Galactose Epimerase Deficiency: Expanding the Phenotype

Abstract

Galactose epimerase deficiency is an inborn error of metabolism due to uridine diphosphate-galactose-4'-epimerase (GALE) deficiency. We report the clinical presentation, genetic and biochemical studies in two siblings with generalized GALE deficiency.Patient 1: The first child was born with a dysmorphic syndrome. Failure to thrive was noticed during the first year. Episodes of heart failure due to dilated cardiomyopathy, followed by liver failure, occurred between 12 and 42 months. The finding of a serum transferrin isoelectrofocusing (IEF) type 1 pattern led to the suspicion of a congenital disorder of glycosylation (CDG). Follow-up disclosed psychomotor disability, deafness, and nuclear cataracts.Patient 2: The sibling of patient 1 was born with short limbs and hip dysplasia. She is deceased in the neonatal period due to intraventricular hemorrhage in the context of liver failure. Investigation disclosed galactosuria and normal transferrin glycosylation.Next-generation sequence panel analysis for CDG syndrome revealed the previously reported c.280G>A (p.[V94M]) homozygous mutation in the GALE gene. Enzymatic studies in erythrocytes (patient 1) and fibroblasts (patients 1 and 2) revealed markedly reduced GALE activity confirming generalized GALE deficiency. This report describes the fourth family with generalized GALE deficiency, expanding the clinical spectrum of this disorder, since major cardiac involvement has not been reported before.

Galactose epimerase deficiency: lessons from the GalNet registry

“…However, a few GALE genetic variants are clearly associated with a mild or severe phenotype. Homozygosity for the variant NM_001008216.2:c.280G > A (p.Val94Met) is associated with a severe phenotype [14]. This is in line with our findings, as 4 of the 6 patients with generalized GALE deficiency were homozygous for this variant.…”

“…However, their long-term outcome is still unclear [9]. The generalized form of GALE deficiency appears to be an extremely rare disorder, with only nine patients (five females and four males) of four families reported in the literature so far [13,14]. In patients with generalized GALE deficiency, the enzyme activity is profoundly decreased in all tissues tested [9].…”

“…The first case of generalized GALE deficiency was reported in 1981, describing a newborn that presented on day five with a severe clinical picture similar to classic galactosemia and with a lack of GALE activity in red blood cells and fibroblasts [15]. Dysmorphic features as well as other long-term complications apparent from birth have been reported in other patients with generalized GALE deficiency [13,14]. These patients are from highly consanguineous families, making it questionable which symptoms are attributable to the GALE deficiency.…”

Through the Looking Glass: Chiral Recognition of Substrates and Products at the Active Sites of Racemases and Epimerases

“…[214][215][216] Interestingly,avarietyo fm utations leading to human GalE variants, often with decreased k cat values, have been identified that causet ype III galactosemia [217] and other disorders. [218,219] In addition to its role in the Leloir pathway,G alE is required for the biosynthesis of av ariety of complex polysaccharides andi s an important virulence factor in some Gram-negative pathogens. [216] GalE is ah omodimer with each monomer comprised of an N-terminal nucleotide-bindingd omain containing as evenstranded, parallel b-sheet flankedo ne ither side by six a-helices arranged in am odified Rossmann-like fold, and aC -terminal domain comprised of five b-strands and four a-helices.…”

Experiences with galactosemia in Croatia

“…Opisane su dugoročne komplikacije poput poremećaja psihomotoričkog razvoja i učenja, zamjedbenog gubitka sluha i kardiomiopatije. 26,27 Galaktozemija tipa IV uzrokovana je nedostatnom aktivnosti enzima GALM. 2 Procijenjena incidencija široko varira od 1 : 10.000 do 1 : 1.700.000.…”