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The unique story of Hereditary ATTR (hATTR) Amyloidosis in the Northwest of Ireland

Genetics

Hereditary ATTR (hATTR) amyloidosis - a genetic condition

hATTR amyloidosis can be passed along generations. A person only needs to inherit one copy of the gene mutation from one parent in order to develop the disease. This pattern of inheritance is known as 'autosomal dominance'.


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Autosomal dominant inheritance

As shown in the diagram below, genes are located on structures known as chromosomes. Every person has two copies of the TTR gene, one inherited from each parent. When one parent carries an autosomal dominant mutation, each individual child will have a 50% chance of inheriting the mutation.


It's important to know that not all individuals with the mutation will develop signs and symptoms of the disease, and the age of onset and symptoms can vary. It can be upsetting to hear that your relatives may be at risk, and you should discuss this with your healthcare professional.


Affected
Unaffected
Chromosome

Symptoms may vary among people with hATTR amyloidosis

Within your family, each person who develops the condition may experience different symptoms, even if he or she has the same mutation.

Although hATTR amyloidosis is a hereditary condition, some families may be unaware of a history of the condition in their family. So while your family members may not have been diagnosed with the condition, they may have experienced symptoms similar to yours. It’s important to talk to your family about any family history that may be related to hATTR amyloidosis.


Image - Donegal

T60A Roots

A common form of hATTR amyloidosis seen in the UK and Ireland2

One of the most common mutations associated with hATTR amyloidosis in the UK is called T60A (sometimes referred to Ala60).2It occurs more frequently in people with Irish ancestry.1Symptoms usually appear between ages 45 and 78, most often after age 60.2It is slightly more common in men than in women.2

The history of the T60A mutation associated with hATTR amyloidosis

The genetic mutation causing hATTR T60A amyloidosis was first identified in an Irish family in the 1980s.1A cluster of cases have been identified in the County Donegal region of North West Ireland, where it has been estimated that 1% of the population have this mutation.1Cases have been described all around the world, but often UK patients with this condition have Irish ancestry.1


Donegal highlighted on Ireland map

County Donegal, Ireland
(where 1% of the population carry the hATTR amyloidosis T60A mutation) .1

What causes hATTR T60A amyloidosis?

This condition is caused by a mutation in the TTR gene which results in the production of an abnormal (‘variant’) TTR protein called T60A. A mutation is a permanent change in the sequence of DNA which makes up the genes in all cells in the body. The DNA acts like a blueprint or recipe for building the proteins that make up the body. The proteins are made up of strings of amino acids, assembled in a precise order. The DNA determines the order in which amino acids are assembled. In people with the T60A mutation, an amino acid called threonine is replaced by an amino acid called alanine at position number 60 in the TTR molecule. This gene mutation can cause the TTR protein to change shape and 'misfold'. This new shape means the protein gathers together in structures known as 'amyloid fibrils', which build up in various parts of the body. This can result in a variety of symptoms.

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References
1. Reilly MM, Staunton H, Harding AE. Familial amyloid polyneuropathy (TTR Ala 60) in North West Ireland: a clinical, genetic, and epidemiological study. J Neurol Neurosurg Psychiatry. 1995; 59:45–49.
2. Sattianayagam PT, Hahn AF, Whelan CJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012; 33:1120–1127.
3. Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy [published online ahead of print, 2020 Jan 6]. J Neurol. 2020;10.1007/s00415-019-09688-0.

Abbreviations
ATTR: Transthyretin amyloidosis
hATTR: hereditary ATTR (hATTR)
MRI: magnetic resonance imaging