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Familial amyloid polyneuropathy (FAP) associated with mutations of the transthyretin (TTR) gene is the most common type of FAP, a devastating disease causing death within 10 years after the first symptoms. Because most of the amyloidogenic mutated TTR is secreted by the liver, transplantation is widely used to treat these patients, but long-term quantitative evaluation of the effects of liver transplantation on the progression of the neuropathy are not available. We have treated 45 patients with symptomatic TTR-FAP, including 43 with the Met30 TTR gene mutation, and report on the results of periodic evaluation of markers of neuropathy in 25 of them, who have been followed for more than 2 years after liver transplantation (mean follow-up 4 years). The overall survival rates at 1 and 5 years were 82 and 60%, respectively. Urinary incontinence and a low Norris score at liver transplantation were associated with poorer outcome. The motor score stabilized in seven of 11 patients (64%) with mild sensorimotor neuropathy (walking unaided) and in two of the eight patients (25%) with severe sensorimotor deficit (walking with aid) at liver transplantation. In five other patients, deterioration of motor deficit occurred only within the first year after liver transplantation, but was progressive after this interval in two patients. None of the six patients with pure sensory neuropathy developed motor loss and superficial sensory loss remained unchanged. Two years after liver transplantation, the rate of myelinated axon loss in nerve biopsy specimens was markedly lower in seven transplanted patients (0.9/mm(2) of endoneurial area/month) than in non-transplanted patients (70/mm(2) of endoneurial area/month). Symptoms of dysautonomia and quantitated cardiocirculatory autonomic tests remained unchanged. In all patients, serum mutated TTR decreased to 2.5% of pre-liver transplantation values and remained at this level during follow-up. We presently recommend liver transplantation in FAP patients at onset of first symptoms and exclusion of those with a Norris score below 55 and/or with urinary incontinence.

A matrix-assisted laser desorption ionization/time-of-flight (MALDI/TOF) mass spectrometry (MS) system was used to detect variant transthyretin (TTR) in immunoprecipitated serum TTR molecules obtained from 6 patients with familial amyloid polyneuropathy (FAP) who were already proven not to have ATTR Val30Met. This simple and quick method showed six different patterns of mass spectra of TTR-related immunoprecipitates from these patients, and in each patient the clearly identified characteristic doublet-shaped ion peaks consisted of normal and variant TTR apart from each other peak with a mass difference between them. DNA sequencing confirmed that the patterns of variant TTR corresponded respectively to ATTR Val30Leu, ATTR Phe33Val, ATTR Asp38Ala, ATTR Ser50Arg, ATTR Ala97Gly and ATTR Ala97Ser. ATTR Asp38Ala and ATTR Ala97Ser are previously unknown variants of TTR leading to the development of FAP. ATTR Phe33Val was found in a Chinese FAP patient and ATTR Ala97Ser in a Taiwanese. Serum analysis using immunoprecipitation and MALDI/TOF MS system can provide useful information when investigating FAP patients with diverse types of variant TTR.

Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.

Transthyretin-Met 30 (TTR-Met 30) is a variant of transthyretin and is usually associated with familial amyloid polyneuropathy. It is rare that patients with TTR-Met 30 will primarily develop amyloid cardiomyopathy. This report presents a patient with late-onset TTR-Met 30 who primarily developed amyloid cardiomyopathy, with less amyloid polyneuropathy in the peripheral nervous system than is usually seen. An autopsy was performed, and histological examination revealed many foreign-body giant cells and macrophages in the area of amyloid deposition that was found in nearly all of the organs.

Background/aims: The primary cause of Familial Amyloidotic Polyneuropathy is a variant transthyretin gene on chromosome 18. Progressive polyneuropathy followed by fatal cardiac and renal failure commonly manifest during middle age. Within 10 years after onset of clinical symptoms, affected individuals usually die due to malnutrition or heart failure. Currently, liver transplantation is the only available therapeutic option., Methods: We performed liver transplantation in two patients with Familial Amyloidotic Polyneuropathy carrying the transthyretin-30 mutant. Two patients aged more than 50 years received the two explanted amyloidotic livers. This procedure is called Domino liver transplantation. We report the outcome in the studied subjects and analyze the metabolic consequences of this procedure., Results: We determined the serum half-life of transthyretin-30 as 2.25 days using daily monitoring of transthyretin-30 levels. An affected amyloidotic patient had an increased serum concentration of lipoprotein(a) of 78 mg/dl before transplantation. The tumor patient, who received the organ from this affected patient, developed an almost identical serum concentration of lipoprotein(a) after liver transplantation, confirming the liver as the primary site of synthesis of this lipoprotein., Conclusion: Once Domino liver transplantation has been performed, the impact of the liver-dependent metabolism of specific proteins of interest can be studied.

A 64-year-old man has suffered from intractable diarrhea since January 1990. He noticed numbness and weakness in the distal portion of four extremities in the following several months. His symptoms were gradually progressive. In June 1992, neurological examination revealed mild muscular atrophy and weakness in the proximal and distal portions of four extremities. There were paresthesia and severe impairment of superficial sensations in the lower limbs, lower half of the trunk and upper limbs. All deep tendon reflexes were reduced or absent. Autonomic dysfunctions such as orthostatic hypotension, impotence and diarrhea were evident. On sural nerve biopsy, myelinated fibers showing axonal degeneration were predominantly seen, and densities of both myelinated and unmyelinated fibers were markedly decreased. No amyloid deposits were found in the endoneurium. Amyloid deposition was identified in the gastric mucosa by Congo red staining and immunostaining with anti-transthyretin (TTR) antibody. Edman degradation showed one amino acid substitution of Lys for Glu at position 61 in the TTR-peptides from the serum. Direct DNA sequencing revealed a new point mutation in the 61st codon of TTR gene. The same point mutation of TTR gene was identified in the DNAs from his 67-year-old brother and 63-year-old sister and one of the paternal cousins, a 64-year-old woman, although their clinical symptoms and signs were negative. Clinical features such as late onset of the symptoms and signs and presence of carriers in their sixties in this family are unique and atypical as compared with those of more frequent Val30-->Met FAP families. A variant TTR, characterized by a Glu61-->Lys substitution (a basic-for-acidic amino acid substitution) found in this family, has not been reported in the literature. In the case of the examination of the patients with autonomic and sensory symptoms and signs of unknown etiology, amyloidotic polyneuropathies, including FAP even in the absence of the family history, should be differentiated. When FAP is highly suspected, the combination of family study and DNA analysis of a possible variant TTR is indispensable for the establishment of the diagnosis.

Background: Finnish-type familial amyloidosis (FAP-IV) is an autosomal, dominantly inherited disorder characterized by progressive polyneuropathy and lattice corneal dystrophy type II. The vast majority of families with this disorder originated from Finland. Only two families, in neighboring districts, have been reported in Japan previously., Methods: The authors report two additional Japanese patients with FAF-IV. The proband, a 70-year-old man, had decreased perspiration and abnormal facial muscle movement. Results of neurologic examination showed bilateral facial and hypoglossal nerve palsies, and an autonomic disturbance, including orthostatic hypotension and dysfunction of perspiration. Histochemical, immunohistological, and DNA studies confirmed the diagnosis of FAP-IV., Results: Results of ophthalmologic examination showed asymptomatic lattice corneal dystrophy of both eyes, but the appearance of the cornea was different from that described in the patients from Finland. Lattice lines in the authors' patient were very fine, short, and glassy and could be observed with indirect retroillumination, but might be missed with direct illumination by the slit-lamp microscope. The proband's younger half-sister, a 68-year-old woman, showed clinical findings and laboratory data similar to those of the proband., Conclusion: The authors report two Japanese patients with lattice corneal dystrophy type II related to FAP-IV. This is the third Japanese family with this disorder, and there is no familial relationship to the two previously reported families in Japan.

We report a Japanese woman with familial amyloidotic polyneuropathy (FAP) with a transthyretin variant that substituted leucine for valine at position 30. Family history was not informative. She had initially suffered from repeated petechiae in the eyelids at the age of 51. Two years later, dysesthesia in the lower extremities appeared. Distal muscle weakness and sensory disturbance gradually developed. Autonomic dysfunction emerged and vomiting and orthostatic hypotension were marked in the late stage of her illness. Because of renal failure, she died at the age of 54. At autopsy, amyloid deposits were prominent in peripheral nerves including autonomic nerves, heart, blood vessels, gastrointestinal tract, kidneys, and bladder. In the nervous system, we found amyloid deposits in anterior roots, posterior roots, posterior root ganglions, peripheral nerves, and sympathetic ganglions. Cardiac weight was increased (595 g) with conspicuous amyloid deposits in the myocardium. The kidneys showed massive deposition of amyloid in the glomeruli and vascular walls. Amyloid accumulated moderately in tongue, submandibular gland, gallbladder, spleen, and pancreas, and slightly in the thyroid gland, lung, liver, and adrenal gland. No amyloid deposits were seen in the CNS with the exception of perivascular deposits in the choroid plexus.

Recent advances in protein chemistry and the molecular biology of amyloid proteins have led to knowledge of the primary etiology of FAP. The protein product of the gene in question was identified, then the chromosomal location and point mutations in the gene were determined. Diagnosis of the disorder now can be made at the protein and DNA levels. Recombinant techniques for producing variant proteins have been established and a transgenic mouse that carries the mutated gene have been produced. Liver transplantation, a curative therapy for FAP, has been used for some patients. Procedures for the diagnosis of TTR-related FAP and the elucidation of TTR abnormality are summarized as follows: TTR-related FAP should be considered when biopsies of abdominal fat, the gingiva, stomach, rectum and sural nerves demonstrate amyloid deposits that are specifically stained by anti-TTR antiserum. Analysis of the TTR gene based on RFLP and single strand conformational polymorphism is useful for detecting the genetic mutations identified so far. Even when no known mutations have been detected, protein sequence analysis of serum TTR and nucleotide sequence analysis of the TTR gene have shown new variant TTRs. These advances in FAP research herald a new era in our investigation of the molecular biology of inherited neuropathy.

Three patients with familial amyloidotic polyneuropathy (FAP) type I underwent liver transplantation from heart-beating cadaveric donors. Since 2 patients underwent blood transfusion during the operation, variant transthyretin (TTR) levels in the plasma did not decrease time dependently. However, in 1 patient without blood transfusion variant TTR levels decreased in a time dependent manner and plasma half life of variant TTR was calculated to be 2.1 days. Total protein, normal, and variant TTR levels in cerebrospinal fluid (CSF) remained unchanged after liver transplantation.

A 28-year-old male patient with familial amyloidotic polyneuropathy (FAP) underwent a liver transplantation from a heart-beating cadaveric donor in Sweden. He had suffered from the disease for 2.5 years. It took 5.5 hours to carry out the operation without blood transfusion. After the liver transplantation, serum amyloidgenic variant transthyretin (TTR) levels became extremely low and diarrhea stopped after the 7th day. On day 13, the patient was discharged from the hospital and one month after the transplantation, his general condition remained quite good. This is the first case of a Japanese patient with congenital metabolic disorders as well as FAP to receive a liver transplantation from a heart-beating cadaveric donor.

We report a family with familial amyloid polyneuropathy (FAP), showing an early-onset and a fatal outcome before age 30. Transthyretin (TTR) gene analysis showed one point mutation (T-->C change) in the second base of codon 55, and the corresponding amino acid substitution of proline (Pro) for leucine (Leu) was confirmed at the protein level. This is the first FAP family of Taiwanese origin demonstrating a causative gene abnormality, and FAP with TTR-Pro55 was considered to be more serious compared with other forms of FAP.

We reported clinical pictures of three siblings homozygous for a transthyretin-Met30 (TTR-Met30) gene in a family with familial amyloidotic polyneuropathy (FAP) type I residing in Kanazawa city, and evaluated their clinical pictures with reference to those of other 10 cases previously reported. Ages at onset of two homozygous patients with FAP were 58 and 68 years. They showed sensory-dominant polyneuropathy and mild autonomic dysfunctions. One of them showed vitreous opacities and the other showed multifocal white sheaths along the retinal blood vessels and obstruction of the vessels. A morphometric study of the sural nerve in one patient showed a marked reduction in both myelinated and unmyelinated nerve fiber densities. The third subject was an asymptomatic carrier aged 59 years. The studies of our cases and those in the literature have shown the clinical features of homozygotes for the TTR-Met30 gene as follows: (1) all the homozygous subjects belong to families with incomplete penetrance of the disorder; (2) the clinical features common to 10 symptomatic homozygotes are late onset, mild autonomic dysfunctions, and high frequency of ocular amyloidosis; (3) there are three asymptomatic cases. In addition to TTR-Met30 abnormality, some unknown mechanisms that control its deposition into the tissues are presumed to be involved for the onset of FAP.