Transthyretin Amyloidosis
(Adapted from a Review in Amyloid: Int J Exp Clin Invest 3:44-56, 1996)
The transthyretin amyloidoses are the most prevalent type of hereditary systemic
amyloidosis. Since the first published recognition of this form of amyloidosis by Andrade in
1952, and the first description of an American kindred by Falls, et al., in 1955, the number of
kindreds with transthyretin amyloidosis has steadily increased (Andrade 1952; Falls, et al., 1955;
Benson, 2000). While it was expected that variations in clinical presentation (FAP-I, II, III, IV)
were the result of heterogeneity in etiology or pathogenesis of the hereditary amyloidosis, it was
not until the discovery by Costa, et al., in 1978 showing transthyretin as a constituent of the fibril
deposits, that the biochemical basis of these syndromes could be pursued (Costa, et al., 1978).
This resulted in the discovery of the first variant form of transthyretin mutation reported in 1983.
In 1989 there were approximately 12 known mutations and in 2002 there are at least 90. Over 80
of these mutations are associated with amyloidosis. In addition, there is evidence that normal
transthyretin may for amyloid especially in the heart and be the basis for senile cardiac
amyloidosis (Westermark, 1990).
The transthyretin amyloidoses were classically associated with peripheral sensorimotor
neuropathy. A number of the more recently discovered transthyretin mutations, however, cause
little if any clinical neuropathy. Isolated carpal tunnel syndrome, vitreous opacities, and
restrictive cardiomyopathy without any clinically significant neuropathy have all been found in
association with specific transthyretin mutations.
The transthyretin amyloidoses by definition are all associated with tissue deposits of
fibrils having transthyretin as a major protein constituent. While there are a number of other
constituents of the amyloid deposits, including proteoglycan, amyloid P component, and various
lipoproteins, it is transthyretin that is the essential ingredient in this type of amyloid.
Transthyretin
Transthyretin is a normal plasma protein synthesized predominantly by the liver as a
single polypeptide chain of 127 amino acids (14,000 daltons) (Kanda, et al., 1974). It folds into
a globular pattern with four -peptide strands in each of two planes (Blake, et al., 1974). The
protein is secreted into the plasma as a tetramer with four noncovalently bound monomers
(Fig.1). Normal plasma concentration is 20-40 mg/dl with significant depression of this level
when the liver is participating in the acute phase in response to injury. It would appear that the
signals for down regulating production of transthyretin (cytokines such as IL1 and IL6) are the
same as those which cause the positive acute phase response of serum amyloid A and C reactive
protein (Costa, et al., 1986). The negative acute phase phenomenon of transthyretin is used by
clinicians to monitor nutritional status of their patients. Transthyretin appears not to be essential
for life since the murine gene knockout model fails to result in any abnormality in fetal
development or life-span of the animals which produce no transthyretin (Episkopou, et al.,
1993). These animals do have very low plasma levels of vitamin A, but show neither signs of
hyperthyroidism nor vitamin A deficiency. Even so, transthyretin is firmly entrenched in the
phylogenetic evolution of vertebrate species being present in both birds and reptiles and its
primary structure has been stable throughout evolution (Richardson, 1994).
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The gene for transthyretin is a single copy on the long arm of chromosome 18 (Wallace,
et al., 1985). It was first localized using mouse/human hybrid cell lines and subsequently more
closely localized using in situ hybridization (18 q11.2-q12.1) (Sparkes, et al., 1987). The gene
spans approximately 7 kb, has 4 exons each of approximately 200 bases (Fig. 2) (Tsuzuki, et al.,
1985; Sasaki, et al.,1985). The first exon codes a 5 region with an 18 amino acid signal peptide
and the first three amino acid residues of the mature protein. Exon 2 codes for residues 4-47,
exon 3, 47-92, exon 4, 93-127. The gene has 5 regulatory regions located within 200 bp of the
initiation codon and further enhancer sequences at least 2,000 bp 5 which may be important for
expression at extra-hepatic sites 12. While plasma transthyretin is predominantly synthesized by
the adult liver, it is also synthesized by the choroids plexus of the brain and mRNA is also
present in the retinal pigment epithelium, pituitary and pancreas19, 20 . Choroid plexus synthesis
would appear to be necessary for the thyroid hormone across the basement membrane into the
cerebral spinal space. Reason for synthesis is yet unknown.
The metabolism of transthyretin is largely unknown. The binding of RBP to transthyretin
saves this small protein (21,000 daltons) from plasma clearance via filtration in the kidney.
However, when the complex gives up retinal, RBP dissociates from transthyretin and goes to
meet its fate. Transthyretin evidently can recirculate to bind more RBP-vitamin A. Plasma
residence time of transthyretin is approximately 20-24 hours, representing a plasma half-life of
no more than 15 hours (Benson, et al., 1996). This is really very rapid turnover for a plasma
protein, compared to plasma residence time of apolipoprotein AI which is 5 days, and that of
albumin which is approximately 27 days (t ½ =19 days).
Transthyretin Amyloidosis
There are now over 90 known mutations in transthyretin (Dwulet and Benson, 1983)
(Fig. 3). The majority are associated with systemic amyloidosis, a late onset autosomal
dominant disease. Some mutations have been found in single families, others in multiple
families, and still others show evidence that the same mutation occurred multiple times. This is
particularly true for the methionine 30 transthyretin variant which can be present on at least three
different haplotypes (Yoshioka, et al., 1989). It has been hypothesized that the presence of the
Met30 mutation on several haplotypes is a result of a “hot spot” at this codon with a CpG
dinucleotide. There are 13 potential mutations that could be the result of “hot spots” in the
transthyretin coding sequence. To date, five have been identified (Gly6Ser, Val30Met,
Arg104Cys, Ala109Thr, Thr119Met, Val122Ile). Of these, Gly6Ser, Thr109 and Met119 are not
associated with amyloid fibril formation. While the sole individual described with Arg104Cys
transthyretin had peripheral neuropathy, nerve biopsy did not show amyloid, and there was not a
family history of amyloid. It is possible that this mutation is not associated with amyloidosis.
Most variants of transthyretin are not associated with amyloidosis. Most variants of transthyretin
are not associated with any postulated “hot spots” in the coding region. The Ser6 variant is the
only known polymorphism, prevalence of approximately 12% in the Caucasian population. All
the other mutations are present in less than 2% of the population, except in the restricted areas of
Northern Sweden where greater than 2% of inhabitants have the Met30 gene and in African
Americans, when considered as a group, where approximately 3% have a Val122Ile mutation.
One possible explanation of the large number of pathogenic mutations in transthyretin is that the
amyloidosis is a delayed onset disease and, therefore, there is a lessened
degree of selection against perpetuation of a pathogenic mutation. Whether there are many more
variants of transthyretin that are not associated with transthyretin has not been determined, since
no large population study has been undertaken to look for nonpathogenic transthyretin mutations.
In reality, there may not be many more nonpathogenic mutations to be discovered. The
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argument can be made that practically any structural change in this heavily -pleated sheet
protein may result in amyloid fibril formation. The fact that normal transthyretin makes amyloid
fibrils argues in favor of this hypothesis.
Clinical Features of Transthyretin Amyloidosis
Peripheral neuropathy is the major clinical manifestation of transthyretin amyloidosis
(Andrade, 1952). This was the basis for naming the syndrome familial amyloidotic
polyneuropathy (FAP). However, it has become obvious that neuropathy does not occur in all
patients with transthyretin amyloidosis, and indeed, many of these syndromes have minor
degrees of peripheral neuropathy. The classic presentation as described by Andrade in his report
of Portuguese families with amyloidosis, is sensory neuropathy starting in the lower extremities.
This usually begins as a typical small fiber neuropathy with inability to discriminate temperature,
then touch, and is followed by varying degrees of dyesthesias which at times may be relatively
debilitating. The signs of neuropathy progress proximally at varying rates. Typically, five years
or more may pass before the sensory neuropathy reaches the level of the knees. By this time the
neuropathy usually affects the hands. The symptoms in the upper extremities may be
complicated by appearance of the carpal tunnel syndrome, a compression neuropathy of the
median nerve. While the neuropathy starts in the lower extremities as pure sensory changes,
evidence of motor neuropathy follows within a few years. This is often noted as relative loss of
extensor function of the toes and foot. A slapping gait ensues and affected subjects are unstable
while walking. The sensorimotor neuropathy often progresses over 10, 15, to 20 years with the
affected individual progressing from use of ankle braces to canes, to crutches, and then to a
wheelchair. Autonomic neuropathy may occur as the first clinical symptom of this disease.
Males are often evaluated for other causes of sexual impotence before the diagnosis of
amyloidosis is suspected. Urinary retention from bladder dysfunction may be found.
Constipation alternating with diarrhea is a common feature as are nausea and vomiting, signs of
delayed gastric emptying. Orthostatic hypotension is common and may be incapacitating. This
feature is most problematic when individuals also have cardiac amyloid deposition with
decreased cardiac filling. Any sudden movement requiring increased cardiac output causes
decreased perfusion of the central nervous system. Late in the course, cachexia is common and
this may severely complicate the deficiencies caused by neuropathy and cardiomyopathy.
Variations on the theme include the involvement of the vitreous of the eye in a number of
the kindreds. Approximately a third of transthyretin mutations are associated with vitreous
deposits of amyloid; however, this finding is not uniform within families. In different kindreds,
a single mutation may have different presentations. Most notably, Swedish patients with Met30
transthyretin have a high incidence of vitreous opacities with presentation at a fairly advanced
age (58 years); whereas Portuguese patients have a lower incidence of vitreous opacities, but
have presentation of neuropathy at an early age (mean 32 or 33 years). Some transthyretin
variants present as pure cardiomyopathy (e.g. Met111) (Frederikson, et al., 1962). The
Indiana/Swiss kindred (Ser84) has 100% incidence of cardiomyopathy (Benson and Dwulet,
1983) and this also appears to be true for the Appalachian kindred (Ala60) (Benson, et al., 1987).
Significant renal amyloidosis is less common than cardiac amyloidosis in most of the
kindreds. Recently attention has been directed toward kindreds having transthyretin amyloidosis
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with extensive leptomeningeal amyloid. This is the hallmark of the Ohio kindred with
oculoleptomeningeal amyloidosis (Gly30) (Goren, et al., 1980; Peterson, et al., 1997) and a
recently reported kindred from Hungary (Gly18) in which the first clinical manifestation is
dementia (Vidal, et al.,1996). There are kindreds (e.g. His114) in which the only clinical
manifestation is carpal tunnel syndrome (Murakami, et al., 1994). The His69 mutation has been
associated with vitreous opacities alone (Zeldenrust, et al., 1994), but in another family causes
oculoleptomeningeal amyloidosis. Features of the disease in particular kindreds make
familiarity with the different clinical expressions of the various transthyretin variants essential.
Following are brief descriptions of reported amyloid syndrome associated with each of the
transthyretin mutations (Table 1). References are given for reported mutations so the reader can
obtain more detail if needed.
Kindreds and Transthyretin Variants
Arginine 10 (C10R): Only one kindred has been described with this variant. The family
lives in Eastern Pennsylvania with ancestors from Hungary (Uemichi, et al., 1992). The clinical
picture includes restrictive cardiomyopathy, polyneuropathy starting in the lower extremities,
gastrointestinal symptoms occurring usually after age 60. Vitreous opacities and carpal tunnel
syndrome have also occurred in affected subjects.
Proline 12 (L12P): One patient from the United Kingdom has been described with this
mutation (Brett, et al., 1999). Intracerebral hemorrage was associated with extensive meningeal
amyloid deposits. This patient also had hepatic amyloid deposits as measured I 123 SAP
scintigraphy. The spleen and the kidney were also positive by this scanning technique (Booth, et
al., 1996).
Glutamic Acid 18 (D18E): A patient from South America was reported to have typical
amyloidotic polyneuropathy (Booth, et al., 1996). This mutation has been found in the United
States associated with cardiac amyloidosis.
Glycine 18 (D18G): Members of a Hungarian kindred were reported to present with
dementia, spasticity, ataxia and hearing loss. Amyloid deposits in the meningeal vessels and
subpial areas were positive for transthyretin by immunohistochemistry. Lesser amounts of
amyloid deposition were found in kidney, skin, ovaries, and peripheral nerves and reported as
clinically nonsignificant (Garzuly, et al., 1996; Videl , et al., 1996).
Asparagine 18 (D18N): Clinical history not reported (Connors, et al., 2001).
Isoleucine 20 (V20I): This mutation has been reported twice; once in a German family in
which the proband was 64 years old and presented with severe cardiac disease (Jenne, et al.,
1996). Vascular amyloid was present in the liver, kidney, and rectal biopsy. The second report
was of a 50 year old male who presented to the Mayo Clinic with a two year history
gastrointestinal discomfort. Again, cardiac amyloidosis was found and an endomyocardial
biopsy was positive when stained for transthyretin. It was not mentioned whether the patient was
of German extraction.
Asparagine 23 (S23N): A 44 year old man of Portuguese descent presented with severe
cardiomyopathy which was ultimately treated by cardiac transplantation. No symptoms of
neuropathy were presented (Connors, et al., 1999).
Serine 24 (P24S): This mutation has been found in only one family originally from
Kentucky (Uemichi, et al., 1995). Affected subjects have carpal tunnel syndrome,
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gastrointestinal involvement with diarrhea and cardiomyopathy. The syndrome usually starts
after age 50 and most patients live to at least age 65 before dying of cardiac complications.
Serine 25 (A25S): This mutation is associated with rapidly progressive neuropathy and
cardiomyopathy starting between age 50 and 60 years. In the one family reported it was the
result of a de novo mutation. (Yazaki, et al., 2002).
Methionine 28 (V28M): A Portuguese man (62 years of age) had peripheral and
autonomic neuropathy without cardio or renal abnormality (De Carvalho, et al., 2000).
Methionine 30 (V30M): The methionine 30 variant of transthyretin is the most common.
It has been found in kindreds from many countries including Portugal, Japan, Sweden, England,
Brazil, Greece, and the United States. While the original description was a typical sensorimotor
neuropathy starting in the lower extremities, practically every variation on the theme has been
seen including vitreous opacities alone, and carpal tunnel syndrome (Andrade, 1952). Extensive
leptomeningeal amyloid has been reported in some kindreds (Julião, et al., 1974; Ushiyama, et
al., 1991).
Alanine 30 (V30A): Only one family of German descent has been described with this
mutation (Jones, et. al., 1992).
Leucine 30 (V30L): The transthyretin variant was reported in a Japanese woman in her
sixth decade that presented with diarrhea, weight loss and sensory neuropathy in the lower
extremities (Murakami, et al., 1992; Nakazato, et al., 1992).
Glycine 30 (V30G): This mutation was first discovered in an American man of French
ancestry with vitreous opacities (Herbert, et al., 1993). It has recently been found in the Ohio
kindred of a German origin which was reported as oculoleptomeningeal amyloidosis (Goren, et
al., 1980; Petersen, et al., 1997). The syndrome as reported had minor systemic deposition of
amyloid and no extensive peripheral neuropathy, but was characterized by vitreous opacities and
extensive leptomeningeal amyloid deposition. Dementia and ataxia we reported as part of the
syndrome.
Isoleucine 33 (F33I): This mutation has been found in one kindred in Israel (Nakazato, et
al., 1984). The family had immigrated to Israel from Poland (Gafni,, et al., 1985). Vitreous
opacities, peripheral neuropathy, diarrhea, and impotence were features of this disease.
Leucine 33 (F33L): Only one individual has been reported with this mutation (Harding,
et al., 1991). He was of Polish and Lithuanian heritage and developed lower limb neuropathy
and cardiomyopathy. There was no family history at the time of this report.
Valine 33 (F33V): This mutation was reported from a single individual in the United
Kingdom with typical FAP. There was no definite family history (Booth, et al., 1996).
Threonine 34 (R34T): This mutation was described in one family with three affected
brothers living in the Puglia area of Italy. The disease presents as polyneuropathy after age 50
with restrictive cardiomyopathy (Patrosso, et al., 1998).
Asparagine 35 (K35N): The one patient reported with this mutation had typical amyloid
polyneuropathy. This patient lived in France, but the country of origin could not be determined.
(Reilly, et al.,1995).
Proline 36 (A36P): This mutation has been described in two kindreds; one American
family of Greek origin and an Ashkenazic Jewish family (Jacobson, et al., 1992; Jones, et al.,
1991). Age of onset may be as early as 28. The syndrome includes peripheral neuropathy,
autonomic neuropathy, and vitreous opacities.
Alanine 38 (D38A): A 63 year old Japanese woman presented with peripheral
neuropathy, atrioventricular heart block, and congestive heart failure (Shimazu, et al., 1998;
Kishikawa, et al., 1999).
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Leucine 41 (W41L): A 45 year old woman presented with vitreous amyloid and no
systemic symptoms (Yakazi, et al., 2002a).
Glycine 42 (E42G): This mutation has been reported from two areas; one in Japan
(Toyama prefecture) with affected subjects having lower limb neuropathy, autonomic
neuropathy, cardiomyopathy, and vitreous opacities (Ueno,, et al., 1990; Uemichi, et al., 1992).
In addition, an American Caucasian family which also has the Asn 90 mutation was reported to
have this disease with cardiomyopathy.
Aspartic Acid 42 (E42D): Amyloid cardiomyopathy was diagnosed in a 62 year old
individual without evidence of neuropathy (Dupuy, et al., 1998).
Serine 44 (F44S): An American man of Irish decent presented with peripheral
neuropathy at age 26. He subsequently developed severe headaches, autonomic neuropathy,
deafness, and cardiomyopathy (Klein, et al., 1998).
Threonine 45 (A45T): This mutation has been reported in an American Family of Irish
and Italian descent with affected individuals dying from restrictive cardiomyopathy (Saraiva, et
al., 1992). Onset is at approximately age 50 to 60 years of age.
Aspartic Acid 45 (A45D): This mutation associated with peripheral neuropathy and
cardiomyopathy has been reported from the United States (Jacobson, et al., 1998). The proband
had Asp 45 and Ser6, while the proband’s father who died of amyloidosis had only Asp45.
Serine 45 (A45S): A 73 year old Swedish man had carpal tunnel syndrome and
cardiomyopathy without evidence of axonal neuropathy (Janunger, et al., 2000).
Arginine 47 (G47R): This was reported as a de novo mutation in transthyretin in a 38
year old Japanese man (Murakami, et al., 1992). Both parents were negative for the mutation.
Autonomic neuropathy started at age 29 with subsequent development of polyneuropathy.
Alanine 47 (G47A): This was first reported in an Italian family with cardiomyopathy and
peripheral neuropathy starting in the fifth decade of life (Ferlini, et al., 1994). The mutation has
also been discovered in a French patient.
Valine 47 (G47V): This mutation was found in a Sri Lankan kindred with
polyneuropathy (Booth, et al., 1993).
Glutamic Acid 47 (G47E): Members of an Italian family had rapidly progressive
neuropathy and cardiomyopathy. Death occurred between 35 and 56 years (Pelo, et al., 2002).
Alanine 49 (T49A): Two distinct kindreds have been described with this mutation; one
in France, one in Italy, both having cardiomyopathy (Almeida, et al., 1992, Benson II, et al.,
1993). The Italian kindred was reported to have vitreous opacities, but not the French kindred.
Both have polyneuropathy and carpal tunnel syndrome starting between ages 35 and 40 and
subsequent development of cardiomyopathy.
Isoleucine 49 (T49I): A 63 year old Japanese woman presented with painful parathesias
in all four extremities. Affected members of kindred had neuropathy and cardiac amyloidosis
(Nakamura, et al., 1999).
Arginine 50 (S50R): Members of a Japanese family presented with perpheral neuropathy
and autonomic neuropathy in their early 40s (Ueno, et al., 1990). Cardiac amyloid deposits were
proven to contain transthyretin amyloid. A French/Italian woman with this mutation was also
reported (Reilly, et al., 1995).
Isoleucine 50 (S50I): This mutation was originally reported from Japan in a 56 year old
Japanese woman with a seven year history of peripheral neuropathy and autonomic neuropathy
(Nishi, et al., 1992, Saeki, et al., 1992). Cardiomyopathy was noted in another affected
individual. In a more recent report, affected subjects were as young as 46 and presented with
carpal tunnel syndrome and cardiomyopathy, as well as peripheral neuropathy.
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Glycine 51(E51G): This mutation was associated with cardiomyopathy (Jacobson, et al.,
1999).
Proline 52 (S52P): This mutation has been reported from the United Kingdom and is
associated with peripheral neuropathy, autonomic neuropathy, cardiomyopathy and renal
amyloidosis (Booth, et al., 1993).
Glutamic Acid 53 (G53E): Members of a French family had leptomeningeal and cardiac
amyloidosis presenting in the 40’s with headaches and subarachnoid hemorrage (Ellie, et al.,
2001).
Gylcine 54 (E54G): This mutation was reported in an English kindred. It gave typical
amyloid polyneuropathy and vitreous opacities. This kindred was reported to also have Ser6
(Reilly, et al., 1995).
Lysine 54 (E54K): A 32 year old Japanese man presented with neuropathy and
cardiomyopathy. He had vitreous opacities (Togashi, et al., 1999).
Proline 55 (L55P): This TTR variant has been reported twice: once in a kindred from
West Virginia which was of Dutch and German descent (Jacobson, et al., 1999). It was also
reported in a Chinese family in Taiwan (Yamamoto, et al., 1994). In both families the syndrome
is characterized by vitreous opacities, peripheral neuropathy, autonomic neuropathy and
cardiomyopathy presenting at a very early age. This syndrome has been noted before age 20 and
often results in death from restrictive cardiomyopathy with all members of one kindred dead by
age 38.
Arginine 55 (L55R): This mutation was reported from Germany and associated with
leptomeningeal amyloidosis (Atland, 1999).
Glutamine 55 (L55Q): This mutation was reported from Germany and associated with
leptomeningeal amyloidosis (Yazaki, et al., 2002).
Arginine 56 (H56R): This mutation was associated (Jacobson, et al., 1999).
Histidine 58 (L58H): This is the mutation of the Maryland/German kindreds originally
reported by Mahloudji, et al, in 1969 (Mahloudji, et al., 1969, Nichols, et al., 1989). It is
associated with slowly progressive peripheral neuropathy starting as early as age 40. Death is
usually from cardiomyopathy. There are many families with this mutation in the United States
and it is presumed that all are descended from German immigrants from Southern Germany in
the 1700s. Only one haplotype has been demonstrated for several families. One homozygous
individual has been described with a more rapid course of neuropathy and death six years after
the presentation at age 46. Recently we have discovered this mutation in a subject in Germany
(Goebel, et al., 1997).
Arginine 58 (L58R): This mutation has been reported in a single Japanese family with
one individual presenting with peripheral neuropathy, autonomic neuropathy, and carpal tunnel
syndrome at age 39 years (Saeki, et al., 1991). Vitreous opacities were also noted.
Lysine 59 (T59K): The mutation was discovered in an Italian kindred with
cardiomyopathy as a major feature of the syndrome (Booth, et al., 1991). Patients also showed
the features of peripheral neuropathy and autonomic neuropathy. Disease onset was between 49
and 64.
Alanine 60 (T60A): This mutation was discovered in a large kindred from West Virginia
which was of Irish descent (Benson, et al., 1987; Wallace, et al., 1986). The syndrome is
characterized by cardiomyopathy, although gastrointestinal symptoms are prominent. Peripheral
neuropathy is present but of less critical significance. Carpal tunnel syndrome has been reported,
vitreous opacities have not been seen. This mutation has been found in many families in the
United States, Ireland, England and also in Australia. So far, all have had the same haplotype
7
suggesting that the mutation is of common origin (Waits, et al., 1995). Disease presents after age
50 and patients may live into the 8th and 9th decade without serious compromise.
Lysine 61 (E61K): This mutation has been reported from Japan and is associated with
peripheral neuropathy (Shiomi, et al., 1993). A patient developed diarrhea at the age of 62 and
then sensorimotor neuropathy.
Leucine 64 (F64L): This mutation was reported in an individual with peripheral
neuropathy and cardiomyopathy presenting at age 66 (Ii, et al., 1991). He was an American of
Italian descent.
Serine 64 (F64S): Members of this Canadian family of Italian origin had severe
migraine, periodic obtundation, psychoses, seizures and endocerebral hemorrage. Pathologic
examination demonstrated amyloid deposition in leptomeneges around the brain and spinal cord
in the retina and in the peripheral nerves (Uemichi, et al., 1999).
Leucine 68 (I68L): This mutation was described in a 61 year old German with
dyesthesias, cardiomyopathy and polyneuropathy, but peripheral nervous system amyloid was
not proven (Almeida, et al., 1991).
Histidine 69 (Y69H): Symptoms of carpal tunnel syndrome were present in one
individual, but amyloid deposition was not proven. One individual died of brain hemorrage at
age 62. A family in Texas with origin in New York was recently found to have this variant
transthyretin as well as a large family in Canada of Swedish descent (Zeldenrust, et al., 1994).
Aspargine 70 (K70N): A New Jersey family with German ancestry reported with this
mutation associated with carpal tunnel syndrome. Disease onset may be as early as age 30 years.
Vitreous opacities were also reported (Izumoto, et al., 1992).
Alanine 71 (V71A): This mutation was found in two loci; one family from Northeastern
France with carpal tunnel syndrome as early as age 35, followed by peripheral neuropathy and
cardiomyopathy; also in subjects from Majorca, Spain. Vitreous opacities were described for
both kindreds (Benson II, et al., 1993).
Valine 73 (I73V): Multiple members of a Bangladeshi family had FAP starting at age 50
(Booth, et al., 1998).
Tyrosine 77 (S77Y): The proband of the German family from Illinois with this mutation
had typical peripheral neuropathy and diarrhea and died with renal insufficiency. However,
many individuals in the family have had cardiomyopathy. This is also the feature of a large
family from Texas, and another from Northern France. Two separate haplotypes have been
described, suggesting separate mutational events (Wallace, et al., 1988).
Phenylalanine 77 (S77F): This mutation is associated with peripheral and autonomic
neuropathy, and cardiomyopathy. Presentation in a French family was between 48 and 68 years
of age (Plante-Bordeneuve, et al., 1998).
Phenylalanine 78 (Y78F): This mutation is associated with late-onset carpal tunnel
syndrome and dermal amyloid in a French family.
Threonine 81 (A81T): A Caucasian man presented with cardiomyopathy in his late 60’s.
He had no neuropathy but had a history of Carpal Tunnel Syndrome (CTS).
Serine 84 (I84S): This is a mutation of the Indiana/Swiss kindred first described by Falls,
et. al., in 1955 and Rukavina, et. al., Rukavina, et. al., in 1956 (Falls, et al., 1955; Rukavina, et
al., 1956; Dwulet, et al., 1986). The syndrome is characterized by carpal tunnel syndrome as
early as age 30, followed by vitreous opacities in the 40s or 50s, then restrictive cardiomyopathy.
Essentially 100% of the patients have vitreous opacities and cardiomyopathy. Death is often in
the 50s, but may not occur until the 70s. Males seem to have a more rapidly progressive course
than females. Subjects with this mutation have very low levels of plasma retinol binding protein
8
and this can be used for genetic screening (Benson and Dwulet, et al., 1983). There also is a
kindred in Hungary with this mutation whose affected members show the same clinical
symptoms (Zólyomi, et al., 1988).
Asparagine 84 (I84N): This mutation has been reported in only one individual of
American and Italian descent who presented with vitreous opacities at age 62 (Skinner, et al.,
1992). Carpal tunnel syndrome and cardiomyopathy were also reported. This individual also
has a low plasma retinol binding protein level.
Threonine 84 (I84T): This mutation was reported in a 60 year old German woman with
cardiomyopathy and peripheral neuropathy (Stangou, et al., 1998).
Glutamine 89 (E89Q): This mutation was reported in a Sicilian family with carpal tunnel
syndrome, cardiomyopathy and neuropathy presenting in the fifth decade (Almeida, et al., 1992).
Lysine 89 (E89K): This mutation was discovered in an American family with peripheral
neuropathy and cardiomyopathy presenting at 55 years (Nakamura, et al., 2000).
Serine 91 (A91S): This mutation was described in a French family with peripheral
neuropathy, carpal tunnel syndrome and cardiomyopathy. The proband presented at 72 years of
age (Mirashi, et al., 1998; Plante-Bordeneuve, et al., 1998).
Lysine 92 (E92K): A 71 year old Japanese man presented with amyloid cardiomyopathy
(Saito, et al., 2001).
Glycine 97 (A97G): This mutation was reported in a Japanese kindred with
cardiomyopathy and peripheral neuropathy (Yasuda, et al., 1994). A patient developed
sensorimotor neuropathy at the age of 52, but showed well preserved autonomic function and
slow progression of the disease.
Serine 97 (A97S): This mutation was found in two Chinese brothers who moved from
Taiwan to the United States. Peripheral and autonomic neuropathy plus cardiomyopathy were
features of the disease (Lachmann, et al., 2000).
Valine 107 (I117V): This mutation was found in two American men of German descent
(Uemichi, et al., 1994). Both presented with carpal tunnel syndrome at age 57 and subsequently
developed peripheral neuropathy.
Methionine 107 (I107M): This mutation is associated with peripheral neuropathy and
cardiomyopathy (Atland, et al., 1999).
Serine 109 (A109S): A 69 year old Japanese woman had severe amyloid peripheral
neuropathy proven by sural nerve biopsy (Date, et al., 1997).
Methionine 111 (L111M): This is the mutation of the Danish kindred reported by
Frederiksen, et al., in 1962 (Fredriksen, et al., 1962; Nordlie, et al., 1988; Ranløv et al., 1992).
Affected individuals have cardiomyopathy and several studies looking for peripheral neuropathy
have failed to reveal any.
Isoleucine 112 (S112I): This mutation was reported from Italy with subjects having
peripheral neuropathy and cardiomyopathy (De Lucia, et al., 1993).
Cysteine 114 (Y114C): This mutation was reported in a kindred from Nagasaki with
peripheral neuropathy and autonomic neuropathy presenting at age 30 with subsequent
development of vitreous opacities (Ueno, et al., 1990). Cardiomyopathy was also a common
feature of this disease.
Histidine 114 (Y114H): This mutation was reported in a kindred living in Niigata
prefecture of Japan. Patients developed CTS in their 50’s without other manifestations of
amyloidosis (Murakami, et al., 1994).
9
Serine 116 (Y116S): A 75 year old French man presented with peripheral neuropathy
and carpal tunnel syndrome. A sibling and a daughter had the same mutation (Misrahi, et al.,
1998).
Serine 120 (A120S): One Afro-Caribbean patient had peripheral and autonomic
neuropathy plus cardiomyopathy (Gillmore, et al., 1999).
Isoleucine 122 (V122I): This mutation occurs in individuals presenting after age 60 and
was originally thought to represent senile cardiac amyloidosis (Gorevic, et al., 1999). The
mutation has been described predominantly in African Americans and it has been now been
reported that approximately 3% of African Americans have this mutation. A number of
individuals homozygous for the mutation have been described (Jacobson, et al., 1990; Nichols, et
al., 1991). Peripheral neuropathy is a minor clinical manifestation of this disease and death is
from congestive heart failure.
 Valine 122 (122V): This is the first deletion mutation transthyretin found to be
associated with amyloidosis (Uemichi, et al., 1997). The proband of this kindred was a 64 year
old man with approximately two years of impotence before developing peripheral neuropathy.
There is also evidence of cardiomyopathy. The proband immigrated to the United States from
Ecuador.
Alanine 122 (V122A): A 47 year old American of Welsh and English descent presented
with cardiomyopathy (Theberge, et al., 1999).
It should be noted that while some of the hereditary amyloid syndromes have been
extensively described (e.g. Met30, Ala60, Ser84), others have been described for only one
affected subject or only a few members of one family. The assumption that many of the
transthyretin variants cause the disease is by analogy alone. There is still much to be learned
about how each of these mutations is related to the clinical disease.
Nonamyloid associated variants of transthyretin include Ser6, His74, Asn90, Ser101,
Arg102, His 104, Thr109, Val109, and Met119 (Almeida, et al., 1991; Izumoto, et al., 1993,
Uemichi, et al., 1994). A mutation of arginine to cysteine at 104 was found in an individual with
symptoms of polyneuropathy, but no definite evidence of amyloid deposition (Torres, et al.,
1995). The mutations at 109 (Thr109 and Val109) are associated with euthyroid
hyperthyroxenemia (Izumoto, et al., 1993; Moses, et al., 1990). Also, some individuals with Met
119 appear to have increased thyroxine binding. Only the Ser6 mutation can be listed as a
polymorphism being present in approximately 12% of the American Caucasian population. As
mentioned, the amyloid associated isoleucine 122 allele may be considered a polymorphism in
the African American population since approximately 3% of this ethnic group carry this
mutation.
Pathogenesis
The pathogenesis of transthyretin amyloidosis is still not well understood. The extensive ß
confirmation of the protein is most certainly important in forming the ß-pleated sheet fibrils
(Fig.1). With the discovery of single amino acid substitution variants of transthyretin, it was
postulated that perturbations in the structure of the protein in some way might lead to
aggregation or polymerization of the subunit protein molecules to form the fibrils. It is not that
simple. Tertiary structure analysis of a number of the transthyretin variants has failed to show
any unifying theme which predicts the transition of soluble plasma protein to isoluble amyloid
fibril (Blake, et al., 1978; Hamilton, et al., 1993; Oatley, et al., 1984). The intramolecular
location or type of amino acid substitution in the transthyretin protein also gives little clues to
pathogenesis. Mutations from neutral to charged residues, from charged to neutral residues,
from hydrophobic to hydrophilic, or hydrophilic to hydrophobic have all been described for this
10
protein. In addition, the mutations are distributed over most of the length of the protein
molecule. All are due to single base changes causing single amino acid substitutions except for
the Val122 which is the result of a loss of codon. If tertiary structure alterations leading to
increased aggregation or polymerization are not the basis for fibril formation, the question
persists. How do single amino acid substitutions lead to fibril formation? One possibility is the
disruption of the stability of the transthyretin tetramer so that altered metabolism and
polymerization may occur (Chakrabartty, 2001; Hammarström, et al., 2001). The fact that
normal transthyretin can result in amyloid fibril formation indicates that there are factors other
than mutation events leading to this pathology. Hypothesized models of amyloid fibril formation
have been formulation are not consistent with the tetramer being the basic building block of the
fibril forming subunit. Limited studies have shown evidence of significant amounts of
proteolysis. Fragments of transthyretin representing amino acid residues 47 to 127, 49 to 127
and 52 to 127 have been demonstrated in extracted fibrils from several tissues, and a relative lack
of the amino terminal portion of transthyretin has also been noted. These findings along with the
demonstration that synthetic peptides of the carboxyl terminal end of transthyretin can give in
vitro formation of fibrils meeting the characteristics of amyloid, suggest that proteolysis may be
a significant factor in the formation of transthyretin amyloid deposits (Fig. 4). Accelerated
metabolism of variant transthyretin may also be a factor. Plasma transthyretin levels are
commonly depressed in individuals with many of the variant forms of amyloidosis. This is
found in mutant gene carriers which are not yet affected with systemic amyloid deposition.
Plasma transthyretin is synthesized predominantly by the liver and is the source of
substrate for amyloid deposits in the vascular tree, the heart, and the kidney. The liver, however,
is rarely involved with significant amyloid deposits nor is the pancreas or spleen. The reason for
organ selectivity is not readily apparent. Transthyretin is also synthesized by choroids plexus
and amyloid deposition in the leptomeninges is probably the result of this intercranial synthesis.
It has not been demonstrated, for certain, that vitreous amyloid is the result of local transthyretin
production (Munar-Quéz, et al., 2000). The predilection for the peripheral nerves also is not
understood. Amyloid deposits are unusually seen within nerve substance; although they may
originally be associated with the vasa nervorum. The involvement of the dorsal root ganglia has
not been fully appreciated, but is probably very important in this peripheral neuropathy. An
interesting observation is that transgenic mice with the methionine 30 variant of transthyretin,
while having amyloid deposits in heart, gastrointestinal tract, kidney, and other organs, have not
yet been shown to develop amyloid in peripheral nerves (Yi, et al., 1991).
Treatment
The only specific therapy for transthyretin amyloidosis is liver transplantation (Holgren,
et al., 1991; 1993; Skinner, et al., 1994). Replacement of the liver results in rapid disappearance
of variant transthyretin from the blood. The procedure has increased risk since individuals with
cardiomyopathy or severe nutritional abnormalities have greater risk of perioperative death.
Most recent reports indicate 78% survival after two years. Partial liver transplant from related
living donors has also been reported (Matsunami, et al., 1995). The reports of the appearance of
vitreous amyloid deposits after liver transplantation and the association of severe leptomeningeal
amyloid deposition with cerebral dysfunction are worrisome (Munar-Quéz, et al., 2000; Dubrey,
et al., 1997; Adams, et al., 2000). In addition, progression of cardiomyopathy has been
documented in some patients. In general, patients with the methionine 30 and the histidine 58
mutations have fared better than patients with the glycine 42 and arginine 10 mutations who have
had disease progression after liver transplantation.
11
Nonspecific therapy for patients with transthyretin amyloidosis, including diligent
management of heart failure, gastrointestinal dysfunction, and renal dialysis when indicated, can
significantly prolong life. The judicious use of cardiac pacing and recognition that any negative
inotropic drugs such as antiarrythmics should be avoided if possible in patients with restrictive
cardiomyopathy, has added to length of survival. A very significant factor in the treatment of
subjects with transthyretin amyloidosis has been genetic screening. This has resulted in the
identification of subjects with this key condition so they can receive timely diagnosis and
therapy.
Diagnosis
As with many rare diseases, diagnosis of transthyretin amyloidosis is a problem, not
primarily because of varied expression of clinical disease, but because it is not expected. It is
easy to criticize the lack of early consideration of amyloidosis in the medical evaluation of
subjects presenting with impotence, chronic diarrhea, carpal tunnel syndrome, angina pectoris, or
proteinuria. These are all early signs of amyloidosis, but they are also early signs of much more
prevalent diseases. There are, however, combinations or signs and symptoms which should
bring the diagnosis of amyloidosis to mind. Peripheral neuropathy or autonomic neuropathy in
combination with any of the major systemic conditions (angina, proteinuria, restrictive
cardiomyopathy, azotemia) demands consideration of hereditary amyloidosis in the differential
diagnosis. Carpal tunnel syndrome or vitreous opacities in a person with sensorimotor
neuropathy and any of the cardiac, renal or gastrointestinal signs raises the chance for
amyloidosis being the correct diagnosis.
Taking a good family history is most important. The presence of similar syndrome in any
relative, no matter how distant, can give reason to suspect hereditary amyloidosis. On the other
hand, the lack of the disease in the family history should not deter consideration of hereditary
amyloidosis. Most of the transthyretin variants are the result of single nucleotide changes.
These are easily detected by SSCP, ASO hybridization, RFLP, or direct DNA sequencing. The
transthyretin gene exons are small and easily amplified by PCR (Nichols, et al., 1989).Results
can be determined within 48 hours. In addition, hybrid isoelectric focusing of plasma has been
used to detect some of the transthyretin variants. Plasma RBP levels can be used to screen
individuals in the Ser84 families.
Our current strategy for DNA testing is based upon PCR of genomic DNA. If a
particular mutation is known for the family under consideration, previously described RFLP tests
are used. This requires amplification of the transthyretin exon having the known mutation and
then digestion of the PCR product with the appropriate restrictive enzyme. If the mutation is
unknown or a novel mutation is expected, all exons are amplified and then subjected to direct
DNA sequencing. If sequencing does not give adequate results, SSCP may localize the mutation
to a specific exon. This can then be studied under greater detail (e.g. M13 cloning and
sequencing).
DNA testing is a valuable tool in the treatment of individuals and families with this
genetic disease. It is also very important for genetic counseling and should be appropriately for
the overall medical care of those affected with transthyretin amyloidosis.
Summary
A tremendous amount of progress has been made in the study of transthyretin
amyloidosis. To date the most visible element of this progress has been the discovery and
description of new transthyretin mutations and the disease they cause. This has been essentially
descriptive research, but that has not been so bad. The generation of descriptive data has formed
the basis for more in-depth research on transthyretin amyloidosis, has resulted in the discovery of
12
apolipoprotein AII forms of hereditary amyloidosis and allowed patients afflicted with these
diseases to benefit from diagnostic testing, genetic counseling, prenatal testing, and treatment
such as liver transplantation. Now we are charged with the task of taking our knowledge base
and pursuing mechanistic research into pathogenesis. This hopefully will lead to a means to
prevent or cure these diseases.
References
Adams D,. Samuel D, Goulon-Goeau C, Nakazato M, Costa PMP, Feray C, Planté V, Ducot B,
Ichai P, Lacroix C, Metral S, Bismuth H and Said G (2000). The course and prognostic factors
of familial amyloid polyneuropathy after liver transplantation. Brain 123, 1495-1504.
Almeida MR, Atland K, Rauh S, Gawinowicz M, Moreira P, Costa PP and Saraiva MJ (1991).
Characterization of a basic transthyretin variant TTR Arg 102 in the German population.
Biochem Biopys Acta 1097, 224-226.
Almeida MR, Ferlini A, Forabosco A, Gawinowicz M, Moreira P, Costa PP and Saraiva MJM
(1991). Two Tranthyretin variants (TTR Ala49 and TTR Gln89) in two Sicillian kindreds with
hereditary amyloidosis. Hum Mut 1, 211-215.
Almeida MR, Hess JA, Steinmetz A, Maisch B, Atland K, Linke RP, Gawinowicz MA and
Saraiva MJM (1991). Transthyretin Leu 68 in a form of cardiac amyloidosis. Basic Res Cardiol
86, 567-571.
Atland K (1999). Common molecular characteristic of amyloidogenic TTR mutations. The 4th
Int’l Symp on FAP and Other TTR Related Disorders, Umeå, Sweden.
Andrade C (1952). A peculiar form of peripheral neuropathy. Familial atypical generalized
amyloidosis with special involvement of the peripheral nerves. Brain 75, 408-427.
Benson MD (2000). Amyloidosis In The Metabolic and Molecular Bases of Inherited Disease,
Eighth Edition, Volume IV, Chapter 209, Part 22 Connective Tissues, pp. 5345-5378. Ed by CR
Scriver, AL Beaudet, WS Sly and D Valle, B Childs, KW Kinzler and B Vogelstein, McGraw
Hill Book Co., New York, NY.
Benson MD and Dwulet FE (1983). Prealbumin and retinol binding protein serum
concentrations in the Indiana type hereditary amyloidosis. Arth Rhuem 26, 1493-1498
Benson MD, Kluve-Beckerman B, Liepnieks JJ, Murrell JR, Hanes D and Uemichi T (1996).
Metabolism of amyloid proteins. In The Nature and Origin of Amyloid Fibrils; pp 104-113, Ciba
Foundation Symposium 199 held at Palácio dos Marqueses de Pombal, Oerias, Portugal October
23-25, 1995. Edited and Published in 1996 by John Wiley & Sons Ltd., West Sussex P019 1
UD, England.
Benson MD, Wallace MR, Tejada E, Baumann H and Page B (1987). Hereditary amyloidosis:
description of a new American kindred with late onset cardiomyopathy. Arth Rhuem 30, 195200.
13
Benson MD II, Julien J, Liepnieks J, Zeldenrust S and Benson MD (1993). A transthyretin
variant (alanine 49) associated with familial amyloidic polyneuropathy in a French family. J Med
Genet 30, 117-119.
Benson MD II, Turpin JC, Lucotte G, Zeldenrust S, LeChevalier and Benson, MD (1993. A
transthyretin variant (alanine 71) associated with familial amyloidic polyneuropathy in a French
family. J Med Genet 30, 120-122.
Blake CCF, Geisow MJ and Swan IDA (1974). Structure of human plasma prealbumin at 2.5 A
resolution. J Mol Biol 88, 1-12.
Blake CCF, Geisow MJ, and Oatley SJ (1978) Structure of prealbumin; Secondary, tertiary and
quarternary interactions determined by Fourier refinement at 1.8Å. J Mol Biol 121, 339-356.
Booth DR, Booth SE, Persey MR, Tan SY, Madhoo S, Pepys MB and Hawkins PN (1996).
Three new amyloidogenic TTR mutations: PRO12, GLU18 and VAL33. Nueromuscular
Discord (Supplement) 6, S28.
Booth DR, Gillmore JD, Persey MR, Booth SE, Cafferty KD, Tennent GA, Madhoo S, Cochrane
SW, Whitehead TC, Pasvol G, and Hawkins PN (1998). Transthyretin Ile73Val is associated
with familial amyloidotic polyneuropathy in a Bangladesh family. Mutations in brief no. 158.
Online
Hum Mutat 12, 135.
Booth DR, Soutar AK, Hawkins PN, Reilly M, Harding A and Pepys MB (1993). Three new
amyloidogenic transthyretin gene mutations: Advantages of direct sequencing. In Amyloid and
Amyloidosis 1993, pp. 456-458, ed. By R Kisilevsky, MD Benson, B Frangione, J Gauldie, TJ
Muckle and ID Young, The Parthenon Pub. Group, Inc., York, PA.
Booth DR, Tan SY, Hawkins PN, Pepys MB and Frustaci A (1995). A novel variant of
transthyretin, 59 ThrLys, associated with autosomal dominant cardiac amyloidosis in an Italian
family. Circulation 91, 962-967.
Brett M, Persey MR, Reilly MM, Revesz T, Booth DR, Booth SE, Hawkins PN, Pepys MB and
Morgan-Hughes JA (1999). Transthyretin Leu12Pro is associated with systemic, neuropathic
and leptomeningeal amyloidosis. Brain 122 (Pt.2), 183-190.
Chakrabartty A (2001). Progress in transthyretin fibrillogenesis research strengthens the amyloid
hypothesis (ATTR): Recent Boston Experience. In Amyloid and Amyloidosis The Proceedings
of the Ixth International Symposium on Amyloidosis: p. 506-508 (11. Diagnosis of Amyloidosis:
11.1.5 Poster and Oral Presentation). Ed. By Miklós Bély, M.D., Ph. D., D.Sc. of the Hungarian
Academy of Science & Ágnes Apáthy, M.D. Published by David Apáthy in Hungary.
Connors TH, Theberge R, Skare J, Costello CE, Falk RH and Skinner M (1999). A new
transthyretin variant (Ser23Asn) associated with familial amyloidosis in a Portuguese patient.
Amyloid Int J Exp Clin Invest 6, 114-118.
14
Costa RH, Lai E, Darnell JE (1986). Transcription control of the mouse prealbumin
(Transthyretin) gene: Both promotor sequences and a distinct enhancer are cell specific. Mol Cel
Biol 6, 4697-4708.
Costa PP, Figuera AS and Bravo FR (1978). Amyloid fibril protein related prealbumin in
familial amyloidic polyneuropathy. Proc Natl Acad Sci 75, 4499-4503.
Date Y, Nakazato M, Kangawa K, Shirieda K, Fujimoto T and Matsukura S (1997). Detection of
three transthyretin gene mutations in familial amyloidic polyneuropathy by analysis of DNA
extracted from formalin-fixed and paraffin-embedded tissues. J Neurol Sci 150, 143-148.
De Carvalho M, Moreira P, Evangelista T, Ducla-Soares JL, Bento M, Fernandes R and Saraiva
MJ (2000) New transthyretin mutation V28M in a Potuguese kindred with amyloid
polyneuropathy. Muscle & Nerve 23, 1016-1021.
De Lucia R, Mauro A, Di Scapio A, Buffo A, Mortara P, Orsi L and Schiffer D (1993). A new
mutation on the transthyretin gene (Ser112Ile) causes an amyloid neuropathy with severe cardiac
impairment. Clin Neuropathol 12, S44.
Dickson PW, Aldred AR, Marley PD, Guo-Fen T, Howlett GJ and Schreiber G (1985). High
prealbumin and tranferrin mRNA levels in the choroids plexus of rat brain. Biochem Biophys Res
Commun 127, 890-895
Dubrey SW, Davidoff R, Skinner M, Bergethon P, Lewis D and Falk RH (1997). Progression of
ventricular wall thickening after liver transplantation for familial amyloidosis. Transplantation
64, 74-80.
Dupuy O, Bletry O, Blanc AS, Droz D, Viemont M, Delpech M, and Grateau G (1998). A novel
variant of transthyretin (Gly42Asp) associated with sporadic late-onset cardiac amyloidosis.
Amyloid: Int J Exp Clin Invest 5, 285-287.
Dwulet FE and Benson MD (1983). Polymorphisms of human plasma thyroxine binding
prealbumin. Biochem Biophys Res Commun 114, 657-662.
Dwulet FE and Benson MD (1986). Characterization of a transthyretin (prealbumin) variant
associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). J Clin Invest 78,
880-886.
Ellie E, Camou F, Vital A, Rummens C, Grateau G, Delpech M and Valleix D (2001). Recurrent
subarachnoid hemorrage associated with new transthyretin variant (Gly53Glu). Neurology 57,
135-137.
Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottsman ME and Robertson
EJ (1993). Disruption of the transthyretin gene results in mice with depressed levels of plasma
retinal and thyroid hormone. Proc Natl Acad Sci 90, 2375-2379.
15
Falls HF, Jackson JH, Carey JG, Rukavina JG and Block WD (1955). Ocular manifestations of
hereditary primary systemic amyloidosis. Arch Ophth 54, 660-664.
Ferlini A, Patrosso MC, Repetto M, Frattini A, Villa A, Fini S, Salvi F, Vezzoni P and Forabosco
A (1994). A new mutation (TTR- Ala-47) in the transthyretin gene associated with hereditary
amyloidosis. Hum Mut 4, 64-64.
Frederikson T, Gotzsche H, Harboe N, Kiaer W, and Mellemgaard K (1962). Familial primary
amyloidosis with severe amyloid heart disease. Am J Med 33, 328-348.
Gafni J, Fischel B, Reif R, Yaron M and Pras, M (1985). Amyloidic polyneuropathy in a Jewish
family. Evidence for the genetic heterogeneity of the lower limb familial amyloidotic
neuropathies. Q J Med 55, 33-44.
Garzuly F, Vidal R, Wisniewski T, Brittig F and Budka H (1996). Familial
meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin. Neurology 47,
1562-1567.
Gillmore JD, Booth DR, Pepys MB and Hawkins PN (1999). Familial amyloid polyneuropathy
in an Afro-Caribbean patient associated with a novel transthyretin variant serine 120. The 4th
Int’l Symp on FAP and Other TTR Related Disorders, Umeå, Sweden.
Goebel HH, Seddigh S, Hopf HC, Uemichi T, Benson MD and McKusick VA (1997). A
European family with histidine 58 transthyretin mutation in familial amyloid polyneuropathy.
Neuromuscular Disorders 7, 229-230.
Goren H, Steinberg MC and Farboody GH (1980). Familial oculoleptomeningeal amyloidosis.
Brain 103, 473-495.
Gorevic PD, Prelli FC, Wright J, Pras M and Frangione B (1989). Systemic senile amyloidosis.
Identification of a new prealbumin (transthyretin) variant in cardiac tissue: Immunologic and
biochemical similiarity to one form of familial amyloidotic polyneuropathy. J Clin Invest 83,
836-843.
Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O and
Steen L (1993). The x-ray crystal structure refinements of normal human transthyretin and the
amyloidgenic Val30Met variant to a 1.7-Å resolution. J Biol Chem 268, 2416-2424.
Hammarström P, Schneider F, Kelly JW (2001). Trans-Suppression of misfolding in an amyloid
disease. Science 293, 2459-2462.
Harding J, Skare J and Skinner M (1991). A second transthyretin mutation at position 33
(Leu/Phe) associated with familial amyloidotic polyneuropathy. Biochem Biophys Acta 1097,
183-186.
16
Herbert J, Younger D, Latov N and Martone RL (1993). Clinical spectrum of familial
amyloidotic polyneuropathy. In Amyloid and Amyloidosis 1993, pp. 486-488, ed. By R
Kisilevsky, MD Benson, B Frangione, J Gaudlie, TJ Muckle and ID Young, The Parthenon
Publishing Group, Inc., York, PA.
Holmgren G, Ericzon B-G, Groth C-G, Steen L, Suhr O, Anderson O, Wallin BGI, Seymour A,
Richardson S, Hawkins PN and Pepys MB (1993). Clinical improvement and amyloid
regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341, 11131116.
Holmgren G, Steen L, Ekstedt J, Groth C-G, Ericzon B-G, Eriksson S, Anderson O, Karlberg I,
Norden G, Nakazato M, Hawkins P, Richardson S and Pepys M (1991). Biochemical effect of
liver transplantation in two Swedish patients with familial amyloidoitic polyneuropathy (FAPmet30). Clin Genet 40, 242-246.
Ii S, Minnerath S, Ii K, Dyck PJ and Sommer SS (1991). Two-tiered DNA-based diagnosis of
transthyretin amyloidosis reveals two novel point mutations. Neurology 41, 893-898.
Izumoto S, Kornberg J and Herbert J (1993). Two transthyretin mutations associated with
euthyroid hyperthyroinemia. J Rhuem 20, 186.
Izumoto S, Younger D, Hays AP, Martone RL, Smith RT and Herbert J (1992). Familial
amyloidotic polyneuropathy presenting with carpal tunnel syndrome and a new transthyretin
mutation, asparagines 70. Neurology 42, 2094-2102.
Jacobson DR, Gertz MA, Kane I and Buxbaum JN (1993). Genetic analysis of 9 unrelated
patients with transthyretin (TTR)-cardiac amyloidosis: Correlation of clinical and genetic
findings and descriptions of 2 new TTR variants. In Amyloid and Amyloidosis 1993, pp. 474476, ed. By R Kisilevsky, MD Benson, B Frangione, J Gauldie, TJ Muckle and ID Young, The
Parthenon Pub. Group Inc., York, PA.
Jacobson DR, Gorevic PD, Buxbaum JN (1990). A homozygous transthyretin variant associated
with senile systemic amyloidosis: Evidence for a late-onset disease of genetic etiology. Am J
Hum Genet 47, 127-136.
Jacobson DR, Kane I, Pan T, Tufau P, Gertz MA, Gallo G and Buxbaum JN (1999). Late-onset
cardiac amyloidosis and transthyretin variants: distinguishing between senile cardiac amyloidosis
and familial amyloid cardiomyopathy. The 4th Int’l Symp on FAP and Other TTR Related
Disorders, Umeå, Sweden.
Jacobson DR, McFarlin DE, Kane I and Buxbaum JN (1992). Transthyretin Pro 55, a variant
associated with early-onset, aggressive diffuse amyloidosis with cardiac and neurologic
involvement. Hum Genet 89, 353-356.
Jacobson DR, Rosenthal CJ and Buxbaum JN (1992) Transthyretin Pro 36 associated with
familial amyloidic polyneuropathy in an Ashkenazic Jewish kindred. Human Genet 90, 158-160.
17
Janunger T, Anan I, Holmgren G, Lovheim O, Ohlsson P-I, Suhr OB and Tashima K (2000).
Brief Report- Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene:
ATTR Ala45Ser. Amyloid: Int J Exp Clin Invest 7, 137-140.
Jenne DE, Denzel K, Blatzinger P, Winter P, Obermaier B, Linke RP and Atland K (1996). A
new isoleucine substitution of Val20 in transthyretin tetramers selectively impairs dimmer-dimer
contacts and causes systemic amyloidosis. Proc Natl Acad Sci USA 93, 6302-6307.
Jones LA, Skare JC, Cohen AS, Hardsin JA, Milunsky A and Skinner M (1992). Familial
amyloidotic polyneuropathy: A new transthyretin position 30 mutation (alanine for valine) in a
family of German descent. Clin Genet 41, 70-73.
Jones LA, Skare JC, Harding JA, Cohen AS, Milunsky A and Skinner M (1991). Proline at
position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy.
Am J Hum Genet 48, 979-982.
Julião OF, Queiroz LS and de Faria JL (1974). Potuguese type of familial amyloid
polyneuropathy. Eu Neurol 11, 180-195.
Kanda Y, Goodman DS, Canfield RE and Morgan FJ (1974). The amino acid sequence of
human plasma prealbumin. J Biol Chem 249, 6796-6805.
Kishikawa M, Nakanishi T, Miyazaki A, Shimizu A, Kusaka H, Fukui M and Nishiue T (1999).
A new amyloidogenic transthyretin variant, [D38A], detected by electrospray ionization/mass
spectrometry. Amyloid: Int J Exp Clin Invest 6, 278-281
Lachmann HJ, Booth DR, Bybee A and Hawkins PN (2000). Transthyretin Ala97Ser is
associated with familial amyloidotic polyneuropathy in a Chinese-Taiwanese family. Online
Human Mutat 16, 180.
Liu K, Cho HS, Lashuel HA, Kelly JW, Wemmer DE (2000). A glimpse of a possible
amyloidogenic intermediate of transthyretin. Nature Structural Biol 7, 754-757.
Mahloudji M, Teasdall RD, Adamkiewicz JJ, Hartmann WH, Lambird PA and McKusick VA
(1969). The genetic amyloidoses: With particular reference to hereditary neuropathic
amyloidosis type II (Indiana or Rukavina type). Medicine 48, 1-37.
Matsunami H, Makuuchi M, Kawasaki S, Hasikura Y, Ikegami T, Nakazawa Y, Miyagawa S,
Takei Y-I, Ikeda S-I and Yanagisawa N (1995). A case of familial amyloid polyneuropathy
treated with partial liver transplantation using a graft from a living donor. Transplantation 60,
301-310.
Misrahi AM, Plante V, Lalu T, Serre L, Adams D, Lacroix DC, and Said G (1998) New
transthyretin variants SER91 and SER116 associated with familial amyloidotic polyneuropathy.
Mutations in brief no. 151. Online. Human Mutat 12, 71.
18
Moses AC, Rosen HN, Moller DE, Tsuzaki S, Haddow JE, Lawlor J, Liepnieks JJ, Nichols WC
and Benson, MD (1990). A point mutation in transthyretin increases affinity for thyroxine and
produces euthyroid hyperthyroxienemia. J Clin Invest 86, 2025-2033.
Munar-Qués M, Salvá-Ladaria L, Mulet-Perera P, Solé M, López-Andreu FR and Saraiva MJM
(2000). Vitreous amyloidosis after liver transplantation in patients with familial amyloid
polyneuropathy: ocular synthesis of mutant transthyretin. Amyloid: Int Exp Clin Invest 7, 266269.
Murakami T, Atsumi T, Maeda S, Tanase S, Ishikawa K, Mita A, Kumamoto T, Araki S and
Ando M (1992). A novel transthyretin mutation at position 30 (Leu for Val) associated with
familial amyloidotic polyneuropathy. Biochem Biophys Res Common 187, 397-403.
Murakami T, Maeda S, Yi S, Ikegawa S, Kawashima E, Onodera S, Shimada K and Araki S
(1992). A novel transthyretin mutation associated with familial amyloidotic polyneuropathy.
Biochem Biophys Res Common 182, 520-526.
Murakami T, Tachibana S, Endo Y, Kawaii R, Hara M, Tanase S, and Ando M (1994). Familial
carpal tunnel syndrome due to amyloidogenic transthyretin His114 variant. Neurology 44, 315318.
Nakamura Y, Hamidi Asl K, and Benson MD, (2000). A novel variant of transthyretin
(Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid 7, 46-50.
Nakamura Y, Ikeda S, Shiomi K, Matsukura S, Yoshida K, Shimizu H, Atsumi T, Kangawa K
and Matsuo H (1992). Identification of a new transthyretin variant (Ile49) in familial amyloidic
polyneuropathy using electrospray ionization mass spectrometry and nonisotopic RNase
cleavage assay. Human Hered 49, 186-189.
Nakazato M, Ikeda S, Shiomi K, Matsukura S, Yoshida K, Shimizu H, Atsumi T, Kangawa K,
and Matsuo H (1992). Identification of a novel transthyretin variant (Val30 to Leu) associated
with familial amyloidotic polyneuropathy. FEBS Lett 306, 206-208.
Nakazato M, Kangawa K, Minamino N, Tawara S, Matsuo H and Araki S (1984). Identification
of a prealbumin variant in the serum of a Japanese patient with familial amyloidotic
polyneuropathy. Biochem Biophys Res Common 122, 712-718.
Nakazato M, Kangawa K, Minamino N, Tawara S, Matsuo H and Araki S (1984). Revised
analysis of amino acid replacement in a prealbumin variant (SKO-III) associated with familial
amyloidotic polyneuropathy of Jewish origin. Biochem Biophys Res Common 123, 921-928
Nichols WC and Benson MD (1990) Hereditary amyloidosis: detection of variant prealbumin
genes by restriction enzyme analysis of amplified genomic DNA sequences. Clin Genet 37, 4453.
19
Nichols WC, Liepnieks JJ, McKusick VA and Benson MD (1989). Direct sequencing of the
gene for Maryland/German familial amyloidotic polyneuropathy type II and genotyping by
allele-specific enzymatic amplification. Genomics 5, 535-540.
Nichols WC, Liepnieks JJ, Snyder EL and Benson MD (1991). Senile cardiac amyloidosis
associated with homozygosity for a transthyretin variant (Ile-122). J Lab Clin Med 117, 175-180.
Nichols WC, Padilla L-M and Benson MD (1989). Prenatal detection of a gene for hereditary
amyloidosis. Am J Med Genet 34, 520-524.
Nishi H, Kimura A, Harada H, Hayashi Y, Nakamura M and Sasazuki T (1992). Novel variant
transthyretin gene (Ser50 to Ile) in familial cardiac amyloidosis. Biochem Biophys Res Commun
187, 460-466.
Nordlie M, Sletten K, Husby G and Ranløv PJ (1988). A new prealbumin variant in familial
amyloid cardiomyopathy of Danish origin. Scan J Immunol 27, 119-122.
Oatley SJ, Blaney JM, Langridge R and Kollman PA (1984). Molecular-mechanical studies of
hormone-protein interactions: the interaction of T and T, with prealbumin. Biopolymers 23,
2931-2941.
Patrosso MC, Salvi F, DeGrandis D, Vexoni P, Jacobson DR, and Ferlini A (1998). Novel
Transthyretin missense mutation (Thr34) in an Italian family with hereditary amyloidosis. Am J
Med Genet 77, 135-138.
Pelo E, De Prato L, Ciaccheri M, Castelli G, Gor F, Pizzi A, Torricelli F and Marconi G (2002).
Familial amyloid plyneuropathy with genetic anticipation associated to a gly47glu transthyretin
variant in an Italian kindred. Amyloid: J Protein Folding Discord 9, 35-41.
Petersen RB, Goren H, Choen M, Richardson SL, Tresser NJ, Lynn A, Gali M, Estes M and
Gambetti P (1997). Transthyretin amyloidosis: a new mutation associated with dementia. Ann
Neurol 41, 307-313.
Plante-Bordeneuve V, Lalu T, Misrahi M, Reilly MM, Adams D, Lacroix C and Said G (1998).
Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy.
Neurology 51, 708-714.
Ranløv I, Alves IL, Ranløv PJ, Husby G, Costa PP, and Saraiva MJM (1992). A Danish kindred
with familial amyloid cardiomyopathy revisited: Identification of a mutant trans-thyretinmethionine 111 variant in serum from patients and carriers. Am J Med 93, 3-8.
Reilly MM, Adams D, Booth DR, Davis MB, Said G, Laubriat-Bianchin M, Pepys MB, Thomas
PK and Harding AE (1995). Transthyretin gene analysis in European patients with suspected
familial amyloid polyneuropathy. Brain 118, 849-856.
20
Richardson SJ, Bradley AJ, Duan W, Wettenhall REH, Harms PJ, Babon JJ, Southwell BR,
Nicol S, Donnellan SC and Schreiber G (1994). Evolution of marsupial and other vertebrate
thyroxine-binding plasma proteins. Am J Physiol 266, R1359-R1370.
Robbins J (1976). Thyroxine-binding proteins. Prog Clin Biol Res 5, 331-355.
Rukavina JG, Block WD, Jackson CE, Falls HF, Carey JH and Curtis AC (1956). Primary
systemic amyloidosis: a review and an experimental, genetic and clinical study of 29 cases with
particular emphasis on familial form. Medicine 35, 239-334.
Saeki Y, Ueno S, Takahashi N, Soga F and Yanagihara T (1992). A novel mutant (transthyretin
Ile-50) related to amyloid polyneuropathy. FEBS Lett 308, 35-37.
Saeki Y, Ueno S, Yorifuji S, Sugiyama Y, Ide Y and Matsuzawa Y (1991). New mutant gene
(transthyretin Arg58) in cases with hereditary polyneuropathy analysis. Biochem Biophys Res
Commun 180, 380-385.
Saito F, Narazato M, Akiyama H, Kitahara Y, Date Y, Iwasaki Y, Harasawa S, Hisaki R, Horie
T, Kinukawa N, Wanabe T, Sakamaki T, Yagi H, Hoshi Y, Yutani C and Kanmatsuse K (2001).
A case of late onset cardiac amyloidosis with a new transthyretin variant (Lysine 92). Human
Path 32, 237-239.
Saraiva MJ, Almeida MR, Sherman W, Gawinowicz M, Costa P, Costa PP and Goodman DS
(1992). A new transthyretin mutation associated with amyloid cardiomyopathy. Am J Hum
Genet 50, 1027-1030.
Sasaki H, Yoshioka N, Takagi Y and Sakaki Y (1985). Structure of the chromosomal gene for
human serum prealbumin. Gene, 37, 191-197.
Shimizu A, Nakanishi T, Kishikawa M, Miyazaki A and Koyama I (1998). Detection and
characterization of aberrant blood proteins and quantification of glycated hemoglobin by mass
spectrometry. Rinsho Byori 46, 461-468.
Shiomi K, Nakazato M, Matsukura S, Obnishi A, Hatanaka H, Tsuji S, Murai Y, Kojima M,
Kangawa K and Matsuo H (1993). A basic transthyretin variant (GLU61 LYS) causes familial
amyloidotic polyneuropathy: protein and DNA sequencing and PCR-induced mutation
restriction analysis. Biochem Biophys Res Commun 194, 1090-1096.
Skinner M, Harding J, Skare I, Jones LA, Cohen AS, Milunsky A and Skare J (1992). A new
transthyretin mutation associated with vitreous opacities. Asparagine for isoleucine at positioon
84. Opthalmology 99, 503-508.
Skinner M, Lewis WD, Jones LA, Kasirsky J, Kane K, Ju S-T, Jenkins R, Falk RH, Simms RW
and Cohen AS (1994). Liver transplantation as a treatment for familial amyloidotic
polyneuropathy. Ann Intern Med 120, 133-134.
21
Soprano DR, Herbert J, Soprano KJ, Schon EA and Goodman DS (1985). Demonstration of
transthyretin mRNA in the brain and other extrahepatic tissues in the rat. J Biol Chem 260,
11793-11798.
Sparkes RS, Sasaki H, Mohandas T, Yoshioka K, Klisak I, Sakaki Y, Heinzmann C and Simon
MI (1987). Assignment of the prealbumin (PALB) gene (familial amyloidotic polyneuropathy)
to human chromosome region 18q11.2-q12.1. Hum Genet 75, 151-154.
Stangou AJ, Hawkins PN, Heaton ND, Rela M, Monaghan M, Nohoyannopoulos P, O’Grady J,
Pepys MB and Williams R (1998). Progressive cardiac amyloidosis following liver
transplantation for familial amyloid polyneuropathy; implications for amyloid fibrillogenesis.
Transplantation 66, 229-233.
Theberge R, Connors L, Skare J, Skinner M, Falk RH and Costello CE (1999). A new
amyloidogenic transthyretin variant (Val122Ala) found in a compound heterozygous patient.
Amyloid: Int J Exp Clin Invest 6, 54-58.
Togashi S, Wanabe H, Nagasaka T, Shindo K, Shiozawa Z, Maeda S, Tawata M, and Onaya T
(1999). An aggressive familial amyloidotic polyneuropathy caused by a new variant
transthyretin Lys54. Neurology 53, 637-639.
Torres MF, Serra J, Ochoa JL and Saraiva MJ (1995). A new transthyretin (TTR) variant- TTR
cysteine 104. In Program and Abstracts from 3rd International Symposium of Familial
Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders, P16.
Tsuzuki T, Mita S, Maeda S, Araki S and Shimada K (1985). Structure of the human prealbumin
gene. J Biol Chem 260, 12224-12227.
Uemichi T, Gertz MA and Benson MD (1994). Amyloid polyneuropathy in two GermanAmerican families: A novel transthyretin variant (Val-107). J Med Genet 31, 416-417.
Uemichi T, Gertz MA and Benson MD (1995). A new transthyretin variant (Ser24) associated
with familial amyloid polyneuropathy. J Med Genet 32, 279-281.
Uemichi T, Liepnieks JJ, Atland K and Benson MD (1994). Identification of a novel nonamyloidogenic transthyretin polymorphism (His74) in the German population. Amyloid: Int J
Exp Clin Invest 1, 149-153.
Uemichi T, Liepnieks JJ and Benson MD (1997). A trinucleotide deletion in transthyretin gene
(V122) in a kindred with familial amyloidotic polyneuropathy. Neurology 48, 1667-1670.
Uemichi T, Murrell JR, Zeldenrust S and Benson MD (1992). A new mutant transthyretin
(Arg10) associated with familial amyloid polyneuropathy. J Med Genet 29, 888-891.
Uemichi T, Ueno S, Fujimura H, Umekage T, Yorifuji S, Matsuzawa Y and Tarui S (1992).
Familial and polyneuropathy related to transthyretin Gly42 in a Japanese family. Muscle Nerve
15, 904-915.
22
Ueno S, Uemichi T, Takahashi N, Soga F, Yorifuji S and Tarui S (1990). Two novel variants of
transthyretin identified in Japanese cases with familial amyloidotic polyneuropathy:
Transthyretin (Glu42 to Gly) and transthyretin (Ser50 to Arg). Biochem Biophys Res Commun
169, 1117-1121.
Ueno S, Uemichi T, Yorifuji S and Tarui S (1990). A novel variant of transthyretin (Tyr114 to
Cys) deduced from the nucleotide sequences of gene fragments from familial amyloidotic
polyneuropathy in Japanese sibling cases. Biochem Biophys Res Commun 169, 143-147.
Ushiyama M, Ikeda S and Yanagisawa N (1991). Transthyretin-type cerebral amyloid
angiopathy in type I familial amyloid polyneuropathy. Acta Neuropathol 81, 524-528.
Vidal R, Garzuly F, Lalowski M. Linke RP, Brittig F, Frangione B and Wisniewski T (1996).
Meningocerebrovascular amyloidosis associated with a novel transthyretin (TTR) missense
mutation at codon 18 (TTRD18G). Am J Pathol 148, 361-366.
Waits RP, Uemichi T and Benson MD (1995). Haplotype analysis of the transthyretin gene:
Evidence for multiple recurrence of the Met30 mutation in the Caucasian population. Amyloid:
Int J Exp Clin Invest 2, 114-118.
Wallace MR, Dwulet FE, Williams EC, Conneally PM and Benson MD (1986). Biochemical
and molecular genetic characterization of a new variant prealbumin associated with hereditary
amyloidosis. J Clin Invest 78, 6-12.
Wallace MR, Dwulet FE, Williams EC, Conneally PM and Benson MD (1988). Identification of
a new hereditary amyloidosis prealbumin variant, Tyr-77, and detection of the gene by DNA
analysis. J Clin Invest 81, 189-193.
Wallace MR, Naylor SL, Kluve-Beckerman B, Long GL, McDonald L, Shows TB and Benson
MD (1985). Localization of the human prealbumin gene to chromosome 18. Biochem Biophys
Res Commun 129, 753-758.
Westermark P, Sletten K, Johansson B and Cornwell GG (1990). Fibril in senile systemic
amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci 87, 2843-2845.
Yamamoto K, Hsu SP, Yoshida K, Ikeda S, Nakazato M, Shiomi K, Cheng SY, Furihata K,
Ueno I and Yanagisawa N (1994). Familial amyloid polyneuropathy in Taiwan: Identification of
transthyretin variant (Leu55Pro). Muscle- Nerve 17, 637-641.
Yasuda T, Sobue G, Doyu M, Nakazato M, Shiomi K, Yanagi T and Mitsuma T (1994).
Familial amyloidotic polyneuropathy with late-onset and well-preserved autonomic function: A
Japanese kindred with novel mutant transthyretin (Ala97 to Gly). J. Neurol Sci 121, 97-102.
Yazaki M, Connors LH, Eagle Jr RC, Leff SR, Skinner M and Benson MD (2002).
Transthyretin amyloidosis associated with a novel variant (Trp41Leu) presenting with vitreous
opacities. Amyloid J Protein Folding Disord., in press.
23
Yazaki M, Yamashita T, Kincaid J, Auger R, Dyck P and Benson MD (2002). Rapidly
progressive amyloid polyneuropathy associated with a novel variant transthyretin Ser25. Muscle
& Nerve 25, 244-250.
Yi S, Takahashi K, Naito M, Tashiro F, Wakasugi S, Maeda S, Shimada K, Yamamura K and
Araki S (1991). Systemic amyloidosis in transgenic mice carrying the human mutant
transthyretin (Met30) gene. Am Pathol 138, 403-412.
Yoshioka K, Furuya H, Sasaki H, Saraiva MJM, Costa PP and Sakaki Y (1989). Haplotype
analysis of familial amyloidotic polyneuropathy. Hum Genet 82, 9-13.
Zeldenrust SR, Skinner M, Hardings J, Skare J and Benson MD (1994). A new transthyretin
variant (His69) associated with vitreous amyloid in an FAP family. Amyloid: Int J Exp Clin
Invest 1, 17-22.
Zólyomi Z, Benson MD, Halász K, Uemichi T and Fekete G (1998). Transthyretin mutation
(Serine84) associated with familial amyloid polyneuropathy in a Hungarian family. Amyloid: Int
J Exp Clin Invest 5, 30-34.
Zhao N, Aoyama N, Benson MD, Skinner M, Satier F and Sakaki Y (1994). Haplotype analysis
of His 58, Ala60 and Tyr77 types of familial amyloidotic polyneuropathy. Amyloid: Int J Exp
Clin Invest 1, 75-79.
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Figure 1
Figure 2
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Figure 3
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Figure 4
Table 1
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