Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin-mediated amyloidosis (hATTR) is a degenerative, progressive, fatal disease involving multiple organs and tissues. The disease occurs due to misfolded transthyretin (TTR) protein.¹ Long before symptoms appear, amyloid fibrils start to accumulate. The disease can affect various organ systems and body tissues as it worsens. While the disease’s progression is varied, some signs and symptoms are more prevalent than others and some appear earlier in the course of illness. Most patients with hATTR experience a combination of signs and symptoms.² The disease has a heterogeneous clinical presentation.¹

The onset of signs and symptoms can start as early as 30 years of age, depending on the specific mutation, however, most people experience them later in life.³ Despite the fact that some symptoms may be linked to specific mutations, hATTR is indeed a multisystemic disease. For instance, roughly 97% of patients with the Val122Ile mutation have cardiac illness, however, more than half also have sensory neuropathy and carpal tunnel syndrome. Similarly, the Val30Met mutation mainly causes polyneuropathy, but cardiac involvement and gastrointestinal symptoms are also seen in a significant portion of patients.¹

Neuropathic Manifestations

Peripheral Neuropathy

Peripheral neuropathy can occur in patients with hATTR due to inflammation or damage resulting from amyloid deposits in the nerves. Tingling, numbness, and burning pain may be seen in any part of the body, but they usually affect the hands, feet, and lower legs. An increased sensitivity to pain or reduced sensitivity to temperature can also occur in some patients. Difficulties in walking and fine dexterity, as well as balance disorders, have also been noted. Early hand involvement may occur in hATTR due to focal neuropathies like carpal tunnel syndrome. On physical examination, signs include sensory loss in the lower limbs, weakness, areflexia, and apallesthesia in the feet.^4,5 

Autonomic Neuropathy

Damage to nerves that support the functioning of organs and organ systems can cause autonomic neuropathy in patients with hATTR. This can affect many organs, and clinical manifestations due to autonomic neuropathy are one of the early signs of hATTR. Internal organs, including the heart, stomach, intestines, and glands, are all under the direction of autonomic nerves. Various symptoms, such as gastrointestinal (eg, early satiety, persistent diarrhea, constipation, and gastroparesis) and genitourinary symptoms, (eg, sexual dysfunction, urinary retention, and urinary incontinence), may be signs of autonomic dysfunction. The inability to control the muscles that dilate or constrict blood vessels, which affects blood pressure, digestion, sweating, and other bodily functions, may result from nerves that have been harmed by hATTR amyloid deposits. Autonomic neuropathy can also cause dizziness due to orthostatic hypotension.^4,5

Cardiac Manifestations

Patients with hATTR are advised to seek medical attention if they experience any possible cardiac symptoms. Cardiac symptoms and signs of cardiomyopathy, congestive heart failure, and arrhythmias (eg, atrial fibrillation) can occur. These include exertional dyspnea or shortness of breath, volume overload, jugular distension, leg edema, cachexia, fatigue, abdominal swelling, excessive exertional tachycardia, syncope, dizziness, bradycardia, palpitations, chest pain, and difficulty sleeping.^4,5 

Gastrointestinal Tract Manifestations

Gastrointestinal signs and symptoms in patients with hATTR can include nausea, vomiting, early satiety, chronic diarrhea, constipation, and severe alternating episodes of constipation and diarrhea. hATTR patients suffer autonomic dysfunction as the function of internal organs, such as the gut, bladder, stomach, and glands are controlled by autonomic nerves.³

Ophthalmologic Manifestations

Ocular symptoms in patients with hATTR can include glaucoma, vitreous opacities, abnormal conjunctival vessels, keratoconjunctivitis sicca, and pupillary abnormalities. Some cases may have visual impairment. Ophthalmologic dysfunction occurs due to amyloid deposits in the vitreous body or ocular autonomic dysfunction.^3,4 

Renal Manifestations 

Signs and symptoms due to kidney dysfunction in patients with hATTR include fatigue, reduced urinary output, excessive proteinuria, and swelling of the lower legs. Patients may also suffer from recurring urinary tract infections due to urinary retention.^3,4

Nonspecific Signs and Symptoms 

Nonspecific signs and symptoms include fatigue, fever, malaise, weight loss, stiffness, and difficulty concentrating. Other rare hATTR symptoms consist of skin changes, hearing loss, anemia, dyspnea, and lumbar spinal stenosis. The condition develops gradually over a long period of time. Due to the rarity of hATTR, doctors frequently mistakenly ascribe its symptoms to other, more widespread conditions. Misdiagnoses frequently result in therapy administered for unrelated illnesses and a delay in receiving adequate treatment.³ 

References

1. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7):S107-S112.
2. What is hATTR amyloidosis? American Heart Association. Accessed July 26, 2022.
3. Disease overview: hereditary transthyretin amyloidosis. Amyloidosis Research Consortium (ARC). Accessed July 26, 2022.
4. Adams D, Algalarrondo V, Polydefkis M, Sarswat N, Slama MS, Nativi-Nicolau J. Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression. Orphanet J Rare Dis. 2021;16(1):411. doi:10.1186/s13023-021-01960-9
5. Hereditary amyloidosis. Amyloidosis Foundation. Accessed July 26, 2022.

Reviewed by Debjyoti Talukdar, MD, on 7/31/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.