New FAP-causing Mutation Found in Elderly Man in Germany

Case underscores need for genetic analysis, history in TTR amyloidosis, researchers said

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An elderly man in Germany was found to carry one copy of a new mutation in the TTR gene that caused both neurological and heart symptoms of familial amyloid polyneuropathy (FAP), which were described in a recent case report.

The man’s case calls for “careful molecular genetic analysis and history taking in every case of TTR amyloidosis … to not overlook rare cases of hereditary TTR amyloidosis and offer appropriate disease-modifying treatments,” the researchers said.

The report, “A novel TTR mutation (p.Ala65Val) underlying late-onset hereditary transthyretin (ATTRv) amyloidosis with mixed cardiac and neuropathic phenotype: a case report,” was published in BMC Neurology.

The TTR gene contains instructions for making a protein called transthyretin. Certain mutations in it can cause the protein to fold into an incorrect shape and clump into amyloid deposits that build up in tissues. Such mutations can run in families and be the cause behind FAP, a form of hereditary transthyretin amyloidosis.

When amyloid deposits build up in the nerves along the body’s extremities, they can cause peripheral neuropathy (nerve damage), often manifesting as numbness, pain, and tingling.

They also can build up in the heart, where they can cause muscles to become stiffer and making it harder for it to pump blood effectively throughout the body. This can cause shortness of breath, an abnormal heartbeat, and swelling.

The first symptoms usually appear before age 50 in patients with a family history of the disorder, but they may arise later.

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Neurological, heart symptoms lead to FAP diagnosis

Researchers in Germany reported the case of a 73-year-old man who had both neurological and heart symptoms.

The man had been having difficulty walking, neuropathic pain in his legs, and dizziness due to postural changes over the previous two to three years. He also had lost 20 kilograms (about 44 pounds) without any apparent reason.

An echocardiogram, an imaging test that allows doctors to examine the heart and nearby blood vessels, revealed enlargement of his left ventricle, the heart’s main pumping chamber. An examination of tissue from the heart revealed amyloid deposits.

He was diagnosed with wild-type transthyretin amyloidosis, a non-hereditary form that usually only manifests after around age 60. He was treated with tafamidis (sold as Vyndaqel, among other brand names), which attaches to transthyretin and stops it from clumping into amyloid deposits.

The man visited the hospital about a year later with weakness in his legs and loss of balance. He was unable to walk unaided and his symptoms had progressed despite tafamidis. His father and two brothers also had neurological and heart symptoms at one time.

Loss of coordination, weakness of the hands, and loss of sensation and reflexes were seen with a physical examination. The man was also unable to move his feet.

A nerve conduction velocity test revealed that electrical signals didn’t travel fast enough through the tibial and sural nerves running down the back of the leg and into the foot.

Genetic testing revealed he had a mutation in one copy of the TTR gene. The mutation, called c.194C>T (p.Ala65Val), was deemed “highly likely” to make transthyretin clump up into amyloid deposits and cause FAP.

While the mutation appeared on a database where it was linked to transthyretin amyloidosis, there are no reports of it in the literature. The man’s only living brother underwent genetic testing and the result came back positive for the mutation.

“Our findings expand the spectrum of known pathogenic [disease-causing] TTR mutations and underline the importance of a thorough diagnostic workup in amyloidosis patients, including careful genetic testing to avoid misdiagnosis and missing of treatment opportunities and to enable cascade testing and tracking of carriers,” the researchers wrote.