Rare Diseases: Shining a light on Hereditary ATTR Amyloidosis (HATTR)

In this short article I want to shine a light on one rare disease namely Hereditary ATTR Amyloidosis and raise awareness on the importance to patients and their families of prompt diagnosis access to treatment and genetic testing and counselling for family members.

In 1993 my late mother was diagnosed with that was then known as Familial Amyloid Polyneuropathy (FAP). Today Familial Amyloid Polyneuropathy now known as Hereditary ATTR Amyloidosis (HATTR) has a significant presence within my immediate family circle. I am also a member of the All-Ireland ATTR Amyloidosis support group and I link with Rare Diseases Ireland for this group. In May 2020 a small group all of whom were patients or family members of individuals with hereditary amyloidosis led by Rosaline Callaghan came together to raise awareness and support patients with the condition and their families and carers. The group lobbied successfully with others to have the drug Patisiran licensed for patients in Ireland. There was a glaring inequality in that patients in the North of Ireland had access to this medication whilst their colleagues in the south did not. Thankfully, this is no longer the case, Patisiran is now available within a managed accessed programme to all patients within the HSE considered suitable for this treatment by their consultant. In May 2022 in conjunction with the Irish Heart Foundation the group hosted a one-day conference in Gweeedore Co Donegal The conference theme Emerging from the Shadows presented a hopeful and positive future for patients and their families and the conference speakers endorsed this positive message. The location of the conference gave recognition to the original families and their antecedents. (See below) The group continues to support patients and their families with Hereditary Amyloidosis.

What is Hereditary ATTR Amyloidosis

The term ‘amyloidosis’ is a general term for a group of conditions where an abnormal protein, called amyloid, accumulates in the tissues. Different types of amyloidosis are named according to the type of amyloid protein which is produced. All begin with the letter ‘A’ which stands for Amyloidosis. The ‘A’ is followed by one or more other letters, which name the amyloid protein. for example: AL amyloidosis, AA amyloidosis and ATTR(Hereditary) amyloidosis https://www.ukmf

Hereditary ATTR Amyloidosis is a rare disease that if left untreated is progressive and fatal. It is an autosomal dominant condition whereby offspring of an affected parent have a 50/50 chance of inheriting the mutation in the TTR (Transthyretin) gene that causes the condition. Hereditary Amyloidosis accounts for 20% of Amyloidosis Case worldwide.

There are over 100 mutations of the TTR(Transthyretin) gene linked to Hereditary ATTR Amyloidosis. The term ATTR Amyloidosis covers all the mutations. Time of onset of symptoms varies depending on the specific mutation. Patients with one of the most common variants the V50M which is found in families from Portugal, France, and Spain also Sweden and Japan can experience symptoms in their 30/40s The V141 variant is most common in African Americans is a later onset disease as are the two variants that are common to the island of Ireland and to people of Irish descent worldwide.

The most common and best known of these, the Thr Ala 60 variant has its origins in Northwest Donegal in an area around modern-day Gweedore. The presence of a cluster of cases of what was then known as Familial Amyloid Polyneuropathy in Northwest Ireland is recognised in literature by Staunton et al (1987 ,1991). Reilly, Staunton and Harding (1995) identified ThrAla 60 the variant as the causative mutation of the TTR gene in this study cohort. ThrAla 60 also known as The Donegal Mutation or colloquially as ‘Donegal Amy’ is still the predominant TTR mutation for Hereditary ATTR Amyloidosis on the Island of Ireland and beyond. It has followed the Irish Diaspora to many parts of the UK, North America Canada and Australia where it has emerged within families of Irish Descent in these parts.

A second lesser-known mutation H110D (H90D) has now appeared within the population in county Cork and its environs. Professor Aisling Ryan and her colleagues in Cork University Hospital have found this variant in a group of families, and it has been recognised in the literature by Jimenez-Zepeda et al (2014).

Of course, given the more multicultural population demographic in Ireland today it is possible that a patient may present with any of given variants depending on their ethnicity.

There is also an acquired condition known as Wild Type Amyloidosis which is not inherited this is often to linked to ageing and can be underdiagnosed.

Hereditary ATTR Amyloidosis previously known as Familial Amyloid Polyneuropathy is a multisystem condition Cardiac Symptoms can be more predominant in the ALA60 variant for example while Neurological Symptoms can be the first symptoms in the H90D variant, but this is not definitive. Patients can present with multiple symptoms and in varying degrees of severity depending on the progression of their condition. For example, Bi-Lateral Carpal tunnel syndrome in an individual might raise a red flag for Hereditary Amyloidosis.

Today the future is much brighter for patients with ATTR Amyloidosis. Thanks to the dedication of professionals and researchers and to the patients who took part in clinical trials the future is so much more hopeful for patients and their families. Whilst there is no cure the condition can be stabilised and its progression halted thanks to the advent of new medication and the innovative advances in Gene Silencing treatments all of which offer such hope to patients and their families with improved quality of life and the reduction of symptoms and distress.

Factors in Raising Awareness

Education of Health Professionals

For patients with Hereditary ATTR Amyloidosis in common with other rare conditions of a complex nature the path to diagnosis is not always straightforward. The education of health professionals to recognise the possibility of a condition such as ATTR Amyloidosis and make the proper referral to have the diagnosis verified is crucial. Dedicated services are now available to patients with Amyloidosis within the HSE structure, provided by a team of specialist professionals led by Professor Emer Joyce at the Mater Hospital (Cardiology), Professor Sinead Murphy Tallaght Hospital (Neurology) and Professor Aishling Murphy at Cork University Hospital. Up to very recently patients had to travel to the National Amyloidosis Centre (NAC) at the Royal Free Hospital in London under the auspices of the treatment abroad scheme (TAS) administered by the HSE. The National Amyloidosis Centre is a world-renowned international centre of excellence and Irish Patients have received excellent treatment in this centre. There is still a considerable degree of co-operations between the professionals within the NAC and the HSE in a collaborative effort to continue to find new and better treatments and guidelines to manage HATTR Amyloidosis. However, a well-funded dedicated home-based service which negates the need to travel must be the best option for patients and their families.

Family History

Another key factor is the importance of family history: Hereditary Amyloidosis is an autosomal dominant condition which means there is a 50/50 chance of inheritance for offspring of affected persons inheriting the mutation of the TTR gene. Health professionals need to be aware that family history can be an oral tradition often shared in anecdotes and stories. Taking time to listen and probe appropriately can yield dividends for both patient and health professionals and hasten the progress to a correct diagnosis.

Genetic Testing /Counselling

Because of the hereditary nature of the condition, clinical diagnosis should be backed up by genetic testing and by genetic counselling for patients and family members. Accessing genetic counselling is not always straightforward and there can be long waiting list for this service.

Development of clear guidelines and protocols as to when genetic testing of family members should be a priority.

In summary Hereditary Amyloidosis can be difficult to recognise and diagnose, not all health professionals are familiar with the symptomology or history of the condition and the presenting symptoms can be similar to other medical conditions.

Family history is a key indicator that a person may have the condition genetic testing and genetic counselling for patients and their families is a priority to confirm the hereditary dimension of the condition.

Access to specialised consultants and diagnostics and the availability of new treatments has heralded a more positive outlook for patients with ATTR Amyloidosis and their families.

To ensure continuity to patients these services should be publicity funded with dedicated ring-fenced funding this will allow continuous development of diagnostic pathways and protocols for managing Hereditary Amyloidosis including guidelines for genetic testing of family members. It would also support staff training and development, recruitment and retention of specialist staff research and development and patient and family support A patient centred dedicated multidisciplinary co-located and accessible service should not be denied to patients and their families, it should be a taken as given for all patients with rare disease who have to deal with the challenges inherent in their condition not only for themselves but very often for their immediate and extended family.

Thanks to all those who are working tirelessly to research new treatments and develop guidelines for the on-going management of Hereditary Amyloidosis which is the focus of this article but is no less relevant to making similar efforts for all rare diseases.

References available on request

Written by Mary Halpin Byrne – ATTR All Ireland Amyloidosis support group – Halpinm1953@gmail.com

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