GALM – Galactosemia 4

Galactosemia type 4 is an autosomal recessive metabolic disorder caused by biallelic mutations in GALM, encoding galactose mutarotase, the first enzyme of the Leloir pathway. Since its initial description in 2018, 52 probands have been reported across independent cohorts, with presentations ranging from neonatal cataracts to transient transaminitis (PMID:35028268; PMID:39350089; PMID:38762772; PMID:30451973).

Inheritance follows autosomal recessive transmission. Segregation analysis in two multiplex sibships identified homozygous c.829G>C (p.Gly277Arg) in at least four siblings, including two asymptomatic individuals (PMID:35028268; PMID:39350089).

Case series include eight patients identified by exome sequencing (PMID:30451973), two clinically ascertained sib pairs (PMID:35028268; PMID:39350089), and a nationwide Japanese survey of 40 individuals (estimated prevalence 1:181 835), in which four of 38 patients (10.5%) developed cataracts that resolved under lactose restriction (PMID:38762772).

The variant spectrum comprises missense (e.g., c.829G>C (p.Gly277Arg), c.799C>G (p.Arg267Gly)), nonsense (c.195C>A (p.Tyr65Ter), c.932G>A (p.Trp311Ter)), and frameshift (c.294del (p.Ile99LeufsTer46)) changes. Two recurrent alleles, c.294del (p.Ile99LeufsTer46) and c.424G>A (p.Gly142Arg), represent 72.5% of pathogenic variants in Japan (PMID:38762772).

In vitro functional assays of 66 variants showed loss of protein expression or activity for 29 variants, supported by immunoblot analyses demonstrating absent GALM in patient cells (PMID:30910422; PMID:30451973).

Computational structural modeling identified binding-site residues (p.Arg82Gly, p.Glu307Gly) with predicted disruption of substrate interaction and increased protein rigidity, reinforcing a loss-of-function mechanism (PMID:36591702).

Collectively, robust genetic and functional data support a definitive gene–disease relationship. Early genetic confirmation of GALM deficiency informs dietary management to prevent cataract formation, highlighting the clinical utility of newborn screening.

References

• JIMD Reports • 2022 • Two siblings with galactose mutarotase deficiency: Clinical differences. PMID:35028268
• BMC Pediatrics • 2024 • Clinical and biochemical evolution after partial dietary liberalization of two cases of galactosemia due to galactose mutarotase deficiency. PMID:39350089
• Genetics in Medicine • 2024 • Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan. PMID:38762772
• Genetics in Medicine • 2019 • Biallelic GALM pathogenic variants cause a novel type of galactosemia. PMID:30451973
• Molecular Genetics and Metabolism • 2019 • The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants. PMID:30910422

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