Rare ATTR-linked mutation cause of late-onset heart damage in 3 adults

Met13dup variant, ID'd in Korea, marked by early and widespread neuropathy

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by Steve Bryson, PhD |

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A newly identified mutation in the TTR gene led to various neurological and heart symptoms of ATTR amyloidosis in three older adults in Korea, a case series reported.

These patients, with an average age of 77, experienced an earlier onset of nerve symptoms affecting the extremities and the autonomic nervous system, which automatically regulates internal organ function. Later heart involvement eventually led to them to be hospitalized due to heart failure.

“We would like to emphasize the importance of TTR genetic testing, regardless of age,” the researchers wrote.

The case series, “A Novel Transthyretin Gene Mutation in Hereditary Transthyretin Amyloidosis: A Case Series of Met13dup Patients,” was published in the Korean Circulation Journal.

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The TTR gene provides the instructions necessary for the production of a protein called transthyretin, sometimes referred to as ATTR. The protein works by transporting cargo throughout the body but must form a four-unit protein complex to function properly.

Mutations in the TTR gene, however, can alter the structure of transthyretin, such that it forms amyloid fibrils, abnormal protein clumps that build up in different tissues. When amyloid fibrils are caused by such mutations, patients are said to have hereditary transthyretin amyloidosis (hATTR).

There are two main forms of hATTR. In familial amyloid polyneuropathy (FAP), also known as hATTR with polyneuropathy, amyloid fibrils tend to accumulate in peripheral nerves — those found outside the brain and spinal cord — leading to nerve damage or polyneuropathy. In contrast, hATTR with cardiomyopathy is marked by fibrils that primarily affect heart tissue.

More than 140 different hATTR-causing TTR mutations have been identified to date, each associated with varying degrees of organ involvement, age of onset, and disease progression. The most common is called Val30Met, which is particularly common in Portugal, Japan, and Sweden. In South Korea, Asp38Ala is the most prevalent TTR mutation.

In this case series, researchers at the Sungkyunkwan University School of Medicine in Seoul described three cases of hATTR caused by a newly reported TTR variant, leading to symptoms of polyneuropathy and cardiomyopathy.

The first patient, a 68-year-old male, was referred to the hospital due to recurrent fainting episodes. He had been repeatedly hospitalized over the past three years due to heart failure, with a worsening in heart function despite treatment. Blood tests showed an NT-proBNP blood level of over 3,000 picograms per mL (pg/mL), above the normal maximum of 900 pg/mL, indicating signs of heart damage.

Gastrointestinal symptoms, such as indigestion and constipation, also were reported, alongside progressive tingling and postural hypotension, when blood pressure drops after standing up. Abnormal heartbeats were detected, as well as an increased thickness of the heart muscle and heart dysfunction. A biopsy of heart tissue confirmed hATTR.

Nerve conduction studies suggested carpal tunnel syndrome, a condition caused by impairment of the median nerve, which runs from the forearm into the palm.

TTR gene analysis detected a variant called Met13dup, which the scientists recently reported to the Transthyretin Amyloid Outcome Survey (THAOS) registry (NCT00628745), the largest global registry of patients with ATTR.

Within his family, his parents had unknown heart diseases, and two out of three siblings also shared neurologic symptoms, such as tingling, swelling in the extremities, and diarrhea. Met13dup variants were detected in his family without signs of heart symptoms at that time.

The second patient, an 82-year-old woman, had a history of high blood pressure and diabetes, and came to the hospital’s emergency department with acute heart failure. Although her blood pressure stabilized, her NT-proBNP level was 16,590 pg/mL, far above the normal range. Further tests indicated irregular heartbeats, heart dysfunction, and heart muscle thickening.

She also had progressive tingling in the lower leg and recurrent indigestion, which had been present for 10 years before heart failure symptoms began. Nerve studies showed signs of carpal tunnel syndrome, problems in the nerve roots in the lower back, and those of the autonomic nervous system.

Peripheral, autonomic neuropathy evident before cardiac amyloidosis

A biopsy of heart muscle confirmed hATTR and gene analysis detected the Met13dup TTR mutation. All four of the woman’s daughters, in their 40s and 50s, carried the same Met13dup variant and had started to experience neurological symptoms but not heart issues.

In the third case, an 82-year-old man experienced recurrent fainting episodes and ongoing irregular heartbeats, coronary artery disease, and mild shortness of breath. Tests showed thickening in his heart muscles and valves, and elevated NT-proBNP at 1,556 pg/mL.

Nerve conduction studies indicated autonomic impairment, a heart muscle biopsy confirmed hATTR, and genetic testing revealed the Met13dup mutation. His son also carried this variant but was without symptoms.

“Patients with Met13dup mutation in our series experienced an earlier onset of peripheral and autonomic neuropathy and later cardiac manifestations that eventually required hospitalization due to heart failure,” the researchers wrote.

“Although the average age at diagnosis of cardiac involvement was similar to that of wild-type ATTR, Met13dup mutation is distinct for the presence of significant peripheral and autonomic neuropathy,” they added. Wild-type ATTR, typically diagnosed in older adults, is marked by a transthyretin protein that starts producing amyloid fibrils in the absence of a genetic mutation and commonly affects the heart.