The Rare Disease That Is Not Rare In Portugal

Familial Amyloid Polyneuropathy, now more precisely called hereditary transthyretin amyloidosis, or ATTRv, is classified worldwide as a rare disease. In this one stretch of Portuguese coastline, it is not rare at all.

A Fishing Town Gives a Disease Its Name

The story begins in 1939, when a young neurologist named Mário Corino da Costa Andrade examined a 37-year-old woman from Póvoa de Varzim. She had lost sensation in her legs, was wasting away, and suffered from severe gastrointestinal problems that no diagnosis at the time could explain. Andrade kept looking and found that it was not an isolated case. Fishermen in the town had long spoken of a condition that crept into families, stole the use of their legs, and killed them young.

Andrade spent nine years documenting 74 cases, visiting patients in their homes and in the regional hospital, before publishing his findings in the journal Brain in 1952. He described a form of amyloidosis, a disease in which misfolded proteins build up in tissue, that targeted the peripheral nerves while sparing the liver and spleen.

Interestingly, Eça de Queiroz, one of Portugal’s most relevant novelists, was born in Póvoa de Varzim and spent his final sixteen years battling exhausting gastrointestinal pain and progressive physical decline, symptoms his doctors attributed to intestinal tuberculosis. Medical historians now consider hereditary amyloidosis a far more plausible explanation, which would mean one of the great figures of Portuguese literature carried the same mutation that still runs through families in his hometown.

A Protein That Falls Apart

To understand why this happens, it helps to know what transthyretin actually does. It is a protein made mostly in the liver, and its job is to ferry thyroid hormone and vitamin A through the bloodstream. Normally, it travels as a stable, four-part structure, folded together. In people who carry the mutation behind ATTRv, a single change in the TTR gene, a swap of one amino acid for another at a specific point in the protein, destabilises that structure. The four parts come apart more easily than they should, and the loose pieces misfold and clump together into fibrils that the body cannot break down.

These fibrils settle into peripheral nerves, the heart, the gut, the kidneys, and the eyes. Nerve damage begins in the feet, with burning pain and loss of sensation, and slowly climbs upward. The autonomic nervous system, which controls things like blood pressure and digestion, is often hit early, which explains why so many patients first present with fainting spells or unexplained diarrhoea rather than anything resembling classic nerve disease. Left untreated, the disease is fatal within roughly a decade of the first symptoms.

Why Portugal, and Why Here Specifically

Genetics cannot explain, alone, a disease cluster. In this case, history and demographics help in showing the bigger picture. The mutation responsible for most Portuguese cases, known as Val30Met, is thought to have arisen in northern Portugal around the fifteenth century, and it spread the way genes do, through generations. In endemic fishing communities, affected parents historically had unusually large families, often well above the national average, which let the mutation propagate widely before anyone understood what it was.

The resulting numbers are striking. A national study using 2016 data put the prevalence of ATTRv in Portugal at roughly 23 cases per 100,000 adults, translating to around 1,865 people living with the disease nationwide. In the endemic core around Póvoa de Varzim and Vila do Conde, prevalence climbs to something in the region of one in every 1,100 inhabitants. For comparison, in most countries, the disease affects roughly one person in every 100,000.

Geography also shapes how the disease behaves. In Portugal, symptoms typically begin in a patient’s early thirties, and the mutation is highly penetrant, meaning most carriers will eventually develop the disease. In Sweden, where a separate endemic focus exists, onset tends to arrive decades later and far fewer carriers ever become symptomatic. In Japan, cases are rarer still and skew heavily male. The same mutation, in other words, does not tell the same story everywhere. Something about the Portuguese population, whether genetic modifiers, diet, or factors not yet identified, shapes how aggressively the disease unfolds.

From a Death Sentence to a Treatable Condition

For most of its history, a diagnosis of Corino de Andrade’s disease meant a slow, difficult decline with no real intervention available. That changed in 1990, when doctors in Sweden performed the first liver transplant specifically to treat the disease, on the logic that replacing the organ that manufactures the faulty protein would stop new damage at its source. Five years later, in Coimbra, the Portuguese surgeon Linhares Furtado went a step further, pioneering what is known as domino transplantation, in which a diseased liver removed from an ATTRv patient, structurally healthy in every way except for the protein it produces, is transplanted into someone dying of unrelated liver failure who would otherwise not survive long enough to receive a standard donor organ.

The past decade has brought a wave of new treatments that go further still. Drugs like tafamidis stabilise the TTR protein directly, holding it together so it cannot fall apart into the fragments that form amyloid in the first place. Newer RNA-based therapies silence the gene’s instructions before the protein is even made, dramatically reducing circulating TTR levels. And in a trial co-led by the Porto-based researcher Teresa Coelho, a single infusion of a gene-editing therapy based on CRISPR technology has shown it can permanently switch off the mutated gene in the liver.

Portugal remains at the centre of this work today. Reference centres in Porto and Lisbon track thousands of patients, offer genetic counselling to families weighing whether to have children, and run some of the clinical trials shaping global treatment. A new study launched in 2025 by NOVA University Lisbon is now looking beyond survival statistics entirely, asking what quality of life actually looks like for people living with the disease their whole lives.

So the next time you are driving along the coast north of Porto, past the fishing boats and the seafood restaurants of Póvoa de Varzim, it is worth remembering that this quiet stretch of shoreline holds one of the densest concentrations of a rare genetic disease anywhere on the planet, and that some of the most important advances in treating it, from the first diagnosis to gene editing, trace directly back to the doctors, patients, and families who lived alongside it.