<i>C1<scp>QA</scp></i> and <i>C1<scp>QC</scp></i> modify age‐at‐onset in familial amyloid polyneuropathy patients

Dias, Andréia; Santos, Diana; Coelho, Teresa; Alves‐Ferreira, Miguel; Sequeiros, Jorge; Alonso, Isabel; Sousa, Alda; Lemos, Carolina

doi:10.1002/acn3.748

Cited by 11 publications

(2 citation statements)

References 40 publications

(43 reference statements)

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“…The phenomena of variable penetrance and anticipation (which is not based on a repeat nucleotide mechanism) of the p.Val50Met mutation suggest that the genetic background of the various populations as well as epigenetic factors may play a role. More specifically, in Cypriot and Portuguese patients, complement C1Q polymorphisms modulate the age of disease onset of the p.Val50Met mutation [ 6 , 16 , 17 ]. Research on transgenic mice supports the role of complement in ATTR amyloidogenesis [ 18 ].…”

Section: Pathogenesismentioning

confidence: 99%

Drug and Gene Therapy for Treating Variant Transthyretin Amyloidosis (ATTRv) Neuropathy

Dardiotis

Kyriakides

2023

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Variant Transthyretin Amyloidosis (ATTRv) neuropathy is an adult-onset, autosomal dominant, lethal, multisystemic disease due to the deposition of mutated transthyretin (TTR) in various organs, commonly involving the peripheral nerves and the heart. Circulating TTR tetramers are unstable due to the presence of mutated TTR and dissociate into monomers, which misfold and form amyloid fibrils. Although there are more than 140 mutations in the TTR gene, the p.Val50Met mutation is by far the commonest. In the typical, early-onset cases, it presents with a small sensory fibre and autonomic, length-dependent, axonal neuropathy, while in late- onset cases, it presents with a length-dependent sensorimotor axonal neuropathy involving all fibre sizes. Its treatment is now available and includes TTR stabilizers, TTR amyloid removal as well as gene silencing, while gene editing therapies are on the way. Its timely diagnosis is of paramount importance for a better prognosis.

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Section: Pathogenesismentioning

confidence: 99%

Drug and Gene Therapy for Treating Variant Transthyretin Amyloidosis (ATTRv) Neuropathy

Dardiotis

Kyriakides

2023

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“…The latter usually affects elderly men and is accompanied by cardiac involvement [ 1 , 2 ]. Several studies in patients with ATTRv amyloidosis suggest that the presence of single nucleotide polymorphisms (SNPs) in genes other than the TTR may influence the development of the disease, affecting its age of onset [ 3 – 6 ]. However, it is currently unknown whether any genetic factors could be involved either in the onset or the development of ATTRwt amyloidosis.…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing of selected functional genes in patients with wild-type transthyretin amyloidosis

Moreno-Gázquez,

Pérez-Palacios,

Abengochea-Quílez

et al. 2023

BMC Res Notes

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Objective Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene. Studies regarding the variant form of ATTR amyloidosis (ATTRv) suggest that the presence of single-nucleotide polymorphisms (SNP) in genes other than the TTR, may influence the development of the disease. However, other genetic factors involved in the aetiopathogenesis of ATTRwt are currently unknown. This work investigates the presence of sequence variants in genes selected for their possible impact on ATTRwt amyloidosis. To do so, targeted sequencing of 84 protein-coding genes was performed in a cohort of 27 patients diagnosed with ATTRwt. Results After applying quality and frequency filtering criteria, 72 rare or novel genetic variants were found. Subsequent classification according to the ACMG-AMP criteria resulted in 17 variants classified as of uncertain significance in 14 different genes. To our knowledge, this is the first report associating novel gene variants with ATTRwt amyloidosis. In conclusion, this study provides potential insights into the aetiopathogenesis of ATTRwt amyloidosis by linking novel coding-gene variants with the occurrence of the disease.

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Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability

Carvalho,

Dias,

Coelho

et al. 2024

J Neurol

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Hereditary transthyretin-related amyloidosis (ATTRv amyloidosis) is a rare and progressively debilitating disease characterized by the deposition of transthyretin (TTR) amyloid fibrils in various organs and tissues, most commonly in the heart and peripheral nerves. This pathological deposition can lead to significant organ dysfunction and, ultimately, organ failure. ATTRv amyloidosis exhibits a broad range of clinical presentations, from purely neurological symptoms to purely cardiac manifestations, as well as mixed phenotypes which result from both neurological and cardiac implications. This wide phenotypical spectrum realistically challenges disease diagnosis and prognosis, especially in individuals without or with an unknown family history. Multiple factors are thought to contribute to this variability, including genetic, epigenetic, and even environmental influences. Understanding these factors is crucial, as they can significantly affect disease expression and progression. This review aims to summarize each of these contributing factors, to help elucidate the current knowledge on the phenotypical variability of ATTRv amyloidosis.

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C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients

Abstract: Objectives Transthyretin ( TTR ) familial amyloid polyneuropathy ( FAP ) ( OMIM 176300) shows a variable age‐at‐onset ( AO ), including within families. We hypothesized that variants in C1 QA and C1 QC genes, might also act as genetic modifiers of AO in TTR … Show more

Cited by 11 publications

References 40 publications

Drug and Gene Therapy for Treating Variant Transthyretin Amyloidosis (ATTRv) Neuropathy

Drug and Gene Therapy for Treating Variant Transthyretin Amyloidosis (ATTRv) Neuropathy

Targeted sequencing of selected functional genes in patients with wild-type transthyretin amyloidosis

Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability

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