Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, inherited, progressive condition characterized by the accumulation of an abnormally folded protein called amyloid. The accumulated amyloid is deposited in multiple organs and organ systems, especially the heart, eyes, gastrointestinal tract, kidneys, and peripheral nervous system. In some cases, amyloidosis may also affect the autonomic and central nervous systems.^1,2  

hATTR Types

Hereditary ATTR is divided into 3 types according to the organ systems affected and the symptoms produced.¹ 

Neuropathic hATTR

Neuropathic hATTR amyloidosis affects the peripheral and autonomic nervous systems. When the peripheral nervous system is affected, muscle weakness and sensory changes may develop. When the autonomic nervous system is affected, control over bodily functions may be reduced, resulting in impotence, bowel and bladder dysfunction, diarrhoea or constipation, sexual impotence, glaucoma, and orthostatic hypotension during positional changes.^1,3

Leptomeningeal hATTR

Leptomeningeal hATTR amyloidosis affects the central nervous system, especially the meninges. The accumulation of amyloid deposits in the leptomeninges may lead to stroke, hydrocephalus, ataxia, cognitive impairment, spastic paralysis, seizures, eye impairments including nystagmus, pyramidal signs with spastic paraparesis, hearing loss, cerebellar ataxia, and subarachnoid hemorrhage in the brain.^1.3

Cardiac hATTR

Cardiac hATTR amyloidosis affects the heart, resulting in arrhythmias, peripheral edema due to chronic heart failure, ascites, hepatomegaly, orthostatic hypotension, syncope, and cardiomegaly. Chronic heart failure may eventually be fatal. Patients may also present with atrial arrhythmias due to amyloid fibril deposition.^1,3 

hATTR Genetics

The inheritance pattern of hATTR amyloidosis is autosomal dominant, so that it can be transmitted to offspring when only one parent is affected. Most cases of hATTR amyloidosis are inherited, but rarely, hATTR amyloidosis may be caused by sporadic mutations that arise de novo.¹ 

Mutations in the transthyretin (TTR) gene cause hATTR amyloidosis. Normal TTR genes encode transthyretin, a protein produced in the liver. Mutated TTR genes interfere with transthyretin protein synthesis and folding, so that a misfolded monomer, amyloid, is produced.^1,2

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hATTR Diagnosis

The workup for a proper diagnosis of hATTR amyloidosis includes a complete family history and possibly genetic testing to identify the causative TTR variant, a thorough physical examination to identify involved organ systems, either a biopsy of involved organ tissue or aspiration of subcutaneous fat to confirm amyloid accumulation, and laboratory testing.³

Laboratory testing should include the following:

• A complete blood cell count to identify normochromic normocytic anemia;
• Kidney function tests to detect proteinuria and a reduced glomerular filtration rate if the kidneys are affected by amyloid deposits;  
• A chemistry panel to identify electrolyte abnormalities caused by malabsorption or heart failure.³

Additional tests, such as nerve conduction studies and electrocardiography, may be performed to determine the extent of nervous system or cardiac damage.³ 

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Imaging studies may include radioactively labeled serum amyloid P-component scintigraphy, computed tomography, cardiac magnetic resonance imaging, nuclear scintigraphy, and 2-dimensional echocardiography.³ 

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hATTR Treatment

Pharmaceutical Management of hATTR

The US Food and Drug Administration (FDA) has approved patisiran, vutrisiran, and inotersen—3 drugs used to treat polyneuropathy resulting from hATTR amyloidosis. The FDA has also approved tafamidis to treat hATTR cardiomyopathy. Diuretics are used to treat patients with cardiac hATTR amyloidosis causing chronic heart failure and peripheral edema.³

Patisiran, vutrisiran, and inotersen are RNA-based therapies that are characterized as TTR gene silencers. These drugs decrease the serum concentrations and tissue accumulation of amyloid, slowing the progression of hATTR amyloidosis.^4,5 

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TTR tetramer stabilizers were created to stabilize the protein during synthesis and folding. Stabilization prevents the dissociation that results in structural changes and the production of amyloid. Tafamidis is one TTR stabilizer. Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID), also stabilizes TTR, slowing the progression of neuropathy and improving patient quality of life. The long-term use of diflunisal may lead to gastrointestinal, renal, or cardiac side effects.⁵ 

Other drug therapies are currently under investigation.³ TTR-stabilizing agents such as epigallocatechin-3-gallate (EGCG), which is found in green tea, are currently being studied to determine their therapeutic benefit in patients with hATTR amyloidosis. Researchers are also investigating monoclonal antibodies that target abnormal TTR proteins and prevent amyloid synthesis. A subcutaneously administered antisense inhibitor, AKCEA-TTR-LRx, is undergoing phase 1 and phase 2 studies to assess its safety, tolerability, and dosing in the treatment of hATTR amyloidosis.⁵

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Surgical Management of hATTR

The gold standard treatment for hATTR amyloidosis is liver transplant because it removes the organ that produces abnormal amyloid protein versions of transthyretin. A heart or kidney transplant may be required if one of these organs is severely affected and failing.³

Patients with peripheral neuropathy caused by hATTR amyloidosis may require carpal tunnel release for continued hand function.³ 

Although most transthyretin is produced in the liver, the retinal pigment and ciliary pigment epithelial cells may also produce abnormal protein locally. If amyloid protein accumulates in the vitreous of the eye, a vitrectomy may relieve eye impairments and slow the progression of ocular disease.³

References

1. Transthyretin amyloidosis. MedlinePlus Genetics. Accessed July 6, 2022.
2. hATTR amyloidosis: disease overview. Accessed July 6, 2022.
3. Roberts JR. Transthyretin-related amyloidosis: practice essentials. Medscape. Updated June 16, 2022. Accessed July 6, 2022.
4. Khella S. Hereditary ATTR amyloidosis. Medscape. Accessed July 6, 2022.
5. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979

Reviewed by Debjyoti Talukdar, MD, on 7/18/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.