Showing papers by "Martha Skinner published in 1994"

Liver transplantation as a treatment for familial amyloidotic polyneuropathy.

Abstract: No definitive treatment exists for familial amyloidotic polyneuropathy (FAP), an autosomal dominant disease associated with a mutant form of the protein transthyretin (prealbumin) [1]. Symptoms usually begin in middle life with peripheral neuropathy, autonomic dysfunction, cardiomyopathy, vitreous opacities, and occasionally renal failure. Death results from cardiomyopathy, malnutrition, or complications of autonomic neuropathy about 10 years after the onset of disease. Treatment of FAP has been limited to supportive measures including cardiac pacemakers, dialysis, parenteral nutrition, and physical therapy. In 1990, investigators in Sweden proposed liver transplantation as a treatment to remove the major source of mutant transthyretin production. Since then, several patients with FAP in Sweden [2], Spain, and now the United States have received liver transplants. We report our experience in seven persons treated with transplantation in the United States. Patients All seven patients were seen and evaluated in the Thorndike Clinical Research Center of the Boston University School of Medicine at Boston City Hospital. All had an identified mutant transthyretin and were from three families known to be affected with FAP. All patients had biopsy results that showed amyloid deposition. Liver transplant evaluation and surgery were done by the liver transplant unit at the New England Deaconess Hospital in six of the patients and at the Cleveland Clinic in one patient. Patients are still receiving several quantitative assessments including sensory and motor neurologic examinations; standard autonomic neuropathy testing as described by Ewing and colleagues [3]; cardiac status testing using electrocardiograms, echocardiograms, and Holter monitoring; ophthalmologic examinations for vitreous opacities; and a quality-of-life health status questionnaire. Family 1 includes a sister (age 35 years) and brother (age 37 years) of Greek ancestry with the transthyretin mutation, valine 30 methionine (Val 30 Met), whose mother, maternal uncle, and grandfather died of FAP at ages 50, 37, and 40 years, respectively [4]. Clinical findings began at ages 32 and 25 years (in the sister and the brother) and included a sensory and motor neuropathy of the legs and arms, foot drop, urinary retention, orthostasis, and diarrhea. The brother had severe wasting, had cardiac conduction defects requiring a pacemaker, and was receiving total parenteral nutrition. Liver transplantations were done in March 1992 and August 1992. Eight months later, the brother died of a pacemaker failure but did not have complications from transplant surgery. Family 2 contains a 40-year-old woman of Greek ancestry, with the transthyretin mutation Val 30 Met, whose father and paternal grandmother died of FAP at ages 44 and 60 years, respectively [4]. Clinical features were present for 5 years and were similar to those in family 1. Liver transplantation was done in July 1992. Family 3 contains four persons of Italian ancestry with the transthyretin mutation, glutamate 42 glycine (Glu 42 Gly): a sister 40 years old, a brother 36 years old, a male cousin 35 years old, and a female cousin 42 years old. These four persons had liver transplantation in June 1992, September 1992, November 1992, and June 1992. Family history showed death due to FAP in the mother, maternal aunt, uncle, and grandfather at ages 50, 46, 40, and 41 years, respectively. All persons have a second mutation on the same transthyretin gene causing an amino acid substitution of histidine 90 asparagine (His 90 Asn) also noted in families of Portuguese and German descent who do not have FAP [5]. Clinical features in this kindred were autonomic neuropathy with diarrhea and orthostasis, cardiomyopathy, vitreous opacities, and mild peripheral neuropathy. Results Seven patients (35 to 42 years old) had liver transplantation ranging 2 to 11 years after the onset of symptoms of FAP. Six liver transplantations were done at the New England Deaconess Hospital, where it was noted that the operative time (median, 5.5 hours), the blood use (median, 4 units), and the intensive care unit time (3 days for one patient) were statistically less than required for transplantation in patients with chronic liver failure. Specimens of liver tissue at the time of transplant were examined for amyloid deposition using Congo red staining. All specimens were positive with perivascular deposits graded as trace to 1+ (on a scale of 0 to 4+); more amyloid was noted in specimens from persons who had had symptoms of FAP for a long time. Serum was collected at multiple times preoperatively and within 1 month postoperatively. Total transthyretin was quantified by an enzyme-linked immunosorbent assay. To quantify the mutant transthyretin, total transthyretin was separated from other serum proteins by a native polyacrylamide gel electrophoresis and was subjected to isoelectric focusing using a modification of a previously described protocol [6] (Figure 1). The relative proportion of normal and mutant transthyretin in each sample was quantified by densitometry (Image Quant software package, Sunnyvale, California). Preoperative transthyretin levels in all patients ranged from 153 to 373 g/mL (normal values, 200 to 400 g/mL); postoperative values were 248 to 458 g/mL. All patients had slightly less mutant transthyretin than normal transthyretin before transplantation (35% to 45%). Postoperatively, sera from all patients showed only normal transthyretin. Figure 1. Isoelectric focusing gels of the serum transthyretin proteins from five patients before and after liver transplantation. Hospital stay after transplant averaged 17 days. No patient had a rejection episode requiring re-hospitalization. No objective changes in neuropathologic or cardiomyopathologic symptoms have been noted since transplantation, although several patients report a decrease in diarrhea. Discussion We describe the first patients who had liver transplantation as a treatment for FAP in the United States. In FAP, a mutant transthyretin protein synthesized by the liver is deposited as amyloid fibrils in various organ systems and is uniformly fatal 7 to 15 years after disease onset in middle life [1]. Treatment options with gene therapy are not expected in the near future; unlike conditions where gene therapy can be used to replace a deficient product, in FAP a need exists to eliminate a deleterious product. Liver transplantation, although a complicated and major surgical procedure, provides the first successful therapy for patients and families who have this disease. The follow-up period for transplantation is still relatively brief (1 to 15 months) for defining neurologic improvement. However, none of the patients have had progression of their disease, a noteworthy observation in FAP. Given the optimistic surgical outlook and the bleak prognosis of FAP, transplantation should be done soon after biopsy results show amyloid deposits, thus confirming disease onset.

Orthotopic liver transplantation for familial amyloidotic polyneuropathy.

Abstract: Orthotopic liver transplantation for inborn errors of metabolism has become a standard indication for transplantation in pediatric and adult patients with alpha-1 antitrypsin deficiency, Wilson's disease and tyrosinemia, amongst several less common diseases. Familial amyloidotic polyneuropathy (FAP) is a rare autosomal dominant disease whose metabolic origin lies in an abnormal protein synthesized primarily in the liver. FAP, also discussed as the autosomal dominant form of amyloidosis, is characterized as a hereditary form of amyloidosis. It is the rarest form of amyloidosis affecting kindreds of specific ethnic backgrounds. The true incidence of this disease in the United States is not known. The mutant protein, called transthyretin or prealbumin, forms amyloid fibrils which accumulate in vital tissues ultimately leading to the patient's death. Liver transplantation for this inherited disease leads to the production of normal transthyretin protein. This theoretically should arrest the disease process. The first 5 patients in the United States with FAP who have undergone transplantation are presented.

Autonomic neuropathy in AL (primary) amyloidosis and its effect on survival

Abstract: The significance of autonomic neuropathy (AN) in primary amyloidosis (AL) is unknown. We describe features of AN in 112 AL patients enrolled in a clinical trial. Those with orthostatic hypotension [drop in systolic/diastolic blood pressure (BP) of220/10 mmHg and increase in pulse of <10 beats/min.J were defined as having definite AN. Patients with two or more abnormal results on autonomic testing fexpiration. inspiration ratio, Valsalva and posture indices, increase in diastolic BP with handgrip, increase in systolic BP with standing], were also defined as having definite AN. Patients with abnormal gastric emptying scans and two nongastroenterologic symptoms of AN (dry eyes and mouth, urinary retention symptoms, impotence) were defined as having possible AN.Of a total of 112 patients, twenty-six patients (23%) were defined as having either definite AN (22 patients) or possible AN (4 patients). Among patients with definite or possible AN, signs and symptoms included orthostasis (69%), early satiety (50%), ...

A new transthyretin variant (His 69) associated with vitreous amyloid in an FAP family

Abstract: Direct sequencing of the TTR gene from a patient with vitreous amyloid deposits revealed heterozygosity for a previously unreported variant transthyretin gene. Both the normal T and mutant C were present at the first position of codon 69, resulting in a substitution of histidine for tyrosine at amino acid 69 of the TTR protein. This mutation can be detected by conventional RFLP analysis, since a novel Dra III restriction site is created by the mutant base. In addition, a variation of the polymerase chain reaction was used to create an alternative method of detection. The patient presented with vitreous opacities and without polyneuropathy or cardiomyopathy which are normally seen in FAP. Mutant transthyretin may be responsible for the formation of vitreous deposits in other instances where there are minimal systemic findings and no family history of disease.

Haplotype analysis of His 58, Ala 60 and Tyr 77 types of familial amyloidotic polyneuropathy

Abstract: Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant genetic disease characterized by the systemic accumulation of amyloid fibrils. Variant types of transthyretin (TTR) have been identified as major components of FAP amyloid. In the United States, several different kindreds with FAP including those with His 58, Ala 60 and Tyr 77 mutations have been found. To determine the origin and spread of the disease, the DNA haplotypes at the TTR locus were examined in two families with the His 58 mutation, four with Ala 60 and four with Tyr 77 (one from Amiens, France). Our results showed that there are at least two independent origins of the Tyr 77 mutation of FAP.

Alterations in the secondary structure of mutant transthyretins associated with familial amyloidotic polyneuropathy after proteolysis by neutrophil serine proteases

Abstract: Transthyretin (TTR), a tetrameric protein with two extensive β-sheets in each monomer, is the precursor protein of the amyloid fibril deposits in persons with an autosomal dominantly inherited disease termed familial amyloidotic polyneuropathy (FAP orATTR). The TTR isolated from four affected heterozygous individuals, each with a different mutation or at a different stage of disease was examined with respect to alteration in conformation after exposure to human neutrophil elastase (HNE) or cathepsin G by circular dichroism (CD), and their spectra compared to normal.Normal untreated TTR exhibits a negative minimum at 214 nm by CD analysis. After enzymatic digestion, minor changes are observed. The mutant TTRs differ from normal with a more marked alteration in β conformation after digestion. The degree of CD alteration of mutant TTR digested with HNE seemed to correlate with the severity of disease in each kinship. In addition, mutant TTRs that are more hydrophilic have more marked CD alteration.