2.1 Hereditary transthyretin (hATTR) amyloidosis is an ultra-rare condition caused by inherited mutations in the transthyretin (TTR) gene. This causes the liver to produce abnormal TTR protein, which accumulates as deposits in body tissues (amyloidosis). These deposits can disrupt the structure and damage the function of affected tissues.
2.2 Because hATTR amyloidosis can affect tissues throughout the body, people may have a range of symptoms affecting 1 or more systems. These can include the autonomic nervous system, peripheral nerves, heart, gastrointestinal system, eyes and central nervous system. The effects and complications of the condition can lead to death within 3 to 15 years of symptoms developing. At the time of the company's evidence submission, there were thought to be around 150 people with hATTR amyloidosis in the UK.
2.3 Neuropathy in hATTR amyloidosis can be classified according to walking ability (described by Coutinho et al. 1980):
Stage 1: people do not need help with walking and have mostly mild sensory and motor neuropathy in the lower limbs.
Stage 2: people need help with walking, there is progression of neuropathy in the lower limbs and symptoms develop in the hands (weakness and muscle wasting).
Stage 3: people are wheelchair bound or bedridden and have severe sensory and motor neuropathy of all limbs.
2.4 People may mainly have symptoms of polyneuropathy or cardiomyopathy, but most patients seen in the NHS will have symptoms of both over the course of the condition. In the UK, the most common genetic mutations associated with both polyneuropathy and cardiac involvement are Val122Ile (39%), Thr60Ala (25%) and Val30Met (17%). The Val30Met mutation is associated with higher survival rates. Val122Ile is primarily associated with cardiomyopathy.
2.5 Current treatment options for people with hATTR amyloidosis are limited. They mainly focus on symptom relief and supportive care including pain management, nutritional and mobility support, and lessening the effects of the condition on other organs (for example, pacemakers, arrhythmia management). There are no disease-modifying treatments for people with hATTR amyloidosis that is being treated in the NHS. Other pharmacological treatments may be used, including diflunisal, which is sometimes used outside of its marketing authorisation to treat hATTR amyloidosis. It is contraindicated in people with cardiac impairment and those taking anticoagulants.
2.6 Liver transplant, which prevents additional amyloid deposits forming, might be an option for some people. However, a transplant can only be done early in the course of the disease, and outcomes are poor in people with cardiac involvement, so it is rarely done in England.
2.7 The National Amyloidosis Centre in London provides the only highly specialised service for people with amyloidosis and related disorders in the UK. People with hATTR amyloidosis are assessed (for overall clinical status, neuropathy progression and cardiac involvement) and followed up every 6 months at the centre, and treatment is started there.