Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant

Abstract

Familial amyloidotic polyneuropathy is an inherited form of amyloidosis associated with a mutant form of a protein called transthyretin. The Methionine-30 variant is the most frequent mutation observed. This disorder is caused by deposition of this protein as amyloid in several organs, such as the heart, kidneys, and peripheral nervous system. The disease is always progressive and fatal, and patients die 7 to 10 years after the onset of symptoms. Liver transplantation is at present the only choice for these patients because it provides improvement of symptoms and/or stops progression of the disease in most patients. We report the case of a patient who showed clear progression of cardiomyopathy and neuropathy after liver transplantation. Copyright 1999 by the American Association for the Study of Liver DiseasesF amilial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited form of amyloidosis associated with a mutant form of a protein called transthyretin or prealbumin. This disorder is caused by the systemic deposition of variant transthyretin molecules as amyloid fibrils in the extracellular matrix of several organs, such as the heart, kidneys, peripheral nervous system, and eyes. 1-3 More than 30 amyloidogenic mutations in the transthyretin gene have been reported, but the Methionine-30 (Met-30) transthyretin variant is the most frequent. 4 Symptoms begin in the middle life with peripheral polyneuropathy, autonomic dysfunction, cardiomyopathy, vitreous opacities, and, occasionally, nephrotic syndrome and renal failure. The disease is always progressive and fatal, and patients usually die 7 to 10 years after the onset of symptoms. 1 The presence of cardiomyopathy is the most important factor that affects patient survival. 5 In 1990, Holmgren et al 6 proposed orthotopic liver transplantation (OLT) as a treatment to remove the major source of variant transthyretin production, thereby arresting the progression of amyloid deposition. Since then, many patients with FAP have received liver transplants in several countries, with a high success rate. Several investigators have reported improvement in autonomic and peripheral neuropathies and nutritional status. 6-9 Although OLT is, at present, the only lifesaving treatment for FAP, recent reports have suggested that cardiomyopathy can progress after OLT for FAP. 10,11 We report the case of a patient who underwent OLT for FAP caused by Tyrosine-77 (Tyr-77) transthyretin variant in whom clinical worsening with progression of cardiomyopathy and neuropathy has been observed after OLT. Case ReportA 61-year-old man had a 2-year history of progressive muscle weakness, sensory impairment (paresthesis and loss of pain and temperature sensations), and deep arreflexia of the limbs, particularly in the legs. In addition, he showed symptoms of autonomic dysfunction with hypotensive episodes, dysuria, impotence, and severe diarrhea accompanied by a weight loss of 12 kg during the last year. The presence of an axonal polyneuropathy was verified by electromyography and n...

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

“…Most often they have increased left ventricle thickness and restrictive cardiomyopathy. Symptomatic cardiomyopathy was more frequent in our Tyr77 FAP patients, in agreement with previous reports 45. Amyloid deposition in conduction pathways requiring pacemaker implantation was also more frequent in non‐Portuguese than PortMet30 patients (see Table 3).…”

Cardiac Amyloidosis: Heterogenous Pathogenic Backgrounds

“…In addition, it has been recently noted that after transplantation rapid deterioration of cardiac function with further thickened ventricular wall occurred in some FAP patients, although polyneuropathy and autonomic failure were stabilized or slightly improved. These findings were originally obtained from the patients with non-Val30Met ATTRs who possibly had substantial amyloid deposition on the myocardium before operation (61)(62)(63). However, a similar finding has been observed in typical FAP patients with Val30Met ATTR (64) and in the pathogenesis of this form of cardiac amyloidosis, wild-type TTR is regarded as playing a central role (65).…”

Outcome of liver transplantation for familial amyloidotic polyneuropathy

“…One of these patients had progression of cardiomyopathy and neuropathy after LT. 23 The other two patients with the TYR77 mutation were reported to undergo combined heart and liver transplantation, and none of these patients had amyloid deposit on routine posttransplantation endomyocardial biopsy. 21,24 Our patient with the TYR77 TTR variant received a liver, heart, and kidney transplant.…”