The V122I variant is a common mutation in African Americans. The heterozygote frequency is approximately 4% in African Americans (PMID:24184229).
The median survival from diagnosis for patients with ATTRm (V122I) was 25.6 months vs 43.0 months for ATTRwt (senile amyloidosis). ATTRm disease caused by V122I appears to confer a particularly high mortality (PMID:22877808).
Hereditary amyloidoses are a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the deposit of unsoluble protein fibrils in the extracellular matrix (summary by Hund et al., 2001). Patients with transthyretin amyloidosis typically present ... Hereditary amyloidoses are a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the deposit of unsoluble protein fibrils in the extracellular matrix (summary by Hund et al., 2001). Patients with transthyretin amyloidosis typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. In later stages of the disease severe diarrhea with malabsorption, cachexia, incapacitating neuropathy, severe cardiac disturbances, and marked orthostatic hypotension dominate the clinical picture. Death usually occurs 5 to 15 years after onset of symptoms. Before the emergence of molecular genetics, hereditary amyloidoses were classified into 4 subtypes according to symptom constellation and ethnic origin (summary by Hund et al., 2001). The course of disease beginning with sensorimotor polyneuropathy that starts in early adulthood symmetrically at the legs and progresses rather rapidly to incapacitate the patient within a few years has been labeled familial amyloid polyneuropathy type I (FAP I), also known as Portuguese, Portuguese-Swedish-Japanese, or Andrade type. FAP I can be considered the prototype of the manifestation of hereditary TTR amyloidosis. The overwhelming majority of cases of FAP I result from a val30-to-met (V30M; 176300.0001) substitution. A course of disease with neuropathy beginning at the hands and frequent carpal tunnel operations has been designated FAP II, also known as the Indiana/Swiss (176300.0006) or Maryland/German (176300.0003) type. Vitreous opacities occur early in the disease course, whereas impotence and renal insufficiency are rare. Amyloidosis due to mutations in the APOA1 gene (107650) has been referred to as FAP III or Iowa type (see 105200 and 107680.0010). The Finnish type of amyloidosis (105120) has been referred to as FAP IV and is caused by mutations in gelsolin (137350). Systems based on clinical phenotypes have historically been used to classify the amyloidoses, but emphasis on the characterization of the amyloid fibril protein has proved more useful (Saraiva, 2002). In addition to hereditary amyloidosis, 2 other major forms of systemic amyloidosis exist. Immunoglobulin (AL) amyloidosis, formerly known as primary amyloidosis, is caused by the accumulation of monoclonal immunoglobulin (Ig) light chains as amyloid fibrils. Reactive (AA) amyloidosis, formerly known as secondary amyloidosis, is associated with chronic inflammatory diseases (e.g., rheumatoid arthritis, 180300; familial Mediterranean fever, 249100), and fibrils are derived from the circulating acute-phase reactant serum amyloid A protein (see 104750). Ando et al. (2005) provided a review of transthyretin-related familial amyloid polyneuropathy. The authors stated that the phenotypes can be classified into neuropathic, oculoleptomeningeal, and cardiac.
Familial amyloid polyneuropathy (FAP) was described by Andrade (1952) in the northern area of Portugal (reviewed by Saraiva, 2001). Kindreds had an age of onset of clinical symptoms in the third or ... - Familial Amyloid Polyneuropathy Familial amyloid polyneuropathy (FAP) was described by Andrade (1952) in the northern area of Portugal (reviewed by Saraiva, 2001). Kindreds had an age of onset of clinical symptoms in the third or fourth decade of life. Early impairment of temperature and pain sensation in the feet and autonomic dysfunction leading to paresis, malabsorption, sphincter dysfunction, electrocardiographic abnormalities, emaciation, and death were typical clinical features. Age at onset varies greatly; within the ethnically and genetically homogeneous Portuguese population, age at onset was between 17 and 78 in the 1,233 patients examined to 1995 (Hund et al., 2001). Most patients present in the third or fourth decade, but onset of symptoms may be delayed until old age (Benson, 2001). Clinical disease usually progresses over 5 to 15 years and ends with death from cardiac failure, renal failure, or malnutrition. However, in some kindreds heterozygotes with late-onset disease have lived past age 90. De Navasquez and Treble (1938) reported a possible case of FAP type I and showed that the patient reported by De Bruyn and Stern (1929) as Dejerine-Sottas progressive hypertrophic polyneuropathy (145900) had in fact suffered from amyloid neuropathy. Since the disorder began with 'pains in the arms, which worried him particularly at night whilst in bed,' he may have suffered from the Indiana variety (176300.0006). Onset was in the 40s. Two brothers and a sister had died of an identical condition 3 years after onset of symptoms. 'The father died of tubercle, the mother of old age.' The disease is milder in females. Vitreous opacities are frequent (Kaufman and Thomas, 1959). In both FAP I and FAP II (see 176300.0006), the amyloid is pericollagenous. In familial Mediterranean fever, it is perireticular. Costa et al. (1978) concluded that the amyloid of familial amyloid polyneuropathy is distinct from the amyloid of acquired 'primary' and 'secondary' amyloidosis and of familial Mediterranean fever. They also concluded that it is closely related to prealbumin, or transthyretin. Interestingly, 'senile' cardiac amyloid (see later) is also derived from prealbumin and is indistinguishable from the amyloid of the hereditary amyloid neuropathies (Gorevic et al., 1982). (Immunoglobulin light chains are the origin of primary amyloid and AA protein is the origin of secondary amyloid.) Costa et al. (1978) were studying cases of the Andrade type of familial amyloidosis; Benson (1980, 1981) was presumably studying cases of the Indiana or Rukavina type (176300.0006). In a Swedish kindred reported by Benson and Cohen (1977), affected persons presented with peripheral neuropathy in the fourth and fifth decades. A progressive sensory and motor loss started in the legs. Subsequently, renal, cardiac, gastrointestinal, ocular, and cutaneous involvement occurred. Histologically, amyloid deposition was mainly in connective tissue, including the unusual sites of the meninges and central nervous system. No abnormality of immunoglobulin or elevation of protein SAA (the serum precursor of secondary amyloid; 104750) was found. Some of the patients had been misdiagnosed as having syringomyelia. Benson (1981) showed partial amino acid sequence homology between human plasma prealbumin and the amyloid deposited in a member of this kindred. Libbey et al. (1984) reported a Texas kindred of German-English ancestry with familial amyloid polyneuropathy showing onset in the seventh decade. By an immunoperoxidase technique, prealbumin was demonstrated in the amyloid deposits. Munsat and Poussaint (1962) described the case of a patient also born in Texas with onset of type I FAP at age 59 years. Sequeiros (1984) suggested that this variation may be due to genetic heterogeneity and that these may be allelic disorders. By amino acid sequencing of abnormal transthyretin in these cases, it is now possible to confirm or reject this hypothesis. Sequeiros and Saraiva (1987) reported a Portuguese-American family originating from Madeira in which amyloid neuropathy due to the usual met30 mutation had its onset in the seventh decade in all affected members of the family. Three asymptomatic relatives (aged 90, 73, and 48) were shown to carry the mutation. Possible mechanisms for the lack of penetrance and the variation in severity were discussed. Ikeda et al. (1987) reported clinicopathologic studies of patients with amyloid polyneuropathy in Japan. One group of patients was from Arao City in the southern island of Kiushu; a second group was from Ogawa village in Nagano Prefecture, located in a mountain valley in the central highlands of Japan. Considerable variability of the clinical picture was noted in the second group. Yamada et al. (1987) described 2 Japanese nonfamilial cases of prealbumin-related amyloid polyneuropathy and referred to other published cases. These may represent new mutations. The molecular nature of the mutations was not determined. The findings of Tanaka et al. (1988) are pertinent. They described a 47-year-old Japanese woman with FAP without apparent familial occurrence of the disorder; however, her 81-year-old mother and 53-year-old sister were found to be asymptomatic carriers of the variant transthyretin as determined by radioimmunoassay. Biopsy of abdominal adipose tissue in the elderly mother showed amyloid deposits. 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). An autosomal dominant form of familial amyloid polyneuropathy in a Japanese kindred originating in the Nagasaki region was described by Ueno et al. (1988). The clinical phenotype most closely resembled that of type I FAP. Clinical manifestations began in the third decade. Affected individuals developed a polyneuropathy of the lower limbs and autonomic dysfunction. Vitreous opacities were seen in 6 of the 9 patients. Typically, death occurred 6 to 15 years after the onset of symptoms. Biopsy specimens from stomach, rectum, and sural nerve stained positive with Congo red. By electron microscopic analysis, amyloid was identified. Immunohistochemical staining with antisera to immunoglobulin light chain, A protein, and prealbumin was negative. Extracted amyloid fibrils did not react with anti-prealbumin serum. Biochemical analysis of the extracted protein showed no resemblance to prealbumin. Southern blot analysis failed to demonstrate any of the restriction fragment sites generated by known prealbumin variants in familial amyloid polyneuropathy. The authors concluded that this is an autosomal dominant variety of amyloidosis, which is not associated with the deposition of a prealbumin-related protein. Coutinho and Sequeiros (1989) described a Portuguese family in which the Andrade type of familial amyloidopathy coexisted with Machado-Joseph disease (109150). Although no individual with both diseases was observed, they considered it not unexpected that they might occur together because of the relatively high frequency of both conditions in one area of Portugal. Sandgren et al. (1991) published skeleton pedigrees showing the common ancestry in the 17th century of seemingly unrelated individuals alive currently. Patients who had vitreous opacities as a first symptom seemed to form a separate group with a later average age of onset. Sandgren et al. (1991) speculated that additional familial factors may modify the expression of the FAP gene, resulting in vitreous opacities. The mean age of onset for vitreous opacities was lower for homozygous than for heterozygous patients. Six homozygotes were shown in their pedigree charts. Although the clinical manifestations and natural history vary, most forms of amyloidosis have polyneuropathy as the predominant feature. The amyloid polyneuropathy tends to involve small unmyelinated fibers, disproportionately affecting the autonomic nervous system in sensations of pain and temperature. Ando et al. (1994) demonstrated that blood flow was decreased in the peripheral tissues of amyloidosis patients and suggested that this effect could be mediated in part by a decreased production of nitric oxide, also known as endothelial-derived relaxing factor. A substitution of methionine for valine at position 30 (GTG-to-ATG) results in the classic Swedish-Portuguese-Japanese amyloid polyneuropathy first delineated by Andrade of Porto, Portugal. The clinical phenotype is a progressive small fiber neuropathy leading predominantly to sensory and autonomic dysfunction. Ducla-Soares et al. (1994) studied 47 individuals with this disorder and found that autonomic dysfunction is the first manifestation in a significant proportion of patients, frequently preceding standard clinical neurologic or electroneurodiagnostic abnormalities. Ando et al. (1995) found that in a patient with type I familial amyloidotic polyneuropathy who underwent liver transplantation without blood transfusion during the operation, variant TTR levels decreased in a time-dependent manner. Plasma half-life of variant TTR was calculated to be 2.1 days. Total protein, normal, and variant TTR levels in cerebrospinal fluid remained unchanged after liver transplantation, however. The authors speculated that, since autonomic dysfunction and sensorineuropathy significantly improve after liver transplantation (see later), the variant TTR produced by the choroid plexus may play only a small role in amyloid deposition in tissues. Kyle (2001) provided a historical review of the development of knowledge concerning amyloidosis, including familial forms. He cited the family reported by De Bruyn and Stern (1929) as one of the earliest. The proband was a 52-year-old man who had had pain and numbness in his limbs for 3 years. He had a loss of energy and appetite and then developed severe diarrhea. Two brothers and a sister had died of a similar illness. Ikeda et al. (2002) reviewed clinical findings and other aspects of familial amyloid polyneuropathy in Japan. They concluded that there is wide variability in phenotype, even among those with the same genotype. Koike et al. (2004) compared the pathologic findings of 11 Japanese patients with onset of FAP before age 50 years who were from the 2 FAP-endemic regions in Japan to that of 11 Japanese patients with later-onset who were not from the 2 endemic regions. All patients carried the common V30M mutation in the TTR gene (176300.0001). Sural nerve biopsies in the early-onset cases showed predominant loss of small myelinated fibers. Sural nerve biopsies of late-onset cases showed variable fiber size distribution, axonal sprouting, more total loss of myelinated fibers, and relatively preserved unmyelinated fibers. Postmortem studies in both groups showed amyloid deposition throughout the length of nerves and in sympathetic and sensory ganglia, but deposition was greater in the early-onset cases. Early-onset cases also showed greater neuronal cell loss in sympathetic ganglia compared to dorsal root ganglia; the opposite was true in late-onset cases. TTR-positive, Congo red-negative amorphous material was more conspicuous in nerves from late- than early-onset cases. In extraneural sites, amyloid was more conspicuous in thyroid and kidney from early-onset cases, and in heart and hypophysis from late-onset cases. In early-onset cases, cardiac amyloid deposition was prominent in the atrium and subendocardium, but was conspicuous throughout the myocardium in late-onset cases. Koike et al. (2004) concluded that the pathology of early- and late-onset FAP TTR V30M mutation carriers correlated well with differences in clinical findings. Liu et al. (2008) reported 5 unrelated Chinese Taiwanese patients with adult-onset rapidly progressive TTR-related amyloidosis. The average age at onset was 51 years. Four presented with paresthesia of the limbs and 1 with diarrhea. Clinical features related to the polyneuropathy included areflexia, impaired sensation, muscle weakness, and carpal tunnel syndrome. Sural nerve biopsy showed axonal degeneration and amyloid deposits. Autonomic dysfunction manifested as orthostatic hypotension, gastrointestinal dysautonomia, erectile dysfunction, and urinary retention. Two patients, and the affected mother of 1 of the patients, had cardiac dysfunction, including arrhythmia, cardiac hypertrophy, and heart failure. One patient had chronic renal dysfunction. All carried the same heterozygous mutation in the TTR gene (A97S; 176300.0052). Yang et al. (2010) reported 19 unrelated Taiwanese patients with FAP and the A97S mutation. 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. Seven patients showed additional rapid declines in neurologic function associated with elevation of protein content in the CSF. 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; degree of loss of these fibers correlated with clinical severity. - Cardiac Amyloidosis Three mutations in TTR are notable for their association with amyloidosis presenting as cardiomyopathy without a significant degree of peripheral neuropathy (Benson, 1991). A thr60-to-ala substitution (T60A; 176300.0004) resulted in amyloidosis formerly termed 'Appalachian type' that was characterized by restrictive cardiomyopathy and autonomic dysfunction. A leu111-to-met mutation (L111M; 176300.0007) was identified in a single Danish family with cardiac amyloidosis and no evidence of peripheral neuropathy. A val122-to-ile substitution (V122I; 176300.0009) is associated with late-onset restrictive cardiomyopathy without significant peripheral neuropathy. This mutation is particularly frequent in African Americans, with an estimated allele frequency of 3.9%; after the age of 60, isolated cardiac amyloidosis is 4 times more common among blacks than whites in the United States (Jacobson et al., 1997). - Leptomeningeal Amyloidosis Leptomeningeal amyloidosis is distinct from other forms of transthyretin amyloidosis in that it exhibits primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment ('oculoleptomeningeal amyloidosis') (Vidal et al., 1996). In a Hessian (German) kindred living in Ohio, Goren et al. (1980) described a form of autosomal dominant amyloidosis with manifestations limited to central nervous and ocular dysfunction: dementia, seizures, strokes, coma, and visual deterioration. The cerebrospinal fluid was xanthochromic with lymphocytic pleocytosis and elevated protein. Neurologic dysfunction was episodic, suggesting transient cortical ischemia. The seizures were attributed to small, superficial cortical infarcts resulting from occluded subarachnoid vessels. Obtundation and headache were attributed to intermittent hydrocephalus. Pathologic examinations showed severe, diffuse amyloidosis of the leptomeninges and subarachnoid vessels associated with patchy fibrosis and obliteration of the subarachnoid space. Amyloid deposits were prominent on the ependymal surfaces. Severe and diffuse neuronal loss and generalized subpial gliosis were found in the cerebrum and cerebellum, as well as occasional superficial brain infarcts. Amyloid was also found in the vitreous, the retinal internal limiting membrane, and the retinal vessels, particularly those in the nerve fiber layer. Only minimal amyloid deposition was found elsewhere. At least 5 instances of male-to-male transmission were observed. Dowell et al. (2007) reported another affected member of the family reported by Goren et al. (1980). She was a 45-year-old woman who presented with progressive central nervous system (CNS) dysfunction over 4 months. Initial symptoms included headache, emesis, aphasia, facial weakness, and lower extremity paresthesias and weakness which progressed to paraplegia, incontinence, visual impairment, and deafness. She had hydrocephalus and died 3 months later. Postmortem examination showed extensive granulomatous vasculitis and inflammation of the leptomeninges consistent with primary angiitis of the CNS. Cerebral blood vessels showed congophilic red staining, and there was infarction and degeneration at all levels of the spinal cord. Dowell et al. (2007) suggested that amyloid deposition may have induced an inflammatory reaction resulting in vasculitis in this patient. Uitti et al. (1988) described a Canadian family of Italian origin in which 3 members had oculoleptomeningeal amyloidosis. The 3 affected members of the family were twin brothers and the son of 1 of them. The clinical features were hemiplegic migraine, periodic obtundation, psychiatric symptoms, seizures, intracerebral hemorrhage, visual impairment, deafness, dysarthria, myelopathy, spasticity, and polyneuropathy. Onset was in the teens or twenties, with death ranging from age 29 to 62. Histopathologic findings were mainly amyloid deposition in the leptomeningeal and retinal vessels, in the vitreous humor, and in perivascular tissue throughout the body. Evaluation of the amyloid showed it to be derived from transthyretin. Uitti et al. (1988) pointed to cases reported by Hamburg (1971) and by Okayama et al. (1978) as representing probable cases of oculoleptomeningeal amyloidosis. Garzuly et al. (1996) described a Hungarian family with autosomal dominant meningocerebrovascular amyloidosis. There were 4 definitely and 3 probably affected members over 4 generations. Clinical features included adult onset, memory disturbances, psychomotor deterioration, ataxia, and hearing loss. Other variable features included migraine-like headaches with vomiting, tremor, spastic paraparesis, nystagmus, hallucinations, and urinary retention. Progressive visual disturbance was absent. CSF protein was markedly elevated in all patients. Postmortem examination of 2 patients showed amyloid deposition in the leptomeninges, brainstem, and spinal cord. There was some systemic amyloid deposition in the heart, kidney, and skin. Hagiwara et al. (2009) reported a 53-year-old Japanese man with leptomeningeal amyloidosis. 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, and no amyloid deposits were identified within the spinal cord, nerve roots, dorsal root ganglia, and peripheral nerves. The spinal cord was compressed by thickened leptomeninges, in which massive amyloid deposits and reactive connective tissue formation was observed. The acoustic nerves and spinal nerve roots were entrapped by thickened leptomeninges. There were varying degrees of demyelination and axonal degeneration depending on the nerve fasicles. There was no visceral organ involvement. - Senile Systemic Amyloidosis Wildtype TTR is mildly amyloidogenic and is deposited as amyloid primarily in the heart of up to 25% of elderly persons, a condition termed senile systemic amyloidosis (Saraiva, 2002; Westermark et al., 1990). Senile systemic amyloidosis, also referred to as senile cardiac amyloidosis, involves the lungs, liver, and kidneys as well as the heart. Crossreaction of antiserum to human prealbumin provides a test for distinguishing senile systemic amyloid from other forms of senile amyloid as well as from amyloid associated with multiple myeloma or primary systemic amyloidosis (Cornwell et al., 1981).
The genetic defect in the kindreds from northern Portugal described by Andrade (1952) was heterozygosity for a valine-to-methionine substitution at residue 30 of transthyretin (V30M; 176300.0001) (Saraiva et al., 1984). Saraiva (2001) reported that over 500 kindreds had ... The genetic defect in the kindreds from northern Portugal described by Andrade (1952) was heterozygosity for a valine-to-methionine substitution at residue 30 of transthyretin (V30M; 176300.0001) (Saraiva et al., 1984). Saraiva (2001) reported that over 500 kindreds had been identified in Portugal, constituting the largest focus of FAP worldwide. The second largest focus of V30M FAP is northern Sweden, where more than 350 families have been diagnosed (Holmgren et al., 1994). A few cases of homozygosity for the V30M mutation have been reported but do not lead to a more severe form of the disease (Holmgren et al., 1988). In a Hungarian family with meningocerebrovascular amyloidosis, Garzuly et al. (1996) and Vidal et al. (1996) identified a mutation in the transthyretin gene (D18G; 176300.0047). Herrick et al. (1996) identified a common mutation in the TTR gene (V30M; 176300.0001) in a woman with leptomeningeal amyloidosis. In a family with oculoleptomeningeal amyloidosis reported by Goren et al. (1980), Petersen et al. (1997) identified a mutation in the TTR gene (176300.0049). In affected members of the family with oculoleptomeningeal amyloidosis reported by Uitti et al. (1988), Uemichi et al. (1999) identified a heterozygous mutation in the transthyretin gene (176300.0048). In a large Swedish family with autosomal dominant oculoleptomeningeal amyloidosis characterized by seizures, dementia, stroke-like episodes, ataxia, and, in some, vitreous amyloid, Blevins et al. (2003) identified a mutation in the TTR gene (176300.0050). In 5 American and 1 Brazilian case of hereditary amyloid polyneuropathy, and in 1 Brazilian case that was typical except for the absence of a positive family history, Dalakas and Engel (1981) demonstrated that the amyloid stained with antiprealbumin, as had been shown in the Portuguese type. No staining was demonstrated with antibodies specific for kappa and lambda proteins. The patients studied included 1 from the large kindred reported by Mahloudji et al. (1969); patients who represented an aggressive, early-adult-onset, autosomal dominant type reported by Kaufman (1958) and Wong and McFarlin (1967), and shown by Jacobson et al. (1992) to have a leu55-to-pro substitution in the TTR gene (176300.0022); and persons of Portuguese extraction and brothers of Greek extraction with an aggressive, mid-adult-onset, autosomal dominant form. The authors suggested that prealbumin-like protein may be a feature common to the amyloid deposits in many and perhaps all the forms of hereditary amyloid polyneuropathy. Hagiwara et al. (2009) reported a 53-year-old Japanese man with leptomeningeal amyloidosis in whom they identified a heterozygous mutation in the TTR gene (A25T; 176300.051). Hagiwara et al. (2009) referred to the studies of Sekijima et al. (2005) who showed that TTR variants of the leptomeningeal type of amyloidosis, such as A25T, have faster homotetrameric dissociation rates compared to other TTR variants. The A25T variant was secreted more efficiently from choroid plexus cells compared to hamster kidney and mouse liver cells, possibly via a T4-chaperoning mechanism. The D18G variant did not form tetramers and was targeted for endoplasmic reticulum (ER)-associated degradation, leading to low secretion levels.