Galactose, a monosaccharide, plays diverse biological roles in energy production, especially in the glycolysis and glycosylation of proteins and lipids. Galactose metabolism is mediated by the Leloir pathway, which comprises four key enzymes. Following lactose hydrolysis, galactose mutarotase (GALM) catalyzes the anomerization of β-D-galactose to α-D-galactose, providing a substrate for the downstream pathway. In 2019, GALM deficiency was defined as the fourth type of galactosemia. Affected individuals may develop cataracts similar to those observed in individuals with galactokinase deficiency, disrupting the subsequent steps in the Leloir pathway. However, cataracts generally occur less frequently and tend to be milder in patients with GALM deficiency, likely because of the partial compensation provided by spontaneous galactose mutarotation in aqueous solutions. Because lactose, the primary dietary source of galactose, is the predominant carbohydrate consumed until weaning, the timely initiation of lactose restriction can prevent or even reverse cataract formation. To date, other complications or adverse events, including those in heterozygous carriers of GALM variants, have not been clearly demonstrated. This review aims to synthesize current knowledge and findings of GALM deficiency on molecular mechanisms, clinical presentation, diagnostic approaches, carrier risk, and dietary management, with particular emphasis on cataract prevention and reversibility through early lactose restriction. By consolidating available evidence, we propose future research directions, with broader implications for newborn screening programs, clinical decision-making, and a deeper understanding of galactose metabolism.

The recommended diet attitude in the recently described galactose mutarotase (GALM) deficiency is not yet established. We describe two 9-years twins who remain asymptomatic despite prolonged partial dietary liberalization from 18 months of age, after two periods of galactose-free diet. It represents the second report in Europe of GALM deficiency. Two male monochorionic diamniotic twins were detected through newborn screening by galactosuria and increased total blood galactose. They started galactose dietary restriction with biochemical normalization. After exclusion of the three previously described types of galactosemia, a progressively galactose reintroduction was initiated. The clinical follow-up developed include neurological assessment and intelligence quotient, annual ophthalmological evaluation and biannual abdominal ultrasound; whereas the biochemical assessment comprises quarterly determinations of galactose 1-phosphate and galactosuria and annual determination of liver and renal function, 25-OH-vitamin D and calcium levels. Sanger sequencing of GALM gene was complemented by the study of gene dose using SNPs array and a protein modeling to study the conformational changes induced in GALM protein. In both siblings a novel and complete deletion of exon 4 in GALM gene was detected. Both remained asymptomatic, with normal growth and intellectual development, despite dietary liberalization. Evolutionarily, the biochemical profile in blood remained normal with intermittent galactosuria. The absence of clinical involvement after 7 years of dietary liberalization is interesting to expand the knowledge about the recommended dietary management in this pathology.

Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency. This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023. We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM_138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency. GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.

Galactose mutarotase (GALM) deficiency (MIM# 618881), also known as type IV galactosemia, is caused by biallelic pathogenic variants of GALM. Cataracts are observed in patients with GALM deficiency as well as in other conditions associated with high levels of blood galactose and can be prevented by consuming a galactose-restricted diet or formula. Galactose restriction is the only known treatment for GALM deficiency and other types of galactosemia. We incidentally found that β-galactosidase might reduce blood galactose levels caused by lactose loading in GALM deficiency. Consequently, we investigated the effectiveness of β-galactosidase in decreasing the level of blood galactose in three patients with GALM deficiency. We performed two lactose loading tests per case: one with and one without β-galactosidase. The add-on administration of β-galactosidase significantly mitigated blood galactose elevations after lactose loading. Although urine galactitol was mildly elevated in all patients with GALM deficiency, β-galactosidase did not prevent increased levels of urine galactitol during the loading tests. No adverse events, including cataracts, were observed during or after the tests. Therefore, β-galactosidase could be a potential novel treatment agent for blood galactose elevation caused by lactose in patients with GALM deficiency. The effectiveness of β-galactosidase could possibly result in loosening of the galactose dietary restrictions or treatment for patients with GALM deficiency.

Galactose mutarotase (GALM) deficiency is an inherited metabolic disease caused by the deficiency of the first enzyme in the Leloir pathway. GALM deficiency was first reported in 2018. To date, eight cases have been reported. We are presenting two siblings with GALM deficiency; one patient presented with cataracts and her brother was asymptomatic. We evaluated the first case due to a cataract at 3 months old. She had elevated galactose and galactose-1-phosphate and normal galactose-1-phosphate uridylyltransferase (GALT) activity. Genetic analysis and other laboratory and clinical findings excluded galactokinase-1 (GALK1) and UDP-galactose 4'-epimerase (GALE) deficiencies. She had a homozygous mutation p. Gly277Arg (c.829G>A) in the GALM (NM_138801) gene. She was 3 years old at the last visit, and her physical examination was normal, except for cataracts. The same mutation was found to be homozygous in the patient's asymptomatic sibling during family screening. He had normal blood galactose and galactose-1-phosphate. This study highlights the importance of evaluating the whole galactose metabolism in terms of GALM deficiency in patients with cataracts.