Korean investigators have discovered a new mutation in the GLA gene — located on the X chromosome — that is likely associated both with Fabry disease and heart disease, according to a case report study.
Titled “Fabry Disease that Phenocopies Hypertrophic Cardiomyopathy: a thorough Genetic ‘Detective’ Identifies the ‘Rogue’ Hidden in the GLA Gene,” the study was published in the Korean Circulation Journal.
Fabry is a rare genetic disorder caused by mutations in the GLA gene, which provides instructions for the production of an enzyme called alpha-GAL A.
These mutations typically affect the activity of alpha-GAL A, leading to the accumulation of a type of fat known as globotriaosylceramide (Gb3) in different tissues and organs. The accumulations can occur in the heart, kidneys, and nervous system, gradually compromising their normal function.
So far, more than 800 GLA mutations associated with Fabry have been reported in the literature. These include some that are considered pathogenic because they lead to the onset of the disease, and others that are considered benign or of unknown pathogenicity, which means they are not associated with the typical signs of Fabry.
In this case report study, physicians from the Seoul National University Hospital in Korea described a patient with a long medical history of heart disease and other complications who was found to carry a new GLA mutation that was likely associated with Fabry disease.
The 59-year-old man had a history of heart disease associated with heart enlargement, had previously received a kidney transplant, and had unusual lesions in some areas of the brain. He arrived at the hospital in cardiac arrest to be resuscitated.
Electrocardiogram and 2D-echocardiography tests confirmed his heart was enlarged and its ability to pump blood was impaired. When physicians performed a heart biopsy, they found that the patient’s heart cells, which are called cardiomyocytes, also were enlarged, had an abnormal shape, and were full of fat deposits.
“Considering the late-onset of clinical events, we strongly suspected a variant form of FD [Fabry disease] and measured the patient’s plasma [alpha-GAL A] level and the enzyme activity,” the clinicians said.
Blood tests confirmed that the man’s levels of alpha-GAL A (4.4 nmol/hr/mg protein) were far below the normal range (35–100 nmol/hr/mg protein) and its enzymatic activity was only 68.3%.
To confirm a Fabry diagnosis, physicians performed genetic sequencing analyses of the patient’s GLA gene. Genetic analyses revealed the man carried a mutation in the fifth exon of the GLA gene that had never been described in the literature. An exon is the coding sequence of a gene that provides instructions to make proteins.
This mutation led to the substitution of the nucleotide cytosine by thymine at position 775 in the GLA gene sequence (c.775C>T). This led to the production of an abnormal protein, in which the amino acid proline had been replaced by serine at position 259 of the alpha-GAL A protein sequence (p.Pro259Ser).
“The genetic variation was located in a functionally critical domain and we found multiple computational evidences supporting the deleterious [negative] effect of the genetic variation,” the physicians said.
“Combining these findings to pathogenicity criteria [established] by the American College of Medical Genetics and Genomics, the novel mutation c.775C>T (p.Pro259Ser) was considered to be likely pathogenic and we concluded the patient had a variant form of FD,” they concluded.
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