Glucose/galactose Malabsorption

A number sign (#) is used with this entry because glucose/galactose malabsorption (GGM) is caused by homozygous mutation in the gene encoding the intestinal sodium/glucose transporter (SLC5A1; 182380) on chromosome 22q12.

Description

Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).

Clinical Features

The intestinal monosaccharide transporter deficiency known as glucose/galactose malabsorption (GGM) produces a clinical picture indistinguishable from that of intestinal disaccharidase deficiency (222900). In GGM, fructose and xylose are absorbed normally. The disorder manifests itself within the first weeks of life, and the consequent severe diarrhea and dehydration are usually fatal unless glucose and galactose are eliminated from the diet. Meeuwisse (1970) pointed out that almost all patients with glucose/galactose malabsorption show a slight, intermittent glucosuria. Elsas et al. (1970) concluded that heterozygotes are detectable and demonstrate a reduced capacity for glucose transport, and that absent intestinal glucose transport is accompanied by partial impairment of renal glucose transport. Lebenthal et al. (1971) observed improvement in the tolerance of glucose and sucrose as an affected child grew older. Elsas and Lambe (1973) likewise found clinical remission with increased age in severe glucose/galactose malabsorption even though active jejunal glucose transport remained absent.

Abdullah et al. (1996) reported 8 children with diarrhea which started immediately after breast- or bottle-feeding. All showed wasting at the time of presentation. The diagnosis was confirmed in each case by blood glucose and galactose levels after loading with glucose or galactose. All improved dramatically on a fructose-based formula.

Xin and Wang (2011) reported GGM in 33 individuals in an extended Old Order Amish pedigree with multiple lines of common descent. After a normal birth, patients presented with watery diarrhea on day 2 or 3 of life soon after breast or formula feeding. The diarrhea was continuous despite normal nursing, and affected infants became dehydrated and lost weight. Other features included distended abdomen, increased bowel sounds, acidic stool, metabolic acidosis, and hypernatremia. There were 3 main clinical courses: a dramatic improvement and normal development if correctly diagnosed and managed; prolonged disease course until correct diagnosis and management, followed by normal development; and lack of correct diagnosis due to less severe symptoms, with chronic diarrhea until correct diagnosis and treatment. All patients slowly developed tolerance to carbohydrates over time, although the speed and degree of improvement varied.

Diagnosis

Prenatal Diagnosis

Martin et al. (1996) performed prenatal diagnosis in 2 subsequent pregnancies in a large consanguineous affected family, using EcoRV restriction digestion. One showed that the fetus was heterozygous and the other showed that the fetus was not a carrier of the D28N mutation (182380.0001). Both children at 2 years of age remained healthy with no diarrhea.

Pathogenesis

Mutation in the SLC5A1 gene (182380) results in a dysfunctional sodium/glucose cotransporter protein. Normally, the cotransporter actively absorbs glucose and galactose into the cells lining the villi of the gastrointestinal tract. Mutations such as nonsense or frameshift that result in a premature stop codon lead to a truncated protein (cotransporter) that does not function properly (Turk et al., 1993). Many of the missense mutations, by contrast, lead to translation of a full protein, but cause a defect in trafficking of the protein to the plasma membrane. Martin et al. (1996) showed that sugar uptake by oocytes was severely impaired in the case of 15 missense mutants, even though Western blot analysis indicated that the amount of mutant protein in oocytes was comparable to wildtype. Both types of defect in the cotransporter gene ultimately lead to unabsorbed carbohydrate in the intestinal lumen, which further causes an osmotic diarrhea, hyperosmolar dehydration, and metabolic acidosis (Wright et al., 2001).

Inheritance

Occurrence in both sexes, familial incidence (Lindquist et al., 1963; Anderson et al., 1965; Elsas et al., 1970), and instances of parental consanguinity (Lebenthal et al., 1971) support autosomal recessive inheritance of glucose/galactose malabsorption.

Lebenthal et al. (1971) described 3 affected offspring from consanguineous marriages in an Iraqi-Babylonian Jewish family. The parents were first cousins in 4 of the 6 affected Arab families reported by Abdullah et al. (1996).

Molecular Genetics

Turk et al. (1991) identified a missense mutation (182380.0001) in 2 related patients with glucose/galactose malabsorption. Martin et al. (1996) screened 30 patients for mutations in the SGLT1 gene (182380) and used a heterologous expression system to link the mutations to the phenotype. Thirty-one novel mutations of SLC5A1 were identified in 25 families with glucose/galactose malabsorption. Martin et al. (1996) performed prenatal diagnosis in 2 pregnancies in affected families using EcoRV restriction digestion. One showed that the fetus was heterozygous and the other showed that the fetus was not a carrier of the D28N mutation. Both children at 2 years of age remained healthy with no diarrhea.

In 33 patients from an extended Old Order Amish pedigree with GGM, Xin and Wang (2011) identified a homozygous mutation in the SLC5A1 gene (R558H; 182380.0003). The mutation, which segregated with the disorder in the families, was not found in a large control database. All patients were also homozygous for 3 additional nonsynonymous variants in the SLC5A1 gene that were found in a large control database (N51S, rs17683011; A411T, rs17683430; and H615Q, rs33954001). All 4 mutations segregated with the disorder in the families. Heterozygosity for the 4 mutations, which were present on a common haplotype, was found in 5% of Amish control alleles, indicating a founder effect. Xin and Wang (2011) noted that N51S occurred at a conserved residue and may also affect the protein. No functional studies were performed, and it was unclear how each individual mutation affected SLC5A1 protein function.