Alternative titles; symbols
ORPHA: 271861, 85447, 85451; DO: 0050638;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q12.1 | Amyloidosis, hereditary, transthyretin-related | 105210 | Autosomal dominant | 3 | TTR | 176300 |
A number sign (#) is used with this entry because hereditary systemic amyloidosis-1 (AMYLD1) is caused by heterozygous mutation in the TTR gene (176300) on chromosome 18q12.
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. Patients with AMYLD1 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 (summary by Hund et al., 2001).
Reviews
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.
Adams et al. (2019) reviewed hereditary transthyretin amyloidosis, discussing epidemiology, phenotypic heterogeneity, genetic heterogeneity and its influence on age of onset, pathophysiology, and the success of phase III studies of gene-silencing therapies.
Genetic Heterogeneity of Hereditary Systemic Amyloidosis
AMYLD2 (105200) is caused by mutation in the fibrinogen A-alpha gene (FGA; 134820) on chromosome 4q31.
AMYLD3 (620657) is caused by mutation in the apolipoprotein A-1 gene (APOA1; 107680) on chromosome 11q23.
AMYLD4 (105120), or Finnish amyloidosis, is caused by mutation in the gelsolin gene (GSN; 137350) on chromosome 9q33.
AMYLD5 (620658) is caused by mutation in the lysozyme gene (LYZ; 153450) on chromosome 12q15.
AMYLD6 (620659) is caused by mutation in the beta-2 microglobulin gene (B2M; 109700) on chromosome 15q21.
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.
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 fascicles. There was no visceral organ involvement.
Sousa et al. (2021) reviewed the current literature on CNS involvement in hereditary transthyretin amyloidosis. CNS symptoms included transient focal neurologic episodes (transient focal CNS dysfunction followed by complete recovery), ischemic and hemorrhagic stroke, cognitive decline, and cranial nerve dysfunction. Onset occurred early, referred to as oculoleptomeningeal amyloidosis (age of onset in the third to fifth decades), in patients with non-V30M TTR variants, or later. Symptomatic leptomeningeal accumulation of amyloid was a frequent late complication, especially in patients with the V30M TTR variant, occurring after at least 14 years of symptomatic peripheral nerve disease. However, pathologic studies in patients with hereditary transthyretin amyloidosis showed amyloid deposits in the leptomeningeal membranes and vessels beginning in early stages of the disease (as early as 3 years after disease onset). Because of improved survival associated with liver transplantation, CNS involvement was expected to become more apparent, with transient focal neurologic episodes observed in 12 to 31%, ischemic stroke in 5 to 16%, and cerebral hemorrhages in 1 to 5% of patients with the V30M variant after liver transplant.
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).
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 (AMYLD3; 620657 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).
In reviewing 1,233 cases of FAP from 489 Portuguese families registered at the Centro de Estudos de Paramiloidose in Porto, Portugal, Coelho et al. (1994) found 159 cases in which neither parent had shown symptoms of this hereditary dominant form of peripheral neuropathy. These cases appeared to form a distinct group with a later age of onset (mean 45.1 years) than the group of patients with 1 affected parent (mean 31.2 years) and a geographic origin somewhat different from the areas where the disease is most prevalent. Although this group was not significantly different from the general group of patients in clinical presentation at onset and severity of the disease, the average interval between onset and diagnosis (mean 4.5 years) reflected the difficulties in diagnosing these patients in the absence of a positive family history. Coelho et al. (1994) suggested that in some families the FAP gene may result in a milder expression or even remain 'silent' for several generations. They pointed out that in Sweden a large proportion of cases are isolated (Drugge et al., 1993) and that in Majorca, 13.6% of patients are said to lack affected antecedents. Coelho et al. (1994) suggested that investigation of the reason for reduced penetrance might lead to elucidation of mechanisms involved in the pathogenetic process.
Holmgren et al. (1991) found that orthotopic liver transplantation caused prompt replacement of variant transthyretin by the donor wildtype in the plasma of patients with the met30 variant of familial amyloid polyneuropathy. Holmgren et al. (1993) reported clinical outcome 1 to 2 years after transplantation in 4 patients. Three of them showed improved general well being, walking ability, and bowel function, and 1 had regained normal bladder and bowel function. There had been little objective improvement in peripheral neuropathy. Although the fourth patient, who had the most severe neurologic deficits and a complicated postoperative course, had not improved, there had been no further deterioration. Two patients followed serially with quantitative scintigraphy using radiolabeled serum amyloid P component showed regression of visceral deposits after transplantation. Another FAP patient, who was monitored prospectively for 2 years but did not undergo transplantation, showed, as expected, progression of neuropathy and increased visceral amyloid deposition.
Amyloidogenic mutations in the TTR gene lead to decreased stability of the protein. Using isoelectric focusing in urea gradients, Altland and Winter (1999) were able to demonstrate a stabilizing effect of sulfite on TTR monomers and tetramers, as well as an increase in the tetramer/monomer ratio. They demonstrated that this ratio, which is decreased in FAP patients, can be increased to beyond normal levels. Altland and Winter (1999) showed that doses of sulfite that are tolerable in vivo produce a significant increase in the tetramer/monomer ratio, and they postulated that sulfite may be a potent drug for delaying the onset and progression of FAP.
Ikeda et al. (2002) noted that although results with liver transplantation had been favorable, the authors noted the need for less invasive and more effective treatments.
Ray and Lansbury (2004) noted that the general strategy of inhibiting potentially pathogenic aggregation by stabilizing native oligomers was proposed and accomplished by Koo et al. (1999), in the context of the aggregation-dependent degenerative disease familial amyloid polyneuropathy. Several approved drugs bind the TTR tetramer in an analogous manner as thyroxine (T4), inhibit TTR dissociation and aggregation, and prevent aggregation-associated toxicity in cell culture (Reixach et al., 2004).
Coelho et al. (2013) reported the results of 2 phase 1 clinical trials of RNAi against transthyretin. Two distinct first- and second-generation formulations were evaluated, the first in 32 patients with transthyretin amyloidosis and the second in 17 healthy volunteers. Rapid dose-dependent durable lowering of transthyretin levels was observed in both trials. Both compounds suppressed the production of both mutant and nonmutant transthyretin, establishing proof of concept for RNAi therapy targeting mRNA transcribed from a disease-causing gene.
Benson et al. (2018) conducted an international randomized double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen, an antisense oligonucleotide inhibitor of the hepatic production of transthyretin, in adults with stage 1 (ambulatory) or stage 2 (ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least 1 dose of a trial regimen, and 139 (81%) completed the intervention period. The primary end points were the change in the modified Neuropathy Impairment Score +7 (mNIS+7) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire. A decrease in scores indicated improvement. Both primary efficacy assessments favored inotersen. Improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were 5 deaths in the inotersen group (4 consistent with progression or complication of underlying disease and 1 from intracranial hemorrhage associated with thrombocytopenia) and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients (3%)) and thrombocytopenia (in 3 patients (3%)), with 1 death associated with 1 of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. Benson et al. (2018) concluded that inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring.
Yamashita et al. (2019) demonstrated that patients with FAP and a non-V30M-TTR mutation had improved survival with liver transplant compared to nontransplanted patients.
Adams et al. (2023) reviewed therapeutic options for FAP, including liver transplant, TTR stabilizers, RNA interference (RNAi), and antisense oligonucleotides (ASO). Liver transplant was shown to double the survival of patients with the V30M mutation (176300.0001). The TTR stabilizer tafamidis was shown to slow progression of neuropathy in patients with the V30M mutation at early stages of disease. Patisiran, a TTR-targeted siRNA lipid nanoparticle agent, resulted in decreased serum TTR by 81% in 18 months and improvements in the mNIS+7. Inotersen, a TTR-targeted ASO, resulted in decreased serum TTR by 74% in 18 months and improvements in the mNIS+7, but was associated with events including thrombocytopenia and glomerulonephritis. Patisiran was also tested in patients with familial cardiac amyloidosis and resulted in improved 6-minute walk test but not survival. In patients with familial cardiac amyloidosis, tafamidis resulted in increased survival at 30 months compared to placebo.
Fontana et al. (2025) reported the results of a double-blind, randomized trial of 665 patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in a 1:1 ratio to receive vutrisiran (25 mg, 326 patients) or placebo (329 patients) every 12 weeks for up to 36 months. Vutrisiran is a subcutaneously administered RNA interference therapeutic agent that inhibits the production of hepatic transthyretin. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; p = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; p = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; p = 0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least 1 primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; p less than 0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; p less than 0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the 2 groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. Treatment with vutrisiran lowered the risk of death and cardiovascular events compared with placebo and preserved functional capacity and quality of life.
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; 176300.0051). 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.
Yi et al. (1991) introduced the human TTR gene carrying the val30-to-met mutation into transgenic mice and demonstrated that amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys 6 months after birth and extended to various other organs and tissues with advancing age. By the age of 24 months, the pattern of amyloid deposition was similar to that observed in human autopsy cases, except for its absence in the choroid plexus and in the peripheral and autonomic nervous systems.
Benson (1986) was of the view that the Portuguese disease was imported from Sweden. From Portugal, it appeared to have spread to Japan.
Coimbra and Andrade (1971) reported somewhat unexpected electron microscopic findings demonstrating that the primary change is one of myelin degeneration, followed by axoplasmic degeneration and only subsequently by accumulation of amyloid deposits which do not cause nerve compression. This suggested that the amyloid accumulations are secondary to the peripheral nerve degeneration.
Coutinho and Sequeiros (1989) suggested that the so-called Iiyama type of FAP seen in Japan and characterized by the same met30 mutation of the TTR gene as in the Portuguese cases but associated with cerebellar and pyramidal signs (Furuya et al., 1987) may represent the simultaneous occurrence of FAP type I and Machado-Joseph disease (MJD; 109150), both disorders of relatively high frequency in Portuguese. The MJD mutation was later determined to be in the ataxin-3 gene (ATXN3; 607047) on chromosome 14q24.3-q33. Ikeda et al. (1996) found that the family studied by Furuya et al. (1987) and others carried mutations in both the TTR and ATXN1 (601556) genes and thus represented the coexistence of FAP and spinocerebellar ataxia-1 (164400).
Ironically, George G. Glenner, who made major contributions to the understanding of amyloidosis, succumbed to cardiac amyloidosis of the transthyretin type (Sipe, 1995). Glenner et al. (1971) reported that the fibrils in primary amyloidosis, or amyloidosis associated with multiple myeloma, are composed of the N-terminal variable region of the immunoglobulin light chain. Glenner et al. (1974) defined the beta-pleated sheet structure of the amyloid fibril. Glenner and Wong (1984) defined the A-beta fibril protein associated with Alzheimer disease (104760).
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).
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