Clinicopathological correlations of sural nerve biopsies in TTR Val30Met familial amyloid polyneuropathy

Abstract

Familial amyloid polyneuropathy with substitution of methionine for valine at position 30 in the TTR gene is the most common type of hereditary transthyretin amyloidosis. Although several authors have previously reported a size-dependent fiber loss, predominantly involving unmyelinated and small diameter myelinated fibers, the mechanisms of nerve fiber loss have not been fully understood. In this study we establish the morphometric pattern of peripheral neuropathy in familial amyloid polyneuropathy patients and asymptomatic mutation carriers in the biopsies from our archive and correlated the pathological findings with clinical features. Ninety-eight patients with familial amyloid polyneuropathy and thirty-seven asymptomatic mutation carriers (TTR Val30Met mutation), aged between 17 and 84 years, that underwent sural nerve biopsy between 1981 and 2017 at Centro Hospitalar Universitário do Porto were studied. Thirty-one controls were included for comparison. The median age at nerve biopsy was 26.0 [(interquartile range = 23.5-39.5] years for asymptomatic mutation carriers, 45.0 [35.0-60.0] years for familial amyloid polyneuropathy patients and 44.0 [30.0-63.0] years for controls. The median duration between nerve biopsy and symptoms onset was 7.0 [3.3-11.8] years (range: 1 to 27 years) in the asymptomatic carriers. Most patients were in an earlier disease stage (93% with a polyneuropathy disability scale ≤ 2). Patients had loss of small and myelinated fibers compared to both asymptomatic carriers and controls (p<0.001), whereas asymptomatic carriers showed loss of small myelinated fibers when compared to controls (p<0.05). The loss of myelinated fibers increased with disease progression (p<0.001), and patients in more advanced clinical stage showed more frequent amyloid deposition in the nerve (p=0.001). There was a positive correlation between large myelinated fiber density and time to symptoms onset in the asymptomatic carriers that developed early-onset form of the disease (r = 0.52, p<0.01). Additionally, asymptomatic carriers with amyloid deposition already present in sural nerve biopsies developed symptoms earlier than those with no amyloid (p<0.01). In conclusion, this study confirms that small fiber size loss is an initial event in familial amyloid polyneuropathy, already present in asymptomatic gene carriers, starting several years before symptoms onset. We show for the first time that large myelinated fibers loss and amyloid deposition are pathological features that correlate independently with short period to symptoms onset for asymptomatic carriers that developed early-onset form of the disease. These findings are therapeutically relevant, as it would allow for a better interpretation of the role of disease-modifying agents in transthyretin familial amyloid polyneuropathy.

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers

“…Analysis of our cohort confirms that Congo red positive deposits are less common with Phe64Leu mutations than with Val30Met mutations. The Congo red positivity of 87% with the Val30Met mutation, on the other hand, was similar to that reported in a recently published paper [32]. In contrast to this study, we did not find any significant correlation between the presence of Congo red deposits and the clinical severity of polyneuropathy, as assessed by PND score [32].…”

“…The Congo red positivity of 87% with the Val30Met mutation, on the other hand, was similar to that reported in a recently published paper [32]. In contrast to this study, we did not find any significant correlation between the presence of Congo red deposits and the clinical severity of polyneuropathy, as assessed by PND score [32]. The proportion of early-onset patients in our cohort might explain this difference.…”

Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study

“…Interestingly, the trend that the positive rate of amyloid deposition of sural nerves was lower in late‐onset patients was found, possibly because the blood‐nerve barrier in the distal part of peripheral nerves may be preserved later in late‐onset ATTR 63 . We found mild to severe loss of myelinated fibers of different diameters, especially the small‐diameter and unmyelinated fibers, which started from the asymptomatic stage of ATTR 64 . Thin myelinated fibers and onion bulb formations were observed occasionally, which indicated involvement of myelin.…”

“…63 We found mild to severe loss of myelinated fibers of different diameters, especially the small-diameter and unmyelinated fibers, which started from the asymptomatic stage of ATTR. 64 Thin myelinated fibers and onion bulb formations were observed occasionally, which indicated involvement of myelin. Similar pathologic findings were observed in previous studies, which revealed severe axonal loss and occasional segmental demyelination-remyelination in nerve biopsy.…”

The neuropathy in hereditary transthyretin amyloidosis: A narrative review

“…[6][7][8] Though the deposition in organs and tissues of TTR amyloid fibrils should represent the feature of ATTRv, actually amyloid deposition finding in nerve biopsy specimens is quite variable and seems to be related to the clinical severity of polyneuropathy. 9 Instead, amyloid deposits are usually found in dorsal root ganglia (DRG) and sympathetic ganglia in both early-and late-onset Val30Met ATTRv. In addition, in early-onset ATTRv the neuronal loss is greater in sympathetic ganglia than DRG, while in late-onset ATTRv cases there is generally an involvement of sensory neurons of all sizes in DRG.…”