Bicep bulge, called Popeye sign, may help diagnose FAP, case study says

Popeye sign may have potential to distinguish FAP from similar conditions

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A 63-year-old man in Japan with a large bulge in his right arm bicep, called “Popeye sign,” was diagnosed with late-onset familial amyloid polyneuropathy (FAP), according to a case report which suggests this sign has potential to diagnose the disease.

The reason behind the symptom remains unclear in this case, but researchers hypothesized it was associated with bicep tendon damage due to the buildup of toxic transthyretin protein clumps that characterizes the disease, in addition to muscle overuse.

While Popeye sign is uncommon in FAP patients, it may have diagnostic potential to distinguish it from similar conditions affecting the peripheral nerves, or those outside the brain and spinal cord, researchers noted.

The case study, “Popeye Sign in Hereditary Transthyretin Amyloidosis,” was published in the journal JAMA Neurology.

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FAP characterized mainly by damage to peripheral nerves

Hereditary transthyretin amyloidosis (hATTR) is a rare disease characterized by the accumulation of an abnormal version of the transthyretin protein in multiple tissues caused by mutations in the TTR gene.

One of the two disease types, FAP is characterized mainly by damage to peripheral nerves, leading to nerve damage, or polyneuropathy. It is therefore also known as hATTR with polyneuropathy. Transthyretin aggregates can also build in the heart, affecting its function.

Common FAP symptoms include numbness, tingling, or muscle weakness. Since these symptoms are often seen in other nerve disorders, such as chronic inflammatory demyelinating polyneuropathy, the diagnosis of FAP is often delayed. Differentiating it from other disorders, however, is vital for initiating proper treatment.

Now, researchers at the Kumamoto University’s Graduate School of Medical Sciences, in Japan, described a case supporting Popeye sign as a potential diagnostic marker for FAP.

The patient had developed abnormal sensations — usually aching, prickling, or burning sensation — in his feet.

He was first misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy, a rare autoimmune disorder in which self-reactive antibodies attack myelin, the protective sheath around nerve cells.

The man was treated with intravenous immunoglobulin, which involves the administration of healthy antibodies that are meant to inactivate the self-reactive antibodies driving the autoimmune attacks. However, his polyneuropathy continued to worsen, the researchers wrote.

Physical examination revealed sensorimotor polyneuropathy, meaning it affected both movement and sensation, as well as the Popeye sign in his right bicep that was present since disease onset.

An MRI scan of the right upper arm revealed bicep tendon degeneration and retraction that caused the large bulge.

Nerve conduction studies, which measured the strength and speed at which a nerve sends out electrical signals, confirmed sensorimotor damage to the peripheral nerves that affected his lower limbs.

Heart imaging scans showed enlargement of the heart’s left pumping chamber and other signs of heart damage, suggesting the accumulation of toxic transthyretin clumps also in the heart’s muscle.

A biopsy of the stomach showed transthyretin clumps, and genetic testing revealed a TTR mutation called Ala97Gly.

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Patient had no family history of FAP disease

All of these findings pointed to FAP, even though he had no history of the disease in his family, and he was diagnosed with late-onset FAP.

“Most patients with late-onset hereditary ATTR amyloidosis do not have a family history of the disease and are commonly misdiagnosed with other diseases several years from the onset,” the researchers wrote.

The man was initiated on Onpattro (patisiran), an approved FAP therapy from Alnylam Pharmaceuticals. Administered via infusions directly into the bloodstream, the therapy works to reduce TTR protein production.

This case demonstrated the presence of Popeye sign in a FAP patient. The team noted that this symptom has been reported in nearly a third of people with wild-type ATTR amyloidosis, a similar, but non-genetic, condition associated with toxic transthyretin clumps.

“Although exact reasons why the bicep tendon was prone to rupture were undetermined in the present case, we speculated that his bicep tendon rupture was associated with tendon degeneration due to [transthyretin clumps] in addition to overuse,” the researchers wrote.

“Popeye sign may be uncommon in patients with hereditary ATTR amyloidosis; however, it can facilitate distinguishing hereditary ATTR amyloidosis from other peripheral neuropathies,” they concluded.