Familial amyloid polyneuropathy (FAP), also known as transthyretin (TTR) amyloid polyneuropathy, is an autosomal dominant genetic disorder that is characterized by the formation of amyloids or abnormal protein aggregates in the peripheral nervous system.
It is caused by mutations in the TTR gene and symptoms include numbness or a burning sensation in the hands and feet (peripheral neuropathy), and disruption of involuntary functions such as blood pressure, digestion, and temperature control (autonomic neuropathy).
The symptoms of FAP vary widely depending on the type of mutation affecting the TTR gene. There are several staging systems in place for FAP, but the most widely used for clinical practice is the Coutinho’s staging system.
Coutinho’s staging system
Coutinho and colleagues established a staging system in 1980 that classifies patients into three stages of the disease based on the severity of symptoms and the extent of disease progression. These stages are:
This is an asymptomatic stage. Patients in this stage do have a mutation in the TTR gene and show evidence of amyloid deposits, but do not show any symptoms of the disease.
Symptoms are mild at this stage, with the functioning of the lower limbs affected but not impaired. This is the stage for early detection of FAP symptoms.
Patients at this stage, especially the younger ones, are ideal candidates for liver transplants, a widely approved therapy for FAP. Thus, patients diagnosed with stage 1 FAP should be placed on a liver transplant waiting list.
The European Medicines Agency has approved Vyndaqel (tafamidis), a transthyretin stabilizer, for treating patients with stage 1 FAP.
Symptoms turn from mild to moderate in severity in stage 2. Lower limb function is even more affected, with patients possibly requiring walking assistance. Further damage to nerves caused by amyloid deposits is observed.
Early stage 2 patients might still be eligible for liver transplants.
The potential benefits of drug treatments for stage 2 patients are being evaluated but there is no concrete data available at this time. Although Dolobid (diflunisal), a nonsteroidal anti-inflammatory drug, has not received regulatory approval for FAP treatment, it can help slow the progression of symptoms, according to a Phase 3 clinical trial (NCT00294671) published in 2014.
Symptoms have significantly worsened in stage 3, and the patient needs a wheelchair for mobility. There is no data to support the efficacy of drug therapies at this stage of the disease.
Polyneuropathy disability (PND) scoring system
The PND scoring system is another method used to classify FAP progression. This system includes the following stages:
At this stage, there is no impairment of nervous function, with no visible symptoms.
In stage 1, there could be sensory disturbances in the lower extremities, but the walking capacity of the patient is not affected.
In this stage, the patient might have some difficulty in walking but usually does not require a walking aid, such as a walking stick or crutches. For patients in either stage 1 or stage 2, Vyndaqel treatment or a liver transplant is recommended, with follow-ups every six months to observe disease progression, especially heart function.
As the disease progresses to stage 3A, the patient might require support from a single walking stick or crutch.
In stage 3B, two walking sticks or crutches are needed. For both stage 3A and 3B, Dolobid treatment might help in slowing disease progression.
This is the most advanced stage of the disease where the patient needs a wheelchair for mobility. There is no data supporting the effectiveness of drug treatments at this stage of the disease.
The Portuguese classification system
The Portuguese classification system helps evaluate the severity of FAP progression by classifying the symptoms into seven levels. These include:
Patients at this level are asymptomatic.
At this level, there is evidence for sensitive or dysautonomic (affecting the autonomic nervous system) symptoms without any major nervous system damage.
The next stage involves sensitive or dysautonomic symptoms with nervous system damage.
This stage includes the symptoms of level 2 with signs of nervous system damage in the lower limbs. Independent walking is not affected.
At this level, there is nervous system damage in both the lower and upper limbs. Independent walking is still possible.
At level 5, there is a worsening of the symptoms seen in level 4, and the patient needs a wheelchair for mobility.
This is the most advanced level of the disease, and the patient is fully dependent on aid for movement.
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