A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK

Carr, AS; Pelayo‐Negro, Ana L.; Evans, Margaret C.; Laurá, Matilde; Blake, Julian; Stancanelli, Claudia; Iodice, Valeria; Wechalekar, Ashutosh; Whelan, Carol; Gillmore, Julian D.; Hawkins, Philip N.; Reilly, Mary M.

doi:10.1136/jnnp-2015-310907

Cited by 55 publications

(50 citation statements)

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“…It is of autosomal dominant transmission due to a point mutation of the transthyretin ( TTR ) gene. The Val30Met mutation, found worldwide, is the most common TTR mutation, although the Thr60Ala mutation is the most common in the UK57 There have been several reports of FAP misdiagnosed as CIDP.…”

Section: Resultsmentioning

confidence: 99%

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

Rajabally

Adams

Latour

et al. 2016

J Neurol Neurosurg Psychiatry

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International audienceDistinguishing between hereditary and inflammatory neuropathy is usually straightforward on clinical grounds with the help of a family history. There are nevertheless cases where the distinction is less clear. The advent of molecular genetics has in the past several years aided confirmatory diagnosis for an increasing proportion of patients with genetic neuropathy. Various reports have described associations of Charcot-Marie-Tooth disease with a suspected or confirmed inflammatory neuropathy occasionally responding to immunotherapy. Possible predisposition to an inflammatory component was suggested in a subset of patients. Such reports have, however, been relatively few in number, suggesting the rarity of such associations and of such a predisposition if it exists. There have been a number of publications detailing clinical presentations suggestive of inflammatory neuropathy in patients with a known or later proven genetic aetiology, and subsequently felt to be part of the phenotype rather than representing an association. A number of genetically mediated multisystemic diseases with neuropathy have otherwise been reported as mimicking chronic inflammatory demyelinating polyneuropathy (CIDP). The most common example is that of familial amyloid polyneuropathy, of particular concern for the clinician when misdiagnosed as CIDP, in view of the therapeutic implications. We review the literature on reported associations, mimics and misdiagnoses of hereditary and inflammatory neuropathy and attempt to determine a practical approach to the problem in clinical practice using clinical features, electrophysiology, histopathology and targeted early genetic testing. The issue of attempting immunomodulatory therapy is discussed in view of the published literature

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Section: Resultsmentioning

confidence: 99%

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

Rajabally

Adams

Latour

et al. 2016

J Neurol Neurosurg Psychiatry

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“…Of note, manifestations consistent with peripheral and autonomic neuropathy involvement have been observed in patients with wtATTR (Connors et al, ; Maurer et al, ). A classic feature of hATTR is length‐dependent peripheral sensorimotor neuropathy (Cappellari et al, ; Carr et al, ). Symptoms typically progress in a distal to proximal direction with feet affected first followed by upper limb involvement (Carr et al, ).…”

Section: Discussion/observationmentioning

confidence: 99%

“…As the disease progresses, patients experience increasing lower limb muscle weakness, walking difficulty, imbalance, and sensory loss (Carr et al, ; Coelho et al, ; Maurer et al, ). Neurologic symptoms and the pattern of progression of neurologic manifestations may vary according to mutation type (Cappellari et al, ; Carr et al, ). Recognizing hATTR as a cause of polyneuropathy may be challenging because of its similarity to more common causes of neuropathy.…”

Section: Discussion/observationmentioning

confidence: 99%

“…Hereditary ATTR manifests as sensorimotor neuropathy, autonomic neuropathy, cardiomyopathy, and nephropathy, whereas wtATTR mainly affects the heart, especially in men ˃60 years old (Table 1) (Carr et al, 2016;Conceicao et al, 2016;Connors et al, 2016;Maurer et al, 2016). Of note, manifestations consistent with peripheral and autonomic neuropathy involvement have been observed in patients with wtATTR (Connors et al, 2016;Maurer et al, 2016).…”

Section: Clinical Presentationmentioning

confidence: 99%

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Advances in the treatment of hereditary transthyretin amyloidosis: A review

et al. 2019

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Introduction Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild‐type ATTR) throughout the body. Two new therapies—inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy—received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR. Methods A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR. Results Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early‐ and late‐stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early‐stage disease, and tafamidis, indicated for the treatment of early‐stage disease in Europe, or diflunisal, a nonsteroidal anti‐inflammatory drug that is used off‐label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities. Conclusions Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.

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“…hTTR is known to exist in various genetic mutant forms. In fact accumulated research has established that mutations in hTTR can be linked to aggregation state and pathogenesis of FAP [12][13][14][15][16]. For example among others hTTR variants with Val 30 Met and Ser 52 Pro mutations became of high interest because of their potential implications in FAP [15,16].…”

Section: Introductionmentioning

confidence: 99%

Proteolytic truncation of human transthyretin linked to amyloidosis is mediated by a trypsin like enzyme: In vitro demonstration using model peptides

Saad¹,

Lu²,

Koya³

et al. 2016

Bio Chem Comp

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Background: A number of human conditions collectively known as amyloidosis were found to be associated with self-aggregation of a specific group of proteins. This fibril like protein aggregates deposit in different tissues including the central nervous system leading to amyloid polyneuropathies (AP), systemic senile amyloidosis (SSA), amyloidotic cardiomyopathy (AC) and carpal tunnel syndrome (CTS). The most common protein in this group is human transthyretin (hTTR). Similar to beta amyloid peptide of Alzheimer's Disease, hTTR forms amyloid type fibrils following its proteolytic cleavage at the C-(carboxy) terminus leading to aggregation. hTTR is normally present in blood where it binds with thyroid hormone thyroxine T4 and Retinol Binding Protein-Vitamin A complex and mediates their transport. It is also present in lower amount in cerebrospinal fluid as a major carrier of thyroxine hormone. Deposition of hTTR fibril aggregates is responsible for SSA usually observed in older population with age >60 years which is regulated by its mutant forms. The exact mechanism of this disorder is still unclear. Studies confirmed that C-terminally truncated hTTR undergoes rapid self-aggregation leading to amyloidosis. The site of this cleavage and the protease involved has not been fully characterized although it is proposed to be at Lys 48 ↓Thr 49 residues.Objective: The major goal of this study is to confirm that hTTR is cleaved by a trypsin like enzyme at the position indicated by vertical arrow Ala-Ser-Gly-Lys 48 ↓Thr 49 -Ser-Glu-Ser and that this cleavage can be blocked by a trypsin-inhibitor. Methods:A 20 mer peptide comprising the wild type sequence from residue (41-60) of hTTR was synthesized, purified by RP-HPLC and fully characterized by mass spectrometry. Three additional mutant peptides namely Lys These results are consistent with those reported for the physiological full length hTTR proteins. Moreover the above cleavage can be blocked efficiently by a trypsin inhibitor (dimethyl formamide), reported for the first time in this study. Energy minimised 3D modeling study revealed that Lys 48 /Ala mutant exhibits a unique structural conformation compared to the corresponding wild type control peptide suggesting its potential role in regulating proteolytic cleavage. Overall our data confirmed the key role of a trypsin like enzyme in hTTR proteolysis leading to its truncation which facilitates its self-aggregation leading to amyloidosis. The study also highlighted a potential therapeutic strategy for hTTR associated amyloidosis by targeting this enzyme with specific inhibitors.

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A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK

Abstract: The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history.

Cited by 55 publications

References 31 publications

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

Advances in the treatment of hereditary transthyretin amyloidosis: A review

Proteolytic truncation of human transthyretin linked to amyloidosis is mediated by a trypsin like enzyme: In vitro demonstration using model peptides

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