Galactose Mutarotase Deficiency as the type IV Galactosemia

 

Yoichi Wada, M.D., Ph.D.

 

Distinguished Senior Assistant Professor (Principal Investigator)
Department of Medical Science and Innovation, SiRIUS Institute of Medical Research, Tohoku University
Department of Pediatrics, Tohoku University Hospital

 

Galactosemia comprises a group of inherited enzyme defects in the Leloir pathway, which metabolizes dietary galactose generated by lactose hydrolysis. Disruption of the Leloir pathway leads to accumulation of galactose and its metabolites. Historically, three enzymatic forms were recognized. In 2019, we identified a fourth form — galactose mutarotase (GALM) deficiency (MIM #618881). GALM (aldose‑1‑epimerase, EC:5.1.3.3) catalyzes the interconversion of α‑ and β‑D‑galactose at the entry point of the Leloir pathway; loss of GALM activity results in accumulation of galactose and its polyol, galactitol, generated from the open‑chain aldehyde. Excess galactitol appears to promote osmotic cataract formation, paralleling other galactosemias. To date, aside from cataracts and transient transaminitis, no additional complications have been consistently documented in GALM deficiency. However, the condition should not be regarded as benign, given clinical experience with irreversible cataracts. A nationwide survey estimated a prevalence of 1 in 181,835, while a separate population‑based estimate 1 in 80,747 derived from genome database analyses and in vitro functional evaluation. Dietary lactose restriction remains the cornerstone of management for galactosemias, including GALM deficiency. Additionally, we have demonstrated that β‑galactosidase supplementation can attenuate elevations in blood galactose in GALM deficiency, supporting its candidacy as an adjunct therapy. This seminar will trace the discovery of GALM deficiency and summarize current understanding, including results of recent research.

 

References

Wada, Y. et al. Biallelic GALM pathogenic variants cause a novel type of galactosemia. Genet Med 21, 1286–1294 (2019).

Iwasawa, S. et al. The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants. Mol Genet Metab 126, 362–367 (2019).

Wada, Y. et al. β-Galactosidase therapy can mitigate blood galactose elevation after an oral lactose load in galactose mutarotase deficiency. J Inherit Metab Dis 45, 334–339 (2022).

Mikami-Saito, Y. et al. Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan. Genet Med. 26, 101165 (2024).