What is glucose galactose malabsorption?

Quick Answer
Glucose galactose malabsorption (GGM) is a rare genetic disorder in which the cells lining the small intestine cannot absorb glucose and galactose obtained with the diet. GGM is linked to mutations in a specific gene and is manifested beginning in early infancy with severe diarrhea after ingestion of glucose, galactose, or complex sugars that contain glucose and galactose units.
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Risk Factors

GGM is an autosomal recessive disease. It manifests if the patient’s parents each carry one copy of the mutated SLC5A1 gene, even if they do not show signs and symptoms; both sexes are equally affected. The familial risk factor is increased in consanguineous marriages. According to the US National Library of Medicine's Genetics Home Reference in 2014, severe GGM is rare (about a few hundred cases worldwide), but up to about 10 percent of the population may have a milder variation of the disorder, resulting in a reduced capacity to absorb glucose and galactose.

Etiology and Genetics

GGM is due to mutations of the SLC5A1 gene, which is located on the long (q) arm of chromosome 22, from base pair 30,769,258 to 30,836,644, and encodes the sodium-glucose cotransporter protein 1 (SGLT1). SGLT1 is located in the cell membrane facing the lumen (food side) of the small intestine. It actively transports glucose or galactose and sodium, followed by water, from the lumen into the absorptive cells. This transmembrane transport is the first step of glucose and galactose absorption. In GGM, mutations in the gene lead to a mutated, malfunctioning SGLT1, which cannot take up glucose and galactose.

More than forty different mutations in the SLC5A1 gene have been identified in GGM. Most are private mutations, found only in the kin of each GGM patient. In more than half of patients, the same mutations are present on both alleles (homozygous mutations); other patients have different mutations on each allele (compound heterozygous mutations). Mutated residues can be present throughout the SGLT1 protein and have been localized in ten out of its fourteen transmembrane helices.

Different kinds of mutations are associated with GGM: missense (a codon for one amino acid is substituted by the codon for a different amino acid), nonsense (a termination codon substitutes an amino acid codon), frame-shift (insertion or deletion of nucleotides, disrupting the reading frame or grouping of the codons), and splice-site (insertion or deletion of nucleotides at the splicing site of an intron, leading to introns in the mRNA and to aberrant proteins). Nonsense, frame-shift, and splice-site mutations result in a truncated SGLT1 protein, which is too short to function. Missense mutations yield a normal-length SGLT1 protein that lacks its normal three-dimensional structure. The misfolded protein cannot be moved to the luminal cell membrane, where it is needed to function as a transporter. When the transporter is either nonfunctional or altogether absent from the luminal membrane, the unabsorbed sugars remain in the intestinal lumen and draw water from the surrounding tissues, resulting in diarrhea.

Symptoms

GGM is an early-onset disease, which presents in the infant with severe watery diarrhea after breast-feeding or bottle feeding and with possible signs of wasting. The osmotic diarrhea leads to dehydration and metabolic acidosis and can be fatal within weeks. A mild glicosuria is also present. All symptoms are reversed when glucose and galactose (and sugars containing them, such as lactose) are eliminated from the diet. The individual is otherwise normal.

Screening and Diagnosis

GGM cases amount to a few hundred worldwide and present with diarrhea since birth and failure to thrive. Since this clinical picture overlaps that of intestinal disaccharidase deficiency, the diagnosis is also based on family history and laboratory investigations, including blood glucose and galactose levels and hydrogen breath test after a load of glucose or galactose. Small-intestinal biopsy, histology, and small-intestinal enzyme assays are documented in various GGM studies. Prenatal diagnosis using EcoRV restriction digestion has been performed in two pregnancies in a consanguineous family.

Treatment and Therapy

The therapy of GGM consists of the removal of glucose, galactose, and complex sugars containing glucose and galactose units from the diet. The diarrhea disappears immediately after the offending sugars are eliminated. In the GGM infant formula, fructose has been successfully used as a substitute sugar. Lifelong sugar substitution (fructose and xylose are well absorbed) allows the child to thrive and to lead a normal life as an adult.

Prevention and Outcomes

There is no effective means of prevention for GGM. Genetic counseling should always be available for the kin of a GGM patient. Newborns with GGM grow and thrive if the offending sugars are eliminated. In some cases, tolerance to glucose may slightly improve with age. Neither the condition nor the lifelong dietary precautions seem to have negative effects on GGM subjects throughout adulthood.

Bibliography

Genetics Home Reference. "Glucose Galactose Malabsorption." Genetics Home Reference. US NLM, 21 July 2014. Web. 24 July 2014.

National Center for Biotechnology Information. "Glucose Galactose Malabsorption." Genes and Disease. Bethesda: NCBI, 1998–. NCBI Bookshelf. NCBI, 15 July 2014. Web. 24 July 2014.

Pomin, Vitor H. Galactose: Structure and Function in Biology and Medicine. New York: Nova, 2014. Digital file.

Vallaeys, L., et al. "Congenital Glucose-Galactose Malabsorption: A Novel Deletion within the SLC5A1 Gene." European Jour. of Pediatrics 172.3 (2013): 409–411. Digital file.

Wright, Ernest M. “Genetic Disorders of Membrane Transport: I. Glucose Galactose Malabsorption.” American Journal of Physiology, Gastrointestinal Liver Physiology 275 (1998): G879–G882. Print.

Wright, Ernest M., Bruce A. Hirayama, and Donald F. Loo. “Active Sugar Transport in Health and Disease.” Journal of Internal Medicine 261 (2007): 32–43. Print.

Wright, Ernest M., Martin G. Martin, and Eric Turk. “Familial Glucose-Galactose Malabsorption and Hereditary Renal Glycosuria.” The Metabolic and Molecular Bases of Inherited Disease. Ed. Scriver, Charles R., et al. 8th ed. New York: McGraw, 2001: 4891–4908. Print.