What are the other Names for this Condition? (Also known as/Synonyms)

• Amyloidosis of Central Nervous System
• Brain Amyloidosis
• Familial Amyloidotic Neuropathy (FAP)

What is Amyloid Neuropathy? (Definition/Background Information)

• Amyloidosis is a group of disorders in which the ‘amyloid protein’ builds up in many organs and tissues of the body. The term “amyloid” is used for protein molecules of any type that stick together owing to misfolding (or incorrect formation of the proteins)
• These protein aggregates are abnormally-formed and arranged into fibrils (slender fibers). An amyloid build-up can occur locally in only one organ, or may occur throughout the body. When the abnormal amyloid proteins get deposited in the nerves and resulting in lesions, it is called Amyloid Neuropathy. The condition is also known as Amyloidosis of Central Nervous System
• There are 5 major types of amyloidosis, all of which can lead to Cardiac Amyloidosis:
  • AL amyloidosis that occurs when bone marrow produces too much amyloid protein, creating light (L) chains
  • AA amyloidosis, when amyloid proteins build up secondary to a chronic disease
  • Hereditary amyloidosis: It is an inherited form of the disease; the amyloid build-up primarily affects the kidneys and nerves
  • Wild-type ATTR amyloidosis: This form leads to amyloid protein deposits in elderly adults, particularly in the heart and tendons
  • Dialysis-related amyloidosis: This occurs in individuals who have undergone dialysis for a long time. The amyloid protein tends to get deposited in the tendons and joints
• Amyloid Neuropathy is generally associated with systemic AL amyloidosis and hereditary amyloidosis. In addition, nerve damage can occur with the AA- and wild-type ATTR- subtypes of amyloidosis
• When the nerves are damaged in hereditary amyloidosis, the condition is termed Familial Amyloidotic Polyneuropathy or FAP. Mutation(s) in the TTR gene are predominantly associated with hereditary amyloidosis that manifests as Amyloid Neuropathy
• Typically, Amyloid Neuropathy affects older adults. The condition can affect both the central and peripheral nerves and result in symptoms of unusual sensations, numbness, tingling, headaches, seizures, and even paralysis
• Generally, Amyloid Neuropathy is a progressive disease with no cure, and the prognosis is guarded. The treatment involves an effective management of amyloidosis and the underlying condition causing it

Who gets Amyloid Neuropathy? (Age and Sex Distribution)

• Amyloid Neuropathy is a rare disorder that is reported worldwide. Although it can occur at any age, typically older adults of both genders are affected
• Amyloid Neuropathy associated with AL amyloidosis is possibly the predominant type noted
• It is reported that men may be more frequently affected than women. However, when the disease occurs as a manifestation of hereditary amyloidosis, both males and females may be equally affected
• In hereditary amyloidosis-associated form of Amyloid Neuropathy, the age of symptom onset may differ in individuals with TTR gene mutation(s), such as:
  • In individuals from Portugal, the onset occurs between 25-35 years of age
  • In those from Switzerland with the same type of gene mutation as Portuguese individuals, the onset is in the 60-70 years’ age range

In the US, hereditary amyloidosis is more common in the African-American population, when compared to Caucasians. This type of amyloidosis is also common in many European countries.

What are the Risk Factors for Amyloid Neuropathy? (Predisposing Factors)

The following are some known risk factors for developing Amyloid Neuropathy:

• Advancing age
• Male gender
• Individuals of African descent
• A family history of amyloidosis
• Any condition that affects the antibody-producing cells in the body, including benign monoclonal gammopathy, malignant lymphoma, and multiple myeloma
• Chronic inflammatory conditions such as
  • Arthritis, including rheumatoid arthritis, juvenile inflammatory arthritis, psoriatic arthritis and ankylosing spondylitis
  • Inflammatory bowel disease (IBD) such as ulcerative colitis
• Chronic infections, including
  • Tuberculosis
  • Leprosy
  • Bronchiectasis
  • Osteomyelitis
  • Skin infections (especially in drug abusers, who use needles to inject themselves)
  • Chronic infection in skin with burns
  • Chronic kidney infections (pyelonephritis)
  • Whipple’s disease
• Poorly-controlled diabetes
• Infectious diseases such as HIV/AIDS
• Cystic fibrosis; individuals with this condition are prone to repeat infections
• Certain cancers such as Hodgkin’s lymphoma and renal cell carcinoma
• Family history of certain hereditary disorders that may include:
  • Familial Mediterranean fever (FMF)
  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)
  • Hyperimmunoglobulin D syndrome and periodic fever syndrome (HIDS)
  • Cryopyrin-associated periodic syndrome (CAPS)
  • Majeed syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Amyloid Neuropathy? (Etiology)

Amyloid Neuropathy is caused as a manifestation of systemic Amyloidosis, which may be of the AL, AA, hereditary, or wild-type ATTR subtypes.

• AL amyloidosis:
  • AL amyloidosis is caused by an abnormal functioning of plasma cells in the bone marrow. The bone marrow is the location of blood generation
  • It is an acquired disorder of the plasma and is typically associated with bone marrow disorders such as dyscrasia, monoclonal gammopathy, lymphoma, multiple myeloma, and Waldenstrom’s macroglobulinemia
• AA amyloidosis:
  • A partial breakdown of serum amyloid A (SAA) leads to the formation and accumulation of the aberrant amyloid A protein (AA protein) that gets deposited in tissues causing symptoms
  • This condition develops from long-term inflammation and certain infections
• Hereditary amyloidosis:
  • A variety of gene mutations are known to cause this condition. Some of these include the TTR, FGA, CST3, and APP genes
  • In majority of cases, inherited Amyloid Neuropathy is caused by mutation(s) in the TTR gene. The mutations are inherited in an autosomal dominant manner
• Wild-type ATTR amyloidosis: In elderly individuals, normal (unmutated) transthyretin protein may get deposited in the various parts of the body including the nerves (typically in the heart and tendons), causing Amyloid Neuropathy.

What are the Signs and Symptoms of Amyloid Neuropathy?

The signs and symptoms of Amyloid Neuropathy may vary among affected individuals in type and severity; it also depends on whether the central or the peripheral nervous system is affected. The following are some known signs and symptoms associated with Amyloid Neuropathy:

Peripheral neuropathy:

• Generalized pain in the body (including muscle spasm)
• Bone abnormalities
• Changes in the skin, nails, and hair
• Numbness and tingling sensation in the limbs
• Unusual sensations (parasthesia) that may be painful
• Insensitivity to extreme temperatures
• Sweating
• Extreme drop in blood pressure while standing up from a seated position
• Lightheadedness
• Loss of voluntary muscle control
• Carpal tunnel syndrome (resulting in weak grip)
• Involuntary urination; inability to empty urinary bladder
• Lack of appetite; feeling of fullness after eating a little food
• Constipation
• Loss of sensation (such as in the hands and feet)
• Loss of coordination and balance
• Inability to respond to emotional inputs
• Having trouble with sleep
• Problems with sexual performance (erectile dysfunction in men)
• Heart-related abnormalities that may lead to a heart attack
• Stomach-related signs and symptoms that include vomiting and diarrhea

Neuropathy of the central nervous system:

• Headache (in some specific areas)
• Vomiting
• Confusion
• Double vision
• Abnormal position of eyelids; drooping eyelids
• Change in the position of eyeballs
• Drowsiness
• Seizures
• Paralysis

The following general symptoms may be present in Amyloid Neuropathy, due to systemic amyloidosis:

• Fatigue
• Swelling in the ankles and legs
• Unintended weight loss
• Pain in hands and feet
• Joint pain
• Skin rashes, which may be purple or red spots
• Rash around eyes
• Eyes that appear puffy
• Anemia
• Clay-colored stools
• Bleeding disorders; problems with proper clotting of blood

How is Amyloid Neuropathy Diagnosed?

Amyloid Neuropathy is diagnosed on the basis of the following tests and exams:

• A thorough physical examination
• Evaluation of personal and family medical history
• Assessment of the presenting signs and symptoms
• Blood test to check for elevated serum proteins
• Testing of the cerebrospinal fluid for amyloid protein content
• Electromyography with nerve conductivity tests
• Imaging tests, to assess amyloid deposits in the body/organs, and to assess damage to the organs, tissues, and bones, which include:
  • X-rays
  • Ultrasound imaging
  • Computed tomography scanning
  • Magnetic resonance imaging
  • Serum amyloid protein (SAP) scintigraphy scan: In this procedure, a small amount of radiolabeled (radioactive iodine) SAP is introduced through injection into the body. After several hours, individuals are scanned with a whole body gamma scanner to check for amyloid deposits in the tissues and organs. Individuals undergoing this procedure ingest potassium iodide before and after the procedure, to prevent the thyroid glands from absorbing the radioactive iodine
• Tissue biopsy: A biopsy of an affected organ or tissue is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy sample under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy sample under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis. In case of amyloidosis,
  • Immunohistochemical analysis of tissue samples using anti-AA serum may be performed, to identify the type of amyloidosis an individual has
  • Amyloid deposit from affected tissue is detected using a staining procedure. When stained with Congo red stain, the amyloid protein deposits appear green under a special type of microscope (polarizing microscope)

In addition to the above tests, the following additional ones may be required to assess damage to other tissues and organs, owing to systemic amyloidosis:

• Blood tests:
  • For complete blood count (CBC)
  • To assess abnormal antibodies
  • To check heart function; cardiac biomarkers for stress on the heart
  • To perform “Freelite assay”, a measurement of light chain immunoglobulins
  • For measuring immunoglobulin by immunofixation electrophoresis
  • For measuring levels of alkaline phosphatase enzyme
• Urine tests:
  • To check for excess protein (a 24 hour urine test is usually performed)
  • Measure immunoglobulin by immunofixation electrophoresis
• Bone marrow aspiration for checking the type of abnormal immunoglobulin light chains
• Electrocardiography and echocardiography for checking heart functions
• Molecular genetic testing to check for mutation(s) in the TTR gene, which is associated with most cases of hereditary amyloidosis
• Molecular testing to check the type of proteins in amyloid deposits (AL or AA chains) through mass spectrophotometry

What are the possible Complications of Amyloid Neuropathy?

The potential complications of Amyloid Neuropathy include:

• Dizziness and risk of fall
• Difficulty with movement
• Reduced quality of life due to loss of voluntary muscle control
• Neuropathy involving involuntary muscle movement that can result in:
  • Heart failure
  • Kidney failure
  • Problems with the gastrointestinal tract
• Inhalation of food or saliva into the lungs during an episode of seizure, causing aspiration pneumonia (bacterial infection of lungs)

How is Amyloid Neuropathy Treated?

Currently, there are no treatment options available to cure Amyloid Neuropathy. The treatment is given to ease the symptoms and slow disease progression. The treatment measures are unique to the individual and depend on the organs affected and may include:

• Anti-seizure medication for neuropathic pain
• Analgesics for pain management
• Anti-depressants

In addition, treatments are also required to address the systemic amyloidosis that manifests as Amyloid Neuropathy, which may include:

• Effective management of the pre-existing condition that initially resulted in amyloidosis
• Liver transplantation for those with familial/inherited amyloidosis (the aberrant amyloid protein in inherited amyloidosis is generated in the liver)
  • Autologous stem cell transplantation
  • Autologous refers to cells obtained from the affected individual himself/herself
  • This type of transplantation may be required when one undergoes chemotherapy for an underlying condition
  • The stem cells from an individual are collected and stored before high-dose chemotherapy is administered
  • After chemotherapy, the damaged stem cells are replaced by the healthy one
• Blood transfusions for anemia
• Diet: Having frequent and small meals through the day, with reduced fat and sodium content
• Removal of spleen
• Restricting fluids, if there is edema
• Moderate exercise
• Diuretics, to get rid of excess salt and water from the body
• Medication for nerve pain, which may include gabapentin and pregabalin
• Medications for restoring normal heart function
  • Beta blockers
  • Angiotensin-converting enzyme (ACE) inhibitors 
  • Angiotensin receptor blockers 
  • Calcium channel blockers
  • Digoxin
• Pacemaker implantation to improve heart function
• Heart transplantation for severe dysfunction of heart
• Dialysis in case of kidney failure
• Kidney transplantation for kidney failure
• Bone marrow transplantation
• Chemotherapy may be used to destroy abnormal cells producing amyloid proteins. The chemotherapeutic drugs may be combined with dexamethasone or prednisone
  • Cyclophosphamide
  • Melphalan
• Targeted therapy such as:
  • Specific monoclonal antibodies that recognize faulty protein and destroy the cells containing such proteins. Examples include elotuzumab and daratumumab
  • Immune modulating medication such as thalidomide, lenalidomide, and pomalidomide
  • Proteasome inhibitors target the proteasome enzyme. This enzyme is responsible for removing defective proteins from cells
• Use of lixelle beta 2-microglobulin apheresis column for dialysis-induced Amyloidosis. This device removes beta-2 microglobulin from blood
• Surgery to repair tears in tendons and ligaments, as well as to remove bone cysts
• A drug under clinical investigation known as eprodisate for AA amyloidosis, which interferes with the formation of amyloid aggregates

How can Amyloid Neuropathy be Prevented?

• Currently, there are no specific methods or guidelines available to prevent Amyloid Neuropathy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Seeking medical attention for pre-existing conditions that can lead to Amyloid Neuropathy is advisable
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

What is the Prognosis of Amyloid Neuropathy? (Outcomes/Resolutions)

• The prognosis for Amyloid Neuropathy may be determined by a number of factors, such as the extent of the condition, subtype of amyloidosis involved, organs affected, overall health of the affected individual, and his/her response to treatment
• Nerve damage to major organs can affect their function and this can be fatal. Also, complications, such as frequent falls and aspiration pneumonia, can lead to fatalities

Additional and Relevant Useful Information for Amyloid Neuropathy:

• Approximately, 30 different proteins with a tendency to form amyloids have been identified. These are known as precursor proteins or amyloidogenic proteins
• The misfolding of proteins can occur due to a number of reasons, including aberrant formation, improper breakdown, or accumulation beyond a critical concentration in serum