Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women

Havndrup, Ole; Christiansen, Michael; Stoevring, Birgitte; Jensen, Morten Kvistholm; Hoffman-Bang, Jakob; Andersen, Paal Skytt; Hasholt, Lis; Nørremølle, Anne; Feldt‐Rasmussen, Ulla; Køber, Lars; Bundgaard, Henning

doi:10.1093/eurjhf/hfq073

Cited by 82 publications

(63 citation statements)

References 41 publications

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“…Even in the 53-year-old father (an age at which male Fabry patients often die), no Fabry-associated manifestations could be determined. Thus, our data challenge the usual way to establish the diagnosis in Fabry disease (Havndrup et al 2010;Weidemann and Niemann 2010): When a male patient shows decreased alpha-galactosidase A activity (like our male patient), the diagnosis is regarded as proven. In female patients with borderline alpha-galactosidase A activity (like in our female patient), genotyping with the search for a Fabry-related mutation is demanded (Weidemann and Niemann 2010).…”

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confidence: 66%

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

et al. 2012

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The X-chromosomal-linked lysosomal storage disorder Fabry disease can lead to life-threatening manifestations. The pathological significance of the Fabry mutation D313Y is doubted, because, in general, D313Y patients do not present clinical manifestations conformable with Fabry disease. This is in contrast to the analysis of the alphagalactosidase A activity, which is reduced in D313Y patients. We report a comprehensive clinical, biochemical and molecular genetic analysis of two patients with a D313Y mutation. The alpha-galactosidase A activity was reduced in both patients. No Fabry symptoms or Fabry organ involvement was detected in these patients. The new biomarker lyso-Gb3, severely increased in classical Fabry patients, was determined and in both patients lyso-Gb3 was below the average of a normal population.Our data for the first time not only clinically but also biochemically supports the hypothesis that the D313Y mutation is not a classical one, but a rare variant mutation.

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confidence: 66%

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

et al. 2012

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“…3,[14][15][16][17][18] In 32 of the 90 probands (36%), 38 disease-causing mutations were identified. Each family was offered screening, and a total of 361 relatives (all ages) were included in the screening program.…”

Section: Study Cohortmentioning

confidence: 99%

“…One relative with unknown genetic status, diagnosed at inclusion, still fulfilled the diagnostic criteria for HCM at follow-up (MWT = 15 mm) (6%; 95% CI, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The other relative with unknown genetic status who fulfilled the criteria for HCM at inclusion (age 5 years) did not fulfill the diagnostic criteria for HCM at follow-up (MWT = 12 mm; Z score = −0.75; age, 17 years; weight, 110 kg).…”

Section: Clinical Findings At Follow-upmentioning

confidence: 99%

“…Two carriers (17%; 95% CI, 5-45) converted to the HCM phenotype during follow-up, but not until 26 and 28 years of age. At follow-up, only 1 child with unknown genetic status (6%; 95% CI, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], already diagnosed at inclusion at the age of 5 years, fulfilled diagnostic criteria. Thus, only 3 (5%; 95% CI, 2-13) of the total group of child relatives (n = 66) or 3 (8%; 95% CI, 3-21) of the child relatives considered at risk of developing HCM, ie, carriers (n = 12) and relatives with unknown genetic status (n = 26), fulfilled the diagnostic criteria for HCM after 12 years of follow-up.…”

Section: Diagnostic Yield and Penetrancementioning

confidence: 99%

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Penetrance of Hypertrophic Cardiomyopathy in Children and Adolescents

et al. 2013

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Background-The penetrance of hypertrophic cardiomyopathy (HCM) during childhood and adolescence has been only sparsely described. We studied the penetrance of HCM and the short-and long-term outcomes of clinical screening and predictive genetic testing of child relatives of patients with HCM. Methods and Results-Ninety probands and 361 relatives were included in a family screening program for HCM (1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001). Eleven sarcomere genes, CRYAB, α-GAL, and titin were screened. Sixty-six relatives and 4 probands were <18 years of age at inclusion. Twelve child relatives were mutation carriers (age, 12 ± 5 years), and 26 had unknown genetic status, ie, relatives from families without identified mutations (n = 21) or not tested (n = 5) (age, 11 ± 5 years). Twentyeight noncarriers (42%; age, 10 ± 4 years) served as control subjects. Two of 38 child relatives (5%) at risk of developing HCM fulfilled diagnostic criteria for HCM at inclusion. After 12 ± 1 years of follow-up, 2 of the 36 (6%; 95% confidence interval, 2-18) at-risk child relatives who were phenotype negative at inclusion had developed the HCM phenotype at 26 and 28 years of age. During follow-up, none of the child relatives experienced serious cardiac events. Participation in the screening program had no long-term negative psychological impact. Conclusions-The penetrance of HCM in phenotype-negative child relatives at risk of developing HCM was 6% after 12 years of follow-up. The finding of phenotype conversion in the mid-20s warrants continued screening into adulthood. Forty-two percent of the child relatives were noncarriers, and repeat clinical follow-up could be safely limited to the remaining children.

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“…When systematically screened, GLA mutations were identified in 3 of 90 (3%) HCM families. 75 Importantly, cardiomyopathy may be the only manifestation of the disease, which is treatable by enzyme replacement therapy.…”

Section: Nonsarcomeric Genes and Hcm Phenocopiesmentioning

confidence: 99%

Genetic Cardiomyopathies Causing Heart Failure

Cahill

Ashrafian

Watkins

2013

Circulation Research

141

117

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Despite the striking advances in medical and surgical therapy, the morbidity, mortality, and economic burden of heart failure (HF) remain unacceptably high. There is increasing evidence that the risk and course of HF depend on genetic predisposition; however, the genetic contribution to HF is heterogeneous and complex. At one end of the spectrum are the familial monogenic HF syndromes in which causative mutations are rare but highly penetrant. At the other, HF susceptibility and course may be influenced by more common, less penetrant genetic variants. As detailed in this review, efforts to unravel the basis of the familial cardiomyopathies at the mendelian end of the spectrum already have begun to deliver on the promise of informative mechanisms, novel gene-based diagnostics, and therapies for distinct subtypes of HF. However, continued progress requires the differentiation of pathogenic mutations, disease modifiers, and rare, benign variants in the deluge of data emerging from increasingly accessible novel sequencing technologies. This represents a significant challenge and demands a sustained effort in analysis of extended family pedigrees, diligent clinical phenotyping, and systematic annotation of human genetic variation. (Circ Res. 2013;113:660-675.)

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Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women

Cited by 82 publications

References 41 publications

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

Penetrance of Hypertrophic Cardiomyopathy in Children and Adolescents

Genetic Cardiomyopathies Causing Heart Failure

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