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Hereditary ATTR amyloidosis
This condition results from changes in the TTR gene, leading to misfolded proteins that deposit in organs like the nerves, heart, and kidneys. It can affect adults and presents with a wide range of symptoms, impacting quality of life.
Overview
Hereditary ATTR amyloidosis, sometimes called familial amyloid polyneuropathy or familial amyloid cardiomyopathy, is a progressive genetic disorder caused by alterations in the TTR gene [PMID:33671239]. These genetic changes lead to the production of an unstable transthyretin protein, which misfolds and forms abnormal deposits called amyloid fibrils. These amyloid deposits accumulate in various tissues and organs throughout the body, interfering with their normal function and causing progressive damage over time.
The condition can manifest differently between individuals, even within the same family, affecting various body systems. The severity and specific symptoms depend on which organs are most affected by the amyloid deposits. While some forms can appear earlier in life, symptoms typically emerge in adulthood.
Symptoms & clinical features
The symptoms of hereditary ATTR amyloidosis are varied and depend on the primary organs affected by amyloid accumulation. Common symptoms often relate to nerve damage, which can include numbness, tingling, burning pain, and weakness, usually starting in the feet and hands [PMID:33671239]. This is known as a peripheral neuropathy and can progress over time.
Heart involvement is also common, leading to symptoms such as shortness of breath, fatigue, swelling in the legs, and an irregular heartbeat. Gastrointestinal issues can occur, including nausea, vomiting, diarrhoea, or constipation, along with unexplained weight loss. Other possible signs include eye problems, carpal tunnel syndrome, and kidney dysfunction, which might be indicated by changes in urination patterns or swelling [PMID:34288865].
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Affected organs
Hereditary ATTR amyloidosis primarily affects the peripheral nerves, leading to neuropathy. The heart is frequently involved, with amyloid deposits causing thickening and stiffening of the heart muscle, leading to a condition called cardiomyopathy [PMID:34288865].
Other commonly affected organs include the gastrointestinal tract, eyes, kidneys, and carpal ligaments in the wrists. Less commonly, the central nervous system can be affected. The wide range of organ involvement means that symptoms can vary significantly from one person to another.
Risks & severity
The severity of hereditary ATTR amyloidosis can vary widely, even among individuals with the same TTR gene change. The age of onset also varies, typically ranging from early adulthood to later life, with some forms appearing after the age of 60. The condition is progressive, meaning symptoms tend to worsen over time if left untreated.
Specific genetic changes within the TTR gene can influence the typical presentation, such as whether heart or nerve symptoms are more prominent. For example, some variants are more strongly associated with a severe form of cardiomyopathy. The exact prevalence of hereditary ATTR amyloidosis is not well established globally due to its variable presentation and historical underdiagnosis, but it is considered a rare disease.
Genetic causes
Hereditary ATTR amyloidosis is caused by pathogenic variants in the TTR gene, which provides instructions for making a protein called transthyretin [PMID:33671239]. Transthyretin is primarily produced in the liver and plays a role in transporting thyroid hormones and vitamin A (retinol) throughout the body.
In its normal, healthy state, transthyretin is a stable protein. However, specific genetic changes in the TTR gene lead to the production of an unstable, misfolded transthyretin protein. These unstable proteins tend to aggregate and form insoluble amyloid fibrils, which then deposit in various tissues and organs. These amyloid deposits disrupt the normal function of the affected organs, leading to the clinical signs and symptoms of hereditary ATTR amyloidosis.
- TTR transthyretin
Inheritance pattern
Hereditary ATTR amyloidosis follows an autosomal dominant inheritance pattern. This means that an individual only needs to inherit one copy of an altered TTR gene from either parent to develop the condition. If a parent has a pathogenic TTR variant, there is a 50% chance with each pregnancy that their child will also inherit the altered gene.
Individuals who inherit the altered TTR gene will typically develop symptoms at some point in their lives, though the age of onset and severity can vary. Family members of an affected individual may be offered genetic counselling to discuss their own risk and options for genetic testing.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of hereditary ATTR amyloidosis often begins with a thorough clinical evaluation based on the individual's symptoms, particularly if there is a family history of similar issues. Confirmation typically requires demonstrating amyloid deposits in affected tissues, which can be done through biopsies of tissues such as fat, nerve, or heart muscle.
Genetic testing for pathogenic variants in the TTR gene is crucial for confirming a diagnosis of hereditary ATTR amyloidosis and differentiating it from other forms of amyloidosis. Genetic testing for hereditary ATTR amyloidosis is available through the NHS Genomic Medicine Service, often initiated following referral to a clinical genetics service. This testing is covered by specific R-codes, such as R301 'Hereditary amyloidosis'.
Management & lifestyle
Management of hereditary ATTR amyloidosis focuses on slowing the progression of the disease and managing symptoms. Advances in treatment mean that there are now specific therapies available that can stabilise the transthyretin protein or reduce the production of the abnormal protein. These treatments aim to halt or slow the deposition of amyloid fibrils and can significantly improve outcomes for many patients.
Individuals with hereditary ATTR amyloidosis receive care within the NHS through specialist centres that have expertise in amyloidosis. Management plans are individualised and may include regular monitoring of organ function, such as heart and nerve assessments. Genetic counsellors play an important role in providing information and support to patients and their families, discussing the genetic implications and inheritance patterns.
UK care pathway
In the UK, individuals suspected of having hereditary ATTR amyloidosis are typically referred to specialist NHS services, often via a clinical genetics department. Genetic testing for the TTR gene is usually performed through the NHS Genomic Medicine Service, which uses specific R-codes (such as R301 'Hereditary amyloidosis') to guide diagnostic pathways. Clinical geneticists and genetic counsellors provide comprehensive support, explaining the diagnosis, inheritance patterns, and implications for family members. This integrated approach ensures access to specialised care and management strategies.
Frequently asked questions
What does 'autosomal dominant' inheritance mean for my family?
Autosomal dominant means that if you have the altered TTR gene, there is a 50% chance that each of your children will also inherit it. It affects both males and females equally, and typically appears in every generation of an affected family.
Can I get tested for hereditary ATTR amyloidosis if it runs in my family?
Yes, if there is a known family history of hereditary ATTR amyloidosis, you can discuss genetic testing options with your GP or a clinical genetics service. This process typically involves genetic counselling to help you understand the implications of testing.
What are the common early signs of hereditary ATTR amyloidosis?
Early signs can be subtle and varied, but often include nerve symptoms like numbness, tingling, or pain in the hands and feet. Fatigue, shortness of breath, or gastrointestinal issues like unexplained diarrhoea or constipation can also be initial indicators.
Are there treatments available for hereditary ATTR amyloidosis?
Yes, significant advances have been made in treating hereditary ATTR amyloidosis. There are now therapies that can help stabilise the transthyretin protein or reduce its production, aiming to slow disease progression and manage symptoms. These treatments are typically managed by specialist NHS teams.
If I have hereditary ATTR amyloidosis, will my symptoms be the same as other family members?
Not necessarily. Even within the same family and with the same genetic change, the symptoms, their severity, and the age at which they appear can vary significantly. This is due to other genetic and environmental factors that can influence how the condition develops.
References
- Ruberg FL, Grogan M, Hanna M. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2019. PMID: 31171094
- Adam MP, Bick S, Mirzaa GM. Hereditary Transthyretin Amyloidosis. 1993. PMID: 20301373
- Gillmore JD, Gane E, Taubel J. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. The New England journal of medicine. 2021. PMID: 34215024
- Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. Journal of neurology, neurosurgery, and psychiatry. 2015. PMID: 25604431
- Kristen AV. Amyloid cardiomyopathy. Herz. 2020. PMID: 32107564
- Sekijima Y, Ueda M, Berk JL. Guidelines for the management of hereditary ATTR amyloidosis 2026. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. 2026. PMID: 42423415
- Record CJ, Pipis M, Skorupinska M. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain : a journal of neurology. 2024. PMID: 38481354
- Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. The American journal of managed care. 2017. PMID: 28978215