Familial amyloid polyneuropathy (hereditary ATTR): TTR gene, inheritance and treatment

Amyloidosis is a group of conditions in which proteins fold abnormally and build up as deposits called amyloid in organs and tissues. The NHS describes amyloidosis as a group of rare conditions where a protein called amyloid builds up in the body and can affect organs such as the heart, kidneys, liver, nerves or digestive system.

Familial amyloid polyneuropathy, often shortened to FAP, was the name given to the form in which the protein transthyretin (TTR) is affected and the nerves are prominent. Current usage tends to say hereditary transthyretin amyloidosis, hATTR or ATTRv amyloidosis, because the same gene change can also affect the heart and other organs. The NHS lists hereditary ATTR amyloidosis as one of the main types, with the cause described as an inherited genetic condition.

The NHS Genomics Education Programme explains that in hereditary amyloidosis single amino acid substitutions or small deletions or insertions in one of twelve different genes destabilise the protein and make it prone to misfold and accumulate. For transthyretin the gene is TTR.

The programme says hereditary systemic amyloidosis is an autosomal dominant condition that is almost always adult-onset, with variable penetrance and expressivity. A person with a variant has one working and one changed copy of the gene, and the chance of passing the variant to a child is 1 in 2, or 50 per cent. Not everyone who has the variant develops disease.

Because penetrance and expressivity vary, the programme points out that the family history may be negative, either because relatives did not develop the disease or because the variant arose newly. Manifestations can also differ between family members who carry the same variant.

For this reason a clinical genetics team usually explains the position to relatives and offers testing to those who wish to know their status, with counselling about what a positive result does and does not mean.

The NHS lists common symptoms of amyloidosis in general as feeling very tired or weak, losing weight without trying, shortness of breath, swollen feet or legs and bruising around the eyes, with other symptoms depending on the organ involved. Pain, numbness or tingling in the hands and feet occur if nerves are affected, a fast or slow heartbeat or chest pain if the heart is affected, and loss of appetite, sickness, diarrhoea or constipation if the digestive system is affected.

For variant transthyretin amyloidosis the programme says the main problems are peripheral and autonomic neuropathy or cardiomyopathy, with notable variation in penetrance and organ involvement, and some individuals develop advanced renal impairment late in the disease course. Autonomic neuropathy affects automatic body functions such as blood pressure and the gut.

The NHS stresses that these symptoms can be caused by many different conditions and that having them does not mean amyloidosis, but that it is important to get them checked by a GP.

The NHS says amyloidosis is often hard to diagnose because symptoms vary and resemble other conditions. A GP who suspects it will refer to a specialist, and the person may be seen in a specialist amyloidosis treatment centre. Tests may include blood and urine tests, an ECG, echocardiogram or MRI scan to check the heart and other organs, a biopsy to look for amyloid, a SAP scan to show where amyloid has built up, and genetic testing to find out whether there is a hereditary type.

The NHS Genomics Education Programme adds that amyloidosis is most often identified when a person presents with cardiomyopathy, heavy protein loss in the urine or neuropathy, that genetic types make up approximately 10 per cent of new diagnoses and are often mistaken for AL amyloidosis, and that genomic testing for hereditary systemic amyloidosis is listed in the National Genomic Test Directory.

The NHS says there is no cure for amyloidosis but some types can be managed well, with treatments depending on the type and the organs involved. Supportive medicines may help symptoms, and some people need dialysis or a transplant when organs are damaged.

For hereditary transthyretin amyloidosis with polyneuropathy there are disease-specific medicines. NICE recommended patisiran in 2019, within its highly specialised technologies programme, for adults with stage 1 or stage 2 polyneuropathy, and recommended vutrisiran in February 2023 for the same group. Both are recommended only if the company provides them under a commercial arrangement.

NICE explains that the condition is usually treated with patisiran and that vutrisiran works in a similar way but is given as an injection under the skin instead of into a vein. Where more than one treatment is suitable, NICE says the advantages and disadvantages should be discussed and the least expensive chosen, taking costs into account. Which treatment is right is a decision for the specialist team.

The NHS says care teams pass information about people with amyloidosis to the National Congenital Anomaly and Rare Disease Registration Service so that scientists can look for better ways to prevent and treat the condition, and that people can opt out at any time.

Because hereditary forms involve several organs, follow-up usually combines neurology, cardiology and other specialties. A GP should be told promptly about new symptoms such as worsening numbness, dizziness on standing, breathlessness or swelling.