Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes

Berglind Adalsteinsdottir; Runolfur Palsson; Robert J Desnick; Marianna Gardarsdottir; Polakit Teekakirikul; Martin Maron; Evan Appelbaum; Ulf Neisius; Barry J Maron; Michael A Burke; Brenden Chen; Silvere Pagant; Christoffer V Madsen; Ragnar Danielsen; Reynir Arngrimsson; Ulla Feldt-Rasmussen; Jonathan G Seidman; Christine E Seidman; Gunnar Th Gunnarsson

doi:10.1161/CIRCGENETICS.116.001639

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes

Berglind Adalsteinsdottir, Runolfur Palsson, Robert J Desnick, Marianna Gardarsdottir, Polakit Teekakirikul, Martin Maron, Evan Appelbaum, Ulf Neisius, Barry J Maron, Michael A Burke, Brenden Chen, Silvere Pagant, Christoffer V Madsen, Ragnar Danielsen, Reynir Arngrimsson, Ulla Feldt-Rasmussen, Jonathan G Seidman, Christine E Seidman, Gunnar Th Gunnarsson

Department of Clinical Medicine

14 Citations (Scopus)

Abstract

The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Methods and Results - Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Conclusions - Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.

Original language	English
Article number	e001639
Journal	Circulation. Cardiovascular genetics
Volume	10
Issue number	4
ISSN	1942-325X
DOIs	https://doi.org/10.1161/CIRCGENETICS.116.001639
Publication status	Published - 1 Aug 2017

Keywords

Adolescent
Adult
Aged
Brain/diagnostic imaging
Cardiomyopathy, Hypertrophic/complications
Child
Fabry Disease/complications
Female
Genotype
Heterozygote
Humans
Kidney Diseases/complications
Late Onset Disorders
Magnetic Resonance Imaging
Male
Middle Aged
Mutation, Missense
Pedigree
Phenotype
Young Adult
alpha-Galactosidase/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/CIRCGENETICS.116.001639

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Adalsteinsdottir, B., Palsson, R., Desnick, R. J., Gardarsdottir, M., Teekakirikul, P., Maron, M., Appelbaum, E., Neisius, U., Maron, B. J., Burke, M. A., Chen, B., Pagant, S., Madsen, C. V., Danielsen, R., Arngrimsson, R., Feldt-Rasmussen, U., Seidman, J. G., Seidman, C. E., & Gunnarsson, G. T. (2017). Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes. Circulation. Cardiovascular genetics, 10(4), [e001639]. https://doi.org/10.1161/CIRCGENETICS.116.001639

Adalsteinsdottir, B, Palsson, R, Desnick, RJ, Gardarsdottir, M, Teekakirikul, P, Maron, M, Appelbaum, E, Neisius, U, Maron, BJ, Burke, MA, Chen, B, Pagant, S, Madsen, CV, Danielsen, R, Arngrimsson, R, Feldt-Rasmussen, U, Seidman, JG, Seidman, CE & Gunnarsson, GT 2017, 'Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes', Circulation. Cardiovascular genetics, vol. 10, no. 4, e001639. https://doi.org/10.1161/CIRCGENETICS.116.001639

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title = "Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes",

abstract = "The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Methods and Results - Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Conclusions - Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.",

keywords = "Adolescent, Adult, Aged, Brain/diagnostic imaging, Cardiomyopathy, Hypertrophic/complications, Child, Fabry Disease/complications, Female, Genotype, Heterozygote, Humans, Kidney Diseases/complications, Late Onset Disorders, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Young Adult, alpha-Galactosidase/genetics",

author = "Berglind Adalsteinsdottir and Runolfur Palsson and Desnick, {Robert J} and Marianna Gardarsdottir and Polakit Teekakirikul and Martin Maron and Evan Appelbaum and Ulf Neisius and Maron, {Barry J} and Burke, {Michael A} and Brenden Chen and Silvere Pagant and Madsen, {Christoffer V} and Ragnar Danielsen and Reynir Arngrimsson and Ulla Feldt-Rasmussen and Seidman, {Jonathan G} and Seidman, {Christine E} and Gunnarsson, {Gunnar Th}",

note = "{\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

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doi = "10.1161/CIRCGENETICS.116.001639",

language = "English",

volume = "10",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

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TY - JOUR

T1 - Fabry Disease in Families With Hypertrophic Cardiomyopathy

T2 - Clinical Manifestations in the Classic and Later-Onset Phenotypes

AU - Adalsteinsdottir, Berglind

AU - Palsson, Runolfur

AU - Desnick, Robert J

AU - Gardarsdottir, Marianna

AU - Teekakirikul, Polakit

AU - Maron, Martin

AU - Appelbaum, Evan

AU - Neisius, Ulf

AU - Maron, Barry J

AU - Burke, Michael A

AU - Chen, Brenden

AU - Pagant, Silvere

AU - Madsen, Christoffer V

AU - Danielsen, Ragnar

AU - Arngrimsson, Reynir

AU - Feldt-Rasmussen, Ulla

AU - Seidman, Jonathan G

AU - Seidman, Christine E

AU - Gunnarsson, Gunnar Th

PY - 2017/8/1

Y1 - 2017/8/1

N2 - The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Methods and Results - Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Conclusions - Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.

AB - The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Methods and Results - Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Conclusions - Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.

KW - Adolescent

KW - Adult

KW - Aged

KW - Brain/diagnostic imaging

KW - Cardiomyopathy, Hypertrophic/complications

KW - Child

KW - Fabry Disease/complications

KW - Female

KW - Genotype

KW - Heterozygote

KW - Humans

KW - Kidney Diseases/complications

KW - Late Onset Disorders

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Pedigree

KW - Phenotype

KW - Young Adult

KW - alpha-Galactosidase/genetics

U2 - 10.1161/CIRCGENETICS.116.001639

DO - 10.1161/CIRCGENETICS.116.001639

M3 - Journal article

C2 - 28798024

SN - 1942-325X

VL - 10

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 4

M1 - e001639

ER -

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes

Abstract

Keywords

UN SDGs

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