Demonstration of genetic mutation in most of the amyloid neuropathies with sporadic occurrence]

The Portuguese type of familial amyloid polyneuropathy (FAP type I) is a disabling autosomic dominant disorder, which is caused by a point mutation in the transthyretin (TTR) gene. Other TTR gene mutations have been reported recently in other FAP. In the absence of monoclonal gammopathy, sporadic amyloid neuropathies raise a problem for their pathogenicity. In this study, we have looked for TTR gene mutations in apparently sporadic cases of amyloid polyneuropathy by Southern's technique. All the patients were of french origin. None had monoclonal gammopathy. The mean age at onset was 64 (50 to 79 years). Most of the patients (9/1) were male. Five patients were found to carry FAP type 1 mutation, and 2 the tyr 77 (German) mutation. This study suggests that investigations in amyloid polyneuropathy with no overt family history should include systematic DNA analysis.     

Transthyretin Ala97Ser in Chinese-Taiwanese patients with familial amyloid polyneuropathy: genetic studies and phenotype expression

BACKGROUND: Transthyretin (TTR) variants of familial amyloid neuropathies (FAP) form a heterogenous group of autosomal dominantly inherited diseases. TTR gene analysis in several nationalities (Japanese, Portuguese, French, and British) has shown many distinguishing characteristics in the genotype-phenotype correlation. In Chinese, there are only a few reports of private TTR gene mutations belonging to single kindred. MATERIALS AND METHODS: We collected five patients with autosomal dominant inheritant sensorimotor polyneuropathy and tissue-proved amyloid deposition. The diagnosis of FAP was established on the mutation of the TTR gene detected by direct sequencing. Haplotype analysis was conducted in four of these patients. RESULTS AND CONCLUSIONS: These five FAP patients shared an identical missense mutation, Ala97Ser, in the TTR gene. This mutation presented with a constellation of late-onset polyneuropathy, preceding carpal tunnel syndrome, and outstanding autonomic dysfunction. Heart was the most frequently involved vital organ. Haplotype analysis hinted independent origins although the numbers were limited. Our study is the first case series gathering from the Chinese-Taiwanese population. We proposed a possible hot-spot mutation of the TTR gene, Ala97Ser, in this ethnic.     

Clinical variant of familial amyloid polyneuropathy

Hereditary amyloidosis with early and prominent peripheral nerve involvement is often designated familial amyloid polyneuropathy (FAP). The abnormality usually lies in the transthyretin (TTR) gene. We describe a patient with a tyr77 TTR gene mutation who presented with sensorimotor polyneuropathy but no other systemic symptoms of amyloidosis. This is one of a few documented cases of the tyr77 mutation in North America. The clinical and electrophysiologic features of this unusual cause of sensorimotor polyneuropathy are discussed.     

New transthyretin mutation V28M in a Portuguese kindred with amyloid polyneuropathy

A 62-year-old Portuguese man, with no history of familial amyloid polyneuropathy (FAP), and a 2(1/2)-year history of tingling in the toes and sexual dysfunction was found neurophysiologically to have a sensory-motor axonal polyneuropathy. Autonomic tests showed slight sympathetic and marked parasympathetic involvement. Heart, kidney, and eyes were normal. Single strand conformation polymorphism (SSCP) mutation analysis for the transthyretin (TTR) gene was performed. The SSCP pattern suggested the presence of a mutation in exon 2, but was different from the pattern observed for a control representing the most common TTR mutation associated with FAP, i.e., TTR V30M. DNA sequencing analysis revealed an A-to-G transition in the first base of codon 28 normally encoding a valine, giving rise to a methionine residue. The presence of this extra methionine was confirmed by peptide mapping and mass spectrometry analysis. Biopsy of nerve and skin of the propositus showed amyloid deposits that were immunoreactive for TTR. This is a new variant TTR related to late-onset amyloid neuropathy with autonomic dysfunction. This case confirms that TTR mutation screening should be considered in patients with a clinical disorder consistent with amyloid neuropathy even in the absence of a family history.     

Transthyretin gene mutations in British and French patients with amyloid neuropathy.

Five patients, two British and three French, with late onset amyloid neuropathy were found to have mutations of the transthyretin (TTR) gene associated with the Portuguese and German types of familial amyloid polyneuropathy. Familial amyloid polyneuropathy is rare in the United Kingdom and has not previously been defined at a molecular genetic level. None of the patients had a history of affected antecedents; the role of TTR gene analysis in diagnosing known or suspected amyloid neuropathy, regardless of family history or ethnic background, is emphasised.     

Liver transplantation and transthyretin amyloidosis

Liver transplantation as a specific treatment of transthyretin amyloidosis was first performed in 1990. The rationale for this treatment was that removal of the source (liver) of the amyloid precursor protein (mutated transthyretin) would stop progression of the disease. Indeed, after orthotopic liver transplantation (OLT), mutant transthyretin (TTR) is rapidly cleared from circulation. In the last 20 years, >2000 familial amyloidotic polyneuropathy (FAP) patients have received liver transplants. For these patients, prospective monitoring has shown prolongation of life compared with FAP patients who have not undergone liver transplantation. The most favorable results have been for FAP patients with the Val30Met TTR mutation. Less favorable results have been seen for patients with other TTR mutations where progression of amyloid tissue deposition has been documented as the result of amyloid fibril formation from normal (wild‐type) TTR. Although it is obvious that OLT has benefited many FAP patients, there remains a need for further therapies. Muscle Nerve, 2013     

Asymptomatic homozygous gene carrier in a family with type I familial amyloid polyneuropathy.

Type I familial amyloid polyneuropathy (FAP) is a molecular disorder with a mutation of the transthyretin (TTR) gene, and most patients previously examined were reported to be heterozygous for this mutant gene. In the present study a rapid and easy DNA diagnostic method employing the polymerase chain reaction revealed an asymptomatic homozygous TTR gene carrier in a Japanese family with type I FAP. The level of the variant TTR (methionine instead of valine at position 30) in his serum was much higher than that usually found in type I FAP patients. However, the histological findings of the biopsied rectum and abdominal fat tissues failed to demonstrate amyloid deposits, and the autonomic nerves from his rectal mucosa were normally preserved. Moreover, his 72-year-old mother (a TTR gene heterozygote) was supposed to start amyloid deposition in her late sixties. It is suggested that in addition to the mutant TTR gene some other factors control the development of the disease.     

Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus

BACKGROUND: Familial amyloid polyneuropathy (FAP) is distributed worldwide with several endemic foci including two major foci in Japan. OBJECTIVE: To elucidate a nationwide epidemiology of FAP in Japan. DESIGN, SETTING, AND PATIENTS: (i) We analyzed the data of FAP patients registered by the Ministry of Health, Labour, and Welfare, Japan, during 2003-2005. (ii) As Ishikawa prefecture was found to be a novel endemic focus, we examined 27 FAP patients in Ishikawa to characterize their clinical and genetic features in comparison with other endemic foci. RESULTS: (i) The prevalence of familial amyloidosis in Japan was estimated to be 0.87-1.1 per 1,000,000 persons. Nagano prefecture had the highest prevalence (11-15.5), followed by Kumamoto (10.1-10.3), and then Ishikawa (3.5-4.2). (ii) All the FAP patients in Ishikawa had transthyretin (TTR) type FAP; all the families had a TTR Val30Met mutation except one family with a Leu58Arg mutation. FAP with Val30Met mutation in Ishikawa was characterized by late onset, high penetrance, and moderate autonomic dysfunction. CONCLUSIONS: Ishikawa prefecture is the third endemic focus of FAP in Japan. FAP with TTR Val30Met mutation in Japan can be classified to (i) early-onset and endemic (Nagano and Kumamoto), (ii) late-onset and endemic (Ishikawa), and (iii) late-onset and non-endemic types.     

Familial amyloid polyneuropathy

Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP.     

Genetic expression of a transthyretin mutation in typical and late-onset Portuguese families with familial amyloidotic polyneuropathy

Two studies were conducted to explore questions concerning the expression of a mutant transthyretin (TTR) gene, found in Portuguese patients with familial amyloidotic polyneuropathy (FAP). In a kindred with typical onset of the disease, complete agreement between genotype and phenotype was seen for all carriers of the variant TTR with a methionine-for-valine substitution at position 30 (TTR[Met30]). In another study involving a FAP kindred with a late onset of clinical disease, TTR(Met30) was found in plasma in asymptomatic persons with ages above the usual age of onset of the disease. No evidence was obtained for the existence of a different mutation in TTR or for repression of the expression of the mutant TTR gene in this kindred. The factors responsible for the delay in the development of clinical manifestations in late-onset patients are not known and warrant further study.     

Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity

Familial amyloid polyneuropathy (FAP) was once considered a disease peculiar to endemic areas, but it is now recognized not to be a rare disease among hereditary neuropathic disorders in Japan. FAP in Japan, the majority of which is caused by transthyretin (TTR)-related amyloid deposition, shows a wide spectrum of clinical pictures. This variability can be explained on the basis of the many causative gene mutations of TTR, but even in the same TTR type of FAP, the clinical phenotypes seem to vary in different kindreds or individuals. Especially in the case of the Val30Met TTR type, the sex ratio and the age at onset are considerably different between patients in endemic foci and those in nonendemic areas. It is also noteworthy that serious cardiac amyloidosis is commonly seen in patients with FAP of the non-Val30Met TTR type. In addition to TTR gene mutation, unknown factors may play an important role in the development of FAP. At present, liver transplantation is the only life-saving treatment, but this therapy is always associated with great stress for the patient and the donor, particularly in living-related transplantation. Less invasive treatments for this disease are required.     

Hereditary and acquired amyloid neuropathies

Amyloid neuropathies occur in a context of hereditary (FAP) or acquired amyloidosis. They present usually as severe and progressive polyneuropathy and carry a poor prognosis. Most FAP are associated with endoneurial deposits of variant transthyretin (TTR) with substitution of one aminoacid and are secondary to a point mutation of the TTR gene. Portugal is the main endemic area of TTR-FAP, secondary to point mutation of exon 2. However, around the world, 50 other TTR gene mutations have been recently reported, each one in few families. Genetic studies are useful for diagnosis of FAP in patients with a positive family history and for identification of the cause of seemingly sporadic cases. TTR gene analysis is also useful for genetic counselling including antenatal diagnosis in variants with early onset. Gelsolin-FAP are the second variety and present as a benign cranial and sensory polyneuropathy and affect essentially Finnish patients. Acquired amyloid neuropathy concerns only immunoglobulin light chain amyloidosis (AL) and are frequently associated with renal manifestations and monoclonal protein in serum or urine. Specific treatment of amyloid polyneuropathy varies with the variety of amyloidosis including liver transplantation in TTR-FAP, at the onset of the disease or chemotherapy for immunoglobulin light chain amyloidosis. Received: 8 March 2001 / Accepted: 12 March 2001     

Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family

Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin (TTR) gene. TTR amyloidosis is linked to a vast number of mutations with varying phenotype and tissue distribution. Several Chinese kindred with FAP type 1 have been reported in Beijing, Hong Kong, Taiwan, and elsewhere. Here, histopathological features and TTR gene polymorphism were analyzed by using autopsy and blood specimens from a Chinese proband of a family with FAP. This proband is a 34-year old man with FAP type 1 who developed motor, sensory and autonomic impairments with neuropathy, gastrointestinal dysfunction, and orthostatic hypotension. Genetic findings of TTR revealed a T to C transition in codon 30 causing the mutation TTR Ala30. This patient died of respiratory and circulatory failure 7 years after onset. Autopsy showed heavy amyloid deposition in the peripheral nerves, liver, testes, thyroid, pancreas and muscles. There was moderate deposition in the heart, kidneys, bladder, gastrointestinal tract, tongue, lung, blood vessels, and gall bladder. The spleen showed only slight deposition, and none was observed in the central nervous system. TTR amyloidosis was confirmed by immunochemical staining with a specific TTR antibody. These results indicate that the distribution of amyloid deposition, (i.e., heavy in the liver, testes and slight in the spleen), is a characteristic feature and reflects the severity of FAP with TTR Val30Ala.     

Reduced Ia-afferent-mediated Hoffman reflex in streptozotocin-induced diabetic rats

Familial amyloidotic polyneuropathy (FAP) is a late-onset inherited disease characterized by the deposition of amyloid fibrils. FAP is associated with mutations on the transthyretin (TTR) gene. A monoclonal antibody, MAb 39-44, reacting with high molecular weight aggregates of TTR but not with tetrameric TTR has recently been generated and characterized. This antibody recognizes a cryptic epitope that is expressed in isolated recombinant amyloidogenic mutants and in ex vivo amyloid. In the present work we show that this amyloid-specific antibody specifically recognizes in a direct enzyme-linked immunoassay (ELISA) plasma TTR from carriers of various mutations associated with FAP, both in asymptomatic individuals and in patients. In contrast, it does not react with plasma TTR from healthy individuals or that from carriers of nonpathogenic mutations. Using the ELISA developed in this study we identified three different TTR mutations in Portuguese patients with neuropathy of unknown cause, later shown to have amyloid tissue deposition. This antibody recognizes conformations that express cryptic epitopes shared by amyloidogenic TTR variants associated with FAP, not present among nonpathogenic TTR molecules. This antibody will contribute to further identify and characterize intermediates of the amyloidogenic cascade. In addition, it will also be useful for screening amyloidogenic TTR mutations in patients with neuropathy of unknown cause, prior to precise molecular diagnosis using protein and/or DNA analysis.     

Amyloid neuropathy with transthyretin mutations: overview and unique Ala97Ser in Taiwan

Familial amyloid polyneuropathy (FAP) is a major etiology in differential diagnosis of symmetric axonalform polyneuropathy, but had been considered an unusual disease in Taiwan. We have reviewed the pathology of nerve biopsies and sequenced the entire 4 exons of transthyretin (TTR), the most common genetic mutation of FAP. Our studies indicated that the mutation of TTR at Ala97Ser (TTR Ala97Ser) was a new mutation only reported in ethnic Taiwanese, and this mutation accounted for the most frequent etiology of adult-onset pan-modality (involving motor, sensory, and autonomic components of peripheral nerves) polyneuropathy with the pathology of axonal degeneration type. Over the past 10 years, there have been advancements in the management of FAP due to TTR mutations: (1) symptomatic treatments of dyaautonomia, especially orthostatic hypotension, and (2) therapies with liver transplantation and small molecules to reduce or stabilize TTR.     

Amyloidogenic transthyretin Val30Met homozygote showing unusually early-onset familial amyloid polyneuropathy

We report an amyloidogenic transthyretin (ATTR) Val30Met homozygote showing extremely early-onset, severe familial amyloid polyneuropathy (FAP). Although homozygotes have been reported to show late-onset and mild clinical manifestations, detailed analyses of the present and previously reported families suggest that homozygotes have a slightly more severe clinical course than heterozygotes. This is the youngest reported patient with ATTR Val30Met FAP, a condition believed to be attributable to homozygosity of this mutation. The clinical severity is consistent with TTR protein instability.     

Familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP), a fatal disorder inherited in an autosomal dominant fashion, is characterized by systemic accumulation of polymerized transthyretin (TTR) in the peripheral nerves and systemic organs. Polyneuropathy is often a major manifestation of FAP. Although FAP was considered to be an endemic disorder, the advanced biochemical and molecular genetic analyses have shown worldwide occurrence. More than 100 different points of single or double mutations, or a deletion in the TTR gene, have been reported, and several different phenotypes of FAP have been documented, even for the same mutation in the TTR gene. Liver transplantation, which stops the production of amyloidogenic TTR in blood and replaces it with normal TTR, has been considered as an acceptable treatment for FAP. However, continuous amyloid deposition can occur from wild-type (normal) TTR in some patients. Currently, research an the inhibition of amyloid deposition by small organic molecules that are hypothesized to affect the fibril-forming ability of TTR is underway.     

Clinical and histopathological features of progressive-type familial amyloidotic polyneuropathy with TTR Lys54

The purpose of this study was to evaluate the clinical and pathological features in patients with progressive-type familial amyloidotic polyneuropathy (FAP) using autopsy and biopsy specimens. A proband is a 33-year-old man with FAP type I who developed motor, sensory and autonomic impairments with neuropathy, heart failure, and anorexia. Genetic findings of transthyretin (TTR) revealed G to A transition in codon 54 causing a rare mutation of TTR Lys54. He died of pneumonia and severe cardiac failure 4 years after onset. Autopsy showed heavy amyloid deposition in the heart, peripheral nerves, thyroid, skin, fat tissue, prostate and testis, moderate in the sympathetic nerve trunk, vagal nerve, celiac plexus, pelvic plexus, bladder, gastrointestinal tract, tongue, pancreas, lung, pituitary, blood vessel, gall bladder, adrenals and muscles, and free in the central nervous system, liver, kidney and spleen. Sural nerve biopsy in a sibling confirmed TTR amyloidosis immunohistochemically. Electronmicroscopic findings of amyloid fibrils were similar to that of FAP Met30. Immunoelectronmicroscopic findings indicated the relationship between amyloid fibrils or non-fibrillar structure and collagen fibers. The distribution of amyloid deposition, heavy in the heart and lacking in the kidney, is a characteristic feature and reflected severity of FAP with TTR Lys54.     

家族性淀粉样多发性神经病一家系病理及基因点突变

目的　对我国首次报道的家族性淀粉样多发性神经病（FAP）家系进行各项研究,以期发现其真正类型。方法　对我国东北某地一家系67人共16例多发性周围神经病患者进行详尽的临床检查,对其中2例患者进行腓肠神经病理检查,和转甲蛋白(TTR)基因的聚合酶链反应(PCR)基因扩增及直接法测序分析。结果　临床上该家系所有患者均以植物神经症状,如排尿障碍、胃肠道症状、阳痿为首发症状。体格检查提示为严重的感觉运动神经病、体位性低血压和消瘦。病理学检查发现2例患者均有刚果红染色阳性的大量淀粉样物沉积于神经束间质及神经内膜中。免疫组化证实淀粉样物与TTR有关。PCR扩增产物酶解及直接法测序,确定异常TTR为基因点突变所致,突变位置为日本及葡萄牙型FAP常见的第二个外显子第30个密码子G由A取代。结论　本研究结果证实,该家系为Met30FAP,填补了我国对该疾病研究的空白。     

Systemic but asymptomatic transthyretin amyloidosis 8 years after domino liver transplantation

As familial amyloid polyneuropathy (FAP) is an adult-onset disease, a long period is expected between domino liver transplantation (DLT) and the occurrence of amyloidosis in recipients of a FAP liver. However, as time passes, and increased numbers of patients have undergone DLT, patients with symptoms suggesting amyloidosis have been reported. The authors describe, for the first time, pathological findings in an autopsy case of a recipient of a FAP liver. A male patient with primary sclerosing cholangitis received a liver graft from a FAP patient with the transthyretin (TTR) Tyr114Cys mutation when he was 30 years old. Although a recurrence of primary sclerosing cholangitis was detected at age 34, he had no symptoms indicating amyloidosis. He died from Burkitt's lymphoma at 38 years of age. TTR immunoreactive amyloid was found in various organs including the heart, lung, gastrointestinal tract, pancreas, spleen, reproductive system and skeletal muscles. In the nervous system, TTR immunoreactive amyloid deposition was obvious in the sympathetic ganglia and the median nerve within the carpal tunnel, while loss of neurons or nerve fibres was not apparent. This case allows for the characterisation of amyloid deposition during the asymptomatic stage of FAP. Widespread amyloid deposition may occur before tissue damage in this disease.