Stages of FAP

Last updated Jan. 11, 2022, by Teresa Carvalho, MS

✅ Fact-checked by Joana Carvalho, PhD

Familial amyloid polyneuropathy (FAP), also known as transthyretin (TTR) amyloid polyneuropathy, is a progressive genetic disorder that is characterized by the formation of amyloids, or abnormal protein aggregates, in nerves and other tissues.

Most often caused by mutations in the TTR gene, FAP symptoms include numbness, tingling, or a burning sensation in the hands and feet (peripheral nerve damage or neuropathy), and often problems with nerves that control involuntary body functions such as blood pressure, digestion, and temperature (autonomic neuropathy).

FAP symptoms 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 staging system.

Coutinho’s staging system

The Coutinho staging system, established in the 1980s, classifies patients into four stages based on symptom severity and the extent of disease progression. These stages include:

Stage 0

Stage 0 an asymptomatic stage. Patients in this stage have a mutation in the TTR gene and show evidence of amyloid deposits, but do not display any symptoms of sensory or motor neuropathy.

Stage 1

Symptoms of sensory, motor and autonomic neuropathy are mild at this stage, with the functioning of the lower limbs affected but not impaired. Early detection of FAP at stage 1, with treatment, can lead to better outcomes.

Patients at this stage, especially younger ones, are considered ideal candidates for a liver transplant, a procedure sometimes used to treat FAP, since the liver is the main source of transthyretin — the protein that clumps together and forms harmful amyloid deposits in FAP patients. Researchers advise that people diagnosed with stage 1 FAP should be placed on a liver transplant waiting list, regardless of age or the type of mutation they carry.

Stage 2

Symptoms turn from mild to moderate in stage 2, affecting the legs, arms, and truck to some degree. Lower limb function is most affected, and patients could need aids to assist walking. Further nerve damage caused by amyloid deposits is also observed. Early stage 2 patients might still be eligible for liver transplants.

Stage 3

Symptoms significantly worsen in stage 3, with patients requiring a wheelchair for mobility or becoming fully bedridden. At this stage, patients show signs of potentially severe nerve damage in all limbs.

Polyneuropathy disability scoring system

The Polyneuropathy disability (PND) scoring system is also used to classify FAP progression, with a focus on how walking is affected. This system includes the following stages:

Stage 0

At this stage, there is no nervous function impairment and no evident disease symptoms.

Stage 1

In stage 1, sensory disturbances may be evident in the lower extremities, but patients retain their ability to walk.

Stage 2

In this stage, patients can find walking more difficult, but usually do not require aids like a walking stick or crutches.

Stage 3a

As the disease progresses to stage 3A, patients typically require assistance with a walking stick or a crutch.

Stage 3b

In stage 3B, two walking sticks or crutches are needed.

Stage 4

In this advanced disease stage, patients have generalized weakness and a lack of reflexes, and are generally bedridden or require a wheelchair for mobility.

The Portuguese classification system

The Portuguese classification system may also be used to evaluate FAP severity and progression. It classifies symptoms into seven levels:

Level 0

Patients at this level are asymptomatic, showing no symptoms of the disease.

Level 1

At Level 1, there is evidence of sensitive or dysautonomic (affecting the autonomic nervous system) symptoms but not of major damage to a nervous system.

Level 2

This stage involves sensitive or dysautonomic symptoms, accompanied by signs of nervous system damage.

Level 3

This stage includes further evidence of nervous system damage — sensory and motor — in the lower limbs. Patients at Level 3 still retain the ability to walk independently.

Level 4

At this level, nervous system damage is evident in both lower and upper limbs, but independent walking is still possible.

Level 5

At level 5, a worsening of the symptoms is seen in all limbs, with patients typically requiring a wheelchair for mobility.

Level 6

This advanced disease level corresponds to patients either fully dependent on a wheelchair or confined to a bed.


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