New FAP-causing gene mutation ID’d in elderly man in Argentina

Case illustrates importance of early diagnosis, treatment

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by Andrea Lobo |

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A new mutation in the TTR gene was identified as the cause of late-onset familial amyloid polyneuropathy (FAP) in an elderly man in Argentina, a small case study indicates.

The case highlights “the importance of including FAP-TTR among early differential diagnosis in patients with presumably idiopathic [of uncertain cause] polyneuropathy,” the researchers wrote in “Late-onset familial amyloidosis polyneuropathy associated with c.186G>C in transthyretin,” which was published in Revista de la Facultat de Ciencias Medicas de Córdoba. Polyneuropathy refers to damage in several nerves and is a hallmark sign of FAP.

FAP is caused by mutations in the TTR gene, which contains instructions for producing the protein transthyretin, or TTR. These mutations cause the protein to fold incorrectly and form toxic clumps, called amyloid fibrils, that accumulate mainly in the peripheral nerves, or those outside the brain and spinal cord, but can also build up in the heart.

Over time, these aggregates damage tissues and affect their function, leading to FAP symptoms. Based on the age when symptoms first appear, FAP can be broadly divided into early-onset (starting at age 50 or younger) or late-onset (after age 50).

Here, researchers in Argentina describe the case of a 74-year-old man with FAP caused by a new TTR mutation.

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Amyloid plaques are shown forming on nerve cells.

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New FAP mutation ID’d

The man, who had no family history of neurological disease, was evaluated for decreased sensitivity in his legs over the past two years and in the arms in the previous year, with loss of strength and difficulty walking. He also had recently developed symptoms associated with damage to his autonomic nerves, peripheral nerves that control involuntary bodily functions, such as constipation and shortness of breath.

A neurological and muscular exam showed loss of reflexes and sensations, low muscle tone, and muscle weakness in the legs, as well as muscle shrinkage in lower leg muscles. He also had reduced sensations in the arms. Blood tests were unremarkable and without signs of kidney or liver problems, autoimmune diseases, or infections.

A further neuromuscular evaluation indicated polyneuropathy of the peripheral nerves that control sensory and motor functions, with signs of nerve damage. Heart tests showed certain abnormalities, including thickening of the heart muscle and an irregular heartbeat.

The man had a genetic analysis on the TTR gene to identify a cause for his polyneuropathy and it revealed a previously unreported genetic mutation — c.186G>C (p. Glu62Asp) — in one of the two copies of the TTR gene. The mutation was located in a region that provides instructions to produce a key functional domain of the TTR protein and led to a change in one amino acid, which is a protein building block.

A similar mutation, predicted to result in the same amino acid change in the TTR protein, was previously reported to cause late-onset amyloid cardiomyopathy, a FAP-related condition marked by amyloid fibrils mostly in the heart.

Based on this, the c.186G>C mutation was considered likely disease-causing.

The clinical difference between these cases with the same amino acid change “may be linked to differences among specific [disease-causing] TTR variants, geographic factors … and several probable environmental factors that are currently unknown,” the researchers wrote.

The man’s son and daughter, who were apparently healthy, were informed of their risk of also carrying the FAP-causing mutation, but both refused genetic testing.

“Being a currently treatable condition, early diagnosis of FAP-TTR is essential for the rapid introduction of drugs that dramatically improve the quality of life and also for genetic counseling for the patient and at-risk family members,” the researchers said.