Galactose epimerase deficiency: lessons from the GalNet registry

Abstract

Background Galactose epimerase (GALE) deficiency is a rare hereditary disorder of galactose metabolism with only a few cases described in the literature. This study aims to present the data of patients with GALE deficiency from different countries included through the Galactosemia Network to further expand the existing knowledge and review the current diagnostic strategy, treatment and follow-up of this not well characterized entity. Methods Observational study collecting medical data from December 2014 to April 2022 of 22 not previously reported patients from 14 centers in 9 countries. Patients were classified as generalized or non-generalized based on their genotype, enzyme activities in different tissues and/or clinical picture and professional judgment of the treating physician. Results In total 6 patients were classified as generalized and 16 as non-generalized. In the generalized group, acute neonatal illness was reported in 3, cognitive and developmental delays were present in 5 and hearing problems were reported in 3. Four generalized patients were homozygous for the genetic variant NM_001008216.2:c.280G > A (p.Val94Met). In the non-generalized group, no clearly related symptoms were found. Ten novel genetic variants were reported in this study population. Conclusion The phenotypic spectrum of GALE deficiency ranges from asymptomatic to severe. The generalized patients have a phenotype that is in line with the 9 described cases in the literature and prescribing dietary interventions is the cornerstone for treatment. In the non-generalized group, treatment advice is more difficult. To be able to offer proper counseling, in addition to red blood cell enzyme activity, genetic studies, transferrin glycoform analysis and enzymatic measurements in fibroblasts are recommended. Due to lack of facilities, additional enzymatic testing is not common practice in many centers nor a tailored long-term follow-up is performed.

Addition of galactose‐1‐phosphate measurement enhances newborn screening for classical galactosemia

“…GALE deficiency is a rare hereditary disorder with only a few symptomatic patients described in the literature 26 . In the 15 years prior to the Israeli NBS for galactosemia, excluding the Bedouin kindred with the atypical presentation, there were not any other known clinical patients of epimerase deficiency.…”

“…GALE deficiency is a rare hereditary disorder with only a few symptomatic patients described in the literature. 26 In the 15 years prior to the Israeli NBS for galactosemia, excluding Bedouin kindred with the atypical presentation, there were not any other known clinical patients of epimerase deficiency. Our routine algorithm (Figure 1B) does not include GALE deficiency; however, our program will refer Arab Bedouin newborns with elevated Gal-1P for hematological workup.…”

The Genetic Basis of Galactosemia in Iranian Patients: Identification of Twenty Novel Mutations in GALT, GALK1 and GALE Gene

“…The A198V mutation of GALK1 gene is designated to be the Osaka variant and was found to be in a signi cant frequency among the Japanese and Korean populations (19). The GALE gene located on chromosome 1p36.11 (20). Various genetic variants have been identi ed and described in the GALE gene.…”

“…The most severe defects in GALE protein were observed in c.280G > A (p.Val94Met), c.269G > A (p.Gly90Glu) and c.548 T > C (p.Leu183Pro) genetic mutations. Homozygosity of c.280G > A (p.Val94Met) has been found in the majority of patients with the generalized phenotype (21).…”