Clinical characteristics: 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 restriction, 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). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

Diagnosis/testing: The enzyme PhK comprises four copies each of four subunits (α, β, γ, and δ).

Pathogenic variants in:

1. PHKA1, encoding subunit α, cause the rare X-linked disorder muscle PhK deficiency;

2. PHKA2, also encoding subunit α, cause the most common form, liver PhK deficiency (X-linked liver glycogenosis);

3. PHKB, encoding subunit β, cause autosomal recessive PhK deficiency in both liver and muscle;

4. PHKG2, encoding subunit γ, cause autosomal recessive liver PhK deficiency.

The diagnosis of PhK deficiency is established in a proband with the characteristic clinical findings, a family history of suspected storage disease, and/or a hemizygous pathogenic variant in PHKA1 or PHKA2 or biallelic pathogenic variants in PHKB or PHKG2 identified by molecular genetic testing.

Management: Treatment of manifestations:

1. Liver PhK deficiency. Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein. When hypoglycemia or ketosis is present, Polycose^® or fruit juice is given orally as tolerated or glucose by IV. Liver manifestations (e.g., cirrhosis, liver failure, portal hypertension) are managed symptomatically.

2. Muscle PhK deficiency. Physical therapy based on physical status and function; optimization of blood glucose concentrations by a metabolic nutritionist based on activity.

Surveillance:

1. Liver PhK deficiency. Regular evaluation by a metabolic physician and a metabolic nutritionist. Monitoring of blood glucose concentration and blood ketones routinely as well as during times of stress (e.g., illness, intense activity, rapid growth, puberty) and reduced food intake. In children younger than age 18 years, liver ultrasound examination should be performed every 12 to 24 months. With increasing age, CT or MRI using intravenous contrast should be considered to evaluate for complications of liver disease. Echocardiogram should be performed at least every two years.

2. Muscle PhK deficiency. Regular evaluation by a metabolic physician, a metabolic nutritionist, and a physical therapist.

Agents/circumstances to avoid:

1. Liver PhK deficiency. Large amounts of simple sugars as they will increase liver storage of glycogen; prolonged fasting; high-impact contact sports if significant hepatomegaly is present; drugs known to cause hypoglycemia such as insulin and insulin secretagogues (the sulfonylureas) or drugs known to mask symptoms of hypoglycemia such as beta-blockers; alcohol (which may predispose to hypoglycemia).

2. Muscle PhK deficiency. Vigorous exercise; medications like succinylcholine and statins that can cause rhabdomyolysis.

Evaluation of relatives at risk: Molecular genetic testing (if the family-specific pathogenic variant[s] are known) and/or evaluation by a metabolic physician (if the family-specific pathogenic variant[s] are not known) allows early diagnosis and treatment for sibs at increased risk for GSD IX.

Pregnancy management: Individualized dietary management is necessary to maintain euglycemia throughout pregnancy.

Genetic counseling: 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.

1. X-linked inheritance. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers); the development of symptoms in individuals depends on the pattern of X-chromosome inactivation. Affected males pass the pathogenic variant to all of their daughters and none of their sons.

2. 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, prenatal testing for pregnancies at risk, and preimplantation genetic testing are possible if the pathogenic variant(s) in the family have been identified.