Phosphorylase kinase-deficient liver
glycogenosis manifests in infancy with
hepatomegaly, growth retardation, and elevated plasma
aminotransferases and
lipids. It can be caused by mutations in three different genes of
phosphorylase kinase subunits: PHKA2, PHKB, and PHKG2. It is usually a benign condition, often with complete resolution of symptoms during puberty. A minority of patients displays a more severe phenotype with symptomatic
fasting hypoglycemia and abnormal liver histology that may progress to
cirrhosis. Three patients with
liver cirrhosis in childhood analyzed previously all had PHKG2 mutations. This suggested that this genotype may generally cause a more severe clinical manifestation, but to date PHKG2 mutations have been identified in only seven patients. Here, we report mutation analysis in three new patients with liver
phosphorylase kinase deficiency and recurrent
hypoglycemia,
liver fibrosis, and lack of
glucagon response but no overt
cirrhosis. In all three patients, PHKG2 mutations were found (H89fs[insC], E157K, D215N, W300X). Three of these mutations are novel, bringing the total number of distinct human PHKG2 mutations to 11, found in 10 patients. We conclude that liver
phosphorylase kinase deficiency with a severe phenotype, with or without
cirrhosis, is indeed often caused by PHKG2 mutations. These patients require active measures to maintain normoglycemia (raw
cornstarch, nocturnal
tube feeding), which may also alleviate growth retardation and the development of abnormal liver histology.