Research Article, J Genet Disor Genet Rep Vol: 15 Issue: 3

Clinical and Molecular Characterization of the GLA c.1124G>C (p.Gly375Ala) Variant in Colombian Patients with Fabry Disease: A Retrospective Cohort Study

Maria Amparo Acosta Aragón, MD, Ph. D^*1,2, Rodrigo Erazo Portilla, MD², Marcela Daza, MD, Msc³, Edison Montenegro, MD, Msc³

¹Department of Pediatrics, Faculty of Health Sciences, Universidad del Cauca. Popayán, Cauca, Colombia

²Center for the Care of Congenital Anomalies and Rare Diseases, Hospital Universitario San José, Popayán, Cauca, Colombia.

³Takeda Pharmaceuticals, Colombia

*Corresponding Author:

Maria Amparo Acosta Aragón, MD, Ph. D
Department of Pediatrics, Faculty of Health Sciences, Universidad del Cauca. Popayán, Cauca, Colombia, Postal Code: 190002
Tel: +57 (2) 820-9900
E-mail: maragon@unicauca.edu.co
ORCID: https://orcid.org/0000-0002-0513-8127

Received: 18-Mar-2026, Manuscript No: jgdgr-26-186638, Editor assigned: 20- Mar-2026, Pre QC No: jgdgr-26-186638 (PQ), Reviewed: 16-April-2026, QC No: jgdgr-26-186638, Revised: 21-April-2026, Manuscript No: jgdgr-26-186638 (R) Published: 27- April-2026, DOI: 10.4172/2327-5790.100001

Citation: Acosta Aragón MA, Portilla RE, Daza M, Montenegro E (2026) Clinical and Molecular Characterization of the GLA c.1124G>C (p. Gly375Ala) Variant in Colombian Patients with Fabry Disease: A Retrospective Cohort Study. J Genet Disor Genet Rep 15: 381

Abstract

Keywords

Fabry disease, GLA gene, c.1124G>C variant, lysosomal storage disorders, missense mutation, enzyme replacement therapy.

Introduction

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene that reduce α-galactosidase A activity [1-3]. Progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) contributes to multisystem involvement, including angiokeratomas, corneal findings, chronic kidney disease, hypertrophic cardiomyopathy, arrhythmias, and cerebrovascular events [4-6]. Without disease-specific therapy, life expectancy is shortened in both males and females [7].

FD spans a phenotypic continuum. The classic phenotype typically begins in childhood or adolescence and is associated with very low or absent enzyme activity, early neuropathic pain, hyperhidrosis, heat intolerance, gastrointestinal symptoms, skin lesions, and progressive renal and cardiac disease [1,8,9]. Later-onset (non-classic) presentations usually retain residual α-galactosidase A activity and may initially appear organ-predominant, most often cardiac, renal, or neurologic [8,9]. This spectrum is clinically relevant in heterozygous females, in whom disease expression is variable and may be delayed because of X-chromosome inactivation patterns and other biologic factors [8]. In this setting, interpretation of variants of uncertain significance (VUS) requires integration of genotype with clinical findings, family segregation, and biomarkers. Plasma lyso-Gb3 has been used to support diagnostic classification and phenotypic stratification in selected contexts, although its performance is lower in some late-onset presentations and in females, so it is best interpreted alongside clinical evaluation and complementary testing [8,10-13].

More than 1,000 GLA variants have been described, and many remain classified as VUS, limiting genotype–phenotype correlation and therapeutic decision-making [6,14,15]. The GLA c.1124G>C (p.Gly375Ala) variant has been reported in different populations and is currently catalogued as a VUS, with limited detailed clinical and biochemical characterization in Latin America [14,16]. In Colombia, FD is recognized as a rare disease under Law 1392 of 2010 and Law 1438 of 2011 [17], yet regional access barriers may delay diagnosis and continuity of care. We aimed to describe the sociodemographic, clinical, biochemical, and treatment characteristics of Colombian patients carrying GLA c.1124G>C (p. Gly375Ala) evaluated at Hospital Universitario San José de Popayán between 2015 and 2023.

Materials and Methods

Study design and setting

We conducted an observational, descriptive, retrospective cohort study based on medical record review. The analysis included all patients diagnosed with FD carrying the GLA c.1124G>C (p. Gly375Ala) variant who were evaluated at the Hospital Universitario San José in Popayán, Cauca (Colombia) between January 2015 and December 2023. The overall objective was to characterize the sociodemographic, clinical, biochemical, and molecular profile of this cohort, as well as to describe organ-specific manifestations, therapeutic management, follow-up conditions, and potential genotype–phenotype correlations.

Study population

The target population consisted of individuals with a confirmed diagnosis of FD established through α-galactosidase A enzymatic activity testing and GLA gene molecular analysis. The accessible population comprised all patients first assessed at the hospital’s clinical genetics service during the study period. The inclusion criteria were a confirmed diagnosis of FD carrying the GLA c.1124G>C (p. Gly375Ala) variant, the availability of complete institutional medical records, and documented follow-up after diagnosis. Patients without follow-up records were excluded. As this was a descriptive study based on the available population, no sample size calculation was performed; the cohort included all detected cases (n=16).

Variables and data sources

Information was collected on sociodemographic characteristics (age, sex, place of residence, socioeconomic status, and education level), clinical manifestations (age at diagnosis and involvement in dermatologic, central nervous system, peripheral nervous system, cardiac, rheumatologic, gastrointestinal, ophthalmologic, auditory, renal, and mental health domains), biochemical parameters (plasma α-galactosidase A activity and serum globotriaosylsphingosine [lyso-Gb3] levels), renal function (serum creatinine and estimated glomerular filtration rate [eGFR]), and treatment-related aspects (type of specific therapy, adherence, treatment modifications, and reasons for discontinuation). Data were obtained exclusively from institutional medical records and laboratory reports. To minimize transcription errors, two independent investigators reviewed all records retrospectively.

Laboratory procedures

α-galactosidase A activity was measured in dried blood spots using a standard fluorometric assay in an external reference laboratory, with results expressed in nmol/h/mL (equivalent to μmol/L/h). This method has very high analytical sensitivity (around 100%) but a lower specificity (about 96%) than assays performed on leukocyte preparations, so all diagnoses were confirmed by GLA sequencing in the clinical context. Serum lyso-Gbâ?? concentrations were quantified by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and reported in nmol/L according to the laboratory standard. Renal function was assessed using serum creatinine, and eGFR was estimated with the CKD-EPI equation standardized to 1.73 m² of body surface area, according to KDIGO 2013 guidelines [18].

Statistical analysis

Descriptive statistics were used to summarize the cohort characteristics. Continuous variables were expressed as means and standard deviations or as medians and interquartile ranges according to their distribution. Comparisons by sex were performed using the Mann–Whitney U test for nonparametric continuous variables and Fisher’s exact test for categorical variables. All analyses were carried out using R software, version 4.4.1 [19]. The proportion of missing data was below 10%, and no imputation methods were applied.

Ethical considerations

The study was approved by the Ethics Committee of the Faculty of Health Sciences at Universidad del Cauca (Acta 6.1-3.24/31, October 29, 2024) and by the Biomedical Research Ethics Committee of the Hospital Universitario San José de Popayán (Approval No. 56-2024). According to Colombian regulations (Resolution 8430 of 1993), retrospective studies based on anonymized clinical records are classified as research without risk and do not require individual informed consent. Both committees waived the requirement for informed consent. The study was conducted in accordance with Colombian regulations and the principles of the Declaration of Helsinki [20].

Results

Individuals of both sexes carrying the GLA c.1124G>C (p. Gly375Ala) variant were identified in the department of Cauca in southwestern Colombia. The geographic distribution showed confirmed cases in the municipalities of Popayán, Patía, La Vega, and Angelia (Figure 1).

Genealogical analysis revealed that carriers belong to two extended families, related to each other, in which multiple members had clinical histories compatible with FD. The pedigree identified an inheritance pattern consistent with X-linked transmission and showed several affected individuals across different generations (Figure 2).

Baseline cohort characteristics

Sixteen patients with a confirmed diagnosis of FD carrying the GLA c.1124G>C (p. Gly375Ala) variant were evaluated at the Hospital Universitario San José in Popayán between 2015 and 2023. Sex distribution was balanced, with 8 males (50%) and 8 females (50%). The mean age at analysis was 40.0 years (SD 16.0) in males and 40.0 years (SD 11.0) in females, with no statistically significant differences between groups. Mean age at diagnosis was similar in both sexes: 32.8 years (SD 16.8) in males and 32.6 years (SD 10.6) in females (P = 0.8). Time from diagnostic confirmation to evaluation ranged from 2 to 15 years, with a median follow-up of 8 years (Table 1).

Table 1. Sociodemographic and baseline characteristics of patients with Fabry disease by sex.

*Socioeconomic status according to the Colombian national stratification system: stratum 1 = lowest socioeconomic level; stratum 2 = low–middle level.

SD: standard deviation. P values were obtained using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables.

Sociodemographic characteristics

All participants self-identified as Mestizo and resided in the department of Cauca. Most lived in rural areas (87.5%, n=14), whereas 12.5% (n=2) lived in municipal capitals. Socioeconomic stratum 1 predominated (81.2%, n=13), followed by stratum 2 (18.8%, n=3), with no significant sex differences (P > 0.9). Regarding education, 62.5% (n=10) had completed primary education, 25% (n=4) secondary education, and 12.5% (n=2) had no formal schooling. All patients were enrolled in the subsidized health insurance regime.

Baseline enzymatic biomarkers

Baseline α-galactosidase A activity was reduced in all patients compared with the reference range of the reporting laboratory (normal ≥15.3 nmol/h/mL). Mean activity in males was 11.0 nmol/h/mL (SD 2.5; range 8.2–14.5), whereas females had a mean of 4.5 nmol/h/mL (SD 5.5; range 0.8–12.3). The difference between sexes did not reach statistical significance (P = 0.052, Mann–Whitney U). The lower mean activity observed in females, opposite to the pattern usually described in classic X-linked FD, should be interpreted considering the small sample size and the use of a fluorometric dried blood spot assay rather than leukocyte-based testing (Figure 3).

Regarding lyso-Gb3, baseline data were available for 8 patients (5 males and 3 females). The laboratory reference value was ≤1.8 nmol/L. In males, concentrations ranged from 1.2 to 1.6 nmol/L, with most values close to the upper normal limit. In females, two patients had values within the reference range (1.4 and 1.5 nmol/L), and one showed a mildly elevated level of 2.5 nmol/L. In several cases, the first lyso-Gb3 measurement was obtained after Fabry-specific therapy had already started, so these values likely underestimate pretreatment substrate burden (Figure 4).

Renal function

The mean eGFR was 66.6 mL/min/1.73 m² (SD 47.4) in males and 96.8 mL/min/1.73 m² (SD 38.6) in females (P = 0.11). Although this difference did not reach statistical significance, the lower values observed in men suggest greater impairment of renal function in this group (Table 2).

Table 2. Renal function parameters and biomarkers by sex.

SD: standard deviation; IQR: interquartile range; α-Gal A: α-galactosidase A; lyso-Gb3: globotriaosylsphingosine; eGFR: estimated glomerular filtration rate. *Mann–Whitney U test.

Serum creatinine concentrations were significantly higher in males (5.8 mg/dL, SD 8.1) than in females (1.6 mg/dL, SD 2.2; P = 0.035), including two male patients with levels above 10 mg/d (Figure 5).

Clinical manifestations by organ system

Multisystem involvement predominated in this cohort (Figure 6). Fifteen of 16 patients (93.8%) had involvement of two or more organ systems (median, 4 systems; mean, 4.5; range, 1–7). Systems were assessed across nine domains (dermatologic, central nervous system, peripheral nervous system, cardiac, rheumatologic, gastrointestinal, ophthalmologic, auditory, and mental health). A domain was classified as affected when at least one Fabry-related manifestation was documented at baseline or during follow-up.

Dermatologic involvement was present in 15/16 patients (93.8%) and included telangiectasias and angiokeratomas among affected individuals. Central nervous system involvement was recorded in 12/16 (75.0%), most commonly categorized as other neurologic events/symptoms (10/16, 62.5%). Peripheral nervous system involvement occurred in 11/16 (68.8%) and included heat intolerance (12/16, 75.0%), acroparesthesias (10/16, 62.5%), hyperhidrosis (7/16, 43.8%), and exercise intolerance (1/16, 6.2%). Cardiac involvement was documented in 8/16 (50.0%), including conduction abnormalities (5/16, 31.2%), left ventricular hypertrophy (3/16, 18.8%), and other cardiac findings (6/16, 37.5%). Rheumatologic involvement was present in 8/16 (50.0%), most often pain or burning in the hands/feet (6/16, 37.5%), severe osteomuscular pain episodes (2/16, 12.5%), and other symptoms (1/16, 6.2%). Gastrointestinal involvement occurred in 7/16 (43.8%), including diarrhea (2/16, 12.5%), abdominal pain (2/16, 12.5%), nausea (1/16, 6.2%), and constipation (1/16, 6.2%).

Ophthalmologic involvement was present in 6/16 (37.5%) and included cornea verticillata (2/16, 12.5%), decreased visual acuity (2/16, 12.5%), and conjunctival vessel tortuosity (1/16, 6.2%). Auditory involvement occurred in 4/16 (25.0%), including tinnitus (4/16, 25.0%), hearing loss (3/16, 18.8%), and vertigo (2/16, 12.5%). Renal involvement was documented in 3/16 (18.8%). Mental health involvement was recorded in 1/16 (6.2%) and corresponded to depression documented in the medical record (Figure 6).

Follow-up and treatment data

Longitudinal follow-up was available for 12 patients (75%) with a mean duration of 6.2 years (range, 2–12). Four male patients (33.3%) showed progression of renal involvement, as evidenced by increased serum creatinine and decreased eGFR. Female patients didn’t exhibit significant renal deterioration during follow-up. Treatment information was available for 14 patients (87.5%), of whom 71.4% received enzyme replacement therapy (ERT) with agalsidase Alfa and 28.6% received migalastat. Documented adherence had a median of 85% (range, 60–95%) (Table 3).

Table 3. Characteristics of specific treatment and clinical course by sex.

SD: standard deviation; IQR: interquartile range. P values calculated using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Calculations were performed only for patients with available data. *Adherence was defined as the proportion of scheduled doses of specific therapy that were actually received.

Treatment continuity

Only five patients (31.3%) maintained their initial therapy throughout the follow-up period. Eleven of 16 patients (68.8%) had at least one episode of temporary or permanent treatment discontinuation, mainly related to administrative difficulties within the health system and suspension of infusions during the COVID-19 pandemic. One female patient permanently discontinued migalastat because of drug intolerance (6.3% of the cohort; 1 of 11 patients with any discontinuation). Overall adherence ranged from 50% to 100%, with lower values in patients who experienced prolonged interruptions.

Therapy switching between migalastat and agalsidase Alfa occurred in five patients (31.3%), usually after administrative interruptions or reassessment of mutation amenability (Table 4).

Table 4. Distribution of patients by initial therapy, reasons for discontinuation, and second-line treatment in the Fabry disease cohort (n=16).

Discussion

This study describes for the first time in Colombia the clinical, biochemical, and sociodemographic characteristics of individuals carrying the GLA c.1124G>C (p. Gly375Ala) variant associated with FD [16]. The substitution of guanine by cytosine at position 1124 of the GLA gene results in a glycine-to-alanine change at position 375 of the α-galactosidase A enzyme. This variant has been reported in individuals evaluated for FD and has been functionally assessed in mutation series [14]. In addition, other changes at the same position have been associated with the disease by Iwafuchi et al. [21], Sawada et al. [22], and Yoshida et al. [23], where patients were reported to have Fabry-related clinical manifestations and low enzyme activity levels (with some residual activity) in both males and females. In ClinVar, this variant is classified as “uncertain significance” (ID:217412), while CENTOGENE and ACMG consider it likely pathogenic (class 2) [14,16,21]).

Emerging evidence suggests that some missense GLA variants can promote protein misfolding and proteostatic dysfunction, with downstream activation of endoplasmic reticulum stress and the unfolded protein response. These mechanisms have been proposed as contributors to phenotypic variability, particularly in variants that retain residual enzyme activity [13,24]. This framework aligns with the concept of an “AGALopathy,” in which altered protein processing and stability may influence the clinical course beyond the degree of substrate accumulation alone [24].

The clinical findings in our cohort show a heterogeneous phenotype, with dermatological and neurological manifestations predominating, and more severe renal involvement in males. These results are consistent with previous reports on other FD variants [8,9].

In our cohort, mean α-Galactosidase A activity was lower in females than in males, although individual values overlapped and the difference did not reach statistical significance. This pattern differs from the typical presentation of classic FD in which men generally show more profound enzyme deficiency, while females demonstrate wider variability due to residual enzyme activity and X-chromosome inactivation [8]. In our study, most females had residual enzymatic activity and preserved glomerular filtration rates relative to males, consistent with delayed renal involvement in many heterozygous female patients, although variability in clinical and biochemical expression remained evident across both sexes.

With respect to biomarkers, lyso-Gb3 values were low and heterogeneous. This pattern may reflect the uncertain clinical significance of the variant under study and the fact that some baseline lyso-Gb3 measurements were obtained after Fabry-specific therapy had already started, which can underestimate pretreatment substrate burden. Prior functional studies also indicate that variants classified as of uncertain significance may have heterogeneous effects on enzyme processing substrate accumulation, reinforcing the need for complementary functional and longitudinal studies to clarify the clinical relevance of p. Gly375Ala [8,13].

Overall, the clinical and biochemical profile in our cohort is compatible with the spectrum described for nonclassical or later-onset Fabry presentations, where residual enzymatic activity and relatively low lyso-Gb3 levels can coexist with clinically relevant organ involvement and diagnostic uncertainty in individual carriers [8,11,13]). In our dataset, most patients (15/16; 93.8%) had involvement of two or more organ systems; however, a single organ system typically exhibited a more severe compromise—the central and peripheral nervous systems in females and the renal system in males. These findings emphasize that later-onset presentations often show a wide variable expressivity and that phenotype assignment should integrate clinical findings with biomarkers and longitudinal assessment [8,11]. In addition to the primary GLA variant, biological modifiers such as variability in enzyme activity among females and proteostatic stress mechanisms have been proposed as contributors to heterogeneity across Fabry phenotypes [8,13,25].

Therapy adherence and continuity were limited. Only five patients maintained the initial treatment throughout follow-up, while ten experienced discontinuations, mostly due to administrative barriers and difficulties in accessing the health system. This pattern is consistent with reports from Latin America and other developing regions, where the availability of targeted therapies is restricted by non-clinical factors [25]. The switch between agalsidase Alfa and migalastat was motivated in some cases by the identification of “amenable” mutations or by restarting treatment after administrative interruptions, reflecting the fragility of therapeutic continuity in the local context.

Comparison with international series is limited, as most published studies focus on classical or late-onset variants with confirmed pathogenicity [6]. Published data on p. Gly375Ala remain scarce. Lukas et al reported this substitution as part of a broader series of GLA mutations and showed that changes at residue 375 can alter enzyme processing and activity [14]. Additional screening and registry reports from Asian and European cohorts have identified carriers of p. Gly375Ala or other substitutions at this position, but phenotypic descriptions are often brief and longitudinal data on renal, cardiac, or dermatologic outcomes are lacking [16,21-23]. Our cohort adds detailed characterization of organ involvement, biomarker profiles, and treatment exposure in a Latin American population, including evidence of renal decline in a subset of men despite relatively low lyso-Gbâ?? levels.

Our study is subject to several limitations. The small sample size and retrospective design limit the ability to establish definitive genotype–phenotype correlations and to robustly evaluate disease progression and treatment response. The absence of complete biomarker data in some patients and frequent therapy interruptions introduce measurement and follow-up biases.

Nevertheless, as most patients were diagnosed through family screening, leading to disease diagnosis across age groups, sexes and disease stages allowing a thorough description of the disease. This study also provides relevant information to characterize an under-studied variant and underscores the need for more effective health policies to ensure timely diagnosis and treatment continuity in rare diseases in Colombia.

Conclusions

Colombian patients carrying the GLA c.1124G>C (p. Gly375Ala) variant exhibited wide variable expressivity and a heterogeneous clinical profile; however, disease manifestations were typically characterized by a more severe involvement of a single predominant organ system (central and peripheral nervous system in females and the renal system in males). The enzymatic activity showed variable reduction, with lyso-Gb3 levels normal or low. Therapy response and adherence were mainly compromised by administrative and access barriers rather than pharmacological intolerance.

The clinical and genetic characterization of this familial variant highlights the importance of integrating genotype–phenotype correlation with longitudinal follow-up and, when uncertainty persists, additional diagnostic approaches such as extended genetic evaluation and selected tissue-based assessments in carefully defined clinical contexts. This approach may facilitate more precise diagnosis, support therapeutic decision-making, and help anticipate clinical progression in affected individuals.

This study expands local knowledge of a poorly characterized variant and emphasizes the need to improve access to molecular diagnosis and guarantee continuity of Fabry-specific therapies in Colombia. Prospective, functional, and multicenter studies are required to clarify the clinical significance of this familial variant and optimize patient management.

Acknowledgments

The authors thank Dr. Jorge Ospina, from EpiThink Health Consulting, for medical writing and editorial assistance funded by Takeda.

Conflicts of Interest

Marcela Daza and Edison Montenegro are employees of Takeda Colombia SAS and do not hold stock/options in Takeda Pharmaceutical Company Ltd. The remaining authors declare no financial or personal conflicts of interest that could have inappropriately influenced the conduct of this research.

Funding

The study was carried out with institutional resources and technical support from the BIMAC Group (Environmental Molecular Biology and Cancer) at the Universidad del Cauca, under the coordination of the Vice-Rector’s Office for Research of the Universidad del Cauca. Takeda provided financial support for data collection, medical editing, and article publication. Medical writing and editorial assistance were provided by Jorge Ospina, MD, from EpiThink Health Consulting, and were conducted independently from the sponsor.

Data Availability

Anonymized data supporting the findings of this study are available upon reasonable request to the BIMAC Group (Environmental Molecular Biology and Cancer), subject to ethical approval and compliance with confidentiality requirements.

Authorship

All authors actively participated in the conceptualization of the study, data collection and validation, interpretation of results, and manuscript preparation. All authors have reviewed and approved the final version of the article and take responsibility for its content.

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