Dataset Information

Novel Mutation in the SLC5A1 Gene Causing Glucose-Galactose Malabsorption: First Confirmed Case From Central America.

ABSTRACT: Congenital glucose-galactose malabsorption is a rare cause of life-threatening diet-induced diarrhea in infants. Mutations in the SLC5A1 gene, which encodes for the sodium-dependent glucose transporter, result in large-volume diarrhea due to aberrant glucose and galactose transport across the intestinal brush border. The diagnosis can be made clinically based on the presence of diarrhea soon after birth, evidence of carbohydrate malabsorption in the stool, and resolution of diarrhea with dietary elimination of glucose and galactose. Genetic testing can confirm the diagnosis. Here we report the first confirmed case of glucose-galactose malabsorption in an infant from Central America due to a novel mutation in the SLC5A1 gene. The patient began growing and thriving after being diagnosed and with the correct dietary interventions.

SUBMITTER: Katz DT

PROVIDER: S-EPMC10684165 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Novel Mutation in the <i>SLC5A1</i> Gene Causing Glucose-Galactose Malabsorption: First Confirmed Case From Central America.

Katz Daphna T DT Curia Suzzette S Fifi Amanda C AC Febo-Rodriguez Liz L Llanos-Chea Alejandro A

JPGN reports 20231113 4

Congenital glucose-galactose malabsorption is a rare cause of life-threatening diet-induced diarrhea in infants. Mutations in the <i>SLC5A1</i> gene, which encodes for the sodium-dependent glucose transporter, result in large-volume diarrhea due to aberrant glucose and galactose transport across the intestinal brush border. The diagnosis can be made clinically based on the presence of diarrhea soon after birth, evidence of carbohydrate malabsorption in the stool, and resolution of diarrhea with ...[more]

PMID: 38034445

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Project description:IntroductionCongenital glucose-galactose malabsorption (CGGM) is a rare autosomal recessive disorder that primarily causes chronic intractable diarrhea. This study aims to describe the clinical history, laboratory profile, diagnostic workflow, and management of the first patient reported with CGGM in Mexico.MethodsThe case involves a Mexican female infant with recurrent admissions to the emergency room since birth due to chronic diarrhea.ResultsThe infant was born at term by C-section with a birth weight of 3.120 kg and height of 48 cm for consanguineous parents. She had been breastfed until day 5 of her life when she presented lethargy, diarrhea, abdominal discomfort, and jaundice. During the first evaluation at the emergency room, the significant laboratory finding was blood tyrosine elevation; afterward, amino acid and succinylacetone determinations were obtained, discarding tyrosinemia. When admitted to the hospital, an abdominal ultrasound detected a duplex collecting system. At this time, rice formula was introduced to the patient. She was discharged with jaundice improvement, but diarrhea persisted. Several formula changes had been made from rice to extensively hydrolyzed casein protein to whey-based, with no clinical improvement; the patient still had 10-12 excretions daily. In the second hospitalization, the patient presented anemia, severe dehydration, hyperammonemia, and renal tubular acidosis. A next-generation sequencing panel for inborn errors of metabolism and congenital diarrhea was performed, identifying a homozygous variant in SLC5A1 (c.1667T > C). The diagnosis of CGGM was made at 3 months of age. The infant was initially treated with a modular galactose-glucose-free formula with oil, fructose, casein, minerals, and vitamins until a commercial fructose-based formula was introduced. This led to a complete resolution of diarrhea and improved nutritional status.DiscussionDiagnosing CGGM is challenging for clinicians, and next-generation sequencing is a valuable tool for providing appropriate treatment. More detailed information on patients with this condition might lead to possible phenotype-genotype correlations. This case's primary clinical and biochemical findings were chronic diarrhea, anemia, jaundice, renal tubular acidosis, hyperammonemia, and initial hypertyrosinemia. Symptoms were resolved entirely with the fructose-based formula.

Project description:The probiotic yeast Saccharomyces boulardii has been extensively studied for the prevention and treatment of diarrheal diseases, and it is now commercially available in some countries. S. boulardii displays notable phenotypic characteristics, such as a high optimal growth temperature, high tolerance against acidic conditions, and the inability to form ascospores, which differentiate S. boulardii from Saccharomyces cerevisiae The majority of prior studies stated that S. boulardii exhibits sluggish or halted galactose utilization. Nonetheless, the molecular mechanisms underlying inefficient galactose uptake have yet to be elucidated. When the galactose utilization of a widely used S. boulardii strain, ATCC MYA-796, was examined under various culture conditions, the S. boulardii strain could consume galactose, but at a much lower rate than that of S. cerevisiae While all GAL genes were present in the S. boulardii genome, according to analysis of genomic sequencing data in a previous study, a point mutation (G1278A) in PGM2, which codes for phosphoglucomutase, was identified in the genome of the S. boulardii strain. As the point mutation resulted in the truncation of the Pgm2 protein, which is known to play a pivotal role in galactose utilization, we hypothesized that the truncated Pgm2 might be associated with inefficient galactose metabolism. Indeed, complementation of S. cerevisiaePGM2 in S. boulardii restored galactose utilization. After reverting the point mutation to a full-length PGM2 in S. boulardii by Cas9-based genome editing, the growth rates of wild-type (with a truncated PGM2 gene) and mutant (with a full-length PGM2) strains with glucose or galactose as the carbon source were examined. As expected, the mutant (with a full-length PGM2) was able to ferment galactose faster than the wild-type strain. Interestingly, the mutant showed a lower growth rate than that of the wild-type strain on glucose at 37°C. Also, the wild-type strain was enriched in the mixed culture of wild-type and mutant strains on glucose at 37°C, suggesting that the truncated PGM2 might offer better growth on glucose at a higher temperature in return for inefficient galactose utilization. Our results suggest that the point mutation in PGM2 might be involved in multiple phenotypes with different effects.IMPORTANCESaccharomyces boulardii is a probiotic yeast strain capable of preventing and treating diarrheal diseases. However, the genetics and metabolism of this yeast are largely unexplored. In particular, molecular mechanisms underlying the inefficient galactose metabolism of S. boulardii remain unknown. Our study reports that a point mutation in PGM2, which codes for phosphoglucomutase, is responsible for inferior galactose utilization by S. boulardii After correction of the mutated PGM2 via genome editing, the resulting strain was able to use galactose faster than a parental strain. While the PGM2 mutation made the yeast use galactose slowly, investigation of the genomic sequencing data of other S. boulardii strains revealed that the PGM2 mutation is evolutionarily conserved. Interestingly, the PGM2 mutation was beneficial for growth at a higher temperature on glucose. We speculate that the PGM2 mutation was enriched due to selection of S. boulardii in the natural habitat (sugar-rich fruits in tropical areas).

Project description:Ingested galactose can enhance postexercise liver glycogen repletion when combined with glucose but effects on muscle glycogen synthesis are unknown. In this double-blind randomized study participants [7 men and 2 women; V̇o2max: 51.1 (8.7) mL·kg-1·min-1] completed three trials of exhaustive cycling exercise followed by a 4-h recovery period, during which carbohydrates were ingested at the rate of 1.2 g·kg-1·h-1 comprising glucose (GLU), galactose (GAL) or galactose + glucose (GAL + GLU; 1:2 ratio). The increase in vastus lateralis skeletal-muscle glycogen concentration during recovery was higher with GLU relative to GAL + GLU [contrast: +50 mmol·(kg DM)-1; 95%CL 10, 89; P = 0.021] and GAL [+46 mmol·(kg DM)-1; 95%CL 8, 84; P = 0.024] with no difference between GAL + GLU and GAL [-3 mmol·(kg DM)-1; 95%CL -44, 37; P = 0.843]. Plasma glucose concentration in GLU was not significantly different vs. GAL + GLU (+ 0.41 mmol·L-1; 95%CL 0.13, 0.94) but was significantly lower than GAL (-0.75 mmol·L-1; 95%CL -1.34, -0.17) and also lower in GAL vs. GAL + GLU (-1.16 mmol·-1; 95%CL -1.80, -0.53). Plasma insulin was higher in GLU + GAL and GLU compared with GAL but not different between GLU + GAL and GLU. Plasma galactose concentration was higher in GAL compared with GLU (3.35 mmol·L-1; 95%CL 3.07, 3.63) and GAL + GLU (3.22 mmol·L-1; 95%CL 3.54, 2.90) with no difference between GLU + GAL (0.13 mmol·L-1; 95%CL -0.11, 0.37) and GLU. Compared with galactose or a galactose + glucose blend, glucose feeding was more effective in postexercise muscle glycogen synthesis. Comparable muscle glycogen synthesis was observed with galactose-glucose coingestion and exclusive galactose-only ingestion.NEW & NOTEWORTHY Postexercise galactose-glucose coingestion or exclusive galactose-only ingestion resulted in a lower rate of skeletal-muscle glycogen replenishment compared with exclusive glucose-only ingestion. Comparable muscle glycogen synthesis was observed with galactose-glucose coingestion and exclusive galactose-only ingestion.

Dataset Information

Novel Mutation in the SLC5A1 Gene Causing Glucose-Galactose Malabsorption: First Confirmed Case From Central America.

Publications

Novel Mutation in the <i>SLC5A1</i> Gene Causing Glucose-Galactose Malabsorption: First Confirmed Case From Central America.

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