Transthyretin asn90 variant: Amyloidogenic or non-amyloidogenic role

Bersano, Anna; Bo, Roberto Del; Ballabio, E.; Cinnante, Claudia; Lanfranconi, Silvia; Comi, Giacomo P.; Baron, Pierluigi; Bresolin, Nereo; Candelise, Livia

doi:10.1016/j.jns.2009.04.015

Cited by 6 publications

(8 citation statements)

References 19 publications

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“…p.D119N has previously been reported to have a combined stability score comparable with wild-type variants and has been assumed to be benign based on a single report . It is unknown whether p.H110N is amyloidogenic, and to our knowledge, a stability score has not been reported . Another variant in the same codon, p.H110D (H90D), has recently been shown to be associated with familial amyloid polyneuropathy …”

Section: Resultsmentioning

confidence: 99%

“…p.D119N has previously been reported to have a combined stability score comparable with wild-type variants and has been assumed to be benign based on a single report . It is disputed if p.H110N is amyloidogenic, and to our knowledge, a stability score has not been reported . Transthyretin concentrations are expressed as median and interquartile range and risk of heart failure as hazard ratios from Cox regression models and 95% CIs.…”

Section: Resultsmentioning

confidence: 99%

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Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

et al. 2021

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IMPORTANCE Several lines of evidence support low plasma transthyretin concentration as an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown.OBJECTIVE To evaluate whether low plasma transthyretin concentration is associated with incident HF in the general population. DESIGN, SETTING, AND PARTICIPANTSThis study included data from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; n = 9582) and the Copenhagen City Heart Study (CCHS; n = 7385). Using these data, first, whether low concentration of plasma transthyretin was associated with increased risk of incident HF was tested. Second, whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF was tested.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

et al. 2021

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“…Physicians should be aware of the leptomeningeal forms of ATTRv amyloidosis, which are associated with cerebral hemorrhage [33][34][35][36] and CNS dysfunction, typically with symptoms related to CNS impairment such as dementia, ataxia, spasticity, seizures, and stroke-like episodes [37][38][39][40]. The abnormal TTR protein deposited in the leptomeninges may be produced in the choroid plexus, making liver transplantation less effective in these patients [37].…”

Section: Misdiagnosismentioning

confidence: 99%

Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy

et al. 2020

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Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

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“…The FAP staging system is widely used for hATTR and focus on the progressive walking impairment and neuropathy severity throughout the disease ( 32 , 63 ). It was developed in Portugal in 1980 and considers three stages: (1) FAP 1 is defined by unassisted walking with mild bilateral foot and leg neuropathy; (2) FAP 2 is defined by the need for assistance in walking by crutches or canes with neuropathy spreading throughout the body; (3) FAP 3 is the most severe stage in which the patient becomes wheelchair-bound or bedridden and the neuropathy is severe.…”

Section: From Treatment To Follow-upmentioning

confidence: 99%

“…Most of them are point mutations, mainly missense pathogenic variants (30). However, a small amount does not lead to an amyloidogenic pathway, and exceptionally few changes (e.g., T119M) have shown a protective role by stabilizing TTR structure and reducing cardiovascular risk (31)(32)(33).…”

Section: Geneticsmentioning

confidence: 99%

Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy

Poli,

Labella,

Cotti Piccinelli

et al. 2023

Front. Neurol.

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Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called “amyloid”. The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.

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Transthyretin asn90 variant: Amyloidogenic or non-amyloidogenic role

Cited by 6 publications

References 19 publications

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy

Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy

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