Clinical Guidance

Pathogenic variants in PHKA1 result in muscle glycogenosis; pathogenic variants in PHKA2 and PHKG2 cause liver glycogenosis; pathogenic variants in PHKB and, rarely, PHKG2 cause liver and muscle glycogenosis (muscle signs are variably present). There is no consistent genotype-phenotype correlation for pathogenic variants in any of the four genes. Pathogenic variants in PHKG2 appear to result in more severe disease with an increased risk of liver fibrosis and cirrhosis, although persons with a milder course have been observed. Progressive liver disease has also been noted in individuals with pathogenic variants in PHKA2.

Source: GeneReviews — "Phosphorylase Kinase Deficiency"

Diagnostic Criteria

Phosphorylase kinase deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase (PhK), an enzyme with a key regulatory role in the breakdown of glycogen. Deficiency of this enzyme, which is composed of four copies each of four subunits (, , , and ), results in considerable clinical variability . For the purposes of this review, phosphorylase kinase (PhK) deficiency has been divided into liver PhK deficiency and muscle PhK deficiency (see and ). Liver PhK deficiency is further divided into three subtypes based on the gene in which pathogenic variants occur (PHKA2, PHKB, and PHKG2) and inheritance pattern. It should be noted that pathogenic variants in PHKB and, rarely, PHKG2 result in PhK deficiency both in liver and muscle.

Source: GeneReviews — "Phosphorylase Kinase Deficiency"

Differential Diagnosis

Table 3. Genetic Disorders to Consider in the Differential Diagnosis of Phosphorylase Kinase (PhK) Deficiency

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with liver PhK deficiency, the following evaluations are recommended if they have not already been completed:

• Measurement of blood glucose concentration (normal 70 mg/dL) for two to three days:

• Upon waking in the morning;

• Prior to meals and nighttime supplementation with oral cornstarch; and

• After activity

• Measurement of blood ketone levels for two to three days:

• Upon waking in the morning;

• Prior to meals and nighttime supplementation with oral cornstarch; and

• After activity.

Elevated blood ketones (beta-hydroxybutyrate 1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.

• Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (e.g., liver cirrhosis).

• Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)

• Prothrombin time

• Lipid panel (cholesterol and triglyceride concentrations)

• Serum creatine kinase measurement (Some individuals with liver PhK deficiency have muscle involvement.)

• Baseline echocardiogram (Baseline echocardiogram may be done as a precaution as interventricular septal hypertrophy was found in an individual with GSD IX caused by pathogenic variants in PHKB .)

Source: GeneReviews — "Phosphorylase Kinase Deficiency"

Clinical Guidance

Liver PhK deficiency. Affected Individuals should avoid the following:

• Large amounts of simple sugars, as they will increase liver storage of glycogen and may result in rapid fluctuations in levels of blood glucose and insulin

• Prolonged fasting

• High-impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.

• Drugs known to:

• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)

• Mask symptoms of hypoglycemia, such as beta-blockers

• Alcohol, as this may predispose to hypoglycemia

• Glucagon, as glycogenolysis is defective

• Augmentin®, as it can cause malabsorption and contains clavulanic acid, which is associated with idiopathic liver disease

• Growth hormone therapy unless there is proven growth hormone deficiency, as it can promote ketosis and development of liver adenomas

Hypoglycemic events in adults with liver PhK deficiency are relatively uncommon; however, caution should be used with drugs causing potential hypoglycemia, particularly in persons with impaired liver function. Muscle PhK deficiency. Affected individuals should avoid the following:

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Phosphorylase Kinase Deficiency"

Surveillance Guidelines

Liver PhK deficiency

• Regular evaluation by a metabolic physician familiar with liver PhK deficiency to monitor medical issues and a metabolic nutritionist to give dietary recommendations and monitor cornstarch requirement

• Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced, or meal and/or cornstarch dose or scheduling is altered.

Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.

• Liver imaging. In children younger than age 18 years, liver ultrasound examination every 12 to 24 months. With increasing age, consideration of CT or MRI using intravenous contrast to evaluate for complications of liver disease such as liver adenomas and cirrhosis

• Follow-up echocardiogram. No guidelines established; follow up approximately every two years or earlier if symptoms are present

Muscle PhK deficiency

Source: GeneReviews — "Phosphorylase Kinase Deficiency"