Abstract
: ObjectivePathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. Patients and Methods: We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin (TTR) mutations. Sural nerve biopsy was performed according to standard protocols. Results: Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Conclusions: Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country.
Highlights
Hereditary transthyretin amyloidosis is an inherited, adult-onset, progressive disorder caused by mutations in the transthyretin (TTR) gene
All biopsies showed evidence of axonal loss, which was severe in 42 cases, moderate in 15 and slight in 4 (Figure 1a,b)
Pathological evidence of amyloid deposition had been the gold standard for diagnosis, but in the last few years, considering the introduction of new possible therapeutic approaches, genetic testing has become the first option after a clinical suspicion
Summary
Hereditary transthyretin amyloidosis (hATTR) is an inherited, adult-onset, progressive disorder caused by mutations in the transthyretin (TTR) gene. The disease is characterized by extracellular deposition of amyloid insoluble fibrils in different organs, leading to a multisystem condition with prevalent peripheral nervous system and cardiac involvement [1]. The most typical presentations of hATTR are either a progressive, length-dependent, mixed sensory and motor peripheral polyneuropathy (hereditary transthyretin amyloidosis polyneuropathy, or hATTR-PN) associated with variable autonomic disturbances, formerly known as familial amyloid polyneuropathy (FAP), or an infiltrative cardiomyopathy (hereditary transthyretin amyloidosis cardiomyopathy, or hATTR-CM) [2]. HATTR is a life-threatening condition with a broad clinical presentation. The clinical course is marked by a progressive worsening, with a mean survival of 10 years since the onset of symptoms [1]. More than 120 TTR gene mutations have been identified as a cause of hATTR. Phe64Leu is the most common mutation in southern Italy [4,5,6]
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