Review Details Recommendations to Improve FAP Diagnosis

Diagnosing hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy, also called familial amyloid polyneuropathy (FAP), is challenging, particularly in in places where the disease is less prevalent, researchers say.

A high level of suspicion on the part of the physician is required to diagnose patients as early as possible, according to the experts who wrote the review “Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy,” which was published in the Journal of Neurology.

Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy (PN) is a rare, genetic disease that is progressive and devastating.

Polyneuropathy refers to damage or disease that affects the peripheral nerves, which manifests as an abnormal sensation in the legs and feet, including numbness, tingling, or burning.

ATTRv is endemic to Portugal, Japan, Brazil and Sweden, meaning that it has been found regularly in these areas. However, it now is considered a worldwide disease.

It is caused by a mutation in TTR gene, which leads to an accumulation of the abnormal TTR protein that misfolds and forms amyloid fibrils (protein aggregates) that deposit in organs and tissues.

Early diagnosis of ATTRv is necessary to initiate treatment promptly. Patients usually are diagnosed based on a family history of the disease, common neurologic symptoms, and presence of the TTR mutation Val30Me, the most common mutation leading to polyneuropathy.

However, in many cases, making a diagnosis of ATTRv can be challenging for the neurologist and may even be delayed by three to four years in non-endemic regions.

Diagnostic delays occur for multiple reasons, but often it is due to highly varied clinical presentation patterns attributed to different TTR mutations.

An international group of researchers set out to outline specific consensus recommendations for best practices in ATTR with predominant PN. These recommendations “were developed through a series of development and review cycles by an international working group consisting of key amyloidosis specialists in collaboration with companies conducting research in ATTR amyloidosis (GSK, Ionis, Pfizer, Alnylam) and the Amyloidosis Research Consortium,” the authors wrote.

In endemic countries, ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN (sensory disturbances that start in the feet and progress upward) with autonomic dysfunction (nerves involved in the functioning of the heart, bladder, intestines, sweat glands, pupils, or blood vessels, being damaged).

Futhermore, a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities (floaters in the eye), or kidney abnormalities also point to a potential diagnosis of ATTR with PN.

In non-endemic countries, ATTRv may emerge as idiopathic (of unknown cause) rapidly progressive sensory motor axonal neuropathy, which refers to a condition characterized by quickly progressing dysfunction of motor axons that control movement.

ATTRv in non-endemic countries also may be seen as atypical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a disease characterized by inflammation of peripheral nerves and destruction of the fatty protective covering (myelin sheath) over the nerves.

Patients in non-endemic areas also will appear with any of the symptoms seen in endemic areas, or with carpal tunnel syndrome, gait disorders, or cardiac hypertrophy (thickening of the heart muscle).

For people in non-endemic areas, diagnosis is likely to be missed. That is why  the authors suggest that increased awareness of ATTRv and its symptoms — as well as better knowledge of simple diagnostic tools — is necessary to enable early diagnosis and optimal treatment of the disease.

There are only two main categories of diagnostic tools in ATTRv: sequencing of the TTR gene sequencing, and tools to detect of amyloid deposits, such as  biopsy.

Therefore, staining a tissue biopsy, typing for amyloid, and screening for TTR mutations by TTR gene are important measures for identifying ATTRv in patients without a family history, the reviewers found.

After diagnosis, physicians must assess the spread of the disease because it is crucial to detect accompanying organ damage. This requires a multidisciplinary approach by several specialists.

“Because ATTRv amyloidosis is a systemic disease, physicians should be aware of manifestations other than those of the peripheral nervous system, such as cardiac, ocular, and renal manifestations,” the authors wrote.

This is necessary because, although the involvement of most organs often is hidden, it may have potentially major consequences, such as heart blocks, glaucoma and kidney problems.

Patients who have been diagnosed with ATTRv should be followed routinely to monitor disease progression — generally every six to 12 months, depending on the severity of the disease and response to therapy.

“Identification of ATTRv amyloidosis with PN can be challenging, particularly in nonendemic regions, and a high level of suspicion is required to diagnose patients as early as possible,” the authors concluded.

“Early and accurate diagnosis of ATTR amyloidosis allows early treatment and will potentially modify disease progression in patients,” they added.