Summary about Disease
Amyloid polyneuropathy, specifically Familial Amyloid Polyneuropathy (FAP), also known as hereditary transthyretin-related amyloidosis (ATTR amyloidosis), is a rare, progressive genetic disorder characterized by the buildup of abnormal amyloid protein, particularly transthyretin (TTR), in the peripheral nerves, heart, and other organs. This deposition disrupts the normal function of these tissues, leading to a variety of symptoms, most prominently affecting the nerves and resulting in neuropathy. The condition is inherited, meaning it is passed down through families via mutated genes. The severity and age of onset vary greatly between individuals, even within the same family.
Symptoms
Symptoms of amyloid polyneuropathy are diverse and can vary widely depending on which organs are most affected. Common symptoms include:
Peripheral neuropathy: Numbness, tingling, burning pain, or weakness in the feet and legs, often progressing to the hands.
Autonomic dysfunction: Problems with blood pressure regulation (orthostatic hypotension), heart rate abnormalities, bowel and bladder control, sweating, and sexual function.
Cardiac involvement: Cardiomyopathy (thickening and stiffening of the heart muscle), leading to shortness of breath, fatigue, and heart failure.
Gastrointestinal problems: Nausea, vomiting, diarrhea, constipation, and weight loss due to impaired digestion.
Kidney problems: Proteinuria (protein in the urine) and kidney failure in some cases.
Eye problems: Vitreous opacities (clouding of the gel-like substance in the eye) and glaucoma.
Carpal tunnel syndrome
Causes
Amyloid polyneuropathy, specifically FAP/ATTR amyloidosis, is caused by a mutation in the TTR gene. This gene provides instructions for making the transthyretin protein, which is primarily produced in the liver. Transthyretin normally transports thyroxine (a thyroid hormone) and retinol (vitamin A) in the blood. Mutations in the *TTR* gene result in a misfolded transthyretin protein that is prone to aggregate and form amyloid deposits. These deposits accumulate in various tissues and organs, causing damage and leading to the symptoms of the disease. The condition is inherited in an autosomal dominant pattern, meaning that only one copy of the mutated gene is needed for a person to be affected.
Medicine Used
The medications used to treat amyloid polyneuropathy aim to stabilize the transthyretin protein, preventing it from misfolding and forming amyloid deposits, or to reduce the production of the abnormal protein. These include:
TTR Stabilizers:
Tafamidis (Vyndaqel, Vyndamax): Stabilizes the TTR protein, preventing its breakdown and the formation of amyloid fibrils.
Diflunisal (off-label use): A nonsteroidal anti-inflammatory drug (NSAID) that can also stabilize TTR, but its use is limited by potential side effects.
TTR Gene Silencers (RNA interference therapies):
Patisiran (Onpattro): An intravenous RNAi therapy that silences the TTR gene, reducing the production of transthyretin protein in the liver.
Inotersen (Tegsedi): A subcutaneous antisense oligonucleotide that also reduces the production of transthyretin.
Liver Transplant: Liver transplantation can be used to replace the source of the mutated TTR protein with a healthy liver that produces normal TTR. This is an older treatment approach and is less common now with the availability of TTR stabilizers and gene silencers.
Symptomatic Treatment: Medications to manage specific symptoms such as pain, diarrhea, constipation, and heart failure are also used.
Is Communicable
Amyloid polyneuropathy (FAP/ATTR amyloidosis) is not communicable. It is a genetic disorder caused by a mutation in the TTR gene and is inherited from parents to offspring. It cannot be spread from person to person through any infectious means.
Precautions
Since amyloid polyneuropathy is a genetic condition, there are no specific precautions to prevent developing it if you have inherited the mutated gene. However, early diagnosis and treatment are crucial to slow down the progression of the disease and manage its symptoms. Precautions and recommendations include:
Genetic counseling: If there is a family history of amyloid polyneuropathy, genetic counseling is recommended to assess the risk of inheriting the mutated gene and to discuss options for genetic testing.
Regular monitoring: Individuals with the mutated gene should undergo regular medical check-ups and screenings to detect early signs of organ involvement.
Healthy lifestyle: Maintaining a healthy lifestyle, including a balanced diet, regular exercise (within limits of physical capacity), and avoiding smoking and excessive alcohol consumption, can help to support overall health and potentially slow disease progression.
Managing symptoms: Promptly addressing symptoms such as pain, diarrhea, or constipation with appropriate medications and lifestyle modifications can improve quality of life.
Avoiding triggers: Certain medications or environmental factors may exacerbate symptoms in some individuals. Identifying and avoiding these triggers can be beneficial.
Cardiac monitoring: Given the potential for cardiac involvement, routine heart health monitoring is essential.
Medication adherence: Strictly adhere to prescribed medications to prevent misfolding of proteins.
Promptly report new symptoms: To healthcare provider.
How long does an outbreak last?
Amyloid polyneuropathy does not have "outbreaks" in the typical sense of an infectious disease. It is a progressive, chronic condition that gradually worsens over time. The rate of progression can vary significantly between individuals, depending on the specific TTR gene mutation, the age of onset, and the organs affected. There is no period of remission or resolution without treatment. Without intervention, the disease progresses steadily, leading to increasing disability and eventually death. Treatments aim to slow down the progression, not to cure the disease.
How is it diagnosed?
Diagnosis of amyloid polyneuropathy typically involves a combination of:
Clinical evaluation: A thorough medical history and physical examination to assess symptoms and neurological findings.
Nerve conduction studies and electromyography (EMG): To evaluate the function of peripheral nerves.
Tissue biopsy: A biopsy of an affected tissue (e.g., nerve, fat pad, heart) to confirm the presence of amyloid deposits. The tissue is stained with Congo red dye, which shows characteristic apple-green birefringence under polarized light.
Genetic testing: To identify the specific TTR gene mutation.
Blood tests: To measure transthyretin levels and assess kidney and liver function.
Echocardiogram or cardiac MRI: To evaluate heart function and detect amyloid deposition in the heart.
Scintigraphy: A nuclear medicine imaging technique where a radioactive tracer is injected into the body and images are taken to show where amyloid has accumulated.
Neurological Examination
Family History Review
Timeline of Symptoms
The timeline of symptoms in amyloid polyneuropathy can vary significantly between individuals. However, a general progression is often observed:
Early Stages: Often begins with subtle symptoms of peripheral neuropathy in the feet and legs, such as numbness, tingling, burning pain, or loss of sensation. These symptoms may be initially mild and intermittent.
Progression of Neuropathy: The neuropathy gradually worsens, affecting the hands as well as the feet and legs. Muscle weakness and wasting may develop.
Autonomic Dysfunction: As the disease progresses, autonomic symptoms may appear, including orthostatic hypotension (dizziness upon standing), constipation, diarrhea, urinary problems, and erectile dysfunction.
Cardiac Involvement: Cardiac symptoms, such as shortness of breath, fatigue, and swelling in the legs and ankles, may develop as amyloid deposits accumulate in the heart.
Advanced Stages: In advanced stages, individuals may experience significant disability due to severe neuropathy, cardiac failure, and other organ involvement. Weight loss, malnutrition, and immobility may occur.
Death: Without treatment, the disease eventually leads to death, usually within 5-15 years after the onset of symptoms, primarily due to cardiac complications or complications from other organ failure. It's important to note that this is a general timeline, and the specific symptoms and rate of progression can vary greatly. Some individuals may experience a more rapid progression, while others may have a slower course.
Important Considerations
Early Diagnosis is Crucial: Early diagnosis and treatment are essential to slow down the progression of amyloid polyneuropathy and improve outcomes.
Genetic Testing: Genetic testing is important for confirming the diagnosis and identifying family members who may be at risk.
Multidisciplinary Care: Management of amyloid polyneuropathy requires a multidisciplinary approach involving neurologists, cardiologists, gastroenterologists, and other specialists.
Supportive Care: Supportive care, including pain management, physical therapy, and nutritional support, is important to improve quality of life.
Clinical Trials: Participation in clinical trials may provide access to new and experimental therapies.
Family Support: Living with a rare and progressive disease like amyloid polyneuropathy can be challenging for individuals and their families. Support groups and counseling can provide emotional and practical support.
Impact on Quality of Life: The chronic pain, disability, and organ dysfunction associated with amyloid polyneuropathy can have a significant impact on quality of life.
Ethical Considerations: Genetic testing raises ethical considerations regarding privacy and potential discrimination.
Liver transplant: Not effective for all mutations of the TTR protein.