Familial and Senile Amyloidosis Caused by Transthyretin

Transthyretin (TTR) is one of the many proteins that are known to misfold and aggregate (i.e., undergo amyloidogenesis) in vivo. The process of TTR amyloidogenesis causes nervous system and/or heart pathology. While several of these maladies are associated with mutations that destabilize the TTR native quaternary and/or tertiary structure, wild type TTR amyloidogenesis also leads to the degeneration of post-mitotic tissue. Over the past twenty years, much has been learned about the factors that influence the propensity of TTR to aggregate. This biophysical information led to the development of a therapeutic strategy, termed “kinetic stabilization”, to prevent TTR amyloidogenesis. This strategy afforded the drug, tafamidis (trade name: Vyndaqel®), which was recently approved by the European Medicines Agency for the treatment of Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP), a common familial TTR amyloid disease. Tafamidis is the first, and currently the only, medication approved to treat TTR-FAP. Here we review the biophysical basis for the kinetic stabilization strategy and the structure-based drug design effort that led to this first-in-class pharmacologic agent.

show abstract

“…59,60,65,74,75 Ultimately, death occurs within approximately a decade after the onset of symptoms. 59,74,75,80–83 …”

Section: Sporadic and Inherited Ttr Amyloidosesmentioning

confidence: 99%

The Transthyretin Amyloidoses: From Delineating the Molecular Mechanism of Aggregation Linked to Pathology to a Regulatory-Agency-Approved Drug

Johnson

Connelly

Fearns

et al. 2012

Journal of Molecular Biology

290

299

View full text Add to dashboard Cite

show abstract

“…Familial amyloid polyneuropathy (FAP) is an autosomal dominant form of fatal hereditary systemic amyloidosis, whose most common cause is mutant (MT) transthyretin (TTR) 1 2. TTR is a plasma protein synthesised mainly in the liver and in the choroid plexus of the brain and retinal pigment epithelial cells; as a homotetramer composed of 127-residue monomeric subunits, it serves as a transport molecule for thyroxine and retinol-binding protein, circulates in blood and cerebrospinal fluid and occurs in aqueous humour.…”

Section: Introductionmentioning

confidence: 99%

“…TTR is a plasma protein synthesised mainly in the liver and in the choroid plexus of the brain and retinal pigment epithelial cells; as a homotetramer composed of 127-residue monomeric subunits, it serves as a transport molecule for thyroxine and retinol-binding protein, circulates in blood and cerebrospinal fluid and occurs in aqueous humour. To date, more than 120 TTR mutations have been identified, most of which result in the development of FAP 2. Sensorimotor polyneuropathy, autonomic dysfunction, cardiac and renal failure and gastrointestinal (GI) tract disorders, all of which may lead to death usually within 10 years, have been documented in patients with FAP caused by amyloidogenic TTR (ATTR) V30M, which is the most common FAP genotype in the world 1.…”

Section: Introductionmentioning

confidence: 99%

Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation

Oshima

Kawahara

Ueda

et al. 2013

Journal of Neurology, Neurosurgery & Psychiatry

View full text Add to dashboard Cite

show abstract

“…Familial amyloidotic polyneuropathy (FAP) is an autosomal-dominant form of fatal hereditary systemic amyloidosis, the most common cause of which is mutant (MT) transthyretin (TTR) 1 2. TTR is a plasma protein synthesised mainly in the liver but also in the choroid plexus of the brain and retinal pigment epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…TTR is a plasma protein synthesised mainly in the liver but also in the choroid plexus of the brain and retinal pigment epithelial cells. To date, more than 120 TTR mutations have been identified, most of which result in development of FAP 2. Sensorimotor polyneuropathy, autonomic dysfunction, heart and kidney failure, gastrointestinal (GI) tract disorders and ocular manifestations that led to death within an average of 10 years have been documented in patients with FAP caused by amyloidogenic TTR (ATTR) V30M, which is the most common FAP genotype worldwide 1…”

Section: Introductionmentioning

confidence: 99%

Pathological changes long after liver transplantation in a familial amyloidotic polyneuropathy patient

et al. 2012

View full text Add to dashboard Cite

Liver transplantation (LT) reportedly prolongs the survival of patients with familial amyloidotic polyneuropathy (FAP), a fatal hereditary systemic amyloidosis caused by mutant transthyretin (TTR). However, what happens in systemic tissue sites long after LT is poorly understood. In the present study, we report pathological and biochemical findings for an FAP patient who underwent LT and died from refractory ventricular fibrillation more than 16 years after FAP onset. Our autopsy study revealed that the distributions of amyloid deposits after LT were quite different from those in FAP amyloidogenic TTR V30M patients not having had LT and seemed to be similar to those observed in senile systemic amyloidosis (SSA), a sporadic systemic amyloidosis derived from wild-type (WT) TTR. Our biochemical examination also revealed that this patient's cardiac and tongue amyloid deposits derived mostly from WT TTR. We propose that FAP patients after LT may suffer from SSA-like WT TTR amyloidosis in systemic organs.

show abstract

Familial and Senile Amyloidosis Caused by Transthyretin

Cited by 17 publications

References 92 publications

The Transthyretin Amyloidoses: From Delineating the Molecular Mechanism of Aggregation Linked to Pathology to a Regulatory-Agency-Approved Drug

The Transthyretin Amyloidoses: From Delineating the Molecular Mechanism of Aggregation Linked to Pathology to a Regulatory-Agency-Approved Drug

Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation

Pathological changes long after liver transplantation in a familial amyloidotic polyneuropathy patient

Contact Info

Product

Resources

About