Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes

Abstract

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. We 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. We 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 hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.

Growth in patients with type 1 diabetes

“…While Mauriac syndrome is invariably observed in the setting of poor glycemic control, only a small fraction of T1DM patients with elevated HgbA1c develop the condition, suggesting that additional risk factors must exist. A potential genetic cause was recently described by MacDonald and colleagues who studied a 13 year old boy with Mauriac syndrome severe enough to cause liver impingement on the diaphragm and respiratory distress 32 . Sequential sequencing of candidate genes in the glycogen metabolism pathway revealed a heterozygous mutation of a highly conserved amino acid in the phosphorylase kinase γ subunit 2 ( PHKG2 ) gene.…”

ISPAD Clinical Practice Consensus Guidelines 2018: Other complications and associated conditions in children and adolescents with type 1 diabetes

“…Recently, a mutation in an enzyme of glycogen metabolism (catalytic subunit of glycogen phosphorylase kinase) was reported in a patient with Mauriac syndrome that increases glycogen content by limiting glycogen breakdown and hence increasing its deposition in the human liver. The postulated mechanism is that this mutant enzyme of glycogen metabolism combines with hyperglycemia to directly inhibit glycogen phosphorylase, resulting in many of the phenotypic features observed in this syndrome …”

Mauriac syndrome — is already a history?

“…Such studies have recently been reported by MacDonald et al [28]. The authors noted that the mutation in PHKG2 (phosphorylase kinase catalytic subunit gamma 2), combined with hyperglycaemia, together with glycogenolysis, caused severe hepatomegaly.…”