Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease

Abstract

Fabry disease (FD) is a rare metabolic disorder of glycosphingolipid storage caused by mutations in the GLA gene encoding lysosomal hydrolase α-galactosidase A (α-gal A). Recently, the diagnostic procedure for FD has advanced in several ways, through the development of a specific biomarker (lyso-Gb3) and the implementation of newborn screenings, which acted as a catalyst to augment general awareness of the disease. Heterologous over-expression of α-gal A variants and subsequent in vitro measurement of enzyme activity provided molecular data to elucidate the relationship between mutation, enzyme damage, lyso-Gb3 biomarker levels, and clinical phenotype. This knowledge is the foundation for improved counseling with regard to prognosis and therapeutic decisions. Herein, we resume the approach of in vitro characterization, with a further 73 mainly novel GLA gene mutations. Patient lyso-Gb3 data were available for most of the mutations. All mutations were tested for responsiveness to pharmacological chaperone treatment and phenotypic data for 61 hemizygous male and 116 heterozygous female patients carrying a mutation associated with ≥ 20% residual activity, formerly classified as "mild" variant, were collected in order to evaluate the pathogenicity. We conclude that a mild GLA variant is typically characterized by high residual enzyme activity and normal biomarker levels. We found evidence that these variants can still be classified as a distinctive, but milder, sub-type of FD.

Enzyme replacement therapy in a patient of heterozygous Fabry disease: clinical and pathological evaluations by repeat kidney biopsy and a successful pregnancy

“…However, the issue of dosage has been confounded by the fact that the label-recommended dose of the two available agalsidase preparations has a fivefold difference. In our patient, abnormal urinalysis was the only initial symptom and the initiation of ERT was relatively early; however, the effectiveness of ERT was different from that observed by Tøndel [8], which showed an obvious clearance of Gb3 from renal cells. In Tøndel's study, complete clearance of inclusions from renal cells was observed only using 1.0 mg/kg eow of agalsidase beta, which was not observed using 0.2 mg/kg eow of agalsidase alfa.…”

“…Genetic analysis revealed that the patient, her mother, and her daughter had a heterozygous mutation c.1124G>A, p.G375E in the GLA gene, which have been previously reported [8]. Based on the mutant enzyme activity in vitro and lyso-Gb3 measurement study, the clinical phenotype of this mutation is relatively benign [8]; however, it is difficult to predict the phenotype severity based on the genetic mutation patterns, including the mutation in this patient, and to decide which patients require ERT for heterozygous FD.…”

“…Based on the mutant enzyme activity in vitro and lyso-Gb3 measurement study, the clinical phenotype of this mutation is relatively benign [8]; however, it is difficult to predict the phenotype severity based on the genetic mutation patterns, including the mutation in this patient, and to decide which patients require ERT for heterozygous FD. Lyso-Gb3 levels are useful marker for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with Fabry disease [9].…”

Plasma lyso-Gb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes

“…Three recent reports have determined the plasma LysoGb3 levels in males and females with the Classic, Later-Onset and benign GLA mutations: Lukas et al [20], Niemann et al [13] and Smid et al [12]. Lukas et al from the Centogene laboratory, reported a variety of mutations and their LysoGb3 levels (typically 1 or 2 females).…”

Identification of a Novel <i>GLA</i> Gene Mutation, p.Ile239Met, in Fabry Disease With a Predominant Cardiac Phenotype

“…For the majority of the metabolic diseases there is the advantage of having the data of the concentration of the effected enzyme in clinical materials and for some few ones also information about the biomarker, like in Fabry disease. 6) As a specific enzyme replacement therapy (ERT) for Fabry disease is availa- 7) early diagnosis of a real FD patient is of great importance to initiate the otherwise invasive and expensive ERT.…”