AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.
Allele specific expression of the transthyretin gene in swedish patients with hereditary transthyretin amyloidosis (ATTR V30M) is similar between the two alleles.
Although TTR mutations were mostly associated with familial amyloid polyneuropathy (FAP), these molecular variants were also found in patients with recurrent stroke, subarachnoidal bleeding and radiological findings of cerebral, cerebellar, cortical-subcortical infarctions and hemosiderosis.We describe a 46 y.o. man with recurrent cerebral haemorrhages carrying Asn90His variant of TTR gene.
Although CTS associated with TTR amyloidosis has been known as an initial symptom in some patients with ATTR non-Val30MetFAP and those with senile systemic amyloidosis, this is the first report of ATTR Val30Met FAP patients starting with upper limb neuropathy including CTS-like symptoms.
Although there are approximately 100 known TTR variants associated with peripheral neuropathy, in Israel only one patient with familial amyloid polyneuropathy (FAP), a patient of Ashkenazi origin with ATTR due to an F33I mutation, has been reported so far.
As the most common form, transthyretin-related hereditary amyloidosis (ATTR amyloidosis) is an autosomal dominant inherited disease due to mutations of TTR.
ATTR, caused by amyloid-forming variant TTR proteins (ATTRm) that arise from point mutations in the TTR gene, were classically referred to as familial amyloid cardiomyopathy (FAC) or familial amyloid polyneuropathy (FAP), reflecting the clinical phenotype.
Autonomic dysfunction, an early symptom of transthyretin amyloidosis (ATTR amyloidosis), requires investigations not readily available in many clinics.
Autonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation.
By using cell culture studies, a mouse model of disease and human clinical samples, we observed that MMP-14: (i) is overexpressed in FAP nerves, correlating with TTR deposition; (ii) is upregulated in sciatic nerves from a preclinical transgenic mouse model, increasing with TTR deposition; (iii) levels in the PNS and plasma are rescued upon treatment of mice with anakinra or <i>TTR</i> siRNA, drugs acting over the IL-1 signaling pathway or TTR liver synthesis, respectively; (iv) increases in Schwann cells upon incubation with amyloid-like aggregates; and, finally, (v) is increased in plasma of FAP patients, correlating with disease progression.
Cardiac amyloidosis occurs in the classical form of FAP with ATTRVal30Met, especially in older patients, and is also a common clinical manifestation in FAP patients with non-Val30MetATTRs.
Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively.
Cardiomyopathy is a major cause of death in both the hereditary form of transthyretin (TTR) amyloidosis and the sporadic late-age-onset transthyretin amyloidosis (ATTR wild-type (ATTR<sub>wt</sub>)).
Circulating TTR is predominantly produced by liver, and the only widely available clinical treatment for FAP is orthotopic liver transplantation (OLT), whereas no treatment currently exists for FAC.
Evidences suggest that transthyretin (TTR), a plasma protein associated with transthyretin amyloidosis or familial polyneuropathy (FAP) interacts with heterologous amyloid proteins including amyloid beta and islet amyloid polypeptide.