The Hereditary Amyloidoses


Protein

cDNA changea

Amino acid changeb

Codon change

Clinical features

Transthyretin

Greater than 120 mutations c
 
Apolipoprotein AI

148G→C

Gly26Arg

GGC26CGC

PN, Nephropathy

172G→A

Glu34Lys

GAA34AAA

Nephropathy

178T→G

Ser36Ala

TCC36GCC

Nephropathy

251T→G

Leu60Arg

CTG60CGG

Nephropathy

220T→C/A

Trp50Arg

TGG50CGG/AGG

Nephropathy

del250-284insGTCAC

del60-71insVal/Thr

del60-71ins GTCAC

Hepatic

251T→G

Leu60Arg

CTG60CGG

Nephropathy

263T→C

Leu64Pro

CTC64CCC

Nephropathy

del280-288

del70-72

del70-72GAGTTCTGG

Nephropathy

284T→A

Phe71Tyr

TTC71TAC

Palatal mass

294insA(fs)

Asn74Lys(fs)

AAC74AAAC(fs)

Nephropathy

296T→C

Leu75Pro

CTG75CCG

Hepatic

341T→C

Leu90Pro

CTG90CCG

Cardiomyopathy, cutaneous, laryngeal

532insGC(fs)

Ala154(fs)

GCC154GGC(fs)

Nephropathy

535delC

His155Met(fs)

535delC

Nephropathy

562G→T

Ala164Ser

GCC164TCC

Nephropathy

581T→C

Leu170Pro

CTG170CCG

Laryngeal

590G→C

Arg173Pro

CGC173CCC

Cardiomyopathy, cutaneous, laryngeal

593T→C

Leu174Ser

TTG174TCG

Cardiomyopathy

595G→C

Ala175Pro

GCX175CCXd

Laryngeal

604T→A

Leu178His

TTG178CAT

Cardiomyopathy, laryngeal

391-393delLys107del
 
delAAG

Aortic intima

Gelsolin

594G→A

Gly167Arg

GGG167AGC

Nephropathy

633C→A

Asn184Lys

AAC184AAA

Nephropathy

640G→A

Asp187Asn

GAC187AAC

PN, lattice corneal dystrophy

640G→T

Asp187Tyr

GAC187TAC

PN

Cystatin C

280T→A

Leu68Gln

CTG68CAG

Cerebral hemorrhage

Fibrinogen A

1718G→T

Arg554Leu

CGT554CTT

Nephropathy

1633G→A

Glu526Lys

GAG526AAG

Nephropathy

1634A→T

Glu526Val

GAG526GTG

Nephropathy

1629delG

Glu524Glu(fs)

GAG524GA_

Nephropathy

1627G→A

Glu524Lys

GAG524AAG

Nephropathy

1622delT

Val522Ala(fs)

GTC522G_C

Nephropathy

1676A→T

Glu540Val

GAA540GTA

Nephropathy

del1606-1620 ATGTTAGGA

GAGTTTinsCA
 
Nephropathy

1618-1622delTTGT

Phe521Ser(fs)
 
Nephropathy

del1636-1650insCA1649-1650
  
Nephropathy

1712C→A

Pro552His

CCT552CAT

Nephropathy

1720-1721del/insTT

Gly555Phe

GGT555TTT

Nephropathy

1670C→A

Thr538Lys

ACA538AAA

Nephropathy, neuropathy

1632delT

Thr525fs

ACT525AC_

Nephropathy

Lysozyme

214T→A

Tyr54Asn

TAT54AAT

Cardiomyopathy

221T→C

Ile56Thr

ATA56ACA

Nephropathy, petechiae

253G→C

Asp67His

GAT67CAT

Nephropathy

244T→C/A

Trp64Arg

TGG64CGG/AGG

Nephropathy/hepatic

223T→A

Phe57Ile

TTT57ATT

Nephropathy

254A→G

Asp67Gly

GAT67GGT

Nephropathy

413T→A

Trp112Arg

TGG112AGG

Nephropathy, GI

Apolipoprotein AII

301T→G

Stop78Gly

TGA78GGA

Nephropathy

302G→C

Stop78Ser

TGA78TCA

Nephropathy

301T→C

Stop78Arg

TGA78CGA

Nephropathy

301T→A

Stop78Arg

TGA78AGA

Nephropathy

302G→T

Stop78Leu

TGA78TTA

Nephropathy


PN Peripheral Neuropathy, fs Frame Shift

acDNA numbering is from initiation codon (ATG)

bAmino acids numbered for N-terminus of mature protein

cList of most TTR mutations (3)

dDeduced





Types of Hereditary Amyloidosis


First, a few words on nomenclature: As with many scientific fields, the nomenclature for the amyloidoses can present difficulties in communication even for those steeped in the history of amyloid. In science, the first descriptions of proteins are usually given names which may relate to the functionality, site of synthesis, or structural characteristics. Later, with developing knowledge, there is usually a tendency to try to improve communication by introducing more appropriate terms and organizing them in a more consistent fashion. This often leads to problems. There are several points in amyloid history which exemplified these problems: (1) The disease we now call reactive amyloidosis was for many years, and even today, called “secondary” to indicate that it occurred in patients who had a primary, usually inflammatory, disease. For the pathologist, it was often referred to as “typical” amyloidosis since the staining with Congo red was usually consistent from one case to another. (2) Immunoglobulin light chain-associated amyloidosis in the past, and to this day, was often called “primary” amyloidosis. “Primary,” of course, has the same meaning as idiopathic or essential, indicating that there is no predisposing condition that explains the development of amyloidosis. This form of amyloidosis was often referred to by the pathologist as “atypical” since the histologic staining pattern with Congo red often varies from case to case, perhaps the result of the varying structures of immunoglobulin light chain fibril components. The use of “primary” has been problematic, however, because you will find some articles describing “primary” familial amyloidosis: an attempt to explain a disease with hereditary characteristics but for which a cause was not known. Now that we have identified many gene mutations that cause hereditary amyloidosis, the use of the word “primary” in this context should be discouraged. It is not only the clinician that has problems with nomenclature, but the basic scientist is also presented with the conundrum of nomenclature problems. Serum amyloid A 2 (SAA 2) which is the amyloid producing SAA in mice is now SAA 1.1 to adhere to the convention of the human gene designation. Islet amyloid-associated peptide and amylin are continuing to have their differences for students of Islets of Langerhans amyloidosis. Even transthyretin (TTR) is still referred to by its old name, prealbumin, which was a name derived from the fact that it traveled faster toward the anode than albumin in protein electrophoresis. Many pathology clinical laboratories still measure “prealbumin” levels and do not have a clue as to what TTR is.

The International Amyloid Society has a Nomenclature Committee which has established suggested designations for the different types of amyloid, and this is updated on a periodic basis for both human and animal systems [1]. In the list of nomenclature scheme, different types of amyloidosis are referred to by first the letter “A” followed by the precursor protein for that type of amyloidosis. As an example, immunoglobulin light chain amyloidosis becomes AL, transthyretin amyloidosis becomes ATTR, reactive or serum amyloid A amyloidosis becomes AA, and apolipoprotein AI amyloidosis becomes AApoAI. More specific designations may be used if felt necessary for better communication. An example would be ALλ or ALκ or ATTR Val30Met to indicate a specific protein mutation.

Transthyretin amyloidosis is the most common form of systemic hereditary amyloidosis. Greater than 120 mutations in transthyretin (also known as prealbumin) are associated with amyloidosis with peripheral neuropathy and cardiomyopathy being the most common clinical manifestations [3]. It is truly a systemic disease with amyloid deposits in vascular walls throughout the body, and a number of transthyretin mutations are associated with deposits in the vitreous of the eye (Fig. 5.1) and the leptomeninges (Fig. 5.2).

A188852_2_En_5_Fig1_HTML.jpg


Fig. 5.1
a Vitrectomy specimen from a patient with TTR Ile84Ser amyloidosis showing fibrillar strands and globules of amyloid. H&E original magnification ×200. b Vitrectomy specimen as in (a) stained with Congo red. c Section in (b) viewed between two crossed polars showing typical green birefringence of amyloid. Original magnification ×100


A188852_2_En_5_Fig2_HTML.jpg


Fig. 5.2
a Leptomeningeal and brain biopsy from patient with TTR Gly53Arg amyloidosis showing amyloid deposits, in leptomeninges, and blood vessel walls. (b) Same section as (a) viewed between crossed polars demonstrating typical green birefringence of amyloid. Original magnification ×100

Transthyretin is a prominent plasma protein present normally at approximately 25 mg/dl in the blood [4]. It is synthesized principally by hepatocytes although some synthesis is a feature of the choroid plexus and the retinal pigment epithelium of the eye. Transthyretin is a single chain protein of 127 amino acid residues [5]. The protein typically folds into seven or eight β-structured sheets in two planes, and then four monomers form a tetramer which is present in the blood as a 56-kDa transport protein for thyroid hormone and retinal-binding protein/vitamin A [6]. Transthyretin has extensive β-structure and, like immunoglobulin light chains, would be expected to be a prime candidate for amyloid β-fibril formation. While there are greater than 120 transthyretin mutations associated with amyloidosis, only a few of the mutations exist in extended kindreds, and due to incomplete penetrance of the genetic defect, many cases appear “sporadic” when in fact more detailed family history will disclose the genetic basis of the disease. Transthyretin amyloidosis is an autosomal dominant trait as would be expected from a defect in a structural protein. The most frequently identified transthyretin mutations include Val30Met which is common in Portugal, Sweden, Japan, and the USA [79], Leu58His which is common in the USA but originated in Germany [10], Thr60Ala which is common in the USA but originated in Ireland [11], Ser77Tyr which was first discovered in the USA but probably originated in Germany [12], Ile84Ser which was discovered in a kindred in the USA but probably originated in Switzerland [13], and Val122Ile which is present in approximately 3 % of African-Americans in the USA and probably originated in the west coast of Africa [14]. Each of these mutations is now worldwide and not limited to just one country. Many of the other mutations have been described in single individuals or single families and, once identified and reported in the scientific literature, tend not to be subject of further research. Now that new forms of treatment for transthyretin amyloidosis may be on the horizon, identification and classification of the transthyretin amyloidoses have become more important. It should be pointed out that wild-type TTR can undergo fibrillogenesis in older patients, who develop senile systemic amyloidosis (SSA). Although it affects primarily myocardium (sometimes termed “senile cardiac amyloidosis”), there is also systemic involvement of the vessels and, not uncommonly, clinical (and pathologic) evidence of pulmonary and carpal tunnel involvement; the involvement of other sites, frequently seen at autopsy, is usually not clinically apparent. It is estimated that 25 % of octogenarians may be affected by senile cardiac amyloidosis, predominantly males. Overall, the progression of ATTR derived from the wild-type transthyretin is slower. Although, ultimately, heart failure ensues, it does so at a slower rate than in hereditary ATTR (in particular, certain “cardiotrophic” mutations) or AL with cardiac involvement [14, 15].

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May 14, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on The Hereditary Amyloidoses

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