Introduction: Enzymatic deficiencies of red blood cells, or erythroenzymopathies, are rare genetic disorders that affect intraerythrocytic metabolism.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary enzymopathy with high prevalence in some parts of the world due to its protective effect against malaria; however, prevalence data are lacking in our country. It is an X-linked condition: affected males are hemizygous, while females may be homozygous or compound heterozygous. It rarely presents as chronic hemolytic anemia and more frequently as intermittent hemolysis (acute hemolytic crises) triggered by oxidative agents such as certain foods (e.g., fava beans—favism), infections, or specific medications.

Due to X-chromosome inactivation (lyonization), approximately half of the red blood cells in heterozygous females have deficient enzyme activity, though they typically do not present significant hemolysis—this is more common in elderly women due to skewed lyonization.

More than 300 mutations in the G6PD gene have been identified at the molecular level, and variants are classified into four groups by the WHO based on clinical behavior.

Objective: To identify the clinical and molecular characteristics of patients with G6PD deficiency, study the prevalence in different regions and risk groups, and analyze clinical-molecular correlations.

Materials and Methods: This is a retrospective, observational, multicenter study conducted by researchers from the Spanish Erythropathology Group of the SEHH. Epidemiological, clinical, and analytical data were collected, along with molecular study results when available. Seventeen researchers from various geographic regions participated.

Results: A total of 176 patients with G6PD deficiency were included, of whom 43 had molecular study results. Of the total, 116 were male (66%) and 60 female (34%), with a median age at diagnosis of 20 years (IQR <1–92). Spanish nationality accounted for 57% of cases, followed by patients from Africa—most commonly Morocco (13.6%). Cases were also recorded from Latin America (8%), Asia (2.9%), and other origins (1.1%).

The most common reason for testing was acute hemolytic crisis (51%), followed by family screening (11.4%), pre-treatment testing (4%), and chronic hemolytic anemia (3%). For 53 patients (30%), the reason for testing was not recorded.

Clinically, 89 patients (50%) presented with acute hemolysis, 10 (6%) with chronic hemolysis and acute crises, and 2 (1%) with chronic hemolysis without crises. In 49 cases (28%), clinical information was unavailable, and 26 patients (15%) showed no hemolysis, having been tested due to family history or other causes.

In 55% of cases (n = 97), no triggering factor was identified or no crises were recorded. Among known triggers, the most frequent were consumption of fava beans (29.5%) and infections (12.5%). Drug-related causes accounted for 5%, with the most common medications being primaquine, rasburicase, COX-2 inhibitors, and chemotherapy/antibiotics.

The median hemoglobin during crises was 7.5 g/dL (range 3.9–11.1), while outside of crises it was 13.1 g/dL (range 10.9–15.3). A total of 9 patients had splenomegaly and 8 had cholelithiasis.

Enzymatic testing was performed in 141 cases, and molecular testing in 43. The most frequent WHO classification among patients with G6PD deficiency was Type III (47.4%), followed by Type II (36.8%). A smaller proportion presented with mixed Type I/II/III variants (7.9%) or isolated Type I variants (7.9%), while no cases of Type IV (asymptomatic variants) were detected.

Seventeen pathogenic variants were identified in 38 patients. In 15 patients (40%), variants were found as cis haplotypes or compound heterozygotes (females), the most frequent combination being c.376A>G/c.202G>A (p.Asn126Asp/p.Val68Met) in 11 patients of various ethnicities, mostly female, representing the G6PD A- haplotype.

Conclusions: Our data highlight the importance of diagnosis to prevent acute hemolytic crises—the main reason for testing in our cohort. In contrast, pre-treatment testing represented a small percentage of cases.

We must reconsider the target population for screening and the most appropriate method to implement it, in order to identify not only affected individuals but also carriers of the disease. Finally, it is worth noting the high genetic variability observed in our country, attributable to the inclusion of patients from diverse geographic backgrounds.

No conflicts of interest.

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2025
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