CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings

Abstract

Our findings indicate that CNS clinical involvement occurs in ATTR-V30M patients regardless of LT. Longer disease duration after LT can provide the necessary time for transthyretin amyloidosis to progress until it becomes clinically relevant. Highly sensitive imaging methods are needed to identify and monitor brain ATTR. Disease modifying therapies should consider brain TTR as a target.

Targeting protein aggregation for the treatment of degenerative diseases

“…These include the 10% mortality due to surgical complications, limited organ availability, the risks of infection associated with life-long immunosuppression, and the emergence of WT TTR aggregation-associated cardiomyopathy upon aging 96 . In addition, because liver transplant-mediated gene therapy does not alter mutant TTR secretion by the choroid plexus into the CSF or by the retinal pigment epithelium cells into the vitreous of the eye, mutant TTR aggregation in the eye 97 and in meningeal vessels 98 appears to lead to ophthalmological and neurological symptoms in the patients treated by liver transplantation. These challenges warrant the development of alternative treatments discussed below.…”

“…3B) leads to a dramatic and rapid improvement in patient health, especially in cardiac function, even though there is overwhelming evidence that the amyloid fibrils are not cleared from the hearts of these patients on this timescale 72 . Although the presence of amyloid in the heart is deleterious , it appears that it is the process of active LC aggregation - including the apparent uptake of proteotoxic misfolded LC monomers or oligomers by cardiomyocytes and other relevant cells - that causes the severe multiple organ system toxicity and pathology 71, 95, 96, 98 . Unfortunately, approximately 30% of the LC amyloidosis patients presenting with severe cardiomyopathy are too sick to tolerate the chemotherapy regimen 99 .…”

Transthyretin-type cerebral amyloid angiopathy: a serious complication in post-transplant patients with familial amyloid polyneuropathy

“…CNS disorders occurred on average 14.6 years after the onset of TTR-FAP, which is beyond the average life expectancy (10.9 years) of non-transplanted patients. Fortunately, CNS symptoms were transient in most of these patients 3. However, TTR-type CAA seems to be a serious complication in post-transplant ATTR Val30Met FAP patients, considering the poor prognosis of TTR-FAP patients with specific mutations that induce CNS-dominant amyloidosis.…”

“…Maia et al 3 report a retrospective analysis of 87 consecutive post-transplant ATTR Val30Met FAP patients. They report that 31% of the patients developed CNS disorders, including TIA-like episodes, stroke, focal seizures and aura-like episodes, probably due to TTR-type CAA.…”

Psychopathological Dimensions in Portuguese Subjects with Transthyretin Familial Amyloid Polyneuropathy

“…The clinical picture is dominated by a mixed sensory, motor, and autonomic neuropathy; severe nephrological, cardiac, ophthalmological, vesical, gastrointestinal, sexual, and central nervous system symptoms are related to systemic amyloid deposition [14,15,16,17,18]. …”