A novel variant of transthyretin, 59Thr→Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family

D. R. Booth, S. Y. Tan, P. N. Hawkins, M. B. Pepys, A. Frustaci

Research output: Contribution to journalArticle

Abstract

Background: Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance. Methods and Results: Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported. Conclusions: We have identified a novel mutation in the transthyretin gene encoding 59Thr→Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.

Original languageEnglish
Pages (from-to)962-967
Number of pages6
JournalCirculation
Volume91
Issue number4
Publication statusPublished - Feb 15 1995

Fingerprint

Prealbumin
Amyloidosis
Familial Amyloidosis
Amyloid
Mutation
Proteins
Genes
Immunoglobulin Light Chains
Sudden Cardiac Death
Angina Pectoris
Peripheral Nervous System Diseases
Heterozygote
Cardiomyopathies
Exons
Heart Diseases
Coronary Vessels
Phenotype
Biopsy
Pain
DNA

Keywords

  • Amyloid
  • Cardiomyopathy
  • Genes
  • Proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

A novel variant of transthyretin, 59Thr→Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. / Booth, D. R.; Tan, S. Y.; Hawkins, P. N.; Pepys, M. B.; Frustaci, A.

In: Circulation, Vol. 91, No. 4, 15.02.1995, p. 962-967.

Research output: Contribution to journalArticle

Booth, D. R. ; Tan, S. Y. ; Hawkins, P. N. ; Pepys, M. B. ; Frustaci, A. / A novel variant of transthyretin, 59Thr→Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. In: Circulation. 1995 ; Vol. 91, No. 4. pp. 962-967.
@article{e3a00295bb2e48fbb1a7786c7fdf6cd2,
title = "A novel variant of transthyretin, 59Thr→Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family",
abstract = "Background: Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance. Methods and Results: Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported. Conclusions: We have identified a novel mutation in the transthyretin gene encoding 59Thr→Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.",
keywords = "Amyloid, Cardiomyopathy, Genes, Proteins",
author = "Booth, {D. R.} and Tan, {S. Y.} and Hawkins, {P. N.} and Pepys, {M. B.} and A. Frustaci",
year = "1995",
month = "2",
day = "15",
language = "English",
volume = "91",
pages = "962--967",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - A novel variant of transthyretin, 59Thr→Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family

AU - Booth, D. R.

AU - Tan, S. Y.

AU - Hawkins, P. N.

AU - Pepys, M. B.

AU - Frustaci, A.

PY - 1995/2/15

Y1 - 1995/2/15

N2 - Background: Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance. Methods and Results: Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported. Conclusions: We have identified a novel mutation in the transthyretin gene encoding 59Thr→Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.

AB - Background: Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance. Methods and Results: Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported. Conclusions: We have identified a novel mutation in the transthyretin gene encoding 59Thr→Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.

KW - Amyloid

KW - Cardiomyopathy

KW - Genes

KW - Proteins

UR - http://www.scopus.com/inward/record.url?scp=0028925450&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028925450&partnerID=8YFLogxK

M3 - Article

C2 - 7850982

AN - SCOPUS:0028925450

VL - 91

SP - 962

EP - 967

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 4

ER -