ClinVar Genomic variation as it relates to human health

Amyloid neuropathy resulting from a val30-to-met (V30M) mutation in transthyretin has been classified as familial amyloid polyneuropathy type I (FAP I; see AMYLD1, 105210). This mutation has been identified in many kindreds in Portugal and Japan, and also in American kindreds of Swedish, English, and Greek origin. It has also been identified in Turkey, Majorca, Brazil, France, and England (Benson, 2001). Both FAP I as a general clinical entity and FAP resulting from the V30M mutation have been referred to as hereditary amyloidosis Portuguese type, Portuguese-Swedish-Japanese type, or Andrade type. Portuguese Patients Andrade (1952) described kindreds with familial amyloidotic polyneuropathy (AMYLD1; 105210) from northern Portugal. Saraiva et al. (1984) demonstrated that the molecular basis of the disorder in these kindreds is a valine-to-methionine substitution at residue 30 of transthyretin (V30M). Saraiva (2001) reported that over 500 kindreds had been identified in Portugal, constituting the largest focus of FAP worldwide. In the Andrade type of hereditary amyloid neuropathy, observed predominantly in persons from the northern coastal provinces of Portugal and in their Brazilian relatives, neuropathic manifestations begin and predominate in the legs, leading to the popular designation of 'foot disease,' or 'doenca dos pezinhos' in Portugal (Lourenco, 1980). Onset is between age 20 and 30 years and death occurs 7 to 10 years later. Saraiva et al. (1983) found that plasma levels of TTR are reduced in patients with Portuguese amyloidosis, that levels of retinol-binding protein and vitamin A transport appear to be normal, that the abnormal TTR in the tissues of patients has a substitution of methionine for valine at position 30, and that the abnormal TTR is present in small amounts in the plasma of patients. A GUG-to-AUG change would account for the amino acid change. Tawara et al. (1983) found the methionine-for-valine substitution at position 30 in Japanese cases and Dwulet and Benson (1984) found it in a Swedish case (Benson and Cohen, 1977). Saraiva et al. (1986) found that the same val-to-met substitution at position 30 of transthyretin was present in plasma in asymptomatic persons from a Portuguese family with unusually late onset of clinical manifestations. The factors responsible for the delay in onset were not known. Swedish Patients A considerable number of cases of amyloid neuropathy were reported from northern Sweden (Andersson, 1970; Andersson and Hofer, 1974). In a Swedish form, later proven by molecular methods to be identical to the Portuguese type, Benson (1980) found evidence of relationship of the amyloid to serum prealbumin. Dwulet and Benson (1984) found substitution of methionine for valine at position 30 in the plasma prealbumin and associated amyloid fibril subunit protein from a Swedish patient with familial amyloid polyneuropathy. The abnormal protein accounted for one-third of plasma prealbumin and two-thirds of the amyloid fibrils. It seems well established that the clinical picture differs in persons from different genetic backgrounds. For example, the methionine-30 mutation in a U.S. family of English descent invariably produces cardiomyopathy, whereas among the Swedes the same mutation is rarely accompanied by cardiomyopathy and instead shows the kidneys as the main target, with patients dying of renal failure. Holmgren et al. (1988) found the same V30M mutation in TTR in 17 Swedish patients with FAP as seen in patients with FAP from Japan and Portugal and in FAP patients of Swedish extraction in the U.S. Curiously, however, the mean age of onset of FAP symptoms for the 17 Swedish patients was significantly later than for the patients from Japan, Portugal, and the U.S. The relatively high frequency of this form of amyloid polyneuropathy in Sweden is indicated by the study of Drugge et al. (1993). Since the first Swedish patients were reported in 1968, more than 230 cases had been diagnosed. The study of Drugge et al. (1993) included 239 patients: 109 patients were linked to 5 large pedigrees and 80 patients belonged to 30 smaller pedigrees or nuclear families. In the remaining 50 cases, no genealogic links were found. Differences in mean age of onset were found both between pedigrees and within pedigrees. They found a tendency for earlier age of onset among patients with a carrier mother than among those with a carrier father. Holmgren et al. (1994) stated that more than 350 patients with clinical manifestations of FAP had been diagnosed in northern Sweden, most of them originating from the areas around Skelleftea and Pitea. The mean age of onset was 56 years, much later than in patients from Japan and Portugal. To estimate the frequency of the met30 mutation in the counties of Vasterbotten and Norrbotten, sera from 1,276 persons aged 24 to 65 years, randomly sampled from a health program, were screened with a monoclonal antibody. In an ELISA test using this antibody, a positive reaction was seen in 19 persons. DNA analysis confirmed the presence of the met30 mutation and showed that 18 were heterozygous and 1 homozygous for the mutation. The mean TTR met30 carrier frequency in the area was 1.5%, ranging from 0.0 to 8.3% in 23 subpopulations. Holmgren et al. (1994) referred to 6 previously reported Swedish homozygotes for this mutation as well as to Turkish, Japanese, and Portuguese homozygotes. The clinical picture in homozygotes appeared to be the same as in heterozygotes. In the Swedish study, the penetrance of the met30 mutation showed considerable variation between families, and the overall diagnostic (predicted) value was as low as approximately 2%. Japanese Patients Araki et al. (1968) reported a kindred from southern Japan with many members affected. Kito et al. (1973) described the second largest concentration of this disorder at Ogawa Village in central Japan, a region notorious as a center of so-called leprosy for several hundred years. The location in Japan makes it unlikely that this was the Portuguese gene; some of the families of amyloid neuropathy seen elsewhere may, however, have a gene introduced by Portuguese. Although the cases of Kito et al. (1980) resembled the Andrade type clinically, immunoglobulin peculiarities suggested a difference. Kito et al. (1980) reported improvement with dimethyl sulfoxide (DMSO) treatment. Yoshioka et al. (1986) studied 25 FAP patients from 2 areas of Japan; 20 were from Ogawa village and 5 from Arao City. All of them were found to have the valine-to-methionine change at position 30. In addition, in 1 patient, Yoshioka et al. (1986) determined the complete nucleotide sequence of the prealbumin gene. In comparison with the normal, the patient's gene was found to be carrying 7 basepair substitutions. The substitution responsible for the val-to-met change was found in exon 2, as expected, and the others were polymorphic changes in introns. Ochiai et al. (1986) described a sporadic case of amyloid polyneuropathy in which the abnormal serum prealbumin typical of the Japanese form of FAP was not found in the serum and the characteristic DNA change was not found. Although it was suggested by the authors that this was a systemic form of senile amyloidosis, it seems more likely that this was a new mutation for a different type of prealbumin change. Furuya et al. (1987) studied a Japanese family in which patients with amyloid polyneuropathy also showed cerebellar ataxia and pyramidal tract signs. The authors found a substitution of methionine for valine at position 30 of TTR, the same mutation as that in the Andrade variety. A submicroscopic deletion with creation of a 'contiguous gene syndrome' was suggested as a possibility to explain the central nervous system (CNS) dysfunction, but close linkage of another mutation giving rise to spinocerebellar ataxia was considered a more likely explanation. Ikeda et al. (1996) detected expansion of a CAG repeat in the spinocerebellar ataxia-1 gene (ATXN1; 601556) in members with CNS dysfunction, some of whom also had a TTR mutation, demonstrating coexistence of FAP and SCA1 in this family. Oide et al. (2004) confirmed at the pathologic level that the disorder in this Japanese family, also known as Iiyama-type FAP, was caused by the incidental coexistence of 2 autosomal dominantly inherited neurologic disorders, amyloid polyneuropathy and spinocerebellar ataxia-1. Imaizumi (1989) pointed out that survival in this disorder in Japan appeared to have increased appreciably, with death occurring at a later age. He granted the possibility that improved recognition of cases may have been responsible. In 6 Japanese families with the val-to-met mutation, Yoshioka et al. (1989) identified 3 distinct haplotypes. Furthermore, they found that the val-to-met mutation can be explained by a C-to-T transition at a CpG dinucleotide mutation hotspot. This approach permitted them to examine the question of whether the mutation in Japan was introduced by Portuguese. They concluded that it was more likely that the familial amyloid polyneuropathy in Japanese families arose as an independent mutation. Misu et al. (1999) analyzed the clinicopathologic and genetic features of late-onset FAP TTR met30 patients in 35 families in Japan, particularly those unrelated to the endemic areas of Japan, and compared them with the cases of early-onset FAP TTR met30 patients in endemic areas. Onset was after 50 years of age in most with paresthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was very high (10.7:1). Asymptomatic carriers, predominantly female, were detected relatively late in life. A family history was evident in only 11 of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic sibs of familial cases showed a late age of onset, male preponderance, and clinical features similar to those of the probands. The geographic distribution of these late-onset, FAP TTR met30 cases was scattered throughout Japan. In 3 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 2 endemic foci of this disease in Japan: Arao City in Kumamoto Prefecture and Ogawa Village in Nagano Prefecture. While axonal degeneration was prominent in myelinated fibers, resulting in severe fiber loss, unmyelinated fibers were relatively preserved. Possible explanations for the differences were explored. Yoshioka et al. (2001) found homozygosity for the val30-to-met mutation in a 56-year-old Japanese man who had a motor-dominant sensorimotor polyneuropathy and unusual sural nerve pathologic findings. He lived in Nakajima, Ishikawa Prefecture, which is believed to be a nonendemic area for type I familial amyloidotic polyneuropathy. In addition to motor-dominant sensorimotor polyneuropathy, he had vitreous amyloidosis, erectile dysfunction, and urinary incontinence; however, he had neither orthostatic hypotension nor indolent diarrhea. Five members of his family were found to be heterozygous for the val30-to-met mutation but there was no family history of a similar neurologic disorder. The sural nerve biopsy showed focal edema and an amyloid deposit in the subperineural tissue, associated with moderate loss of myelinated and unmyelinated fibers. In the patient reported by Yoshioka et al. (2001), the first clinical symptom was vitreous amyloidosis, observed when he was 45 years old. This age of onset was younger than the average reported by Yoshinaga et al. (1994) in 3 sibs homozygous for this mutation in whom the mean age at onset was 57.3 years. The patient had distally predominant muscle atrophy and marked fasciculation. In general, patients homozygous for the val30-to-met mutation do not appear to suffer from more severe disease (Holmgren et al., 1992), and asymptomatic homozygous val30-to-met gene carriers have been described (Ikeda et al., 1992). Variability with this and other TTR mutations may be due to the fact that they merely set the stage for amyloid fibril formation. The factors interplay to determine the final consequence of the mutation. Koike et al. (2002) presented 82 Japanese families with early-onset FAP TTR met30 and 59 families with late onset. In families with late onset, neuropathy showed male predominance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. Families with early onset showed higher penetrance, concentration in 2 endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. Other Ethnic Groups Saraiva et al. (1986) found the met30 mutation in a Greek family with FAP; thus, it has been identified in Portuguese, Japanese, Swedish and Greek persons. Saraiva et al. (1988) showed that the change in TTR in 2 Italian kindreds with amyloid polyneuropathy was not a substitution of methionine at position 30. In a study of 13 European families, Holt et al. (1989) found that all 8 Cypriot families with familial amyloid polyneuropathy had the val30-to-met mutation as did 1 Greek family and 1 French family. Another French family and 1 British and 1 Italian family did not show the met30 mutation. Patients from 7 of the 10 kindreds with the met30 mutation were not known to have genetic disease before the study, which demonstrated the mutation in 16 of 43 clinically unaffected relatives; 2 of these were over 50 years of age. Diagnosis Studying Japanese cases of the val30-to-met mutation that had been found in Portuguese cases, Sasaki et al. (1984) demonstrated that direct gene diagnosis is possible. The nucleotide substitution results in new restriction sites when the restriction enzymes BalI and NsiI are used. Sasaki et al. (1985) described presymptomatic diagnosis of heterozygosity for familial amyloidotic polyneuropathy by recombinant DNA techniques. Nakazato et al. (1984) developed a radioimmunoassay based on a nonapeptide (positions 22-30) of the prealbumin variant. Five-microliter serum was treated with cyanogen bromide followed by trypsin before RIA. They found the variant and normal prealbumins to be present in a ratio of 1:1 in 8 biopsy-proven cases. High levels of variant were present regardless of duration of disease. Affected persons could be distinguished from unaffected relatives in the preclinical period. In Japanese cases of 30 valine-to-methionine amyloidosis, Nakazato et al. (1985) could diagnose the disorder in asymptomatic children by an immunologic method specific for the variant prealbumin. With a radioimmunoassay for the variant TTR (with methionine substituted for valine-30), Nakazato et al. (1986) demonstrated the presence of the gene in 9 symptom-free children of affected persons and its absence in 15 other children. Benson and Dwulet (1985) described a method for identifying affected persons with the methionine-30 defect in the preclinical stages. Whitehead et al. (1984) found that the val30-to-met mutation creates a unique NsiI restriction site in the prealbumin gene of these patients. Saraiva et al. (1985) documented the predictive value of finding the met30 mutation in the plasma. In 2 cases of familial amyloid polyneuropathy from different families and apparently of non-Portuguese ancestry, living in upstate New York, Koeppen et al. (1985) found immunologic indications that the amyloid fibrils were of transthyretin origin. Peptide fragments of fibronectin were also detected in the fibrils but no amyloid P protein. Maeda et al. (1986) found that the 2 types of mRNA, mutant and wildtype, are approximately equal in the liver of a heterozygote. Using PCR-amplified DNA, Almeida et al. (1990) performed prenatal diagnosis on 2 at-risk fetuses. The met30 mutation was detected in the amniotic fluid of a DNA-positive fetus whose father was a carrier. Morris et al. (1991) reported diagnosis of the val30-to-met mutation in a fetus on the basis of DNA studies of chorion villus samples; the parents chose to continue the pregnancy. Homozygosity Holmgren et al. (1988) presented molecular evidence for homozygosity for the met30 mutation of TTR in 2 Swedish sibs. The proband, a 56-year-old man, had typical manifestations; his older sister likewise appeared to be homozygous but had no evidence of FAP and no demonstrable amyloid deposits on skin biopsy. In 2 members of a Turkish family with FAP, Skare et al. (1990) found homozygosity for the val30-to-met mutation. The parents of these 2 were not consanguineous and there was no history of abnormality in the ancestors. Both sons of 1 of the men had 1 normal TTR gene and 1 met30 TTR gene. The 2 affected brothers had onset in their early fifties. Skare et al. (1990) cited observations in Sweden where about 3% of the population in 1 region are met30 heterozygotes and some of these heterozygotes have been demonstrated to live to age 80 without developing symptoms; 15 of 35 Swedish FAP patients had no family history of FAP. Holmgren et al. (1992) presented clinical data on 7 homozygotes, including 3 new cases. They were 59 to 74 years of age, and onset of symptoms had been at 52 to 65 years of age. Two of them were sibs, one of whom was still healthy at the age of 64 years. Three of the patients had no relatives with FAP. The progress of symptoms was the same as that seen among patients heterozygous for the val30-to-met mutation. Thus, like Huntington disease (143100), this disorder may be a complete dominant. In a 15-year follow-up of 9 Swedish FAP patients who were homozygous for the V30M mutation, Holmgren et al. (2005) found that all developed vitreous amyloidosis, which was the presenting feature in 4 patients. In 2 patients, vitreous amyloidosis was the only FAP manifestation. Although the mean age at onset was similar to that of 35 heterozygous V30M patients (approximately 55 years), the homozygous patients had a longer survival (17 and 12 years, respectively). Holmgren et al. (2005) concluded that homozygosity for the V30M mutation does not implicate a more severe phenotype for Swedish FAP patients. Origin of Mutation By analyzing the decay of haplotype sharing among 60 patients with the V30M mutation from Portugal, Sweden, and Brazil, Zaros et al. (2008) estimated the most recent common ancestor in Portuguese and Brazilian patients to have lived 750 and 650 years ago, respectively. The most recent common ancestor estimated for Swedish patients was 375 years ago. The findings supported the Portuguese origin of the mutation among Brazilians and confirmed the hypothesis that the mutation arose independently in Sweden. Clinical Manifestations Ducla-Soares et al. (1994) studied 47 individuals with amyloid polyneuropathy of the Portuguese type carrying the val30-to-met mutation in TTR and found that autonomic dysfunction was the first manifestation in a significant proportion of patients, frequently preceding standard clinical neurologic or electroneurodiagnostic abnormalities. In a patient with leptomeningeal amyloidosis characterized by fluctuating mental status, myelopathy, and enhanced, thickened meninges on MRI, Herrick et al. (1996) identified the V30M mutation. The authors noted the variable clinical manifestations of patients with this mutation. Ando et al. (1997) performed ocular examinations in 37 FAP type I patients (with the met30 mutation) from once to 12 times over a period of 1 to almost 13 years. On initial examination, abnormal conjunctival vessels were observed in 75.5%, pupillary abnormalities in 43.2%, keratoconjunctivitis sicca in 40.5%, glaucoma in 5.4%, and vitreous opacity in 5.4%. All ocular manifestations increased with the progression of FAP, and the incidence of abnormal conjunctival vessels reached 100% during follow-up. The abnormal conjunctival vessels were detected by slit-lamp biomicroscopic examination and could be helpful in the diagnosis of FAP (Ando et al., 1992). In a 62-year-old patient with cardiac and renal amyloidosis, whose predominant clinical feature was neuropathy, Lachmann et al. (2002) identified heterozygosity for the V30M mutation in the TTR gene. Kimura et al. (2003) reviewed the clinical features and surgical outcomes of the treatment of secondary glaucoma associated with TTR-related familial amyloidotic polyneuropathy. Secondary glaucoma was detected in 24% of 49 patients in the series, although the incidence of secondary glaucoma in patients with the val30-to-met mutation (17%) was lower than for the other FAP genotypes. Of 20 glaucomatous eyes, amyloid deposition on the pupil and anterior surface of the lens was found in 18 eyes. Amyloid deposition was detected prior to the onset of glaucoma in 11 of 20 eyes. Surgical treatment of glaucoma was required in 15 out of 20 eyes. In 9 out of 11 eyes treated with trabeculectomy, intraocular pressure was well controlled during the follow-up period. Kimura et al. (2003) concluded that glaucoma is not a rare condition in patients with FAP, especially since liver transplantation enables patients with FAP to live longer. Careful observation of amyloid deposition along the pupil allowed the prediction of glaucoma onset. In 37 patients with FAP, Koga et al. (2003) found vitreous opacities in 14 eyes of 9 patients. They found that the val30-to-met and tyr114-to-cys (176300.0011) mutations induced different types of vitreous opacities. However, vitreous surgery combined with phacoemulsification and implantation of an intraocular lens was a safe and useful treatment in these patients. The authors advised long-term follow-up of these patients postoperatively. Modification of Effect Anticipation, a phenomenon characterized by progressively earlier onset or increased severity of clinical symptoms in succeeding generations, was recognized in the V30M form of FAP in Portugal (Soares et al., 1999), Sweden (Drugge et al., 1993), and Japan (Tashima et al., 1995). Yamamoto et al. (1998) eliminated some of the possible sources of ascertainment biases described by Penrose (1948) in their study of the V30M form of FAP in Japanese kindreds, indicating that anticipation also occurs in this population. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Soares et al. (1999) used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the 10 possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the 10 trinucleotide repeats analyzed. The distribution of maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. Thus, no support was obtained for a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP. Munar-Ques et al. (1999) reported 2 pairs of proven monozygotic twins with the V30M mutation and reviewed data from 2 other pairs of presumed monozygotic twins who were discordant for age of onset and clinical features of FAP. By comparison with twin pairs with other mendelian disorders, Munar-Ques et al. (1999) concluded that in addition to modifier genes, there must be a significant contribution to the phenotype from nongenetic factors, either environmental or stochastic events. To analyze factors contributing to the phenotypic variability of FAP, Soares et al. (2004) characterized variations within the wildtype and mutant V30M TTR genes and their flanking sequences from 170 Portuguese and Swedish carriers of V30M. They identified 10 new polymorphisms in the TTR untranslated regions, 8 resulting from single-base substitutions and 2 arising from insertion/deletions in dinucleotide repeat sequences. The data suggested that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456). Soares et al. (2004) also identified the first instance of intragenic haplotype III associated with V30M FAP in the Portuguese population. (less)

Hypermetropia (present) , Abnormality of vision (present) , Abnormal oral cavity morphology (present) , Abnormality of the nose (present) , Atrophic scars (present) , Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal curvature of the vertebral column (present) , Abnormality of the bladder (present) , Abnormality of the male genitalia (present) , Abnormality of the urethra (present) , Abnormality of urine homeostasis (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Movement disorder (present) (less)