med review article inherited amyloidosislated bronchopulmonary amyloidosis, lichen amyloidosis, most...

J Med Genet 1991; 28: 73-78

Review article

Inherited amyloidosis

Merrill D Benson

The amyloidoses are a group of deposition diseases inwhich the tissue deposits are composed of proteinfibrils. These fibrils are the result of aggregation ofspecific precursor proteins into ordered structureswhich are resistant to proteolytic digestion andsolubilisation. The ordered structure of the fibrilscauses the deposits to be birefringent and, whenhistological sections are stained with Congo red, acharacteristic green birefringence is seen by polarisa-tion microscopy.The amyloidoses can be classified into broad groups

on the basis of distribution: (1) localised and (2)systemic (table 1). Both of these broad groups includehereditary and non-hereditary forms of depositiondisease. Immunoglobulin (primary) amyloidosis is themost common form of non-hereditary systemicamyloidosis. In this disease the amyloid fibrils arecomposed of monoclonal immunoglobulin light chainmolecules or degradation products of these lightchains. Reactive (secondary) amyloidosis is usuallyseen in association with chronic inflammatory diseases.The amyloid fibrils in this disease contain a degrada-tion product of the acute phase serum protein SAA.Amyloidosis associated with chronic haemodialysishas fibres synthesised from P2-microglobulin. Whilethis type of amyloidosis is usually restricted to bonesand joints, some systemic deposits may occur. Thelocalised forms of non-hereditary amyloidosis includeisolated amyloidosis of the genitourinary tract, iso-lated bronchopulmonary amyloidosis, lichenamyloidosis, most cases of Alzheimer's disease, thehyalinised islets of Langerhans in non-insulindependent diabetes mellitus, and a number of others.

Familial amyloidotic polyneuropathy (FAP) asso-ciated with variants of plasma transthyretin (pre-albumin) represents the most frequent form ofinherited amyloidosis. ' In these syndromes theamyloid fibril deposits contain the variant trans-

Table I Systemic amyloidoses.Type Chemical subunit

Immunoglobulin (AL)/primary Ig light chainsKappaLambda

Reactive (AA)/secondary Amyloid AHereditary (AH)/FAP Transthyretin

Apo AIOthers

P2-microglobulin/dialysis P2-microglobulin

thyretin and usually some normal transthyretin aswell. FAP is not specific for the transthyretinvariants, however. Recently it has been shown thatFAP can also be caused by a variant form ofapolipoprotein Al. The possibility of other proteinvariants causing FAP must be considered.

Localised forms of inherited amyloidosis can becaused by a number of protein variants. Hereditarycerebral haemorrhage with amyloidosis described asan autosomal dominant condition in Iceland is asso-ciated with Congophilic angiopathy in which theamyloid fibril deposits contain a variant of cystatin C(y trace). Hereditary cerebral haemorrhage withamyloidosis of the Dutch type has now been shown tohave Congophilic angiopathy in which the amyloidfibril deposits contain a variant of the Alzheimer 3protein. Approximately 10% of Alzheimer's diseasepatients have an inherited form of the disease, but nodefmite protein mutations have yet been described.Medullary carcinoma of the thyroid is associated withamyloid deposits containing procalcitonin.While recent advances in protein chemistry have

given us more insight into the pathogenesis of theinherited amyloidoses, perhaps the best clinicalapproach to these syndromes is from the perspectiveof the type of neuropathy and related factors such asethnicity, age of onset, and organ system involve-ment. The clinician's most frequent contact withinherited amyloidosis will be some form of FAP.While FAP is not a specific term, if the pattern of apatient's polyneuropathy is thoroughly evaluated, itwill often lead to the correct diagnosis. Althoughthere is considerable overlap, there are three basiccategories of FAP: (1) symmetrical polyneuropathy

Rheumatology Division, Department of Medicine,Indiana University School of Medicine, Clinical Building492, 541 Clinical Drive, Indianapolis, Indiana 46223,USA.M D Benson

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starting in the lower extremities with progressionproximally and association with autonomic neuro-pathy; (2) upper extremity neuropathy related tocompression of the median nerve (carpal tunnelsyndrome) followed by a more generalised, slowlyprogressive polyneuropathy with varying degrees ofautonomic involvement; (3) little or clinically insigni-ficant degree of sensorimotor neuropathy withvarying degrees of autonomic dysfunction.

Familial amyloidotic polyneuropathy type IAs originally described by Andrade,2 FAP-I starts inthe lower extremities. First there are usually paras-thaesiae and, not uncommonly, painful dysasthaesiaebefore numbness and progressive sensory loss occurs.Occasionally, however, a patient may be asymptomaticuntil he or she suffers painless injury to the feet orlegs. It has been reported that amyloid neuropathymay be associated with dissociation of the sensorymodalities such that early lack of discrimination oftemperature sensation occurs. This finding, while notspecific, may be an early clue to the diagnosis. Theneuropathy progresses relatively rapidly to involvemotor function with foot drop occurring early. Motorloss is progressive and walking becomes increasinglydifficult. Many patients spend their final years inwheelchairs. The upper extremities become involvedmonths to years after the lower extremity involvementstarts and has essentially the same progression ofparasthesiae, dysasthaesiae, and motor loss. Whilefine manipulation suffers considerably, patients areusually able to attend to activities of daily livingalthough often requiring adaptive devices. The upperextremity involvement does limit the use of prostheticdevices (canes, crutches) required to maintainambulation. Carpal tunnel syndrome occurs in a fairnumber of patients with FAP type I, but is usually notthe presenting feature. If it occurs early in thesyndrome, carpal tunnel release may be effective inrelieving dysasthaesiae in the hands, but often itoccurs after significant infiltrative neuropathy hasoccurred. At this point median nerve decompressionmay have minimal effect on alleviating symptoms.Autonomic nervous system involvement occurs in

most patients with FAP type I. Orthostatic hypo-tension is common. Bowel involvement commonlygives alternating constipation and diarrhoea and canbe severe with gastric retention and distension. Thisoften leads to malnutrition and, in patients withminiimal cardiac or renal involvement, malnutrition isa major factor in patients' death. Sexual impotence iscommon and occurs in the majority of males.Impotence occasionally can be the presenting featurein FAP-I and a patient may be referred from theurologist or the psychiatrist. Bladder retention can beanother feature of FAP-I.

Rarely, patients with FAP-I may have cranial nerve

involvement with changes in facial features and thescalloped pupil deformity. This latter finding isprobably the result of ciliary nerve involvement givingirregular constriction of the iris. It will be missed ifthe eyes are treated with a cycloplegic before examina-tion. Occasionally, involvement of the laryngeal nervewill give hoarseness.

Anhidrosis can be a feature of FAP and, while notusually a clinically important feature, should beconsidered when patients are exposed to prolongedraised ambient temperatures.The peripheral neuropathy of FAP-I often leads to

foot ulcers which can give chronic cellulitis andosteomyelitis. When the sensory neuropathy pro-gresses much more rapidly than the motor neuro-pathy, Charcot joint may occur, especially in theknee. Vitreous deposits of amyloid occur in severaltypes of FAP-I and may be the initial presentingfeature. Indeed, some patients may have loss of visionwithout symptoms of peripheral neuropathy. In theFAP-I Portuguese/Swedish syndrome (methionine 30transthyretin), vitreous deposits are seen in patientswho present at an older age.FAP-I is usually associated with a variant form of

plasma transthyretin (prealbumin). It is an autosomaldominant condition and most patients are hetero-zygous for the variant transthyretin. Patients homo-zygous for two different variants (methionine 30 andisoleucine 122) have been reported, but show noclinical features to distinguish them from theirheterozygous fellow sufferers. There are now 10single amino acid variants of plasma transthyretin thathave been found to be associated with inheritedamyloidosis. The majority of these are associated withneuropathy of the FAP type I. The classical descrip-tion is the methionine 30 variant which was originallyreported in patients in Northern Portugal, but hassubsequently been found to be the cause of amy-loidosis in Swedish, English, and Japanese families.2It has also been described in Greece, Majorca,Cyprus, Turkey, and Brazil. The clinical features inpatients with this mutation vary considerably fromone family to another, but the peripheral neuropathyis usually ofthe FAP-I variety. The age ofpresentationcan vary considerably. In Portuguese families theaverage age at onset is 32 or 33 years. In Swedenthe average age of onset is 59 years. In the Portuguesepatients progression of disease is over 10 to 15 years.Gastrointestinal, cardiac, and renal symptoms vary,but are the usual cause of death. In the Swedishpopulation vitreous opacities are frequent.The single patient with the isoleucine 33 trans-

thyretin variant (Jewish) also had FAP-I. Severegastrointestinal involvement was present. Onset ofdisease was in the late twenties and vitreous involve-ment was also a feature of the syndrome. The tyrosine77 (Illinois/German) type of inherited amyloidosis isusually associated with an FAP-I neuropathy. The

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proband of the original kindred had renal involve-ment, but his family also had members who died withcardiac disease. A French kindred with tyrosine 77transthyretin amyloidosis has predominantly cardiacdisease associated with a typical FAP-I neuropathy.FAP-I is not always associated with variants of

transthyretin. The neuropathy in an Iowa kindreddescribed by Van Allen et al3 in 1969 is typical of thetype I variety. At that time, a high association of thesyndrome with gastric ulcer led to a separate classi-fication of FAP type III. Recently it has been shownthat this syndrome is associated with a variant ofapolipoprotein Al." No transthyretin abnormality hasbeen found in this kindred and the apolipoprotein Alvariant (arginine 26) has been shown to be associatedwith the syndrome over three generations. Theamyloid deposits are composed of a truncated portionof the apolipoprotein Al molecule containing thevariant arginine 26 residue. No normal apolipoproteinA1 was present in the amyloid deposits of the onepatient that was studied in detail. Renal failure hasbeen the usual cause of death although severalpatients had perforated gastric ulcers late in theclinical course. Vitreous deposits are not a feature ofthis disease.A number of kindreds with typical FAP-I have

been described in which variants of transthyretin havenot yet been found. There have been reports thatnormal transthyretin can cause amyloidosis, but thishas not been conclusively proven at the gene level.Two recently described forms of hereditary amy-

loidosis associated with transthyretin variants wouldappear to belong in the category ofFAP-I neuropathy.These include the asparagine 90 variant and thecysteine 114 variant of transthyretin.5 6 Both of thesehave a lower limb neuropathy. The Japanese patientwith cysteine 114 was described as having significantautonomic involvement with decreased libido.Vitreous opacities were present in patients with boththe asparagine 90 and cysteine 114 amyloidosis.

Familial amyloidotic polyneuropathy type IIFAP type II was originally described in two separatekindreds of different origin: (1) a large Swiss familyfrom Indiana and (2) a kindred comprising 11different families of German origin living in theMaryland/Pennsylvania/Virginia area. FAP-Il ischaracterised by the early onset of carpal tunnelsyndrome which usually occurs around the age of 40,but may occur as early as the late 20s. Surgicaldecompression of the median nerve usually givesrelief. The flexor retinaculum and surrounding tissuesare infiltrated by amyloid deposits. A more generalisedperipheral neuropathy starts later and progressesslowly. In the Indiana kindred this gives mildproblems with walking in the later stages of thedisease. In the Maryland/German families peripheral

neuropathy can give severe, generalised, painfuldysasthaesiae as well as motor neuropathy. Boweldysfunction with alternating constipation and diar-rhoea are frequent, as is impotence. Orthostatichypotension which occurs in the Indiana/Swisskindred is more often related to the restrictivecardiomyopathy that all members of this kindreddevelop and which is the usual cause of death. Bothsyndromes usually occur at about the age of 40 andprogress over a 15 to 20 year period. Restrictivecardiomyopathy occurs in the Maryland/Germansyndrome, but not with the frequency of the Indiana/Swiss, where all persons have the cardiomyopathy.Another distinguishing feature between the twosyndromes is eye involvement. The Indiana/Swissfamily has essentially 100% incidence of vitreousopacities whereas this is not a reported feature of theMaryland/German disease.The Indiana/Swiss FAP-II is associated with a

transthyretin variant having a serine for isoleucinesubstitution at position 84. This transthyretin varianthas not been found in any other kindred so far. TheMaryland/German FAP-II is associated with ahistidine substitution at position 58 ofthe transthyretinmolecule.7 This has been found in other families withno definite connection to the original Germankindred. The reason for the early development ofcarpal tunnel syndrome with these two mutations isnot obvious. While the carpal tunnel syndrome doesoccur in other forms of FAP, the early appearanceof the syndrome in the Indiana and Maryland familiesis a distinguishing feature which is helpful in diag-nosis.

Familial amyloidotic polyneuropathy withoutsignificant neuropathyThere are a number of inherited amyloidoses asso-ciated with variants of transthyretin which do notshow clinically significant degrees of peripheralneuropathy. The alanine 60 transthyretin amyloidosisusually presents as restrictive cardiomyopathy.Peripheral neuropathy is usually present, but not of aclinically significant degree. The carpal tunnelsyndrome may occur later in the course of the disease.Autonomic involvement is a greater feature and mayresult in constipation, diarrhoea, gastric distension,impotence, and bladder retention. The onset of thissyndrome is usually after the age of 50 and manypatients live to 70 or 80 years before dying ofrestrictive cardiomyopathy. Gene carriers have beenknown to reach the age of 90 without significantdisease.The methionine 111 transthyretin variant causes

the cardiac amyloidosis originally described by Frede-riksen et al in 1962. At that time no neuropathy wasreported and subsequent re-evaluation of patients inthis kindred has not found evidence of peripheral

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Table 2 Transthyretin amyloidoses.

Amino acidsubstitution Position Clinical name Clinical feature Kindreds

Methionine 30 FAP-I LLN, bowel, AN, eye Portugal/Japan/USA/Sweden

Isoleucine 33 Jewish LLN, eye IsraelHistidine 58 FAP-II/Maryland CTS, heart USA/MarylandAlanine 60 Appalachian Heart, CTS USA/West VirginiaTyrosine 77 Illinois/German Kidney, bowel, LLN USA/IllinoisSerine 84 FAP-II/Indiana CTS, heart, eye USA/IndianaAsparagine 90 Italian LLN, eye USAMethionine 111 Danish Heart DenmarkCysteine 114 Japanese LLN, eye JapanIsoleucine 122 Senile cardiac Heart USA/Scandinavian

LLN=lower limb neuropathy. AN=autonomic neuropathy. CTS=carpal tunnel syndrome.

neuropathy. The isoleucine 122 transthyretin variantis also associated with restrictive cardiomyopathywithout significant degree of peripheral neuropathy.This type of amyloidosis presents in older persons andhas been called senile cardiac amyloidosis or senilesystemic amyloidosis.

Other FAP syndromesFAP type IV (Finnish) was originally described byMeretoja.9 This syndrome is associated with latticecorneal dystrophy, which has little or no morbidity,and cranial neuropathy. Patients may develop sys-temic amyloid deposits. Recently these deposits havebeen found to contain a portion of plasma gelsolin.10No specific mutation has been reported for thisautosomal dominant condition.

Amyloid proteinsHereditary amyloidosis is most frequently associatedwith variants of plasma transthyretin, the product of asingle copy gene on chromosome 18 (18q11.2-q12.1)(table 2). The gene has four exons which code for the127 amino acid residue mature protein and an 18residue signal peptide. The first exon codes for thesignal peptide and the first three amino acids of themature protein. No mutations in this exon have beenreported. Exon 2 codes for amino acids 4 to 47 andcontains two defined point mutations associated withamyloidosis (methionine 30 and isoleucine 33). Exon3 contains five point mutations associated withhereditary amyloidosis (histidine 58, alanine 60,tyrosine 77, serine 84, asparagine 90). Exon 4 containsan additional three point mutations reported to beassociated with hereditary amyloidosis (methionine111, cysteine 114, and isoleucine 122). The molecularmass of the transthyretin monomer is 14 500, but inplasma transthyretin is a homotetramer (55 kd)having four units which are non-covalently bound.The monomer shows extensive 13 structure with eight13 pleated sheets arranged in two parallel planes. Two

monomers associate to give a dimer having eight 13strands in each of two planes. Two dimers non-covalently bond to give the circulating tetramer. Thisextensive 13 structure is probably why prealbumin hassuch a tendency to form the 13 amyloid fibrils.

Transthyretin has two known functions. It bindsthyroxine in a central channel of the tetramer and isresponsible for about 20% ofplasma thyroxine bindingin humans. Transthyretin also associates with retinolbinding protein and presumably transports retinolwithout loss of the small RBP (21 000 daltons)molecule through the kidney. Variants of prealbuminwhich have not been found to be associated withhereditary amyloidosis include serine at position 6,threonine at position 109, and methionine at position119.Apolipoprotein Al is part of the HDL complex and

is not projected to have extensive 13 structure.However, the first 55 residues of the 83 residue aminoterminal fragment that is found in the Iowa type ofhereditary amyloidosis is predicted to have mostly 13pleated sheet structure. The gene for apolipoproteinAl is on chromosome 11 and is linked to apolipoproteinC. Pathogenic mechanisms in this type of amyloid-osis may be similar to reactive amyloidosis whereserum amyloid A (SAA) is partially degraded to a 76amino acid moiety, which becomes the building blockof amyloid fibrils. SAA is also a part of HDL andindeed may displace apo Al from the HDL particle.SAA does not cause amyloid deposits in peripheralnerve and there have been no point mutations in SAA,which have been reported to give reactive amyloidosisa hereditary nature.The gene for gelsolin exists as a single copy on

chromosome 9. It codes for a circulating proteinwhich has a mass of 93 000 daltons." Only a 9000molecular weight fragment which must be from themiddle of the molecule is deposited in the amyloiddeposits of the Finnish type (FAP-IV). Gelsolin is anactin binding protein which may be involved indissolution of actin. Two separate proteins, oneintracellular and one extracellular with an additional

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25 amino acid residues on the amino terminus, are theproducts of the same gene with different transcriptionstart sites.

Proteins which are associated with localised formsof inherited amyloidosis include cystatin C, which is aprotease inhibitor, and also the i protein ofAlzheimer'sdisease, which may also be a protease inhibitor. iprotein is coded on chromosome 21 and only thecarboxy terminal 42 amino acid residues are incor-porated into amyloid fibrils.

Detection of gene carriersThe hereditary amyloidoses are an excellent exampleof molecular genetics in medicine. The use ofmolecular biology to identify genetic mutations whichdirectly relate to clinical syndromes has made a basisfor in depth studies on pathogenesis. In addition, theuse of molecular biology techniques to identify genecarriers of the many different variant alleles has vastlyexpanded the scope of the clinical approach to thesediseases.The inherited amyloidoses are all delayed onset and

autosomal dominant. The ability to detect genecarriers has not only been of value in geneticcounselling and diagnosis, it has also allowed therecognition of inherited diseases which have less thancomplete penetrance or develop at a very advancedage. It has allowed analysis of differences in clinicalsyndromes in different ethnic groups where theidentical mutation is found.

Since the complete genomic structure of thetransthyretin gene is known, it has been relativelyeasy to develop methods to detect the various variantalleles. Most of the mutations in transthyretin that areassociated with amyloidosis have resulted in changesin the restriction enzyme pattern of the transthyretingene (table 3). This originally allowed the develop-ment of tests for these genes using standard Southernanalysis with radiolabelled probes. More recently, thedevelopment of enzymatic amplification of genomic

Table 3 Direct DNA tests.

Variant Mutation Restriction enzyme

TransthyretinMet 30 G-,A Nstllie 33 TA BclIHis 58 T -A None*Ala 60 A--G PvuIITyr 77 C--A SspISer 84 T G AluIAsn 90 C--A SphIMet 111 C- A DdeICys 114 A--G None*Ile 122 G-A MaeIII

Apo AlArg 26 G-pC None*

*Use allele specific PCR.

segments using the polymerase chain reaction hasallowed development of more rapid testing. 12 In thismethod, specific oligonucleotide primers are used toamplify each of the relatively short exons of thetransthyretin gene. Restriction enzymes can then beused to detect the mutant allele associated withamyloidosis. Since we now have 10 different mutationsassociated with transthyretin amyloidosis, theclinician must have some preliminary information toask for the appropriate test. First, if the patient withneuropathy belongs to a kindred in which the specificmutation has been previously identified, the appro-priate test can be requested. If the patient does nothave such a history, then the clinician must useknowledge of the hereditary amyloidoses to proceedwith the diagnosis. Since amyloidosis is usuallydiagnosed by biopsy, appropriate staining with anti-transthyretin antibody can usually identify the trans-thyretin nature of the amyloidosis and exclude non-hereditary forms and hereditary amyloidoses resultingfrom other proteins such as apolipoprotein Al orgelsolin. Unfortunately, immunohistochemistry is notcompletely specific in all cases. If a patient issuspected of having a transthyretin type of familialamyloidotic polyneuropathy, it is important to knowthe ethnic origin of the patient and the pattern ofneuropathic involvement (type 1 versus type 2 neuro-pathy). For example, if a patient is Portuguese andhas a typical type 1 neuropathy, then the first test tobe done is for the methionine 30 gene. This wouldinvolve amplification ofexon 2 and restriction analysisof the amplified product with the restriction enzymeNsiI. If a patient presents with carpal tunnel syn-drome, the first test might be for the serine 84transthyretin allele or the histidine 58 allele. Both ofthese mutations are in exon 3 of transthyretin. If thesetests are negative, the next most appropriate mutationcan be pursued. Once the appropriate mutation isfound, the patient's family can easily be screened forthat particular mutation. While most of the trans-thyretin variants can be detected by restrictionenzyme analysis on PCR products, some of the diseasealleles do not give changes in restriction enzymepattern. For this reason, allele specific analysis hasbeen developed in which amplification of genomicDNA only occurs if the mutation is present. In thistest, which is used for the histidine 58 mutation, anoligonucleotide primer is made such that the mutationis at the 3' end of the oligonucleotide. Only in thepresence of the point mutation will the primer annealappropriately and give amplification. This test may benecessary for the cysteine 114 mutant which also doesnot change the restriction pattern.

Similar testing has been developed to detect thearginine 26 mutant of apolipoprotein Al in the Iowatype of hereditary amyloidosis. In this test a specificoligonucleotide with the 3' mismatch gives amplifica-tion only in the presence of the variant allele. Peovle

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with two normal apo Al alleles do not show anyamplification and therefore are not gene carriers.13

Genetic counsellingThe inherited amyloidoses are autosomal dominantdiseases as would be expected with a structural genedefect. The majority of persons with transthyretinamyloidoses are heterozygous, having one normalallele and one variant allele of transthyretin. A fewpatients who are homozygous for the methionine 30transthyretin allele have been described but with nomore severe disease than those who are heterozygotes.Since this is a single copy gene and one mutant allelepredicts the disease, each offspring of an affectedperson has a 50% chance of receiving the allele andtherefore developing the disease. Since hereditaryamyloidosis is a delayed onset disease, most subjectshave already had their children before development ofclinical symptoms. Development of the direct DNAtests has now allowed detection of gene carriers beforehaving children and therefore presumably might givemore effective genetic counselling. So far this has notshown a definite effect on marriage patterns or familyplanning. Even prenatal testing, which is now avail-able and which has been done for two of the differentmutations, has not been used as a method to preventtransmission of the mutant alleles. It would appearthat subjects with the transthyretin amyloidosis arenot as concerned with transmission of this delayedonset disease as one might project. On the other hand,the ability to test persons at risk for a mutant gene anddetermine that they are free of the disease allele can beof considerable psychological benefit. One benefitfrom recognition of the inherited nature of familialamyloidotic polyneuropathy and the ability to testsubjects for the disease allele is in the realm ofdiagnostic medicine. If a person is shown to have agene for amyloidosis, that person may be protectedfrom misdiagnosis and therefore not be treated forimmunoglobulin or reactive amyloidosis when that isnot appropriate. Also, patients with transthyretinrestrictive cardiomyopathy are frequently mis-diagnosed and treated as for other forms of heartdisease.

Therapy and future prospectsAt the present time there is no specific therapy for anyform of hereditary amyloidosis. Since the diseases arethe result of point mutations which cause amino acidsubstitutions in structural proteins, some mechanismof altering gene expression would be necessary toprevent the disease at the genetic level. As weunderstand more about the biochemistry of proteinssuch as transthyretin, other measures may be used toalter the biochemistry and therefore the formation offibrils which cause the disease. Of particular impor-

tance may be the understanding of why some subjectswith a particular mutation develop the clinicalsyndrome much later than others with the exact samemutation. Studies on the serine 84 transthyretin hasindicated that amyloid fibril deposition does not occurat a young age and progress to a clinical thresholdamount. It would appear that fibril synthesis anddeposition is indeed a delayed phenomenon involvingother biochemical mechanisms and not gene expres-sion.Although there are no specific therapies for inherited

amyloidoses, modern medicine has much to offer tothe person afflicted with these diseases. Neuropathicsymptoms may be alleviated in large part by medi-cines such as amitryptoline. Physical therapy andadaptive devices may prolong a person's functionallife and feeling of well being. A few patients with endstage renal disease have received transplants or renaldialysis or both. Cardiac disease may be treated withartificial pacemakers for conduction defects andmedicines which alleviate symptoms of restrictivecardiomyopathy. Surgical removal of vitreousdeposits has restored sight to many subjects withamyloid eye involvement. Hopefully, more specifictherapy for these syndromes will be developed asmore insight into pathogenesis is obtained.

1 Benson MD, Wallace MR. Amyloidosis. In: The metabolic basis ofinherited disease. New York: McGraw-Hill, 1989:2439-60.

2 Andrade C. A peculiar form of peripheral neuropathy. Familialatypical generalized amyloidosis with special involvement of theperipheral nerves. Brain 1952;75:408-26.

3 Van Allen MW, Frohlich JA, Davis JR. Inherited predispositionto generalized amyloidosis. Neurology 1969;19:10-25.

4 Nichols WC, Dwulet FE, Liepnieks J, Benson MD. Variantapolipoprotein Al as a major constituent of a human hereditaryamyloid. Biochem Biophys Res Commun 1988;156:762-8.

5 Skare JC, Saraiva MJ, Alves IL, et al. A new mutation causingfamilial amyloidotic polyneuropathy. Biochem Biophys ResCommun 1989;164:1240-6.

6 Ueno S, Uemichi T, Yorifuji S, Tarui S. A novel variant oftransthyretin (TyrI14 to Cys) deduced from the nucleotidesequences of gene fragments from familial amyloidotic poly-neuropathy in Japanese sibling cases. Biochem Biophys ResCommun 1990;169:143-7.

7 Nichols WC, Liepnieks JJ, Benson MD, McKusick VA. Directsequencing of the gene for Maryland/German familialamyloidotic polyneuropathy type II and genotyping by allele-specific enzymatic amplification. Genomics 1989;5:535-40.

8 Frederiksen T, Gotzsche H, Harboe N, Kiaer W, MellemgaardK. Familial primary amyloidosis with severe amyloid heartdisease. Am J Med 1962;33:328-48.

9 Meretoia J. FamiLial systemic paramyloidosis with lattice dys-trophy of the cornea, progressive cranial neuropathy, skinchanges and various internal symptoms (a previously un-

recognized heritable syndrome). Ann Clin Res 1969;1:314-24.10 Maury CPJ, Alli K, Baumann M. Finnish hereditary amyloidosis

amino acid sequence homology between the amyloid fibrilprotein and human plasma gelsoline. Febs Lett 1990;260:85-7.

11 Kwiatkowski DJ, Stossel TP, Orkin SH, Mole JE, Colten HR,Yin HL. Plasma and cytoplasmic gelsolins are encoded by a

single gene and contain a duplicated actin-binding domain.Nature 1986;323:455-8.

12 Nichols WC, Benson MD. Hereditary amyloidosis: detection ofvariant prealbumin genes by restriction enzyme analysis ofamplified genomic DNA sequences. Clin Genet 1990;37:44-53.

13 Nichols WC, Gregg RE, Brewer HB, Benson MD. Charac-terization of a genetic mutation (apolipoprotein AT-Iowa)associated with familial amyloidotic polyneuropathy type III.Genomnics 1990;8:318-23.

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