Familial Amyloidotic Polyneuropathy

What is familial amyloidotic polyneuropathy (FAP)?

The disease was first described by Dr. Corino de Andrade in Portugal. Since it usually begins with pain and loss of strength in the legs and feet, it became known as the “little feet disease.” It is a rare, hereditary (passed from affected parent to child), and degenerative condition that causes an accumulation of abnormal proteins (amyloid substance) in the body’s organs and nerves. This affects skin sensitivity and causes intense pain in the lower limbs as the initial symptom in most cases.

Incidence

This amyloid substance is formed due to a genetic mutation in transthyretin (TTR), where methionine is replaced by valine at position 30 of the TTR protein (Val30Met or V30M). This mutation is responsible for the Portuguese variant of the disease, which is the most common form in Brazil due to Portuguese colonization. However, over 100 mutations have been described worldwide, and some have also been found in Brazil. This mutated protein is mainly produced by the liver (95%), with the remainder produced by the retina and choroid plexus in the brain.

Currently, the estimated number of FAP carriers worldwide is around 10,000. The main clusters are in northern Portugal (Póvoa de Varzim and Vila do Conde), where prevalence reaches 1 in 1,100, as well as in Sweden, Japan, and Brazil.

The age of onset of symptoms in the Portuguese type of FAP varies. It is most frequent between ages 25 and 35, but may begin later, after age 50.

Symptoms

The clinical presentation and symptoms vary among FAP carriers, and genetic and environmental factors appear to influence disease progression. As the disease advances, it leads to physical disability and requires constant multidisciplinary medical care. If left untreated (without addressing the underlying cause), it inevitably leads to death within seven to ten years.

There are asymptomatic cases, meaning the individual carries the mutated TTR gene but does not develop the disease, dying from other causes. However, because it is an autosomal dominant disease, recent research indicates a high likelihood (about 87%) that a gene carrier will develop the disease by age 60.

The main symptoms are related to peripheral polyneuropathy, affecting sensory and motor nerves—first in the lower limbs and later in the upper limbs. Symptoms include pain, burning, tingling, electric shocks and needle-like sensations, paresthesia, numbness, progressive loss of sensitivity (first to temperature, then to pain), weakness, muscle atrophy, paralysis, and inability to walk.

Involvement of the autonomic nervous system (which controls vital functions such as breathing, blood circulation, temperature regulation, and digestion) can lead to gastrointestinal dysfunctions (constipation, chronic diarrhea, poor nutrient absorption, nausea, loss of appetite, vomiting), genitourinary dysfunctions (affecting the bladder, causing incontinence or urinary retention, and sexual impotence), and orthostatic hypotension (a sudden drop in blood pressure when standing up quickly, which can cause dizziness and fainting). Over time, other organs may also be affected, including the eyes, heart, kidneys, and brain.

Diagnosis

Diagnosis is usually quick when performed by a physician familiar with the disease. However, because it is rare, patients often take years to receive a confirmed diagnosis. There is usually a family history of the disease.

The mutated FAP gene is detected through DNA sequencing using PCR (polymerase chain reaction) from blood or mucosal cells. Individuals must be over 18 years old and seek genetic counseling before undergoing this test. The presence of amyloid deposits can be confirmed through tissue biopsy (salivary glands, subcutaneous tissue, nerves, or intestines). Neurological exams such as electroneuromyography can confirm peripheral nerve damage.

Treatment

Treatment of FAP symptoms and complications involves a multidisciplinary team, including doctors, physical therapists, psychologists, and others. Genetic counseling is essential to prevent transmission to children and should always be guided by a specialized physician. Symptomatic medications can help, especially for leg pain, digestive issues, diarrhea, or constipation.

Liver transplantation is a therapeutic option, as it removes the organ that produces most of the abnormal substance, thereby halting disease progression. However, it is a complex surgery and may cause long-term complications.

In 2011, Tafamidis—a new drug that stabilizes mutated TTR—was approved for commercial use by the European Medicines Agency as the first treatment for FAP. In November 2016, it was registered in Brazil (Anvisa) and incorporated into the public health system (SUS) formulary in 2018. Recently, new therapies have been tested, including drugs that stabilize, inhibit, or remove mutated TTR, opening new horizons for treating this disease.

By Einstein Editorial Board