An Atypical Variant of Fabry's Disease with Manifestations Confined to the Myocardium

W, von Scheidt; Cm, Eng; Tf, Fitzmaurice; Erdmann, E; Hübner, G; Eg, Olsen; Christomanou, H.; Kandolf, Reinhard; Df, Bishop; Rj, Desnick

doi:10.1056/nejm199102073240607

Cited by 347 publications

(220 citation statements)

References 30 publications

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“…The expression of alternative 5 0 UTRs represents an evolutionary gain of transcriptional and translational control pathways, allowing tissue-specific expression patterns and expanding the repertoire of expression from a single gene locus (Barrett et al 2012). Although GLA is a housekeeping gene, aGal activity levels vary greatly from organ to organ and in different cell types (Brady et al 1967;von Scheidt et al 1991). It is possible that either transcription factors (TF) or RNA-binding proteins (RBP) that bind to specific sequences in the GLA 5 0 UTR contribute to the regulation of GLA gene expression in a tissue-specific manner.…”

Section: Discussionmentioning

confidence: 99%

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

2015

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Lysosomal a-galactosidase A (aGal) is the enzyme deficient in Fabry disease (FD). The 5 0 -untranslated region (5 0 UTR) of the aGal gene (GLA) shows a remarkable degree of variation with three common single nucleotide polymorphisms at nucleotide positions c.-30G>A, c.-12G>A and c.-10C>T. We have recently identified in young Portuguese stroke patients a fourth polymorphism, at c.-44C>T, co-segregating in cis with the c.-12A allele. In vivo, the c.-30A allele is associated with higher enzyme activity in plasma, whereas c.-10T is associated with moderately decreased enzyme activity in leucocytes. Limited data suggest that c.-44T might be associated with increased plasma aGal activity. We have used a luciferase reporter system to experimentally assess the relative modulatory effects on gene expression of the different GLA 5 0 UTR polymorphisms, as compared to the wild-type sequence, in four different human cell lines. Group-wise, the relative luciferase expression patterns of the various GLA variant isoforms differed significantly in all four cell lines, as evaluated by non-parametric statistics, and were cell-type specific. Some of the post hoc pairwise statistical comparisons were also significant, but the observed effects of the GLA 5 0 UTR polymorphisms upon the luciferase transcriptional activity in vitro did not consistently replicate the in vivo observations. These data suggest that the GLA 5 0 UTR polymorphisms are possible modulators of the aGal expression. Further studies are needed to elucidate the biological and clinical implications of these observations, particularly to clarify the effect of these polymorphisms in individuals carrying GLA variants associated with high residual enzyme activity, with no or mild FD clinical phenotypes.

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Section: Discussionmentioning

confidence: 99%

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

2015

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“…The marked deficiency or absence of GAL activity results in the systemic accumulation of globotriaosylceramide and related glycosphingolipids within the lysosomes, particularly in microvascular endothelial cells, vascular smooth muscle cells, renal tubular cells, podocytes, and cardiomyocytes 3, 4, 5, 6, 7…”

Section: Introductionmentioning

confidence: 99%

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Frustaci

Verardo

Grande

et al. 2018

JAHA

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BackgroundGlycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy (FDCM).Methods and ResultsMyocarditis, defined as CD3+ T lymphocytes >7/mm2 associated with necrosis of glycolipid‐laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with FDCM: 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with FDCM (38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes. CD3+ cells/mm2 correlated with myocyte necrosis, antimyosin autoantibody titer, and MWT (P<0.001,r=0.79; P<0.001, r=0.84; P<0.001, r=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4.ConclusionsMyocarditis is detectable at histology in up to 56% of patients with FDCM. It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of FDCM and resistance to enzyme replacement therapy.

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“…It leads to impaired glycosphingolipid metabolism and resultant intracellular accumulation of globotriaosylceramide (Gb3). Metabolites of Gb3 induce inflammation, hypertrophy and fibrosis, especially of vascular endothelium and smooth muscle cells (von Scheidt et al 1991). Clinical manifestations are widespread with the heart, kidneys, cerebrovascular system, peripheral nerves and skin most severely affected (Mehta et al 2009;Zarate and Hopkin 2008).…”

Section: Introductionmentioning

confidence: 99%

Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease

et al. 2016

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Objectives: To assess the prevalence of sleep disorder(s) in males with Fabry disease and explore possible association with disease phenotype.Background: Fabry disease, an X-linked lysosomal storage disease caused by deficiency in a-galactosidase, results in intracellular accumulation of globotriaosylceramide. It causes organ dysfunction, most significantly affecting renal, cerebrovascular and cardiovascular systems. Respiratory involvement may include obstructive lung disease, reduced diffusing capacity and thickened soft and hard palates. Patients commonly develop small-fibre sensory peripheral neuropathy manifested by acroparaesthesia and pain crises. Combined with self-reported sleep disturbance and snoring, these features suggest an increased risk of sleep disorders.Methods: In-laboratory polysomnography (PSG) studies and sleep inventory assessments, including Epworth Sleepiness Scale (ESS), were performed in a cohort of male Fabry patients. PSGs were reviewed by a sleep physician. Sleep-disordered breathing and periodic leg movements were targeted for analysis. Associations with renal, cardiovascular and cerebrovascular function were sought.Results: Twenty males underwent overnight PSG. Patient baseline characteristics included age 43.9 AE 10.7 years, BMI 24.3 AE 3.8 kg/m 2 , neck circumference 39.7 AE 3.3 cm and ESS 9.8 AE 5.1 (7/20, abnormal ESS >10). Abnormal periodic leg movement index (PLMI) was present in 95% (mean frequency 42.4 AE 28.5/min) and sleep-disordered breathing in 50% patients. Periodic leg movements were associated with pain and depression but not with increased cortical arousal.Conclusions: Sleep-disordered breathing and abnormal PLMI are highly prevalent in patients with FD.

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An Atypical Variant of Fabry's Disease with Manifestations Confined to the Myocardium

Cited by 347 publications

References 30 publications

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease

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