is still present, but differences in chemical shifts and amide-exchange rates reflect a small distortion. This is in keeping with observations that several other mutant forms of transthyretin display similar subunit interactions and those that have been structurally analysed possess a near native structure. We propose that the Ser84 mutation induces only subtle perturbations to the transthyretin structure which predisposes the protein to amyloid formation. (+info)Role of sympathetic nervous system in cyclosporine-induced rise in blood pressure. (4/76)
To clarify the role of the sympathetic nervous system in the development of cyclosporine A (CsA)-induced rise in blood pressure (BP), the effects of CsA on 24-hour ambulatory BP (ABP) were studied in patients with familial amyloid polyneuropathy (FAP) who underwent a liver transplantation. On the basis of autonomic function tests, patients with absent or mild-to-moderate sympathetic damage (Group A, n=11, age 29 to 43 years, disease duration 2 to 6 years) and patients with severe sympathetic damage (Group B, n=9, age 27 to 38 years, disease duration 3 to 9 years) were identified. Both groups were followed for 1 year. The daily doses of CsA and the CsA whole blood trough levels between the groups did not differ. Pretransplantation values of daytime and nighttime ABP were, respectively, 117+/-8/76+/-7 mm Hg and 108+/-12/68+/-9 mm Hg in group A and 107+/-6/66+/-4 mm Hg (P<0.05 group A versus group B) and 102+/-6/62+/-4 mm Hg in group B. In response to CsA, BP increased in all patients, but more so in patients of group B than in patients of group A. One year after transplantation, daytime and nighttime ABP had increased by 6+/-9/3+/-11% and 12+/-10/14+/-14% in group A and by 12+/-6/13+/-10% (P<0.05) and 21+/-11/27+/-21% (P<0.01) in group B. In both groups, the increase in nighttime ABP was greater than the increase in daytime ABP, which resulted in an attenuation or, even, a reversal of the diurnal BP rhythm. Because the rise in BP was greater in patients with more advanced sympathetic dysfunction, the sympathetic nervous system appears to counteract the CsA-induced rise in BP rather than causing it. This implies involvement of factors other than sympathetic activation in the pathogenesis of CsA-induced rise in BP in patients with familial amyloid polyneuropathy. (+info)Identification of a new transthyretin variant (Ile49) in familial amyloidotic polyneuropathy using electrospray ionization mass spectrometry and nonisotopic RNase cleavage assay. (5/76)
Mutation of the transthyretin (TTR) plasma protein and gene in a Japanese patient with amyloid polyneuropathy was investigated by electrospray ionization mass spectrometry (ESI-MS) and nonisotopic RNase cleavage assay (NIRCA), respectively. ESI-MS analysis showed normal TTR peaks and additionally a variant TTR with 12-dalton-higher molecular weight than normal TTR. NIRCA suggested that the mutation existed near either the 5' or 3' end of exon 3. Direct DNA sequencing revealed both a normal ACC (threonine) and a variant ATC (isoleucine) at codon 49, which was located near the 5' end of exon 3. The molecular weight shift of this mutation was 12 D, consistent with the result of ESI-MS. (+info)Regulation of neural differentiation by normal and mutant (G654A, amyloidogenic) gelsolin. (6/76)
Gelsolin belongs to a family of proteins that modulate the structural dynamics of cytoskeletal actin. Gelsolin activity is required for the redistribution of actin occurring during membrane ruffling, cell crawling, and platelet activation. A point mutation (G654A) in the gelsolin gene causes a dominantly inherited systemic amyloidosis called familial amyloidosis of the Finnish type (FAF). This disease is characterized by a cranial neuropathy that cannot be explained solely by amyloid deposits. To address the question of whether gelsolin has a specific role in neural cell development, we transfected cDNA for wild type and G654A point-mutated gelsolin into a neural cell line, Paju, which can be induced to differentiate by treatment with phorbol 12-myristate 13-acetate. Overexpressed wild type gelsolin inhibited neural differentiation whereas mutated gelsolin did not, indicating that appropriate gelsolin activity is essential for neural sprouting. The G654A mutant gelsolin induced stabilization of F-actin and reduced the plasticity of neural development. This provides a novel etiopathogenetic mechanism for the neuronal dysfunction in FAF. (+info)Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30. (7/76)
Twin studies are an important tool in medical genetics for the evaluation of the relative roles of genetic and non-genetic factors in several diseases. Familial amyloidotic polyneuropathy type I (FAP-I), TTR Met 30, was present in two sets of proven monozygotic (MZ) twins, one from Majorca and the other from Portugal. Monozygosity was established by analysis of DNA polymorphisms. Both pairs were discordant for age at onset and some clinical manifestations of FAP-I. We reviewed the differences in age at onset and clinical features in both sets and in two other pairs of presumed MZ twins with FAP-I and compared them with those in MZ twin pairs with other Mendelian disorders, such as neurofibromatosis type 1, Huntington's disease, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. We conclude that, in addition to the postulated modifying genes, there must be a significant contribution from non-genetic factors to the phenotypic variability of FAP-I (age at onset and clinical expression), either because of environmental differences or stochastic events during (or after) the twinning process. (+info)Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features. (8/76)
Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified. (+info)Amyloid neuropathies are a group of peripheral nerve disorders caused by the abnormal accumulation of amyloid proteins in the nerves. Amyloid is a protein that can be produced in various diseases and can deposit in different organs, including nerves. When this occurs in the nerves, it can lead to damage and dysfunction, resulting in symptoms such as numbness, tingling, pain, and weakness in the affected limbs.
There are several types of amyloid neuropathies, with the two most common being:
1. Transthyretin (TTR)-related hereditary amyloidosis: This is an inherited disorder caused by mutations in the TTR gene, which leads to the production of abnormal TTR protein that can form amyloid deposits in various organs, including nerves.
2. Immunoglobulin light chain (AL) amyloidosis: This is a disorder in which abnormal plasma cells produce excessive amounts of immunoglobulin light chains, which can form amyloid deposits in various organs, including nerves.
The diagnosis of amyloid neuropathies typically involves a combination of clinical evaluation, nerve conduction studies, and tissue biopsy to confirm the presence of amyloid deposits. Treatment options depend on the underlying cause of the disorder and may include medications, chemotherapy, stem cell transplantation, or supportive care to manage symptoms.
Familial amyloid neuropathies are a group of inherited disorders characterized by the accumulation of abnormal deposits of amyloid proteins in various tissues and organs of the body. These abnormal deposits can cause damage to nerves, leading to a peripheral neuropathy that affects sensation, movement, and organ function.
There are several types of familial amyloid neuropathies, each caused by different genetic mutations. The most common type is known as transthyretin-related hereditary amyloidosis (TTR-HA), which is caused by mutations in the TTR gene. Other types include apolipoprotein A1-related hereditary amyloidosis (APOA1-HA) and gelsolin-related amyloidosis (AGel-HA).
Symptoms of familial amyloid neuropathies can vary depending on the type and severity of the disorder. Common symptoms include:
* Numbness, tingling, or pain in the hands and feet
* Weakness or loss of muscle strength in the legs and arms
* Autonomic nervous system dysfunction, leading to problems with digestion, heart rate, blood pressure, and temperature regulation
* Carpal tunnel syndrome
* Eye abnormalities, such as vitreous opacities or retinal deposits
* Kidney disease
Familial amyloid neuropathies are typically inherited in an autosomal dominant manner, meaning that a child has a 50% chance of inheriting the mutated gene from an affected parent. Diagnosis is usually made through genetic testing and confirmation of the presence of amyloid deposits in tissue samples.
Treatment for familial amyloid neuropathies typically involves managing symptoms and slowing the progression of the disease. This may include medications to control pain, physical therapy to maintain muscle strength and mobility, and devices such as braces or wheelchairs to assist with mobility. In some cases, liver transplantation may be recommended to remove the source of the mutated transthyretin protein.
Prealbumin, also known as transthyretin, is a protein produced primarily in the liver and circulates in the blood. It plays a role in transporting thyroid hormones and vitamin A throughout the body. Prealbumin levels are often used as an indicator of nutritional status and liver function. Low prealbumin levels may suggest malnutrition or inflammation, while increased levels can be seen in certain conditions like hyperthyroidism. It is important to note that prealbumin levels should be interpreted in conjunction with other clinical findings and laboratory tests for a more accurate assessment of a patient's health status.
Amyloidosis is a medical condition characterized by the abnormal accumulation of insoluble proteins called amyloid in various tissues and organs throughout the body. These misfolded protein deposits can disrupt the normal function of affected organs, leading to a range of symptoms depending on the location and extent of the amyloid deposition.
There are different types of amyloidosis, classified based on the specific proteins involved:
1. Primary (AL) Amyloidosis: This is the most common form, accounting for around 80% of cases. It results from the overproduction and misfolding of immunoglobulin light chains, typically by clonal plasma cells in the bone marrow. The amyloid deposits can affect various organs, including the heart, kidneys, liver, and nervous system.
2. Secondary (AA) Amyloidosis: This form is associated with chronic inflammatory diseases, such as rheumatoid arthritis, tuberculosis, or familial Mediterranean fever. The amyloid fibrils are composed of serum amyloid A protein (SAA), an acute-phase reactant produced during the inflammatory response. The kidneys are commonly affected in this type of amyloidosis.
3. Hereditary or Familial Amyloidosis: These forms are caused by genetic mutations that result in the production of abnormal proteins prone to misfolding and amyloid formation. Examples include transthyretin (TTR) amyloidosis, fibrinogen amyloidosis, and apolipoprotein AI amyloidosis. These forms can affect various organs, including the heart, nerves, and kidneys.
4. Dialysis-Related Amyloidosis: This form is seen in patients undergoing long-term dialysis for chronic kidney disease. The amyloid fibrils are composed of beta-2 microglobulin, a protein that accumulates due to impaired clearance during dialysis. The joints and bones are commonly affected in this type of amyloidosis.
The diagnosis of amyloidosis typically involves a combination of clinical evaluation, imaging studies, and tissue biopsy with the demonstration of amyloid deposition using special stains (e.g., Congo red). Treatment depends on the specific type and extent of organ involvement and may include supportive care, medications to target the underlying cause (e.g., chemotherapy, immunomodulatory agents), and organ transplantation in some cases.
Amyloid is a term used in medicine to describe abnormally folded protein deposits that can accumulate in various tissues and organs of the body. These misfolded proteins can form aggregates known as amyloid fibrils, which have a characteristic beta-pleated sheet structure. Amyloid deposits can be composed of different types of proteins, depending on the specific disease associated with the deposit.
In some cases, amyloid deposits can cause damage to organs and tissues, leading to various clinical symptoms. Some examples of diseases associated with amyloidosis include Alzheimer's disease (where amyloid-beta protein accumulates in the brain), systemic amyloidosis (where amyloid fibrils deposit in various organs such as the heart, kidneys, and liver), and type 2 diabetes (where amyloid deposits form in the pancreas).
It's important to note that not all amyloid deposits are harmful or associated with disease. However, when they do cause problems, treatment typically involves managing the underlying condition that is leading to the abnormal protein accumulation.
Diabetic neuropathies refer to a group of nerve disorders that are caused by diabetes. High blood sugar levels can injure nerves throughout the body, but diabetic neuropathies most commonly affect the nerves in the legs and feet.
There are four main types of diabetic neuropathies:
1. Peripheral neuropathy: This is the most common type of diabetic neuropathy. It affects the nerves in the legs and feet, causing symptoms such as numbness, tingling, burning, or shooting pain.
2. Autonomic neuropathy: This type of neuropathy affects the autonomic nerves, which control involuntary functions such as heart rate, blood pressure, digestion, and bladder function. Symptoms may include dizziness, fainting, digestive problems, sexual dysfunction, and difficulty regulating body temperature.
3. Proximal neuropathy: Also known as diabetic amyotrophy, this type of neuropathy affects the nerves in the hips, thighs, or buttocks, causing weakness, pain, and difficulty walking.
4. Focal neuropathy: This type of neuropathy affects a single nerve or group of nerves, causing symptoms such as weakness, numbness, or pain in the affected area. Focal neuropathies can occur anywhere in the body, but they are most common in the head, torso, and legs.
The risk of developing diabetic neuropathies increases with the duration of diabetes and poor blood sugar control. Other factors that may contribute to the development of diabetic neuropathies include genetics, age, smoking, and alcohol consumption.
Amyloid beta-peptides (Aβ) are small protein fragments that are crucially involved in the pathogenesis of Alzheimer's disease. They are derived from a larger transmembrane protein called the amyloid precursor protein (APP) through a series of proteolytic cleavage events.
The two primary forms of Aβ peptides are Aβ40 and Aβ42, which differ in length by two amino acids. While both forms can be harmful, Aβ42 is more prone to aggregation and is considered to be the more pathogenic form. These peptides have the tendency to misfold and accumulate into oligomers, fibrils, and eventually insoluble plaques that deposit in various areas of the brain, most notably the cerebral cortex and hippocampus.
The accumulation of Aβ peptides is believed to initiate a cascade of events leading to neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal death, which are all hallmarks of Alzheimer's disease. Although the exact role of Aβ in the onset and progression of Alzheimer's is still under investigation, it is widely accepted that they play a central part in the development of this debilitating neurodegenerative disorder.
Serum Amyloid A (SAA) protein is an acute phase protein produced primarily in the liver, although it can also be produced by other cells in response to inflammation. It is a member of the apolipoprotein family and is found in high-density lipoproteins (HDL) in the blood. SAA protein levels increase rapidly during the acute phase response to infection, trauma, or tissue damage, making it a useful biomarker for inflammation.
In addition to its role as an acute phase protein, SAA has been implicated in several disease processes, including atherosclerosis and amyloidosis. In amyloidosis, SAA can form insoluble fibrils that deposit in various tissues, leading to organ dysfunction. There are four subtypes of SAA in humans (SAA1, SAA2, SAA3, and SAA4), with SAA1 and SAA2 being the most responsive to inflammatory stimuli.
Peripheral Nervous System (PNS) diseases, also known as Peripheral Neuropathies, refer to conditions that affect the functioning of the peripheral nervous system, which includes all the nerves outside the brain and spinal cord. These nerves transmit signals between the central nervous system (CNS) and the rest of the body, controlling sensations, movements, and automatic functions such as heart rate and digestion.
PNS diseases can be caused by various factors, including genetics, infections, toxins, metabolic disorders, trauma, or autoimmune conditions. The symptoms of PNS diseases depend on the type and extent of nerve damage but often include:
1. Numbness, tingling, or pain in the hands and feet
2. Muscle weakness or cramps
3. Loss of reflexes
4. Decreased sensation to touch, temperature, or vibration
5. Coordination problems and difficulty with balance
6. Sexual dysfunction
7. Digestive issues, such as constipation or diarrhea
8. Dizziness or fainting due to changes in blood pressure
Examples of PNS diseases include Guillain-Barre syndrome, Charcot-Marie-Tooth disease, diabetic neuropathy, and peripheral nerve injuries. Treatment for these conditions varies depending on the underlying cause but may involve medications, physical therapy, lifestyle changes, or surgery.
The Amyloid Beta-Protein Precursor (AβPP) is a type of transmembrane protein that is widely expressed in various tissues and organs, including the brain. It plays a crucial role in normal physiological processes, such as neuronal development, synaptic plasticity, and repair.
AβPP undergoes proteolytic processing by enzymes called secretases, resulting in the production of several protein fragments, including the amyloid-beta (Aβ) peptide. Aβ is a small peptide that can aggregate and form insoluble fibrils, which are the main component of amyloid plaques found in the brains of patients with Alzheimer's disease (AD).
The accumulation of Aβ plaques is believed to contribute to the neurodegeneration and cognitive decline observed in AD. Therefore, AβPP and its proteolytic processing have been the focus of extensive research aimed at understanding the pathogenesis of AD and developing potential therapies.
Amyloid plaque is a pathological hallmark of several degenerative diseases, including Alzheimer's disease. It refers to extracellular deposits of misfolded proteins that accumulate in various tissues and organs, but are most commonly found in the brain. The main component of these plaques is an abnormally folded form of a protein called amyloid-beta (Aβ). This protein is produced through the normal processing of the amyloid precursor protein (APP), but in amyloid plaques, it aggregates into insoluble fibrils that form the core of the plaque.
The accumulation of amyloid plaques is thought to contribute to neurodegeneration and cognitive decline in Alzheimer's disease and other related disorders. The exact mechanisms by which this occurs are not fully understood, but it is believed that the aggregation of Aβ into plaques leads to the disruption of neuronal function and viability, as well as the activation of inflammatory responses that can further damage brain tissue.
It's important to note that while amyloid plaques are a key feature of Alzheimer's disease, they are not exclusive to this condition. Amyloid plaques have also been found in other neurodegenerative disorders, as well as in some normal aging brains, although their significance in these contexts is less clear.
Hereditary Sensory and Motor Neuropathy (HSMN) is a group of inherited disorders that affect the peripheral nerves, which are the nerves outside the brain and spinal cord. These nerves transmit information between the brain and muscles, as well as sensations such as touch, pain, heat, and cold.
HSMN is characterized by progressive degeneration of these peripheral nerves, leading to muscle weakness, numbness, and tingling sensations, particularly in the hands and feet. The condition can also affect the autonomic nervous system, which controls involuntary functions such as heart rate, blood pressure, and digestion.
HSMN is caused by genetic mutations that are inherited from one or both parents. There are several types of HSMN, each with its own specific symptoms, severity, and pattern of inheritance. The most common form is Charcot-Marie-Tooth disease (CMT), which affects both motor and sensory nerves.
Treatment for HSMN typically focuses on managing the symptoms and preventing complications. This may include physical therapy, bracing or orthopedic surgery to support weakened muscles, pain management, and lifestyle modifications such as avoiding activities that aggravate symptoms. There is currently no cure for HSMN, but ongoing research is aimed at developing new treatments and therapies to slow or halt the progression of the disease.
Islet Amyloid Polypeptide (IAPP), also known as amylin, is a 37-amino acid peptide co-secreted with insulin from pancreatic beta-cells in response to meals. It plays crucial roles in regulating glucose homeostasis by suppressing glucagon secretion, slowing gastric emptying, and promoting satiety. In type 2 diabetes, IAPP can form amyloid fibrils, which deposit in pancreatic islets, contributing to beta-cell dysfunction and death. This contributes to the progressive nature of type 2 diabetes.
Cerebral amyloid angiopathy (CAA) is a medical condition characterized by the accumulation of beta-amyloid protein in the walls of small to medium-sized blood vessels in the brain. This protein buildup can cause damage to the vessel walls, leading to bleeding (cerebral hemorrhage), cognitive decline, and other neurological symptoms.
CAA is often associated with aging and is a common finding in older adults. It can also be seen in people with Alzheimer's disease and other forms of dementia. The exact cause of CAA is not fully understood, but it is believed to result from the abnormal processing and clearance of beta-amyloid protein in the brain.
The diagnosis of CAA typically involves a combination of clinical evaluation, imaging studies such as MRI or CT scans, and sometimes cerebrospinal fluid analysis. Treatment for CAA is generally supportive and focused on managing symptoms and preventing complications. There are currently no approved disease-modifying treatments for CAA.
Hereditary Sensory and Autonomic Neuropathies (HSANs) are a group of inherited disorders that affect the sensory and autonomic nerves. These nerves are responsible for transmitting information about senses such as touch, pain, temperature, and vibration to the brain, as well as controlling automatic functions like blood pressure, heart rate, and digestion.
HSANs are caused by genetic mutations that result in damage to the peripheral nerves. There are several types of HSANs, each with its own specific symptoms and patterns of inheritance. Some common features include:
* Loss of sensation in the hands and feet
* Pain insensitivity
* Absent or reduced reflexes
* Autonomic dysfunction, such as abnormal sweating, blood pressure regulation, and digestive problems
The severity and progression of HSANs can vary widely depending on the specific type and individual factors. Treatment is generally focused on managing symptoms and preventing complications, such as injuries from lack of pain sensation or falls due to balance problems. Early diagnosis and intervention are important for optimizing outcomes.
Ischemic optic neuropathy (ION) is a medical condition that refers to the damage or death of the optic nerve due to insufficient blood supply. The optic nerve is responsible for transmitting visual information from the eye to the brain.
In ION, the blood vessels that supply the optic nerve become blocked or narrowed, leading to decreased blood flow and oxygen delivery to the nerve fibers. This results in inflammation, swelling, and ultimately, damage to the optic nerve. The damage can cause sudden, painless vision loss, often noticed upon waking up in the morning.
There are two types of ION: anterior ischemic optic neuropathy (AION) and posterior ischemic optic neuropathy (PION). AION affects the front part of the optic nerve, while PION affects the back part of the nerve. AION is further classified into arteritic and non-arteritic types, depending on whether it is caused by giant cell arteritis or not.
Risk factors for ION include age (most commonly occurring in people over 50), hypertension, diabetes, smoking, sleep apnea, and other cardiovascular diseases. Treatment options depend on the type and cause of ION and may include controlling underlying medical conditions, administering corticosteroids, or undergoing surgical procedures to improve blood flow.
Serum Amyloid P-component (SAP) is a protein that is normally present in the blood and other bodily fluids. It is a part of the larger family of pentraxin proteins, which are involved in the innate immune response, meaning they provide immediate defense against foreign invaders without needing to adapt over time. SAP plays a role in inflammation, immune complex clearance, and complement activation.
In the context of amyloidosis, SAP binds to misfolded proteins called amyloid fibrils, which can deposit in various tissues and organs, leading to their dysfunction and failure. The accumulation of these amyloid fibrils with SAP is a hallmark of systemic amyloidosis.
It's important to note that while SAP plays a role in the pathogenesis of amyloidosis, it is not directly responsible for causing the disease. Instead, its presence can serve as a useful marker for diagnosing and monitoring the progression of amyloidosis.
Polyneuropathy is a medical condition that refers to the damage or dysfunction of peripheral nerves (nerves outside the brain and spinal cord) in multiple areas of the body. These nerves are responsible for transmitting sensory, motor, and autonomic signals between the central nervous system and the rest of the body.
In polyneuropathies, this communication is disrupted, leading to various symptoms depending on the type and extent of nerve damage. Commonly reported symptoms include:
1. Numbness or tingling in the hands and feet
2. Muscle weakness and cramps
3. Loss of reflexes
4. Burning or stabbing pain
5. Balance and coordination issues
6. Increased sensitivity to touch
7. Autonomic dysfunction, such as bowel, bladder, or digestive problems, and changes in blood pressure
Polyneuropathies can be caused by various factors, including diabetes, alcohol abuse, nutritional deficiencies, autoimmune disorders, infections, toxins, inherited genetic conditions, or idiopathic (unknown) causes. The treatment for polyneuropathy depends on the underlying cause and may involve managing underlying medical conditions, physical therapy, pain management, and lifestyle modifications.
The sural nerve is a purely sensory peripheral nerve in the lower leg and foot. It provides sensation to the outer ( lateral) aspect of the little toe and the adjacent side of the fourth toe, as well as a small portion of the skin on the back of the leg between the ankle and knee joints.
The sural nerve is formed by the union of branches from the tibial and common fibular nerves (branches of the sciatic nerve) in the lower leg. It runs down the calf, behind the lateral malleolus (the bony prominence on the outside of the ankle), and into the foot.
The sural nerve is often used as a donor nerve during nerve grafting procedures due to its consistent anatomy and relatively low risk for morbidity at the donor site.
Amyloid precursor protein (APP) secretases are enzymes that are responsible for cleaving the amyloid precursor protein into various smaller proteins. There are two types of APP secretases: α-secretase and β-secretase.
α-Secretase is a member of the ADAM (a disintegrin and metalloproteinase) family, specifically ADAM10 and ADAM17. When APP is cleaved by α-secretase, it produces a large ectodomain called sAPPα and a membrane-bound C-terminal fragment called C83. This pathway is known as the non-amyloidogenic pathway because it prevents the formation of amyloid-β (Aβ) peptides, which are associated with Alzheimer's disease.
β-Secretase, also known as β-site APP cleaving enzyme 1 (BACE1), is a type II transmembrane aspartic protease. When APP is cleaved by β-secretase, it produces a large ectodomain called sAPPβ and a membrane-bound C-terminal fragment called C99. Subsequently, C99 is further cleaved by γ-secretase to generate Aβ peptides, including the highly neurotoxic Aβ42. This pathway is known as the amyloidogenic pathway because it leads to the formation of Aβ peptides and the development of Alzheimer's disease.
Therefore, APP secretases play a crucial role in the regulation of APP processing and have been the focus of extensive research in the context of Alzheimer's disease and other neurodegenerative disorders.
Alzheimer's disease is a progressive disorder that causes brain cells to waste away (degenerate) and die. It's the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently.
The early signs of the disease include forgetting recent events or conversations. As the disease progresses, a person with Alzheimer's disease will develop severe memory impairment and lose the ability to carry out everyday tasks.
Currently, there's no cure for Alzheimer's disease. However, treatments can temporarily slow the worsening of dementia symptoms and improve quality of life.