The study, “Clinical Diversity in Patients with Anderson-Fabry Disease with the R301Q Mutation,” was published in Internal Medicine.
Fabry disease is a rare genetic disorder caused by mutations in the GLA gene — located on the X chromosome — that provides instructions for the production of an enzyme called alpha-galactosidase A (α-GAL A). These mutations typically affect the function of α-GAL A, leading to the accumulation of a type of fat called globotriaosylceramide (Gb3) in several tissues and organs.
As a result, Fabry disease patients may experience a wide range of symptoms, including burning sensation in the hands and feet, wart-like papules in the skin, decreased sweating, corneal opacities (cloudy cornea), and progressive vascular disease of the kidneys, heart, and central nervous system.
Importantly, previous studies have reported that individuals from the same family may experience different symptoms and varying degrees of disease severity, indicating that factors other than genetics may play a role in how the disease emerges.
In this case report study, Japanese investigators analyzed 10 cases of Fabry disease patients (three men and seven women) from five families who shared the same missense genetic mutation (single nucleotide mutation that alters protein composition) on exon six of the GLA gene, called R301Q. (Nucleotides are proteins’ building blocks and an exon is the protein-coding sequence of a gene.)
The clinical characteristics, alpha-galactosidase A activity and plasma levels of globotriaosylsphingosine (a molecule similar to Gb3, Lyso-Gb3) were assessed in all patients.
Although all 10 patients shared a few core clinical features, including cardiomyopathy (heart disease) and kidney disease, the degree of variability in their symptoms was substantial, especially considering they shared the same genetic mutation.
“In general, male AFD [Anderson-Fabry disease] patients with complete deficiency of α-GAL A activity (classical type) show severe symptoms, whereas female patients with residual α-GAL A activity show symptoms restricted to the heart or kidney, even at a relatively old age,” researchers wrote.
One of the explanations proposed by researchers is epigenetics, which is change in organisms brought about by modification of gene expression, rather than by alteration of the genetic code in the form of DNA. For example, one may be born with a capacity to be tall; however if that child is undernourished he or she likely will not grow as much as genes would allow.
Of note, gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.
“Epigenetic changes should be considered in order to explain the phenotypic [disease symptoms] diversities among patients with the same mutations. In addition, acquired factors, such as hypertension [high blood pressure], diabetes mellitus, and obesity, may contribute to the clinical manifestations of AFD,” they added.
“Future studies in a larger number of patients are needed to elucidate the factors relevant to the phenotypic variabilities in AFD patients,” researchers concluded.