<p>Multiple phenotypic domains of Fabry disease and their relevance for establishing genotype&ndash;phenotype correlations</p>

Abstract

Fabry disease (FD) is a rare X-linked glycosphingolipidosis resulting from deficient α-galactosidase A (AGAL) activity, caused by pathogenic mutations in the GLA gene. In males, the multisystemic involvement and the severity of tissue injury are critically dependent on the level of AGAL residual enzyme activity (REA) and on the metabolic load of the disease, but organ susceptibility to damage varies widely, with heart appearing as the most vulnerable to storage pathology, even with relatively high REA. The expression of FD can be conceived as a multidomain phenotype, where each of the component domains is the laboratory or clinical expression of the causative GLA mutation along a complex pathophysiologic cascade pathway. The AGAL enzyme activity is the most clinically useful marker of the protein phenotype. The metabolic phenotype and the pathologic phenotype are diverse expressions of the storage pathology, respectively, assessed by biochemical and histological/ultrastructural methods. The storage phenotypes are the direct consequences of enzyme deficiency and hence, together with the enzymatic phenotype, constitute the more specific diagnostic markers of FD. In the pathophysiology cascade, the clinical phenotypes are most distantly linked to the underlying genetic causation, being critically influenced by the patients' gender and age, and modulated by the effects of variation in other genetic loci, of polygenic inheritance and of environmental risk factors. A major challenge in the clinical phenotyping of patients with FD is the differential diagnosis between its nonspecific, later-onset complications, particularly the cerebrovascular, cardiac and renal, and similar chronic illnesses that are common in the general population. Comprehensive phenotyping, whenever possible performed in hemizygous males, is therefore crucial for grading the severity of pathogenic GLA variants, to clarify the phenotypic correlations of hypomorphic alleles, to define benign polymorphisms, as well as to establish the pathogenicity of variants of uncertain significance.

Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients

“…In our study, these haplotypes were found in males with enzymatic activity below the cut-off (~1.73 μmol/L/h), equivalent to a decrease of 21% of α-Gal A activity, indicating that c.-10C > T may cause this decrease. Residual enzyme activity of about 40% of the mean normal level can be considered enough to degrade the substrate, not promoting Gb3 accumulation [6,7]. However, recent studies have demonstrated that, despite not altering the enzyme structure, patients with the haplotype 7 had significant levels of Gb3 accumulation when compared with controls [32,33].…”

“…However, it is estimated that the cutoff for diagnosing FD is 30-35% of mean normal α-Gal A. Some GLA mutations cause a reduction of enzyme activity to less than 10-15% of the wild type and are considered pathogenic [6]. However, others promoting a residual enzyme activity of at least 40% of the wild type protein can be considered as non-pathogenic [7].…”

Sudden onset of nephrotic syndrome in an asymptomatic Fabry patient: a case report

“…a-Gal A is a dimeric glycoprotein that catalyzes the removal of terminal nonreducing a-D-galactose residues in ceramide trihexoside [3,15]. Impairment of a-Gal A activity may result in obstacle of the glycolipid conversion from globotriosylceramide (GL-3) to lactosylceramide (GL-2), leading to widespread intralysosomal accumulation of glycolipid in different tissue and organs [16]. Kidney is the most common organ involved in FD, and the older the patient, the more severe the kidney damage [17].…”

Different Phenotypes of Anderson-Fabry Disease Identified with Cardiac Magnetic Resonance Imaging in a Family with the Same Late-Onset Mutation

“…That is in keeping with the findings from the present study, because positive LGE was found only in the patient with severe LVH. The different cardiac features between brothers evidence that late-onset AFD phenotype is influenced not only by the underlying pathogenic mutation, sex or age, but also by individual polygenic heritage and environmental risk factors, which produces a complex pathophysiologic cascade pathway that finally determines the disease expression [ 19 ].…”