Hereditary ATTR amyloidosis

People with mutations in the TTR gene produce abnormal, amyloidogenic, ‘variant’ TTR throughout their lives. Amyloid deposits start to form and then build up until they cause clinical disease, mainly affecting the nerves and/or heart, and sometimes the kidneys and eyes. Symptoms may appear at any time from early adult life onwards. This condition runs in families.

Hereditary ATTR amyloidosis was traditionally referred to as familial amyloid polyneuropathy (FAP) when disease mainly affected the nerves or familial amyloid cardiomyopathy (FAC) when disease mainly affected the heart. But it is now understood that most TTR mutations can cause amyloid deposits in both the nerves and the heart, so the term hereditary ATTR amyloidosis is used to describe disease caused by ATTR amyloid deposits in all patients with TTR gene mutations.

• More than 150 amyloid forming variants of TTR have been observed.
• The most common mutation worldwide is called TTR Val30Met (V30M).
  • People with this mutation often start to experience symptoms in their 30s.
  • Peripheral and autonomic neuropathy are the main symptoms and heart problems are rare.
• The most common mutation in the UK is called TTR Thr60Ala (T60A), often seen in people with Irish ancestry.
  • People with this mutation often start to experience symptoms between age 45- 78, most often after age 60.
  • The heart is almost always affected and about 2/3 of patients also have neuropathy.
  • Autonomic neuropathy symptoms such as diarrhoea and/or constipation are more common than peripheral neuropathy.
  • Hereditary ATTR amyloidosis  is extremely rare in most parts of the world, but common in some very localised parts of the following countries, and in people with ancestors originating from these countries:
    • Portugal
    • Sweden
    • Japan

• It may also be common, but under-diagnosed in several other regions including Spain, France, Brazil, Argentina, Cyprus, Bulgaria.
• Hereditary ATTR amyloidosis is sometimes seen in people living in the UK, with ancestors from these regions.
• Sometimes people carrying a TTR mutation never develop disease. For example, about 1 in 500 people in northern Portugal carry a Val30Met TTR mutation, and 80% of them develop disease. About 1 in 25 people in northern Sweden carry this same mutation but only 11% of them develop disease. The reason for this geographic variation is unclear.
• The Val122Ile mutation  has been found in 1 in 25 African Americans and is associated with late onset (over age 60) hereditary ATTR amyloidosis mainly affecting the heart and often also causing carpal tunnel syndrome.
• Val122Ile associated hereditary ATTR amyloidosis has only been recognised in the past few years. Although it is believed to be probably widely underdiagnosed, it is believed to have low penetrance, meaning that most people carrying this mutation do not ever develop disease.

Symptoms

Symptoms may include:

• peripheral neuropathy: limb weakness and pain, loss of sensation
• autonomic neuropathy: disturbances of bowel, bladder and blood pressure and sexual dysfunction
• heart failure – symptoms result from stiffening of the heart due to amyloid deposits (restrictive cardiomyopathy). They may include:
  • shortness of breath, sometimes just after mild exertion
  • palpitations and abnormal heart rhythms, most frequently atrial fibrillation or atrial flutter
  • leg swelling (oedema)
  • weight loss
  • nausea
  • fatigue
  • dizziness and collapse (syncope or fainting), which may occur after exertion, or after eating
  • disrupted sleep
  • angina (chest pain)
• disease due to amyloid deposits in the :
  • eye
  • kidneys
  • thyroid gland
  • adrenal glands
  • blood vessels

Symptoms may appear as early as age 20, or as late as age 80. There is often little correlation between the underlying mutation and the clinical disease features. Within families the pattern is usually quite consistent for:

• age of onset
• rate of disease progression
• involvement of different body systems

In some families all affected members have mainly neuropathy, while in other families all affected members have both neuropathy and cardiac disease. In a few cases certain mutations have been associated with either particularly severe disease or with relatively limited disease. Val122Ile associated hereditary ATTR amyloidosis mainly affects the heart and may also cause carpal tunnel syndrome.

Patients carrying a mutation in their genes do not always develop disease. Cases have been reported where people over age 60 have no disease despite having two copies of the TTR gene mutation which causes production of the Val30Met TTR protein variant. Most people carrying the Val122Ile mutation do not develop disease.

More on diagnosis and treatment