Galactose Epimerase Deficiency: Expanding the Phenotype.

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Galactose epimerase deficiency is an inherited metabolic disorder caused by uridine diphosphate-galactose-4'-epimerase (GALE) deficiency.
• Congenital disorders of glycosylation (CDG) can manifest with a wide range of clinical symptoms.
• Generalized GALE deficiency is a rare form of CDG.

Purpose of the Study:

• To report the clinical, genetic, and biochemical findings in two siblings with generalized GALE deficiency.
• To expand the understanding of the clinical spectrum of GALE deficiency.
• To highlight novel clinical manifestations, such as significant cardiac involvement.

Main Methods:

• Clinical case reporting of two affected siblings.
• Genetic analysis using a next-generation sequence panel for CDG syndrome.
• Biochemical studies including enzymatic activity assays in erythrocytes and fibroblasts.
• Serum transferrin isoelectrofocusing (IEF) for glycosylation pattern analysis.

Main Results:

• Both siblings were found to have the homozygous c.280G>A (p.[V94M]) mutation in the GALE gene.
• Markedly reduced GALE enzymatic activity was confirmed in patient erythrocytes and fibroblasts.
• Patient 1 presented with dysmorphic syndrome, failure to thrive, dilated cardiomyopathy, liver failure, psychomotor disability, deafness, and cataracts.
• Patient 2 exhibited short limbs, hip dysplasia, and died neonatally due to intraventricular hemorrhage and liver failure.
• This represents the fourth reported family with generalized GALE deficiency.

Conclusions:

• Generalized GALE deficiency can present with severe systemic involvement, including significant cardiac issues not previously reported.
• The study expands the recognized clinical spectrum of GALE deficiency.
• Accurate diagnosis requires a combination of clinical, genetic, and biochemical investigations.