Introduction:
Andrade described the first case of familial amyloid polyneuropathy in Portuguese more than 65 years ago. The disorder is related to the defective formation of the transthyretin protein (a transport protein) caused by mutations in the transthyretin gene. The disease has an autosomal dominant pattern of inheritance. The defective protein will accumulate in the form of amyloid in several body tissues and organs. It is a severe disorder and, if not treated, will lead to death due to infections, cachexia (a syndrome associated with loss of skeletal muscles and fat), or cardiac dysfunctions. The mean survival time for patients varies from seven to eleven years.
What Is the Pathophysiology of Familial Amyloid Polyneuropathy?
- The disorder is caused by mutations in the transthyretin gene in chromosome 18. Transthyretin genes are responsible for providing the necessary information to produce transthyretin protein. The transthyretin proteins are transport proteins that carry vitamin A and the hormone thyroxine throughout the body. For the purpose of transport, four transthyretin proteins are linked together to form a tetramer (a unit of four proteins). They are produced primarily from the liver. However, some amounts are made from the intestine, choroid plexus, and retinal epithelium as well.
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A mutation in the transthyretin gene will break the tetramer unit and form a fibrous clump called amyloid with toxic functions. The amyloid is carried by the blood to different body parts and gets deposited in the organs, nerves, and peripheral tissues resulting in their defective function.
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More than a hundred transthyretin gene mutations have been described to date, the most common being V30M. The difference in geographical areas shows variations in the frequency of mutations. The variations are responsible for genetic and phenotypic heterogeneity.
What Is the Prevalence of Familial Amyloid Polyneuropathy?
The first incidence of the disease was observed in Portuguese, and it was thought to be limited to certain places like Portugal, Japan, and Sweden and was considered endemic. However, advanced genetic studies revealed the prevalence of the disease worldwide. The disease prevalence varies among the endemic and non-endemic regions. The disease prevalence can be as high as one in 1000 to one in 10,000 in endemic areas. Exact data are not available to predict the prevalence of the disease in non-endemic countries.
What Are the Clinical Features of Familial Amyloid Polyneuropathy?
The clinical features of familial amyloid polyneuropathy vary greatly based on the type of mutations on the transthyretin gene. The age of onset, clinical symptoms, systemic involvement, and kind of neuropathy differ considerably. Some gene mutations are associated with polyneuropathy, whereas some are associated with cardiac manifestations.
The age of onset of the disease shows remarkable variation with the geographic location. In endemic areas like Portuguese and Japan, people with the V30M mutation of the transthyretin gene have an early onset. In contrast, people with the same mutation in Sweden have a late start. In non-endemic regions, the disease onset is in the sixth or seventh decades of life. The disease course is more severe in late-onset cases and has a male predominance with a 1/10 ratio.
The characteristic feature of familial amyloid polyneuropathy is length-dependent sensory-motor neuropathy with autonomic nervous system involvement. The disease is presented in three stages.
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Stage 1: Initially, tiny fibers are affected, and patients are presented with neuropathic pain (pain from different parts of the nervous system).
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Stage 2: The second stage is associated with worsening neurologic pain and loss of sensation in the lower extremities. The patients might need walking aids. The loss of sensation begins in the lower extremities first and extends to the trunk region.
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Stage 3: In stage three, patients lose their ability to walk and depend on wheelchairs or are bedridden.
Severe complications arise if there is autonomic involvement in the disease process. The patient may experience diarrhea, orthostatic (a fall in blood pressure on standing up), and impotence (erectile dysfunction). Erectile dysfunction is mainly associated with a lack of sensation. Autonomic involvement in the later stages of life can result in life-threatening conditions. Amyloid deposition in the transverse carpal ligament leads to carpal tunnel syndrome. It results in numbness, weakness, and tingling in the hands and arms due to compression of the median nerve.
Central nervous system involvement:
The deposition of transthyretin amyloids in the meninges and fluid-filled spaces surrounding small arteries and veins of the brain will manifest as central nervous system symptoms. One of the most common features is amyloid spells (stroke-like effects). Some rarely seen symptoms are hydrocephalus (accumulation of fluid in deep cavities of the brain), dementia (memory loss), and myelopathy (spinal cord injury). Different types of mutations are associated with central nervous system amyloidosis.
Cardiac involvement:
Cardiac involvement is the most common systemic manifestation of familial amyloid polyneuropathy after nervous system involvement. As a result, patients are presented with heart failure, arrhythmias (defective heart rhythm), and syncope attacks.
Ocular manifestations:
Amyloid deposits in the vitreous body, keratoconjunctivitis sicca, abnormal conjunctival vessels, glaucoma, and pupillary abnormalities are observed in patients with ocular manifestations. The transthyretin amyloids are seen as cotton wool in the vitreous body.
What Are the Treatment Options for Familial Amyloid Polyneuropathy?
Earlier, a liver transplant was considered the first treatment option for the disease because it would remove the production of defective transthyretin causing the disease. However, with the introduction of new and better therapeutic approaches, a liver transplant is rarely used.
Recently introduced therapeutic approaches include
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The anti-amyloid treatment regimen will help modify the disease. These drugs show their effect by altering or modifying the defective transthyretin or by reducing the production of defective transthyretin from the liver. The drugs acting on the transthyretin tetramer are called tetramer stabilizers.
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The treatment approach is based on the symptoms presented. Medications for polyneuropathy and other systemic manifestations.
Conclusion:
Familial amyloid polyneuropathy has a rare prevalence but is life-threatening. The disease is presented with variable symptoms that depend upon the type of mutation, geographical factors, and age of onset. Therefore, early implementation of appropriate treatment is necessary for better results. Recent research and studies have proposed new treatment options that promise a better prognosis.
