Alternative titles; symbols
HGNC Approved Gene Symbol: TTR
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38): 18:31,591,877-31,598,821 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | [Dystransthyretinemic hyperthyroxinemia] | 145680 | Autosomal dominant | 3 |
| Amyloidosis, hereditary, transthyretin-related | 105210 | Autosomal dominant | 3 | |
| Carpal tunnel syndrome, familial | 115430 | Autosomal dominant | 3 |
Transthyretin (TTR) is an evolutionarily conserved serum and cerebrospinal fluid (CSF) protein that transports holo-retinol-binding protein (RBP; 180250) and thyroxine (T4). It is a homotetrameric protein synthesized mainly in liver, choroid plexus, retinal pigment epithelium, and pancreas. Mutant and wildtype TTR give rise to various forms of amyloid deposition (amyloidosis), originally defined pathologically by the formation and aggregation of misfolded proteins which result in extracellular deposits that impair organ function. The clinical syndromes associated with TTR aggregation are familial amyloid polyneuropathy (FAP) and cardiomyopathy (FAC), in which mutant TTR protein aggregates in peripheral and autonomic nerves and heart, respectively; and senile systemic amyloidosis (SSA), a late-onset disorder in which wildtype protein deposits primarily in heart, but also in gut and carpal tunnel (summary by Buxbaum and Reixach, 2009).
This normal plasma protein was originally called 'prealbumin' or 'thyroxine-binding prealbumin' because it migrates ahead of albumin on standard protein electrophoresis. However, it has no structural relationship to albumin. Use of the term 'transthyretin' is recommended to avoid possible confusion with proalbumin (103600) and with other 'prealbumins.' The name transthyretin refers to the transport properties of the protein, which binds both thyroxine and retinol-binding protein (summary by Benson, 2001).
Using direct amino acid sequence analysis, Kanda et al. (1974) determined the complete sequence of plasma thyroxine-binding prealbumin (transthyretin).
Mita et al. (1984) isolated transthyretin-specific cDNA clones from an adult human liver cDNA library. The mature protein consists of 127 residues after cleavage of a 20-amino acid signal peptide. Results were in agreement with those of Kanda et al. (1974).
Whitehead et al. (1984) isolated transthyretin-specific cDNA clones from an adult human liver library and found that the nucleotide sequence was identical to that reported by Mita et al. (1984). Wallace et al. (1985) likewise isolated a cDNA clone.
The transthyretin molecule consists of a tetramer of identical 127-amino acid subunits. Transthyretin is a plasma transport protein for thyroxine (T4) and for retinol (vitamin A), through the association with retinol-binding protein (see RBP4, 180250) (summary by Saraiva, 2001).
Episkopou et al. (1993) demonstrated that the TTR protein maintains normal levels of retinol, retinol-binding protein, and thyroid hormone in the circulating plasma. Using gene targeting techniques, they generated a null mutation at the mouse Ttr locus. Although the resultant mutant animals were phenotypically normal, viable and fertile, they had significantly depressed levels of these serum metabolites.
Shirahama et al. (1982) reported that prealbumin is a constituent common to the neuritic plaques, neurofibrillary tangles, and microangiopathic lesions of senile cerebral amyloid. TTR represents a disproportionate fraction (25%) of CSF protein, prompting the suggestion that it is either selectively transported across the blood-CSF barrier or synthesized de novo within the central nervous system (CNS). Herbert et al. (1986) demonstrated that the latter is the case and that the epithelial cells of the choroid plexus are the site of synthesis in both rats and humans. It is curious that in amyloid polyneuropathy, amyloid deposits do not occur in the CNS, with the exception of the blood vessels. Within the CNS, TTR is the only known protein synthesized solely by the choroid plexus.
As reviewed by Ray and Lansbury (2004), TTR encodes a tetrameric protein that is responsible for carrying thyroxine (T4) in plasma and CSF. Two equivalents of T4 bind in symmetry-related sites in the central cavity of TTR. T4 binding stabilizes the TTR tetramer and slows the rate of tetramer dissociation, which is the rate-determining step of in vitro TTR fibril formation.
Whitehead et al. (1984) and Wallace et al. (1985) independently assigned the PALB gene to chromosome 18 by analysis of somatic cell hybrid panels.
Using a human genomic probe in the study of mouse-human somatic cell hybrids and by in situ hybridization, Sparkes et al. (1987) assigned the human PALB gene to chromosome region 18q11.2-q12.1. Jinno et al. (1986) performed Southern analyses in various chromosome 18 abnormalities and, by gene dosage effect, assigned the TTR gene to 18p11.1-q12.3, most likely to 18cen-q12.3.
Using molecular probes in the analysis of an interspecific backcross between C57BL/6J and Mus spretus, Justice et al. (1992) demonstrated that the prealbumin gene is located on mouse chromosome 18.
Crystal Structure
Eneqvist et al. (2000) found that the structure of the highly amyloidogenic TTR triple mutant gly53 to ser/glu54 to asp/leu55 to ser determined at 2.3-angstrom resolution revealed a novel conformation, the beta slip. A 3-residue shift in beta strand D placed leu58 at the position normally occupied by leu55, now mutated to ser. The beta slip was best defined in 2 of the 4 monomers, where it made new protein-protein interactions to an area normally involved in complex formation with retinol-binding protein. This interaction created unique packing arrangements, where 2 protein helices combined to form a double helix in agreement with fiber diffraction and electron microscopy data. Based on these findings, a novel model for transthyretin amyloid formation was presented.
Dystransthyretinemic Hyperthyroxinemia
Substitutions at codon 109 of transthyretin (A109T, 176300.0015; A109V, 176300.0038) have been identified in individuals with dystransthyretinemic hyperthyroxinemia (DTTRH; 145680), and lead to an increase in the affinity for thyroxine (Saraiva, 2001).
Amyloidosis
Many distinct forms of amyloidosis (105210) have been related to different point mutations in the 127-amino acid TTR. In most of these, inheritance is autosomal dominant; homozygosity has been reported in the val30-to-met (V30M; 176300.0001) and val122-to-ile (V122I; 176300.0009) mutations.
Refetoff et al. (1986) studied T4 binding by 4 prealbumin variants associated with amyloid polyneuropathy. They found that the TBPAs from subjects with types 1 and 2 familial amyloid polyneuropathy (shown to have substitutions at amino acids 30 and 84, respectively) have a relatively low affinity for T4. The authors felt, however, that hypothyroidism in these patients is probably due to the fortuitous occurrence of Hashimoto thyroiditis and/or the partial destruction of the thyroid gland by amyloid deposits.
Benson (1991) reviewed the hereditary amyloidoses and listed 10 TTR mutations associated with amyloidosis together with restriction enzymes which are useful for DNA diagnosis in 8 of the cases. In the other 2 cases, allele-specific PCR must be used.
Ii and Sommer (1993) suggested that founder effect can be rejected as the cause of the high frequency of the val30-to-met mutation (V30M; 176300.0001) in familial amyloid polyneuropathy (FAP). In a sample of 11 unrelated North American patients, they found this mutation in 6. Since relatives were not available, they used the PCR-based method called double-PASA (Sarkar and Sommer, 1991) to determine the haplotypes. In the 6 patients with the V30M mutation, 4 different haplotypes were observed. Ii and Sommer (1993) speculated on why a late-onset disorder such as this, which should interfere little with reproduction, should lack evidence of founder effect. They suggested that the mutation rate for V30M is probably the highest among the FAP TTR mutations because it is the only one that occurs in a CpG dinucleotide. Reilly et al. (1995) also found haplotype evidence for multiple founders in a sampling of European patients with familial amyloid polyneuropathy.
Saraiva (1995) tabulated more than 40 different mutations in the TTR gene associated with amyloid deposition. She pointed to the problem of correlating the clinical heterogeneity with the genetic heterogeneity. Saraiva (1995) observed that most of the mutations are neuropathic, but only some give rise to cardiomyopathy or to vitreous opacities. Saraiva (2001) stated that over 80 different disease-causing mutations in the TTR gene had been reported. Only a small proportion of TTR mutations are apparently nonamyloidogenic. Among these are mutations responsible for hyperthyroxinemia. Compound heterozygous individuals have been described; noteworthy is the clinically protected effect exerted by a nonpathogenic mutation over a pathogenic mutation, which in the usual heterozygous state would result in amyloid deposition.
In 13 patients with systemic amyloidosis in whom a diagnosis of the acquired monoclonal immunoglobulin light-chain type (AL; see 254500) had been made on the basis of clinical and laboratory findings and by the absence of a family history, Lachmann et al. (2002) found heterozygosity for point mutations in the TTR gene (see, e.g., 176300.0001, 176300.0004, and 176300.0009); 3 of the mutations represented previously undescribed variants. All 13 of the patients presented with cardiac amyloidosis and variable degrees of autonomic and peripheral neuropathy. Scintigraphy with radioiodine-labeled serum amyloid P component (104770), a technique for quantitatively imaging amyloid deposits in vivo in cases of AL amyloidosis, revealed no amyloid deposits in the liver or bone in these cases; such deposits had not been noted in transthyretin-associated amyloidosis.
Ikeda et al. (2002) reviewed the diagnosis, epidemiology, clinical and genetic variability, and treatment options of familial amyloid polyneuropathy in Japan. The authors detailed the clinical findings associated with the common V30M mutation as well as the findings associated with other known mutations and concluded that there is wide variability in phenotype, even among those with the same genotype.
Hammarstrom et al. (2003) described a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation thr119 to met (176300.0018), which ameliorates familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.
Soares et al. (2005) analyzed alleles of genes involved in either TTR function or amyloid deposits, including APCS (104770) and RBP4 (180250), for possible association with age of disease onset and/or susceptibility in Portuguese FAP patients with the V30M mutation (176300.0001) and unrelated controls. Estimates of genetic distance indicated that controls and the classic-onset group were furthest apart, whereas the late-onset group appeared to differ from both. The data also indicated that genetic interactions among the multiple loci evaluated, rather than single-locus effects, were more likely to determine differences in the age of disease onset. Multifactor dimensionality reduction indicated that the best genetic model for the classic-onset group versus controls involved the APCS gene, whereas for late-onset cases, 1 APCS variant (APCSv1) and 2 RBP variants (RBPv1 and RBPv2) were involved. Soares et al. (2005) concluded that although the V30M mutation was required for the disease in Portuguese patients, different genetic factors may govern the age of onset, as well as the occurrence of anticipation.
The D18G (176300.0047) and A25T (176300.0051) variants of TTR are associated with the leptomeningeal form of amyloidosis (see 105210), specifically targeting the central nervous system with minimal or absent visceral involvement. Sekijima et al. (2005) demonstrated that a choroid plexus cell line was more permissive in its ability to secrete the highly destabilized A25T TTR variant compared to BHK or MMH cells and that in BHK cells secretion of A25T and D18G was sensitive to T4 (metabolite) chaperoning. Secretion by choroid plexus cells may increase the extracellular concentration and rate of A25T TTR amyloidogenesis in the CNS. In contrast, murine hepatic cells secreted A25T TTR at significantly lower levels, perhaps due to lower levels of T4, resulting in lack of visceral involvement. The most highly destabilized TTR variants, such as D18G, were retained in the endoplasmic reticulum (ER) and likely targeted for ER-associated degradation (ERAD), leading to low secretion levels. More stable variants like L55P (105210.0022) were not targeted for ERAD, and can be secreted at near-wildtype levels. Sekijima et al. (2005) suggested that tissue-specific differences determine which pathogenic variants are targeted for ERAD and which are secreted.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including TTR, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
The prealbumins, serum proteins which migrate faster than albumin in acidic starch gels, include alpha-1-antitrypsin (107400), thyroxine-binding prealbumin, and orosomucoid, an alpha-1-acid glycoprotein (138600). Polymorphism of prealbumin is known in the mouse and pig (reviewed by Lush, 1966) and in monkeys (Rall, 1977). Fagerhol and Braend (1965, 1966) demonstrated polymorphism of serum prealbumin by starch gel electrophoresis and presented family data supporting genetic control by 3 codominant alleles. This polymorphism was later shown by Fagerhol and Laurell (1967) to be identical to alpha-1-antitrypsin.
Using isotopic in situ hybridization, Qiu et al. (1992) mapped the Ttr gene to mouse chromosome 4. The mouse cDNA probe used was that of Wakasugi et al. (1985).
Neuropathy resulting from a val30-to-met (V30M) mutation in transthyretin has been classified as familial amyloid polyneuropathy type I (FAP I; see 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 (FAP; 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.
The amyloid polyneuropathy (105210) in a Jewish patient was said by Pras et al. (1981, 1983) to have substitution of glycine for threonine at position 49 and by Nakazato et al. (1984) to have substitution of isoleucine for phenylalanine at position 33 (F33I). According to Benson (1988), the assignment of the change at position 33 is well established. Benson (2001) noted that the F33I mutation was verified by DNA sequence studies, which failed to show any mutation at codon 49. Severe gastrointestinal involvement was present (Benson, 1991). This variant was referred to as familial amyloid polyneuropathy, Jewish type.
Substitution of histidine for leucine at position 58 (A-to-T change) of the TTR gene (L58H) results in the amyloid polyneuropathy (105210) observed in the large Maryland kindred of German extraction studied by Mahloudji et al. (1969) and thought by them on clinical grounds alone to have the same disorder as that reported by Rukavina et al. (1956); see 176300.0006. This was the first amyloidosis-producing mutation in TTR to be identified by direct sequencing after amplification of the gene by PCR. Nichols et al. (1989) demonstrated a T-to-A substitution at the second base of the codon for leucine 58 causing a change to histidine. Since the mutation did not result in a change in the restriction pattern of the prealbumin gene, Nichols et al. (1989) developed a new method for direct detection of single-base changes in genomic DNA using PCR and an allele-specific oligonucleotide primer. Mendell et al. (1990) diagnosed the defect in the Maryland/German type by allele-specific enzymatic amplification of genomic DNA to demonstrate the his58 mutation.
Hund et al. (2001) noted that the Maryland/German type of familial amyloid polyneuropathy (described by Mahloudji et al. (1969) and resulting from a L58H substitution) had been classified as familial amyloid polyneuropathy type II (FAP II). FAP II is characterized by a course of disease with polyneuropathy beginning at the hands and frequent carpal tunnel syndrome operations. Benson (2001) noted that in FAP resulting from the L58H mutation, death is frequently caused by cardiomyopathy. The Maryland/German type is distinguished from the Indiana/Swiss type (176300.0006) by a lack of vitreous opacities.
Although they also lived in the Maryland area, the family originally reported by Shulman and Bartter (1956), Kaufman (1958), Kaufman and Thomas (1959), Wong and McFarlin (1967), and Dalakas and Engel (1981) was thought to have had a different mutation (Jacobson et al., 1987; Buxbaum, 1987). The disorder in this kindred was unusually severe with relatively early death and extensive involvement of the ocular vitreous. Jacobson et al. (1992) indeed demonstrated a distinct mutation: a leu55-to-pro substitution in the TTR gene (176300.0022).
Wallace et al. (1986) found substitution of alanine for threonine at position 60 of transthyretin (T60A) in an Irish kindred with FAP (105210) from the Appalachian region of the United States. As in the Indiana form (176300.0006), major deposits of amyloid occurred in the heart, but otherwise the disorder appeared 'to have a unique disease progression.' Benson et al. (1987) gave the clinical description of the Appalachian kindred with hereditary amyloidosis and late-onset cardiomyopathy. The family was partially of Irish ancestry (Benson, 1988). The proband of the family was 65 years old when he died of cardiomyopathy. For several years he had symptoms of peripheral neuropathy, including chronic diarrhea, bladder dysfunction, and sexual impotence. Bladder and prostatic biopsies were positive for amyloid. During the last few months of his life, he developed severe congestive heart failure and heart block that required a pacemaker. There were at least 22 affected individuals in the family. Although in general the late onset of the ailment placed it in type II amyloid polyneuropathy, the authors believed that the lack of eye involvement set the entity apart from the Indiana form of the disease. They pointed out the hazard that patients with this disorder will be misdiagnosed as having the immunoglobulin type of systemic amyloidosis, an error that might lead to chemotherapy and unjustified risk to the patient.
Amyloidosis resulting from this variant has been referred to as the Appalachian type (Wallace et al., 1988; Benson, 2001).
Koeppen et al. (1990) restudied the family reported by Koeppen et al. (1985). They updated and revised the pedigree and determined that the underlying mutation was thr60-to-ala, the Appalachian mutation.
Staunton et al. (1987) described transthyretin-derived amyloid polyneuropathy of a hereditary nature in County Donegal, Ireland. The clinical picture was most consistent with that of the Portuguese type, although the age of onset was somewhat older. In fact, however, as reported by Staunton et al. (1991), the mutation proved to be the thr60-to-ala Appalachian mutation which had been found in a family of Irish ancestry living in the Appalachian region of the U.S.
In 5 patients with cardiac amyloidosis, 3 of whom also had renal and or splenic involvement, Lachmann et al. (2002) identified heterozygosity for the T60A mutation in the TTR gene. The predominant clinical feature in these patients was cardiomyopathy and/or neuropathy.
Wallace et al. (1986) described a prealbumin variant associated with autosomal dominant amyloidosis (105210) in an American patient of German ancestry living in Wisconsin. This involved substitution of tyrosine for serine at position 77 (S77Y) resulting from a C-to-A mutation in that codon. Using the restriction enzyme SspI and a specifically tailored genomic prealbumin oligonucleotide probe, Wallace et al. (1986, 1988) detected a single-nucleotide change in codon 77 of the variant prealbumin gene. Satier et al. (1990) found the same mutation in a family from Picardy, which is located in northern France, east of Normandy. Clinical onset was in the fifth and sixth decades with decreased sensation in the lower limbs followed by involvement of the arms. Motor changes appeared later. Cardiac involvement with congestive heart failure and arrhythmias was the cause of death. They stated that the American family of German origin was living in Illinois and that another American family with French Huguenot ancestors had been found with the tyr77 mutation.
Amyloidosis resulting from this variant has been referred to as the Illinois/German type (Wallace et al., 1988).
After the met30 mutation (176300.0001), the tyr77 mutation is the most prevalent. Blanco-Jerez et al. (1998) presented clinical and pathologic features of an extensive Spanish family with the tyr77 mutation of TTR. Twelve individuals over 4 generations were affected. They found that an initial and sometimes prolonged carpal tunnel syndrome, beginning between the sixth and seventh decades, characterized the tyr77 mutation. In most cases, this evolved to generalized peripheral nerve involvement, restrictive cardiomyopathy, and intestinal malabsorption. Blanco-Jerez et al. (1998) suggested that, although survival with the tyr77 mutation is usually high, there are progressive cases that should be candidates for liver transplant, before severe impairment develops.
Substitution of serine for isoleucine at position 84 of transthyretin (I84S) is found (Wallace et al., 1986) in the Indiana Swiss family with FAP (105210) originally reported by Rukavina et al. (1956). Amyloidosis resulting from this variant has been referred to as the Indiana/Swiss type (Wallace et al., 1988; Benson, 2001).
Neuropathic manifestations begin and predominate in the upper limbs. Carpal tunnel syndrome (pain, numbness and weakness referable to the median nerve and atrophy of the abductor pollicis brevis muscle) is the characteristic feature and is relieved by decompression of the carpal tunnel. Onset is usually in the 40s and progression to generalized neuropathy is slow so that survival for 20 years or more after onset is the rule. The disease is milder in females. Amyloidosis with this course of disease has been designated FAP type II (Hund et al., 2001). Vitreous opacities and visceral manifestations are less conspicuous than in amyloidosis I (see 176300.0001). The Indiana type was observed by Rukavina et al. (1956) in many members of a religious sect of Swiss origin living in Indiana. Mahloudji et al. (1969) observed what they thought to be the same disorder in an equally large number of persons of German extraction living in Frederick and Washington counties of Maryland. This proved to be a different mutation; see 176300.0003.
In the kindred studied by Rukavina et al. (1956), Benson and Dwulet (1983) found that prealbumin and retinol-binding protein were low in 9 patients. Offspring of affected persons fell into 2 groups: one with prealbumin and RBP levels like those in the normal parent and the other with prealbumin and RBP levels like those in affected persons. Thus, serum abnormalities may be present long before development of clinical disease.
Benson and Dwulet (1985) and Dwulet and Benson (1986) found a prealbumin with substitution of serine for isoleucine at position 84 in the original Indiana kindred with FAP type II. The change from isoleucine to serine results from substitution of guanine for thymine as the second nucleotide in codon 84. Substitution at 84 reduces affinity of prealbumin for RBP. The low serum levels may be explained thereby, because RBP unbound to PALB is quickly cleared by the kidney. By Southern blot analysis of a genomic prealbumin probe, Wallace et al. (1988) demonstrated that the T-to-G change in codon 84 creates an extra AluI site in DNA. This can be used as a direct, reliable DNA test for the ser84 prealbumin gene.
Benson (1986) suggested that there is a higher incidence of vitreous and heart involvement and possibly a higher incidence of carpal tunnel syndrome in the Indiana kindred than in the Maryland kindred. Harats et al. (1989) found no evidence of amyloid in the skin, rectum, or carpal tunnel in patients aged 26 to 37 from the Indiana kindred with no clinical evidence of the disease, but with biochemical evidence (in serum) of being affected.
Zolyomi et al. (1998) described the same ile84-to-ser TTR mutation in affected members of a Hungarian family with familial amyloid polyneuropathy. This is said to be the first demonstration of this mutation in Europe. Although no genealogic link has been established between the Indiana kindred with Swiss/German origin and the Hungarian kindred, haplotype analysis suggested that they had a common origin.
Frederiksen et al. (1962) in Denmark described a family in which 7 of 12 sibs had progressive heart failure due to cardiac amyloidosis (105210). The onset of heart failure was at about age 40 years, with progression to death in 3 to 6 years. Cardiac catheterization showed constrictive-type right-ventricular pressure curves. The children and grandchildren of the affected persons were too young to show the condition. The father was living and well at age 74. The mother, who died in the influenza epidemic of 1918, was said to have been always sickly and to have swollen legs, but did bear 12 offspring.
Husby et al. (1986) found a substitution of methionine for leucine at position 111 in transthyretin (L111M) as the basis of the cardiac amyloidosis described in Danes by Frederiksen et al. (1962).
Nordvag et al. (1992) described a diagnostic test for the molecular detection of this mutation. DdeI digestion of PCR-amplified genomic DNA from patients revealed 3 bands by gel electrophoresis, whereas amplified DNA of controls showed 2 bands. Nordvag et al. (1993) applied this test in a retrospective study of DNA from 65 formalin-fixed, paraffin-embedded tissues obtained at autopsy or biopsy from 29 members of the Danish family. The leu111-to-met mutation was found in 10, whereas 13 were not affected. The results were consistent with known clinical data and with corresponding serum TTR examinations.
Ranlov et al. (1992) gave a follow-up on the original Danish kindred. They had available stored, frozen serum samples obtained in 1959 and 1960 from 36 of 40 living members of the kindred. They found that none of the 18 members of the kindred who tested negative for the leu111-to-met mutation had developed cardiomyopathy. The leu111-to-met carrier who died as a result of an accident at age 22 showed no postmortem evidence of amyloid deposits. All 7 persons who developed amyloidosis had the mutation. In an accompanying editorial, Benson (1992) pointed out features of amyloid cardiomyopathy that should be considered when there are systemic features such as nephrotic syndrome, gastrointestinal motility disturbance, neuropathy, and purpura. Cardiac amyloidosis can result in angina pectoris when there is no significant coronary vessel disease, possibly because of small vessel rigidity due to amyloid deposits. The typical electrocardiogram shows changes usually interpreted as 'anteroseptal myocardial infarction, age undetermined.' The 'pseudoinfarction' pattern results presumably from dense amyloid infiltration. Left atrial enlargement results from the restrictive nature of the process. The echocardiogram may be interpreted as showing 'good systolic function'; the pathophysiologic problem is in filling, not emptying, of the ventricle. Nordvag (1995) indicated that carpal tunnel syndrome was the presenting symptom in the Danish kindred with familial amyloid cardiopathy, although the heart was the major affected organ. Patients with the leu111-to-met mutation had significantly depressed free thyroxine serum levels.
Benson (2001) noted that the kindred originally described by Frederiksen et al. (1962) was the only one to be reported with this mutation. This form of amyloidosis had been referred to as the Danish or cardiac type.
Strahler et al. (1987) described substitution of valine for tyrosine at position 116 in TTR in a family of French-Canadian descent. The variation had no evident pathologic consequences. Because this change requires 2 nucleotide substitutions, the authors proposed that it arose through mutation in a rare variant or a hitherto undetected polymorphic allele of human TTR. Either phenylalanine or glutamic acid at residue 116 are possible 'intermediate' alleles. Strahler et al. (1987) stated that although several electrophoretic variants of TTR had been described, this was the first definition of the underlying molecular substitution in a variant other than those that accompany amyloidosis.
Benson (2001) noted that the val122-to-ile mutation in transthyretin (V122I) was discovered in an individual with cardiomyopathy but no family history of amyloidosis (105210) (Gorevic et al., 1989). It was first believed to explain some cases of senile cardiac amyloidosis. Both homozygous and heterozygous patients have been described. All affected individuals have been elderly, presenting after the age of 60 with cardiomyopathy, and nearly all have been African American. The mutation has been found in nearly 4% of selected African American cohorts and may be the cause of heart failure in a significant portion of the elderly in this population (Jacobson et al., 1996). Peripheral neuropathy has been reported, but is a minor clinical manifestation of this syndrome. Because transthyretin amyloidosis is an autosomal dominant trait, the high allele frequency makes this one of the most important genetic mutations in the United States.
Jiang et al. (2001) stated that the V122I variant is the most common amyloidogenic variant worldwide, with an estimated 1.3 million heterozygotes. Although the age of onset (typically older than 60 years) is similar for senile systemic amyloidosis and familial amyloidotic cardiomyopathy V122I patients, the latter are much more likely to suffer cardiac failure, especially in the case of V122I homozygotes. V122I cardiac disease penetrance approaches 100%, whereas senile systemic amyloidosis, involving wildtype TTR amyloid deposition in the heart, affects less than 25% of the population above age 80.
In a case of senile systemic amyloidosis in a 68-year-old black male, Jacobson et al. (1988, 1990) found an apparently homozygous substitution of isoleucine for valine at position 122 (V122I). No family members were available for study. This change predicted a genomic G-to-A transition, destroying an MaeIII restriction site. Homozygosity was established by the demonstration that the patient's DNA was entirely resistant to MaeIII cleavage. The variant was found in none of either 24 controls or 6 other patients with senile systemic amyloidosis. The only other report of homozygosity for a transthyretin mutation causing amyloidosis is the report by Holmgren et al. (1988) concerning the val30-to-met mutation (176300.0001).
Gorevic et al. (1989) found that isolated amyloid fibrils from 3 cases of systemic senile amyloidosis contained subunit proteins that were transthyretin. Complete sequence analysis of 1 (presumably the same case as that studied by Jacobson et al. (1988, 1990)) showed the presence of a new variant TTR molecule with a single amino acid substitution of isoleucine for valine at position 122. Thus, systemic senile amyloidosis may, in some cases at least, be a genetically determined disease expressed late in life.
Snyder et al. (1989) provided evidence for the hereditary nature of senile cardiac amyloidosis. They identified 2 brothers, both homozygous for the isoleucine-for-valine substitution at position 122. The substitution predicts a guanine-to-adenine substitution at the nucleotide corresponding to the first base of codon 122 (i.e., GTC to ATC) which would result in the loss of a MaeIII restriction endonuclease recognition site. The same change was found in the DNA of the son of 1 of the brothers in heterozygous state and was confirmed by analysis of the plasma prealbumin.
Westermark et al. (1990) found that the transthyretin molecule is normal in cases of the common form of senile systemic amyloidosis that affects to some degree 25% of the population over 80 years of age. For this reason they concluded that factors other than the primary structure of TTR must be important in its pathogenesis. They suggested that the cardiomyopathy that is similar to senile systemic amyloidosis and is associated with the val122-to-ile mutation represents another rare form of amyloidosis separate from the common disorder. Using PCR around codon 122 and digestion with MaeIII, Jacobson et al. (1991) investigated the frequency of the val122-to-ile mutation in 177 black persons without amyloidosis and without overt cardiac disease. The MaeIII restriction site is eliminated by the val122-to-ile mutation. They found 4 examples of the MaeIII-negative gene among 354 chromosomes, giving a frequency of 1.1% (95% confidence interval 0.32-2.7%). Thus, the variant is relatively common in blacks. HLA genotyping did not suggest that the val122-to-ile heterozygotes were of closely related genetic background. DNA testing for this variant may be useful in the clinical evaluation of black patients with unexplained cardiomyopathy.
It is useful to distinguish TTR-related cardiac amyloidosis from that due to deposition of immunoglobulin light chains, AL amyloid (Olson et al., 1987). The TTR disease has a better prognosis than does AL amyloidosis involving the heart. Chemotherapy, which is thought to be beneficial in AL amyloid (Kyle et al., 1985), may be of no value in TTR-amyloidosis.
With a specific test for the val122-to-ile mutation, Jacobson (1992) confirmed that the mutation was present in heterozygous state in 4 of 177 healthy black individuals and as a homozygous variant in a person with cardiac amyloidosis. He suggested that genetic testing for this mutation would be worthwhile in the evaluation of patients with unexplained cardiomyopathy. Nichols et al. (1991) had found the val122-to-ile mutation in homozygous state in anther black patient with cardiac TTR-amyloidosis, and Saraiva et al. (1990) had found it in heterozygous state in a black patient with the same disorder.
After the age of 60, isolated cardiac amyloidosis is 4 times more common among blacks than whites in the United States; 3.9% of blacks are heterozygous for the amyloidogenic V122I (ile122) allele. Jacobson et al. (1997) presented evidence that a high prevalence of transthyretin ile122 is at least partially responsible for the increased frequency of senile cardiac amyloidosis among blacks. They studied cardiac tissue from 32 blacks and 20 whites over 60 years of age with isolated cardiac amyloidosis. Transthyretin amyloidosis was identified in 31 of the 32 cardiac tissue samples from the black patients and in 19 of the 20 samples from the white patients. In 6 of the 26 analyzable DNA samples (23%) from the black patients and none of the 19 samples from the white patients, heterozygosity for the ile122 variant was found. In a second, age-matched cohort of blacks without amyloidosis at the same institution, 4 of 125 DNA samples obtained at autopsy (3.2%) were heterozygous for the ile122 allele. On reexamination, the cardiac tissue from these 4 patients contained small amounts of amyloid not detected at the initial autopsies. All subjects with the ile122 variant had ventricular amyloid. Jacobson et al. (1997) concluded that the assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the ile122 allele.
Benson (1997) stated that the best way to detect cardiac amyloidosis is with echocardiography. By the time a patient presents with symptoms of heart failure, the intraventricular septum and left ventricular posterior wall are thickened and the left atrium is often enlarged, an indication of the presence of restrictive cardiomyopathy of the left ventricle. Endomyocardial biopsy is also a valuable means of diagnosing cardiac amyloidosis and is recommended for patients scheduled to undergo cardiac catheterization because of a restrictive hemodynamic pattern. DNA testing is useful to confirm the hereditary nature of the disease and in counseling patients and their families. In the treatment of heart failure due to amyloidosis the avoidance of negative inotropic agents (including most antiarrhythmic medications) and overdiuresis and the maintenance of normal sinus rhythm contribute to a better outcome.
Askanas et al. (2003) reported a 70-year-old African American man with sporadic inclusion body myositis (147421) and cardiac amyloidosis associated with the V122I mutation. Cultured skeletal muscle fibers from the patient showed vacuolar degeneration, congophilic inclusions, and clusters of colocalizing beta-amyloid and TTR immunoreactivities, none of which were found in normal cultured muscle fibers. Overexpression of the amyloid precursor protein gene (APP; 104760) resulted in accelerated fiber degeneration, greater congophilic inclusions, and accumulation of heavy beta-amyloid oligomers. Askanas et al. (2003) suggested that the V122I mutation may have predisposed the patient to inclusion body myositis by increasing beta-amyloid deposition in skeletal muscle.
Jiang et al. (2001) demonstrated that the V122I variant, producing familial amyloidotic cardiomyopathy primarily in individuals of African descent, increases the velocity of rate-limiting tetramer dissociation, thus resulting in accelerated amyloidogenesis. Chakrabartty (2001) pointed out that the in vitro studies of Jiang et al. (2001) provided a biophysical explanation of how disease-associated mutations in TTR affect the course of TTR amyloidoses, thus strengthening the amyloid hypothesis.
In 2 Afro-Caribbean patients with cardiac amyloidosis, aged 63 and 74 years, respectively, Lachmann et al. (2002) identified heterozygosity for the V122I mutation in the TTR gene. Cardiomyopathy was the predominant clinical feature in both patients, and 1 of them also displayed neuropathy.
To assess the effect of the V122I variant on long-term morbidity and mortality, Quarta et al. (2015) genotyped 3,856 black participants in the Atherosclerosis Risk in Communities study and assessed cardiac structure and function as well as features suggestive of cardiac amyloidosis in participants older than 65 years of age. The authors identified carrier status for the V122I variant in 124 participants (3%). After 21.5 years of follow-up, Quarta et al. (2015) did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1,382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval, 0.73-1.36; p = 0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% confidence interval, 1.03-2.10; p = 0.04). On echocardiography at visit 5, carriers had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers, although carriers had a low prevalence of overt manifestations of amyloid cardiomyopathy. Quarta et al. (2015) did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasted with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low.
Buxbaum and Ruberg (2017) reviewed the TTR V122I allele. The frequency of this amyloidogenic allele is 0.0173, and it is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicated that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. Genotyping of tissues from 112 consecutive autopsies of African Americans age 65 or over identified 4 samples (3.9%) positive for the V122I allele; heart tissues from all 4 carriers showed some degree of cardiac amyloid deposition. However, the clinical penetrance varied, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. The authors reported potential forms of therapy in clinical trials and suggested testing for this variant in older African Americans with heart disease.
In a family of Italian-Sicilian origin with amyloidosis polyneuropathy (105210) described by Skare et al. (1989), the proband, a 39-year-old woman, developed sensory neuropathy at age 34 and vitreous opacities that required vitrectomy in the left eye. Her mother, a maternal uncle, and a maternal aunt died of amyloidosis manifested by peripheral neuropathy, vitreous opacities, and cardiomyopathy. The vitreous amyloid had the immunohistologic characteristics of transthyretin. Previously identified mutations in transthyretin were excluded. A new 7.0-kb SphI restriction site in exon 3 was found. The mutation that could produce the restriction site would result in a substitution for glu89, his90, or ala91. Skare et al. (1991) later demonstrated that the transthyretin variant in this patient had lost an SphI cleavage site within exon 3 and acquired a BsmI cleavage site not present in normal transthyretin. This led to the conclusion that histidine-90 was replaced by asparagine, and amino acid analysis supported the conclusion. Saraiva et al. (1991) found the same variant, H90N, as a seemingly nonpathogenic variant with a low pI in 2 of 4,000 German subjects and in 4 of 1,200 Portuguese subjects. In all carriers of the asn90 variant, no association with traits characteristic of FAP were found. One individual from an FAP kindred was simultaneously a carrier of the met30 substitution and the acidic variant. One individual from the randomly selected Portuguese sample had only the acidic monomer, i.e., was homozygous.
In studies that attempted to find the reason for the amyloidogenic effects of the mutation in some families, Alves et al. (1992) demonstrated differences in the mobility pattern on isoelectric focusing between the nonpathogenic and pathogenic variants. However, DNA sequencing revealed no additional mutation distinguishing the 2. Alves et al. (1992) suggested that 'an as yet unknown post-translational modification may have occurred in the FAP-associated Asn 90 variant, turning it into an amyloidogenic molecule.'
Ueno et al. (1990) studied a kindred with familial amyloid polyneuropathy (105210) from the Osaka area of Japan. Although they stated that the patients in whom they performed molecular studies were sibs, they were in fact cousins. Symptoms of decreased libido, fecal incontinence, pitting pretibial edema and numbness in the legs began at about age 30. Vitreous opacities were described. Sudden death occurred in the late thirties in both patients. The family was traced back 4 generations to 1835 at which time the family was in the Nagasaki area of Japan. In exon 4 a single base change of A to G was found at position 6752, which resulted in substitution of cysteine (TGC) for tyrosine (TAC) at position 114 of the 127-residue TTR molecule (Y114C). Both subjects were heterozygous. Ueno et al. (1992) provided further information; by 1992, 12 of 36 known members of 6 generations were affected. Autonomic disturbances, especially postural hypotension, were the most debilitating symptoms. The duration from onset to death was under 10 years. Heart failure caused by heavy amyloid deposits was the common cause of sudden death.
Haagsma et al. (1997) described a Dutch kindred with the Y114C transthyretin mutation (called cys114 by them). The variant had previously been identified only in Japan.
In a Japanese kindred with amyloid polyneuropathy (105210), Ueno et al. (1990) found a single base change from A to G at position 1135 in exon 2 of the TTR gene, resulting in replacement of glutamate by glycine at position 42 (E42G). Uemichi et al. (1992) provided further details. Six persons had polyneuropathy. The mean age of onset was 38 for 4 males and 54 for 2 females. Amyloid cardiomyopathy was present in 3.
In a Japanese kindred with autosomal dominant amyloid polyneuropathy (105210), Ueno et al. (1990) found a T-to-G transversion at position 3252 in exon 3 of the TTR gene resulting in replacement of serine by arginine at position 50 (S50R). The mutant was discovered by randomly sequencing recombinant clones containing the entire length of each of the 4 exons selectively amplified by PCR. The base change produced a change in restriction site RFLPs, and allele-specific oligonucleotide hybridization confirmed the base change. Takahashi et al. (1992) described the same mutation in a member of another family.
Jones et al. (1990, 1992) showed that a dominantly inherited amyloid polyneuropathy (105210) in a family of German descent was due to a cytosine for thymine substitution in the second base of codon 30, resulting in substitution of alanine for valine (V30A). This mutation created a novel CfoI restriction endonuclease site in exon 2. This represented a hydrophilic substitution at a hydrophobic core position. The change is in the same codon as the val30-to-met mutation found in the Andrade or Portuguese type (176300.0001); see also the val30-to-leu mutation (176300.0024).
In a family with euthyroid hyperthyroxinemia (DTTRH; 145680) in 8 persons spanning 3 generations (Moses et al., 1982), Moses et al. (1990) found a change in 50% of TTR clones in which exon 4 had a substitution of adenine (ACC) for guanine (GCC) in codon 109, resulting in the replacement of threonine for alanine. The mutation was confirmed by amino acid sequencing of tryptic peptides derived from purified plasma TTR. The single-nucleotide substitution abolished 1 of 2 Fnu4HI restriction sites in exon 4. PCR amplification of exon 4 of TTR and restriction digestion with Fnu4HI confirmed that 5 affected family members with increased binding of radiolabeled T4 to TTR were heterozygous for the threonine-109 substitution.
Refetoff et al. (1996) noted that of 3 TTR variants with increased affinity for T4, ala109 to thr, thr119 to met (176300.0018) and gly6 to ser (176300.0036), only ala109 to thr has a high enough affinity for T4 to produce consistent hyperthyroxinemia in heterozygotes. Because the GCC-to-ACC mutation causing ala109 to thr destroys a BsoFI site in exon 4 of the TTR gene, use of this enzyme was suggested as a way to screen for ala109-to-thr substitutions in subjects with euthyroid hyperthyroxinemia. Another mutation at the same codon, ala109 to val (176300.0038), has an affinity for T4 which approaches that of TTR-thr109 and is sufficient to produce consistent hyperthyroxinemia in heterozygotes.
In a family of Greek descent with FAP (105210), Jones et al. (1991) found a CCT-to-GCT change in codon 36 of the TTR gene resulting in a substitution of proline for alanine (A36P). Jacobson et al. (1992) found the same mutation in an Ashkenazi Jewish kindred with FAP.
The substitution of methionine for threonine at codon 119 (T119M) influences the clinical outcome of met30 carriers with amyloidosis (176300.0001), with met119 exerting a protective effect.
In a North American kindred of Swedish ancestry, Harrison et al. (1991) identified an apparently benign, electrophoretic variant of prealbumin, which they designated prealbumin Chicago. They identified a C-to-T mutation in exon 4 of the TTR gene which resulted in replacement of threonine by methionine at position 119 of the mature molecule (T119M). The variant was found incidentally in a girl with classic alpha-1-antitrypsin (AAT) deficiency (107400) and in her father during AAT phenotyping by an electrophoretic method. Five heterozygotes in 3 generations were studied. There was no evidence of amyloidosis in the family. Mean values of serum prealbumin and retinol binding protein levels were higher in the carriers than in normal relatives, but the difference was not statistically significant. The substitution at position 119 occurred in a CpG dinucleotide that may be a point mutation hotspot, as has been postulated for the methionine-30 and isoleucine-122 TTR mutations.
Ii et al. (1992) also found this variant. Since thr119 is invariant in 5 mammalian species, it is presumably important to normal protein function. To determine the frequency of the variant, Ii et al. (1992) screened persons of northern- and western-European descent by means of a PASA (PCR amplification of specific alleles) assay. In all, they found 5 instances of the met119 allele in 1,666 genes, to give a frequency of 1/333. Clinical records, initial clinical interviews, and family history of these patients suggested a high frequency of early-onset venous insufficiency and perhaps mild renal dysfunction. Haplotype analysis suggested that the variant derived from a common ancestor. Ii et al. (1992) commented that although traditionally clinical research has sought to determine the molecular basis of clinical signs and symptoms, increasingly the process will be reversed, as structural protein variants are discovered.
Scrimshaw et al. (1992) identified the same mutation, ACG-to-ATG at position 119, in 4 unrelated persons with euthyroid hyperthyroxinemia (145680). The mutation created a new NcoI restriction endonuclease cleavage site which permitted its detection by a rapid and simple assay based on PCR. Scrimshaw et al. (1992) concluded that although the thr119-to-met mutation was associated with increased binding of thyroxine, the hyperthyroxinemia in the patients who brought the variant to their attention had some other explanation because many persons with the variant had normal serum thyroxine concentrations.
Alves et al. (1993) found another family with this mutation during a screening program for TTR mutations in the Portuguese FAP population. Cyanogen bromide peptide mapping and DNA RFLP analyses showed that the proband was a compound heterozygote for 2 TTR variants: his90-to-asn (176300.0010) and thr119-to-met, inherited from the father and mother, respectively. Neither the compound heterozygote nor his parents had symptoms of FAP. Alves et al. (1993) confirmed that TTR binding of T4 was increased in association with the met119 mutation.
Coelho et al. (1996) found that compound heterozygotes of transthyretin met30 and met119 were protected from the devastating effects of familial amyloid polyneuropathy.
The V30M mutation (176300.0001) is a prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas the thr119-to-met mutation (T119M) on the second TTR allele protects V30M carriers from disease. Hammarstrom et al. (2001) demonstrated that the incorporation of 1 or more T119M TTR subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation, which is required for amyloid formation. Hammarstrom et al. (2001) concluded that their findings provided a molecular explanation for intragenic trans-suppression of amyloidosis.
By single-strand conformation polymorphism (SSCP), Saeki et al. (1991) detected a T-to-G base change in exon 3 resulting in substitution of arginine for leucine-58 (L58R) in a 39-year-old Japanese man with amyloid polyneuropathy (105210). The patient had a 3-year history of weakness and dysesthesia in the hands, muscular atrophy in the distal part of all limbs, orthostatic hypotension, and impotence. The mutation was also found in his 62-year-old mother, who had had weakness and dysesthesia in the hands for 15 years and had surgical decompression of the carpal tunnels without relief. She had vitreous opacities since the age of 53 years.
In a Japanese patient with familial amyloid polyneuropathy (105210), Murakami et al. (1992) demonstrated a de novo mutation in the TTR gene, a G-to-C substitution resulting in replacement of glycine by arginine at position 47 (G47R). The patient had onset of weight loss and diarrhea at the age of 29 years and orthostatic hypotension at the age of 32 at which time sensory loss in the legs and hypohidrosis were also present. There were no vitreous opacities. He died from emaciation at the age of 38. Neither his parents nor 2 brothers had symptoms of FAP and neither parent showed the mutation.
Ferlini et al. (2000) described the same mutation in an Italian family. The proband presented at the age of 16 years with a typical mixed polyneuropathy, confirmed by electromyography. Muscle biopsy showed amyloid deposits by Congo Red staining. She died of heart failure at the age of 33 years during a liver transplant. A sister was similarly affected. The father presented at the age of 39 years with polyneuropathy and autonomic dysfunction, was bedridden by the age of 41 years, and died at age 42 from cardiac failure.
See 176300.0043 for the gly47-to-arg mutation of the TTR gene due not to a G-to-C substitution, but rather to a G-to-A substitution. See 176300.0035 for the gly47-to-ala mutation, involving the same codon.
In a 58-year-old male of Irish and Italian descent with amyloidosis (105210) who first presented with an enlarged heart at age 50, Saraiva et al. (1992) demonstrated a G-to-A transition in codon 45 of the TTR gene, predicted to result in substitution of threonine for alanine (A45T). The patient began to show persistent diarrhea and genitourinary disturbances at the age of 53 years. Heart failure had its onset at age 54 years. Although there were no ocular symptoms or peripheral neuropathy, biopsies of skin, rectal fat, and bladder all showed the presence of amyloid. His mother was reported to have died of amyloidosis, and one sister, aged 54 years, had pedal edema. A maternal aunt also died of amyloid heart disease, confirmed at autopsy.
In the West Virginia kindred of Dutch and German descent with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement (105210) reported by Shulman and Bartter (1956), Kaufman (1958), Wong and McFarlin (1967), and Dalakas and Engel (1981), Jacobson et al. (1992) found a T-to-C transition at position 2 of codon 55 of the TTR gene, corresponding to a leu-to-pro substitution (L55P). The abnormality was initially detected by a single-strand conformation polymorphism analysis. Jacobson et al. (1992) tabulated the clinical manifestations in 7 cases, of which 4 had autopsy. Onset was as early as age 14, with death at 19; the oldest survivor was 38 at death.
McCutchen et al. (1993) compared the amyloidogenicity of leu55-to-pro TTR to wildtype transthyretin. The overlap-extension PCR method was used to introduce the leu55-to-pro mutation into the TTR DNA sequence. The variant was expressed with a leader sequence to ensure secretion into the periplasmic space of E. coli. They found that the mutant TTR tetramer was significantly less stable than the wildtype. Characteristic amyloid fibrils were produced from leu55-to-pro TTR in vitro. Several lines of evidence had suggested that lysosomes may be the source of amyloid fibril formation in vivo. McCutchen et al. (1993) observed formation of amyloid fibrils from leu55-to-pro TTR at the normal operating pH of a lysosome. They proposed that their observations explained the unusual pathogenicity of this TTR mutant.
The same mutation was found by Yamamoto et al. (1994) in a Taiwanese FAP family with clinical manifestations very similar to those in the West Virginian family.
In a Japanese patient with familial cardiac amyloidosis (105210), Nishi et al. (1992) demonstrated a ser50-to-ile mutation in the TTR gene resulting from a G-to-T transversion. The patient had 2 sibs out of 8 who had died with cardiac amyloidosis. Electrocardiogram showed first-degree atrioventricular block and complete left bundle branch block. Two-dimensional echocardiography showed symmetrical left ventricular hypertrophy with preserved systolic function. The thickened cardiac walls demonstrated a granular sparkling texture. Amyloid deposits were found in biopsy specimens from the rectum and skin. None of the 3 patients showed evident polyneuropathy.
In a Japanese patient with amyloid polyneuropathy, Saeki et al. (1992) used SSCP analysis of PCR products to demonstrate mutation in exon 3. Direct sequencing demonstrated a G-to-T transversion resulting in substitution of isoleucine for serine-50. See 176300.0013 for another mutation affecting serine-50 in a Japanese patient. Saeki et al. (1992) described their patient as a 56-year-old Japanese woman living in Oita Prefecture who had a 7-year history of sensory disturbance and muscular atrophy in the lower limbs. The autonomic dysfunction, especially orthostatic hypotension, limited her ambulation. Amyloid deposition was proven by sural nerve biopsy,
In a Japanese patient with familial amyloid polyneuropathy (105210), Murakami et al. (1992) used single-strand conformation polymorphism analysis and sequence analysis of PCR-amplified exons of TTR to demonstrate a val30-to-leu (V30L) mutation. The mutation created a Cfr13I site. The change is in the same codon as the val30-to-met mutation found in the Andrade or Portuguese type (176300.0001); see also the val30-to-ala mutation (176300.0014).
The pathogenic significance of the V30L mutation was confirmed by Utsugisawa et al. (1998), who demonstrated the same mutation in 3 members of a Japanese family with type I FAP. The proband was a 46-year-old woman who gradually developed sensory dullness, muscle weakness, and atrophy of the legs and the arms. The pupils were dilated and did not react to light and accommodation, but were hypersensitive to both 0.1% pilocarpine and 0.125% epinephrine. Tendon reflexes were absent or diminished in the extremities. She showed severe hypesthesia in the distal parts of the extremities, but sparing joint sensation. Orthostatic hypotension was demonstrated with no change in pulse rate on assuming the standing position. Her father died at age 53 years, having had similar symptoms.
In a Sicilian kindred with amyloid neuropathy and cardiomyopathy (105210), Almeida et al. (1992) identified a mutation in the TTR gene resulting in substitution of alanine for threonine-49 (T49A). The disease started in the fifth decade with the appearance of vitreous opacities which was followed, several years later, by polyneuropathy and cardiomyopathy (Salvi et al., 1991). Benson et al. (1993) found the thr49-to-ala mutation in a French family with amyloid polyneuropathy described by Julien et al. (1983). Onset occurred in the third decade with carpal tunnel syndrome as the first manifestation. By direct genomic DNA sequencing, an A-to-G transition was found in the position corresponding to the first base of TTR codon 49. Since the DNA mutation did not result in the creation or abolition of a restriction endonuclease recognition site, Benson et al. (1993) applied a new DNA analysis technique in which site-directed mutagenesis is used to create a RFLP when the introduced mutation is in proximity to the natural mutation. Since the Italian kindred had later onset with vitreous deposits as the first feature and there was no mention of carpal tunnel syndrome, Benson et al. (1993) raised the question of possible error in identification of the mutation in that family. Benson (2001) noted that both families had cardiomyopathy and a similar age of onset.
In a Sicilian family, Almeida et al. (1992) identified a glu89-to-gln substitution in transthyretin (E89Q) as the basis of amyloidosis presenting as neuropathy and cardiomyopathy (105210). In this and another Sicilian family (see 176300.0025), the TTR variants had been detected by isoelectric focusing (IEF); one was a neutral TTR variant and the other (E89Q) was basic. Three patients in the family with the E89Q mutation presented with carpal tunnel syndrome as the initial manifestation. Many years later, it was followed by polyneuropathy and cardiomyopathy responsible in 1 patient for intractable heart failure and death (Salvi et al., 1990).
Izumoto et al. (1992) reported familial amyloid polyneuropathy (105210) in a pedigree of German ancestry residing in New Jersey. Eight affected persons presented in the third to seventh decade with carpal tunnel syndrome and 1 member of the family presented with vitreous opacification. Affected subjects were found to be heterozygous for a lys70-to-asn (K70N) mutation in the TTR monomer.
In a kindred with systemic amyloidosis (105210) presenting as peripheral neuropathy in the sixth and seventh decades of life, Uemichi et al. (1992) demonstrated a T-to-C transition at nucleotide 1038 of the TTR gene leading to substitution of arginine for cysteine at position 10 of the TTR protein molecule (C10R). The mutation created a new restriction recognition site, thus allowing easy diagnosis. The mutation was identified in 7 persons: none of 3 female mutant gene carriers, who were 87, 85, and 76 years old, had symptoms of the disease, while 4 of 5 male carriers, including 1 patient whose DNA was not available for testing, developed the disease in their fifties or sixties. It had been observed in other types of FAP that males are affected predominantly or at earlier ages than females. Affected subjects showed sensory and motor neuropathy, bowel disorder, sexual impotence, cardiomyopathy, and vitreous opacity, but no kidney dysfunction. Benson (2001) noted that arg10 replaces the only cysteine in the transthyretin molecule.
In a French woman with amyloidosis (105210) who presented at the age of 40 with neuropathy in all 4 limbs, diarrhea, and orthostatic hypotension, Benson et al. (1993) found a T-to-C transition converting codon 71 from GTG (valine) to GCG (alanine). The patient was heterozygous. The father died with a similar clinical picture, which included vitreous opacities. Two of 5 children were positive for the mutation. Almeida et al. (1993) found the same mutation in a Spanish kindred.
In a German family with cardiac amyloidosis (105210) in which the index patient presented at the age of 63 years with anginal pain and arrhythmia, Hesse et al. (1993) demonstrated an ile68-to-leu mutation in transthyretin (I68L). Electrocardiography showed a pseudoinfarction pattern. Amyloid was identified by immunohistochemistry in the endomyocardial biopsy specimen. The patient died in an accident before the investigations were completed, but an asymptomatic 22-year-old son was found to be heterozygous for the mutant TTR protein.
In a Japanese family, Shiomi et al. (1993) found that a glu61-to-lys (E61K) mutation in transthyretin was responsible for amyloid polyneuropathy (105210). This was said to be the first variant TTR with replacement of an acidic amino acid by a basic amino acid to be found in an amyloid precursor protein of FAP. The proband was a 64-year-old man with watery diarrhea beginning at the age of 62 years and progressive sensory and motor changes in the distal parts of all extremities beginning thereafter. A 66-year-old brother was an asymptomatic carrier of mutation.
Yasuda et al. (1994) found a novel mutation causing amyloid polyneuropathy (105210) in 1 member of a Japanese family. The same mutation was found in 2 asymptomatic carriers. The clinical features were somatic sensory and motor neuropathy with well-preserved autonomic function, late onset, and slow, insidious progression. There were massive amyloid deposits with transthyretin in the myocardium and sural nerve. Molecular genetic studies revealed a substitution of glycine for alanine-97 (A97G) in transthyretin. The first manifestation was a tingling sensation in the proband's toes at the age of 56 years. A 39-year-old daughter and a 17-year-old grandson were the carriers. The presence of myeloid deposits was discovered when a permanent pacemaker was implanted for treatment of complete heart block. Indeed, the diagnosis of amyloidosis was first made at that time, when he was 67 years old.
Murakami et al. (1994) presented the cases of a 68-year-old Japanese woman and her 67-year-old brother with carpal tunnel syndrome (115430). At the time of surgical carpal tunnel release, Congo-red stained biopsy material was obtained demonstrating the presence of amyloid. There were no other neurologic abnormalities, no orthostatic hypotension, no gastrointestinal problems or sphincter disturbances, and no vitreous opacities. The father, who had had symptoms of carpal tunnel syndrome, died at the age of 76 of pneumonia. Single-strand conformation polymorphism analysis and sequence analysis of PCR-amplified exons of the TTR gene revealed a T-to-C transition converting codon 114 from TAC (tyr) to CAC (his) (Y114H). The same codon is involved in a tyr-to-cys mutation (176300.0011) in which the manifestations are more characteristic of amyloid polyneuropathy.
In 2 American patients of German descent with amyloid polyneuropathy (105210), Uemichi et al. (1994) identified heterozygosity for an ATT (isoleucine) to GTT (valine) transition in the codon corresponding to amino acid 107 of mature TTR (I107V). The mutation created a new MaeIII restriction site which could be used in diagnosis. Although clinical and family information were limited, Uemichi et al. (1994) indicated that both patients had had a diagnosis of carpal tunnel syndrome at the age of 56 and subsequently developed polyneuropathy in the legs. The father of 1 of the patients had died at the age of 60 of a similar illness, and necropsy showed amyloidosis.
In a family originating from Abruzzi, Italy, Ferlini et al. (1994) described amyloid polyneuropathy and cardiomyopathy (105210) in members of 3 generations caused by a substitution of the second nucleotide of codon 47 of transthyretin, which caused a change from glycine to alanine (G47A). A substitution in the first nucleotide of codon 47 had been found as the cause of a gly47-to-arg mutation (G47R; 176300.0020).
Ferlini et al. (2000) described another Italian family with the glycine-to-alanine substitution caused by a G-to-C transversion in the penultimate nucleotide of codon 47. The proband was a 61-year-old woman originating from Tuscany. She presented with a 4-year history of weakness, exercise dyspnea, peripheral edema, and progressive weight loss. Left carpal tunnel surgery had been performed at the age of 56 years. Abdominal fat biopsy showed amyloid deposits. Echocardiography showed restrictive cardiomyopathy with a concentrically thickened left ventricle and reduced ejection fraction.
Jacobson et al. (1995) found that the TTR ser-6 (gly6-to-ser) allele had a frequency of 0.06 (33 in 558) in Caucasians, a frequency of 0.01 (3 in 242) in African Americans, and a frequency of 0 in 140 Africans and 208 Asians. The authors interpreted the data as indicating that this allele is a nonamyloidogenic population polymorphism in Caucasians with a single Caucasian founder and in the estimated 25% admixture of 'Caucasian' genes in the African American population. Alternatively, as the variant arose from a G-to-A transition at a CG dinucleotide hotspot, it may have arisen on multiple occasions.
Ii et al. (1991) described a phe64-to-leu (F64L) mutation in transthyretin in an American patient of Italian origin with amyloid polyneuropathy (105210). Ferlini et al. (1996) described the same mutation in a family originating in Pescara in Central Italy with several members affected by amyloid polyneuropathy and in a single case in a man who had been adopted as a baby. The 6 affected members in 2 generations of the family were affected by polyneuropathy and/or cardiomyopathy with the onset of the disease in the seventh decade of life. In the sporadic case, onset was at 49 years and the disorder progressed rapidly so that the patient was tetraplegic by the age of 53 years. Whereas the familial cases were heterozygous, the sporadic case appeared to be homozygous. A son of the presumed homozygote was asymptomatic with a normal neurologic examination at the age of 36 years, but was heterozygous by molecular analysis.
Refetoff et al. (1996) investigated a family with dominantly inherited euthyroid hyperthyroxinemia (DTTRH; 145680) in which 2 of 8 affected members had ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected individuals had above-normal serum reverse T3 levels, mean T4 levels 50% above those of their unaffected relatives, and total T3 and TSH levels within the normal range. While loss of the BsoFI site in 1 TTR allele suggested the presence of an ala109-to-thr substitution (176300.0015), sequencing of the TTR gene revealed a GCC-to-GTC mutation in codon 109 that produces an ala109-to-val substitution. Association constants for T4-binding to TTR-ala109, -thr109, and -val109 were 1.3, 13.6, and 9.5 x 10 -7 M(-1), respectively. Thus, the TTR-val109 variant has an affinity for T4 which approaches that of TTR-thr109 and is sufficient to produce consistent hyperthyroxinemia in heterozygotes. Assuming that mutant and normal alleles are equally expressed and that 20% of serum T4 is bound to TTR, the calculated mean serum T4 levels of TTR-val109 heterozygotes is increased 50%, agreeing with the observed 55% increase.
In a German 3-generation family, Jenne et al. (1996) identified a 'new' amyloidogenic val20-to-ile (V20I) mutation in the TTR gene. The index patient suffered from severe amyloid cardiomyopathy (105210) at the age of 60. Conformational stability and unfolding behavior of the mutant ile20 monomer in urea gradients was found to be almost indistinguishable from that of wildtype TTR. In contrast, tetramer stability was significantly reduced in agreement with the expected change in the interactions between 2 opposing dimers via the side chain of ile20. The TTR molecule consists of 4 identical, noncovalently linked subunits of 127 amino acids each that form a pair of dimers in the plasma protein complex. The observations of Jenne et al. (1996) led them to conclude that amyloidogenic amino acid substitutions in TTR facilitate the conversion of tetrameric TTR complexes into conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential.
Independently, Jacobson et al. (1997) found the V20I mutation in a 50-year-old white man with a 2-year history of exertional epigastric distress, occasional lightheadedness without syncope, and a 1-year history of symptoms consistent with carpal tunnel syndrome. The patient had previously been diagnosed with congestive heart failure and treated with a diuretic. The patient showed mild postural hypotension. Orthotopic cardiac transplantation was performed. The patient's mother had bilateral carpal tunnel release at age 70 and symptoms and findings consistent with cardiac amyloidosis in her late seventies. Three of her brothers had died of heart failure after age 70.
Amyloid polyneuropathy has been related to a phe33-to-ile mutation in transthyretin (F33I; 176300.0002). Familial amyloidosis (105210) due to a phe33-to-leu (F33L) mutation was reported in one patient by Ii et al. (1991) and Harding et al. (1991) and in another patient by Myers et al. (1998). In both instances the patient was of Polish-American ethnicity, had no family history of amyloidosis, and had a late onset of symptoms. In the patient who was doubly reported, onset was at age 53 with paresthesias, sensory loss, and areflexia of the lower limbs due to a sensorimotor polyneuropathy along with constipation, impotence, and orthostatic hypotension due to autonomic neuropathy. The patient progressed to upper- and lower-limb sensorimotor polyneuropathy and an infiltrative cardiomyopathy. The patient reported by Myers et al. (1998) initially presented with symptomatic ascites and showed asymptomatic mild peripheral neuropathy, carpal tunnel syndrome, and mild cardiomyopathy at the age of 65 years.
Brett et al. (1999) described the case of a middle-aged woman with a leu12-to-pro (L12P) mutation of the TTR gene product, an extensive amyloid deposition in the leptomeninges and liver as well as the involvement of the heart and peripheral nervous system, typical of familial amyloid polyneuropathy caused by variant TTR (105210). Clinical features attributed to her leptomeningeal amyloid included radiculopathy, central hypoventilation, recurrent subarachnoid hemorrhage, depression, seizures, and periods of decreased consciousness. MRI showed a marked enhancement throughout her meninges and ependyma, and TTR amyloid deposition was confirmed by meningeal biopsy. The simultaneous presence of extensive visceral amyloid and clinically significant deposits affecting both peripheral and central nervous system extended the spectrum of amyloid-related disease associated with TTR mutations. Brett et al. (1999) suggested that leptomeningeal amyloidosis should be considered part of the syndrome of TTR-related familial amyloid polyneuropathy. Their index case was 38 years old when she first began to notice easy bruising. Five years later she began to get persistent headaches, and 6 months later presented with severe headache of sudden onset. CT and lumbar puncture confirmed subarachnoid blood, but angiograms showed no definite bleeding point. Two months later she had another subarachnoid bleed. About 4 years later, she started to notice hearing loss bilaterally, increasingly severe headaches, unsteadiness, urinary frequency, incomplete bladder emptying, and poor urinary stream. A CT scan showed hydrocephalus; insertion of a right lateral ventriculoperitoneal shunt was complicated by a small subdural hematoma. After the shunt, her unsteadiness and urinary symptoms partially improved. After a complicated and distressing course the patient died at the age of 53 years. The family history showed that the mother had committed suicide at the age of 62 after 2 years of depression and physical illness that included urinary symptoms, constipation, and falls. However, histologic study of sections of heart, lung, and kidney from the mother's postmortem material showed no amyloid.
In a 64-year-old Japanese male suffering from very slowly progressive amyloidosis (105210), Terazaki et al. (1999) demonstrated compound heterozygosity for an arg104-to-his (R104H) mutation in the TTR gene, which was present in heterozygous state in his father, and the val30-to-met mutation (V30M; 176300.0001), which was present in heterozygous state in his mother. The total TTR and retinol-binding protein (see 180260) concentrations in the serum samples of the proband were very high compared with those of patients with the val30-to-met mutation and control subjects. The patient showed decreased visual acuity due to glaucoma and vitreous opacity. Sensory disturbances were present below the knee with mild muscle weakness of the peripheral muscle groups in the upper and lower extremities. Autonomic dysfunction was also found with signs of gastrointestinal, bladder, and pupillary abnormalities. He had undergone a vitrectomy 10 years prior to the report because of amyloid deposits.
Ferlini et al. (2000) described an gly47-to-arg (G47R) mutation in the TTR gene resulting in amyloidotic polyneuropathy (105210) due not to a G-to-C transversion in the first nucleotide of codon 47 (CGG; see 176300.0020), but to a G-to-A transition in the first nucleotide (AGG). The proband presented at the age of 19 years with progressive muscle weakness and atrophy. Skin biopsy was positive for amyloid by Congo Red staining. Echocardiography showed restrictive cardiomyopathy. By the age of 25 years, he developed peripheral polyneuropathy and had an episode of congestive heart failure. The mother and 2 maternal uncles had generalized muscle atrophy and cardiac failure and died in their forties.
Uemichi et al. (1997) described a trinucleotide deletion in the transthyretin gene leading to loss of valine-122 (V122del) in a patient of Ecuadorian origin with familial amyloid polyneuropathy (105210). The patient had onset, at 57 years of age, of numbness and paresthesia in the legs, later developing sexual impotence, alternating constipation and diarrhea, urinary frequency, difficulty in walking, and cardiac involvement. Munar-Ques et al. (2000) reported a Spanish family from Granada with the same TTR val122 deletion. The proposita, a 51-year-old female, and her 4 sibs all presented with carpal tunnel syndrome. The next manifestation was progressive cardiac failure due to restrictive cardiomyopathy consistent with the finding of amyloid deposits seen on echocardiography. In later years, all were handicapped by a progressive lower limb sensorimotor neuropathy.
In an American patient of Irish descent with amyloid peripheral neuropathy (105210), Klein et al. (1998) identified a phe44-to-ser (F44S) mutation in the TTR gene.
Murakami et al. (2002) reported vitreous amyloidosis in a Japanese patient with the ser44 mutation in transthyretin, which had not previously been shown to cause vitreous opacities. The patient's visual acuity improved from 20/200 to 20/20 after pars plana vitrectomy. The patient had few signs of systemic amyloidosis. The authors noted that the patient reported by Klein et al. (1998) had no ocular symptoms.
In 3 French sibs with leptomeningeal amyloidosis (see 105210), Ellie et al. (2001) identified a heterozygous G-to-A transition in the TTR gene, resulting in the replacement of glycine by glutamic acid at codon 53 (G53E). Two of the patients experienced recurrent subarachnoid hemorrhages and the third had headaches and episodic weakness and dysphasia. MRI of all 3 patients showed leptomeningeal enhancement.
In a Hungarian family with meningocerebrovascular amyloidosis (see 105210), Garzuly et al. (1996) and Vidal et al. (1996) identified a mutation in the transthyretin gene, resulting in an asp18-to-gly (D18G) substitution.
In affected members of the family with oculoleptomeningeal amyloidosis (see 105210) reported by Uitti et al. (1988), Uemichi et al. (1999) identified a heterozygous 3293T-C transition in the TTR gene, resulting in a phe64-to-ser (F64S) substitution. The authors noted that another mutation in codon 64 (176300.0037) had been described in a family with amyloidosis without CNS involvement.
In a family with oculoleptomeningeal amyloidosis (see 105210) reported by Goren et al. (1980), Petersen et al. (1995) identified a mutation in the TTR gene, resulting in a val30-to-gly (V30G) substitution (see also Petersen et al., 1997. Other mutations in this codon have been found in patients with a clinically distinct amyloid polyneuropathy (see, e.g., 176300.0001, 176300.0014), and 176300.0024).
In a large Swedish family with autosomal dominant oculoleptomeningeal amyloidosis (see 105210) characterized by seizures, dementia, stroke-like episodes, ataxia, and vitreous amyloid in some, Blevins et al. (2003) identified a heterozygous mutation in the TTR gene, resulting in a tyr69-to-his substitution (Y69H).
In a 53-year-old Japanese man with leptomeningeal amyloidosis (see 105210), Hagiwara et al. (2009) identified a heterozygous mutation in the TTR gene, resulting in an ala25-to-thr (A25T) substitution. The patient presented at age 48 years with chronic progressive polyradiculoneuropathy, severe sensory ataxia, bilateral sensorineural hearing loss, and cerebellar ataxia. There was no visceral organ involvement. He died at age 52 of multiple intracranial hemorrhages. Postmortem examination showed dense hyaline material in the piaarachnoid and leptomeningeal vessels of the brain that were positive for anti-TTR antibodies. Amyloid deposits involved the adventitia, media, and external elastic lamina of the vessels. The spinal cord was compressed by thickened leptomeninges, in which massive amyloid deposits and reactive connective tissue formation were observed. There was no visceral organ involvement. Hagiwara et al. (2009) referred to the studies of Sekijima et al. (2005) who showed that the TTR A25T variant had faster homotetrameric dissociation rates compared to other TTR variants and could be secreted more efficiently into the CNS by the choroid plexus via a T4-chaperoning mechanism.
In 5 unrelated Chinese Taiwanese patients with TTR-related amyloidosis (105210), Liu et al. (2008) identified a heterozygous 349G-T transversion in exon 4 of the TTR gene, resulting in an ala97-to-ser (A97S) substitution in a highly conserved residue. The phenotype consisted of late-onset polyneuropathy, carpal tunnel syndrome, and autonomic dysfunction particularly affecting the gastrointestinal tract. Heart was the most frequently involved vital organ. Haplotype analysis suggested independent origins for the mutation.
Yang et al. (2010) identified the A97S mutation in 19 unrelated Taiwanese patients with a generalized disabling polyneuropathy. The age at symptom onset ranged from 48 to 68 years, and severe disease progression occurred within 5 years. All had motor, sensory, and autonomic symptoms with loss of sensation to thermal stimuli and loss of proprioception. Sural nerve biopsies showed an eosinophilic deposition of TTR-positive amyloid and a pattern of axonal degeneration with loss of large and small myelinated fibers. Skin biopsies of all patients showed a severe loss of intraepidermal nerve fiber density and sparse degenerated fragmented dermal nerve fibers compared to controls; the degree of loss of these fibers correlated with clinical severity. The mutation was not found in 365 Taiwanese controls.
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