U.S. Department of Health and Human Services

Study of a Rare Genetic Disorder of Metabolism Leads to a Promising Therapeutic Approach

​A recent analysis has clarified understanding of the metabolic disorder glycogenesis type XIV, and found that dietary supplementation with the sugar galactose may be a practical approach to alleviate some of the disorder’s symptoms.  People with glycogenesis type XIV are unable to make phosphoglucomutase 1, an enzyme that helps supply some of the specific carbohydrate (sugar) “building blocks” used to make glycoproteins, an important group of molecules with diverse roles in the body.  Phosphoglucomutase 1 is also involved in the storage of carbohydrates in liver and muscle, as well as in the utilization of that stored energy.  The study began with a pair of brothers with an unusual combination of symptoms: muscle weakness, liver disease, short stature, cleft palate, and recurring hypoglycemia (low blood glucose).  Genetic testing revealed that both boys had mutations in each of their two copies of the gene for phosphoglucomutase 1, with the effect that they produced none of the enzyme.  The researchers identified 17 more individuals who were similarly unable to produce active phosphoglucomutase 1 and experienced a similar (though somewhat variable) constellation of symptoms.

To investigate how lacking phosphoglucomutase 1 might cause the symptoms of glycogenesis type XIV, the researchers compared the array of sugars available for making glycoproteins in cells from people with and without the enzyme. They found that people without the enzyme are unable to make significant amounts of a compound called UDP-galactose.  Although the body normally produces UDP-galactose via a process utilizing phosphoglucomutase 1, an alternative path exists whereby the body can make UDP-galactose from the naturally occurring sugar, galactose.  Galactose by itself is not normally a significant part of a person’s diet, although it is bonded to another sugar, glucose, in the milk sugar, lactose.  The scientists found that adding a small amount of galactose to the diet of six of the people lacking phosphoglucomutase 1 significantly improved their ability to make glycoproteins and alleviated some of their symptoms within days.  Supplemental lactose, on the other hand, had no effect.  In addition, the researchers developed a blood test which may help diagnose glycogenesis type XIV.  Long-term studies will be needed to determine whether galactose is a safe and effective treatment for people with this rare genetic disease.

Tegtmeyer LC, Rust S, van Scherpenzeel M, Ng BG, Losfeld ME, Timal S, Raymond K, He P, Ichikawa M, Veltman J, Huijben K, Shin YS, Sharma V, Adamowicz M, Lammens M, Reunert J, Witten A, Schrapers E, Matthijs G, Jaeken J, Rymen D, Stojkovic T, Laforêt P, Petit F, Aumaître O, Czarnowska E, Piraud M, Podskarbi T, Stanley CA, Matalon R, Burda P, Seyyedi S, Debus V, Socha P, Sykut-Cegielska J, van Spronsen F, de Meirleir L, Vajro P, DeClue T, Ficicioglu C, Wada Y, Wevers RA, Vanderschaeghe D, Callewaert N, Fingerhut R, van Schaftingen E, Freeze HH, Morava E, Lefeber DJ, Marquardt T. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 370: 533-542, 2014.