Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth retardation, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). Symptoms and biochemical abnormalities of liver PhK deficiency are thought to improve with age.
The enzyme PhK comprises four copies each of four subunits (alpha, beta, gamma, and delta). Mutations in PHKA1, encoding subunit alpha, cause the rare X-linked disorder muscle PhK deficiency; mutations in PHKA2, also encoding subunit alpha, cause the most common form, liver PhK deficiency (X-linked liver glycogenosis); mutations in PHKB, encoding subunit beta, cause autosomal recessive PhK deficiency in both liver and muscle; and mutations in PHKG2, encoding subunit gamma, cause autosomal recessive liver PhK deficiency. Diagnosis is based on clinical findings, assay of PhK activity in erythrocytes, or liver or muscle tissues (depending upon presentation) and confirmatory findings on molecular genetic testing.
PHKA2-related liver PhK deficiency and PHKA1-related muscle PhK deficiency are inherited in an X-linked manner. PHKB-related liver and muscle PhK deficiency and PHKG2-related liver PhK deficiency are inherited in an autosomal recessive manner. X-linked inheritance: If the mother is a carrier, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Affected males pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at risk are possible if the disease-causing mutation in the family has been identified. Autosomal recessive inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible if the disease-causing mutations in the family have been identified.