FAP-like profile seen in brothers with heart damage-linked mutation

More studies report nerve damage with V122I mutation

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by Andrea Lobo |

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Amyloid plaques are shown forming on nerve cells.

Two Italian brothers carrying V122I, a TTR gene mutation often linked to hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM), developed neurological symptoms that resembled familial amyloid polyneuropathy (FAP), with little or no heart involvement, a study shows.

The cases add to the growing number of studies reporting symptoms of nerve damage along with, or before, heart damage symptoms in people with the V122I mutation.

“Although V122I variant is commonly associated with cardiac [heart] disease, clinicians should not underestimate a possible neurological onset, particularly in light of the availability of new drugs that can delay or halt the disease progression if early started,” the researchers wrote in “Neurological onset in patients with V122I hereditary transthyretin amyloidosis: a glitch in the paradigm,” a letter to the editor published in Neurological Sciences.

Both FAP and hATTR-CM are forms of hereditary ATTR amyloidosis, diseases marked by toxic clumps of the transthyretin (TTR) protein accumulating in tissues due to mutations in the TTR gene.

In FAP, or hereditary ATTR amyloidosis with polyneuropathy, TTR clumps form mainly in the peripheral nerves, which are outside the brain and spinal cord, causing neurological symptoms. But these toxic aggregates may also accumulate in the heart. It’s classified as hATTR-CM when it’s characterized mostly by toxic TTR buildup in the heart where it can lead to structural and functional abnormalities.

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V122I mutation with neurological symptoms

More than 130 disease-causing mutations have been identified in the TTR gene, each influencing the disease’s profile, such as symptoms, age of disease onset, and disease progression. V122I, one of the most common TTR mutations, is usually associated with heart disease and hAATR-CM.

Researchers in Italy described the case of two brothers in Apulia in southern Italy with the V122I mutation who had mainly neurological symptoms.

The older brother was diagnosed with hATTR amyloidosis when he was 72. He had problems walking, stocking-glove paresthesia, and erectile dysfunction in the previous year. Stocking-glove paresthesia is when nerve damage causes people to feel as if they’re wearing stockings or gloves, and numbness, weakness, or pain in the hands and feet. He had mild weakness in both legs and no reflex in the ankle when it was tapped at his first neurological examination.

Nerve conduction studies, which measure the strength and speed a nerve can transmit an electric signal to other parts of the body, revealed damage in the peripheral nerve fibers and carpal tunnel syndrome, a condition that affects nerves in the wrist.

The symptoms suggested hATTR amyloidosis and a genetic test detected the V122I mutation in one of the two copies of the TTR gene, confirming the diagnosis. Given the mutation’s common link to heart damage, the man had a heart evaluation, which showed tissue enlargement with TTR clumps and irregular beating.

Given the presence of hATTR amyloidosis with a “mixed profile,” that is, characterized by both neurological and heart symptoms, the patient started treatment to suppress the TTR gene’s activity.

His relatives were also tested for TTR mutations and V122I was detected in his younger brother, aged 60, who was apparently healthy. A physical examination revealed pain and abnormal temperature-related sensation in his feet and reduced tendon reflexes.

Nerve conduction studies were normal, but lower nerve fiber density in the skin, suggesting damage to small nerve fibers, were seen in an examination. Small skin nerve fibers detect pain, plus heat and itching sensations in the skin.

A heart examination showed normal heart structure and function, with no TTR protein clump deposits in the heart tissue.

The younger brother was also started on specific TTR-silencing therapy due to the presence of small nerve fiber damage.

“Both siblings experienced a clinical onset characterized by neuropathy [nerve damage], with instrumental cardiological abnormalities only in the older sibling,” wrote the researchers, who noted that while V122I, the most common TTR mutation in the U.S., is usually associated with hATTR-CM, a growing number of studies in the past three years have reported nerve damage symptoms with this variant.

Specifically, in a U.S. study, people carrying this mutation “frequently present mild sensory-motor neuropathy concurrently with or even prior to cardiac symptoms, despite being diagnosed only after cardiac evaluation,” the researchers wrote. “Considering the disease’s broad [variability], it is essential to recognize early signs of [hATTR amyloidosis] regardless of genotype-phenotype correlation,” or the association between the genetic and symptomatic profiles.

Given that neurological symptoms may be limited to small fibers, “in case of strong suspicion, but normal nerve conduction studies, it is necessary to proceed with the investigation of the small fibers,” they said.