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Research Team Uses Gene Sequencing to Solve 85-year-old Diabetes Mystery

A team of researchers at the University of Wisconsin School of Medicine and Public Health has identified the genetic cause for a rare syndrome in children with poorly controlled type 1 diabetes.

The research, led by emeritus professor of pediatrics Dr. Michael MacDonald, was published in the July issue of the journal Diabetes. The rare disease, Mauriac syndrome, is characterized by massive liver enlargement, growth failure and delayed puberty. It’s seen only in a small subset of children with high blood sugar from poorly controlled type 1 diabetes. Mauriac syndrome was first described 85 years ago.

According to the Juvenile Diabetes Research Foundation, as many as three million Americans have type 1 diabetes, and approximately 15 percent of those are children.  Although more than 100 scientific papers have been published on Mauriac syndrome, it took the emerging technology of gene sequencing combined with biochemical studies to discover the cause.  The researchers sequenced the DNA of a patient and looked at all of the genes that encode enzymes involved in glycogen metabolism.

“We found a cause for a syndrome that has baffled doctors for 85 years,” said MacDonald. “Although poorly controlled diabetes is common and is present in at least 20 to 30 percent of children with type 1 diabetes, extreme liver enlargement with growth failure is rare, occurring in way lower than one percent of children with type I diabetes.”

Through DNA sequencing of one family they were able to find the cause.  After identifying the mutation in the gene that encodes a key enzyme of glycogen metabolism, they expressed that mutant enzyme in human liver cells in culture and found it suppressed the enzyme’s activity and caused glycogen to accumulate to a very high level, thus explaining the liver enlargement.  However, the patient’s mother had the same genetic mutation but no enlarged liver or diabetes.

High blood sugar (hyperglycemia) itself can occasionally cause a slight increase in liver size due to increased glycogen.  The patient’s father had neither the gene mutation nor an enlarged liver, but did have poorly controlled type 1 diabetes. “This case is a perfect storm. Each parent had one component of the syndrome that alone was insufficient to cause overt the overt syndrome. This case demonstrates how the effect of the mutant enzyme acted together with the hyperglycemia and combined to cause the enormous liver loaded with glycogen and the growth failure,” said MacDonald. “Like many other genetic discoveries, it just sheds more light on the cause and hopefully in the future, when gene therapy or a new medicine becomes a treatment option, the lives of these youngsters can be improved.”

MacDonald, who has researched diabetes for more than 40 years, now hopes to perform DNA sequencing on more patients with Mauriac syndrome to search for more mutations. A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown.

Researchers discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. The authors show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient’s mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly.  His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure.

This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyper-inhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.

Practice Pearls

  • Mauriac syndrome is characterized by massive liver enlargement, growth failure and delayed puberty.
  • A mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyper-inhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.
  • A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes.

Press Release: School of Medicine and Public Health, University of Wisconsin-Madison, July 2016

Michael J. MacDonald, Noaman M. Hasan, Israr-ul H. Ansari, Melissa J. Longacre; Diabetes Volume 65, July 2016 2051: Diabetes 2016;65:2051–2059 | DOI: 10.2337/db16-0099