Glucose-galactose malabsorption (ORPHA:35710)
A rare, potentially lethal, autosomal recessive metabolic disease characterized by impaired glucose-galactose absorption resulting in severe watery diarrhea and dehydration with onset in the neonatal period.
Epidemiology
Glucose-galactose malabsorption (GGM) is a rare disease, with fewer than 1,000 cases reported worldwide, which is most frequently reported in populations with a high incidence of consanguinity. The frequency of the Northern-Sweden founder mutation, Q457R, is 45-fold higher than other mutations linked to the disease in the general European population.
Clinical description
This disease usually presents within the first week of life with severe life-threatening diarrhea, metabolic acidosis, and hyperosmolar dehydration.
Etiology
GGM is due to mutations in the gene coding for the intestinal brush border sodium-glucose cotransporter protein SGLT1 (SLC5A1), disrupting the absorption of glucose and galactose from lactose in breast milk. As this disease is mainly reported in populations with high incidence of consanguinity, many mutations causing the disease are homozygous missense, nonsense, frame-shift, or splice-site mutations. In non-consanguineous probands, heterozygous mutations are inherited from each parent. Mutations producing premature stop codons result in non-functional truncated proteins, while missense mutations generally result in proteins that do not reach the brush border membrane. It should be cautioned that not all identified missense mutations produce inactive transporters. In the oldest known GGM pedigree -dating back to the 17th century in Northern Sweden- a homozygous missense mutation identified in 14 patients results in a non-functional protein in the brush border membrane.
Diagnostic methods
If the child is in hospital, i) a duodenal biopsy is frequently taken to ensure normal histology, and ii) an oral glucose tolerance test or a hydrogen breath test is conducted to evaluate glucose absorption. However, the most straightforward test in the hospital or at home is to eliminate lactose, glucose, and galactose from the feeds by withholding breast milk and feeding with a sugar-free formula. The diarrhea will cease but return immediately on refeeding breast milk or formula with glucose, but not with fructose. Sanger and next-generation sequencing methods are readily available. Molecular testing is not required if the intestinal biopsy is normal, and the child's diarrheal symptoms resolve on a glucose/galactose restricted-diet.
Differential diagnosis
The differential diagnosis GGM includes other forms of nutrient-specific congenital diarrhea such as congenital lactase deficiency and congenital sucrase-isomaltase deficiency.
Antenatal diagnosis
Antenatal diagnosis is possible when molecular testing has previously identified the mutation causing glucose malabsorption.
Genetic counseling
As GGM is an autosomal recessive disorder, the parents of children with GGM should be advised that additional children have a 25% chance of inheriting the disease. Carriers of GGM mutations have an extremely low chance of parenting children with the disease, as the frequency of mutation in the general population is less than 1 in 15,000. The only exception is where carriers are restricted by geography or culture to communities where GGM is prevalent, and in these cases, prospective partners ought to be screened for mutations.
Management and treatment
The symptoms of GGM are resolved on a diet free of glucose, galactose, and lactose, and several infant formulas are available for young children in Europe and North America. As children enter late infancy, it becomes more challenging to maintain a carbohydrate-free diet and parents are encouraged to consult a well-qualified-dietician or parent-support group.
Prognosis
After dealing with the challenges of dietary carbohydrates (lactose, sucrose, glucose, galactose) restriction to control diarrhea and dehydration in newborns and young children, the prognosis is excellent for adults who lead a normal healthy life.

                            Last update: 
                            November 2023


                            - Expert reviewer(s): 
                            Pr Martin MARTIN  - Pr Ernest WRIGHT