Clinical and pathological findings in familial amyloid polyneuropathy caused by a transthyretin E61K mutation

Murakami, Tatsufumi; Nishimura, Hirotake; Nagai, Toshiaki; Hemmi, Shoji; Kutoku, Yumiko; Ohsawa, Yutaka; Sunada, Yoshihide

doi:10.1016/j.jns.2017.08.017

Cited by 6 publications

(13 citation statements)

References 11 publications

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“…Isolated CTS has been found in our cohort, which could be an early neuropathy pattern of ATTR 4,5 . Sural biopsy was less likely to detect amyloid deposition, but several other biopsy sites other than nerves may contribute more to the diagnosis of ATTR 62 . 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 .…”

Section: Discussionmentioning

confidence: 58%

“…4,5 Sural biopsy was less likely to detect amyloid deposition, but several other biopsy sites other than nerves may contribute more to the diagnosis of ATTR. 62 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.…”

Section: Discussionmentioning

confidence: 91%

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Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study

Wang

et al. 2021

Ann Clin Transl Neurol

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Objective This study aims to report the genotypes and phenotypes of hereditary transthyretin amyloidosis (ATTR) in a large Chinese cohort, yet the clinical and genetic profiles of ATTR remain elusive in mainland China. Methods Fifty‐four patients with molecularly confirmed ATTR from 39 unrelated families were identified by sequencing the TTR gene. Sural nerve biopsies were performed in 40 of these cases. The clinical and electrophysiological data were retrospectively collected and analyzed. Results The male/female ratio was 42:12. The average age of patients at the onset of the disease was 47.8 ± 13.0 years. The late‐onset type occurred in 29 cases (53.7%). Twenty‐two probands (56.4%) had a family history with ATTR. The initial symptoms were limb paresthesia in 33 cases (61.1%), autonomic dysfunction in 15 cases (27.8%), and blurred vision in 6 cases (11.1%). A total of 22 different TTR mutations were identified, including Val30Met (25.6%) in 10 families in North China and Ala97Ser in 4 families (10.3%) in South China. Electrophysiological studies revealed general sensorimotor axonal polyneuropathy in 33/44 cases (75.0%), mixed neuropathy with axonal and demyelinating impairment features in 9/44 cases (20.5%) and isolated carpal tunnel syndrome in two cases. Sural nerve biopsies revealed positive Congo red staining in 16/40 cases (40.0%). Conclusion Chinese patients with ATTR exhibited heterogeneous TTR genotypes and clinical phenotypes. Val30Met remains the most common mutation type in mainland China.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 91%

Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study

Wang

et al. 2021

Ann Clin Transl Neurol

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“…We recently reported a late‐onset FAP TTR E61K patient who showed sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis (Murakami et al., 2017). Sural nerve biopsy was performed 7 years after disease onset.…”

Section: Resultsmentioning

confidence: 99%

“…Though myelinated fibers were severely reduced to 180/mm 2 (normal: 6,000–8,000/mm 2 ), amyloid deposits were not detected in the endoneurium or perineurium of the nerve by Congo red, TFT, DFS stain, or electron microscopy. In contrast, amyloid deposits were detected in other tissues, including brevis peroneus muscle, salivary gland, and the heart (Murakami et al., 2017).…”

Section: Resultsmentioning

confidence: 99%

“…The sural nerve, brevis peroneus muscle, salivary gland, and heart samples were obtained from our FAP TTR E61K patient, immersion‐fixed in 10% (V/V) buffered formalin, and embedded in paraffin (Murakami et al., 2017). To assess amyloid deposits in the tissues, random paraffin sections of the samples were stained with Direct Fast Scarlet 4BS (DFS), and observed with a BZ‐X700 microscope (Keyence).…”

Section: Methodsmentioning

confidence: 99%

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A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy

Murakami

Yokoyama

Mizuguchi

et al. 2020

Journal of Neurochemistry

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Patients with transthyretin (TTR)‐type familial amyloid polyneuropathy (FAP) typically exhibit sensory dominant polyneuropathy and autonomic neuropathy. However, the molecular pathogenesis of the neuropathy remains unclear. In this study, we characterize the features of FAP TTR the substitution of lysine for glutamic acid at position 61 (E61K). This FAP was late‐onset, with sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis. Interestingly, no amyloid deposits were found in the endoneurium of the four nerve specimens examined. Therefore, we examined the amyloidogenic properties of E61K TTR in vitro. Recombinant wild‐type TTR, the substitution of methionine for valine at position 30 (V30M) TTR, and E61K TTR proteins were incubated at 37°C for 72 hr, and amyloid fibril formation was assessed using the thioflavin‐T binding assay. Amyloid fibril formation by E61K TTR was less than that by V30M TTR, and similar to that by wild‐type TTR. E61K TTR did not have an inhibitory effect on neurite outgrowth from adult rat dorsal root ganglion (DRG) neurons, but V30M TTR did. Furthermore, we studied the sural nerve of our patient by terminal deoxynucleotidyl transferase dUTP nick end labeling and electron microscopy. A number of apoptotic cells were observed in the endoneurium of the nerve by transferase dUTP nick end labeling. Chromatin condensation was confirmed in the nucleus of non‐myelinating Schwann cells by electron microscopy. These findings suggest that E61K TTR is low amyloidogenic, in vitro and in vivo. However, TTR aggregates and amyloid fibrils in the DRG may cause sensory impairments in FAP because the DRG has no blood–nerve barrier. Moreover, Schwann cell apoptosis may contribute to the neurodegeneration.

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Transthyretin Amyloid Neuropathy: The Schwann Cell Hypothesis

Murakami

Sunada

2019

Advances in Experimental Medicine and Biology

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Clinical and pathological findings in familial amyloid polyneuropathy caused by a transthyretin E61K mutation

Cited by 6 publications

References 11 publications

Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study

Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study

A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy

Transthyretin Amyloid Neuropathy: The Schwann Cell Hypothesis

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