Type IX Glycogen Storage Disease - Causes, Types, Diagnosis and Treatment

Introduction

The disorder known as glycogen storage disease type IX (GSD IX) is brought on by a problem with the breakdown of a complex sugar called glycogen. The condition's various manifestations may impair the breakdown of glycogen in muscle or liver cells or, occasionally, both. Lack of glycogen breakdown impairs the affected tissue's ability to operate normally. The other names for this condition are

• GSD IX.

• GSDIX.

• PhK deficiency.

• Phosphorylase B kinase deficiency.

• Phosphorylase kinase deficiency.

What Are the Causes of GSD IX Deficiency?

GSD IX has been associated with mutations in the PHKA1, PHKA2, PHKB, or PHKG2 genes. With the help of these genes, an enzyme called phosphorylase b kinase can be built up from its parts or subunits. The alpha, beta, gamma, and delta subunits comprise four of the enzyme's 16 subunits. The subunits combine to generate at least two distinct forms of phosphorylase b kinase, one of which is mainly found in liver cells and the other in muscle cells. The phosphorylase b kinase alpha subunit is made using instructions from the PHKA1 and PHKA2 genes. While the protein made from the PHKA2 gene is a component of the liver enzyme, the protein produced from the PHKA1 gene is a subunit of the muscle enzyme. The beta subunit is made according to instructions from the PHKB gene and can be found in the liver and muscle. The gamma subunit of the liver enzyme is made according to instructions from the PHKG2 gene.

What Is the Pathophysiology of GSD IX?

Whether in the muscles or the liver, phosphorylase b kinase is crucial for supplying energy to cells. A simple molecule called glucose serves as cells' primary energy source. Glycogen is a form of glucose storage found in liver and muscle cells. When glucose is required to maintain normal blood glucose levels between meals or for energy during exercise, glycogen can be broken down quickly. The enzyme that breaks down glycogen is activated (turned on) by phosphorylase B kinase. Mutations in the PHKA1, PHKA2, PHKB, and PHKG2 genes decrease the activity of phosphorylase b kinase in liver or muscle cells and blood cells.

In contrast, the consequences of gene mutations on the corresponding protein components are unknown. The ability of this enzyme to break down glycogen is reduced. As a result, cells become damaged by the buildup of glycogen and cannot use glucose for energy. Hepatomegaly is caused by a buildup of glycogen in the liver, while hypoglycemia and ketosis are brought on by the liver's inability to convert glycogen to glucose. Muscle wasting, discomfort, and cramping are caused by the muscles' reduced ability to produce energy.

What Is the Inheritance Pattern of the GSD IX?

Depending on the underlying genetic etiology of the disorder, GSD IX can have various patterns of inheritance.

• X-Linked Recessive Pattern - GSD IX is inherited in an X-linked recessive form when PHKA1 or PHKA2 gene mutations cause the condition. One of the two sex chromosomes, the X chromosome, contains these genes. One mutated copy of the gene in each cell is sufficient to induce the disease in males (who have only one X chromosome). A mutation would need to occur in both copies of the gene in females (who have two X chromosomes) for it to result in the condition. However, some females with one mutated copy of the PHKA2 gene experience GSD IX signs and symptoms, such as moderate hepatomegaly or early-onset short stature. While these characteristics are typically not severe, in rare instances, they might be. Males have X-linked recessive illnesses significantly more commonly than females since it is unusual that females will have two mutated copies of this gene. Fathers cannot pass on X-linked qualities to their sons, a trait of X-linked inheritance.

• Autosomal Recessive Pattern - When the PHKB or PHKG2 gene is mutated, the disorder is inherited in an autosomal recessive form, meaning both gene copies in every cell are mutated. Each parent of a person with an autosomal recessive disorder carries one copy of the defective gene, although usually, neither parent exhibits the disease's signs and symptoms.

What Are the Types of GSD IX?

The glycogen storage disease type IX (GSD IX), caused by phosphorylase kinase (PhK) deficiency, is brought on by a lack of the enzyme phosphorylase b kinase, which plays a significant regulatory role in the breakdown of glycogen. The two types of PhK deficiency are

• Liver PhK Deficiency - Manifests as early onset hepatomegaly and growth limitation, as well as frequently, though not always, fasting ketosis and hypoglycemia.

• Muscle PhK Insufficiency - Less common and characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness

What Are the Symptoms of GSD IX?

The various symptoms of GSD IX according to the type of Phk deficiency are as follows.

1. Liver PhK Deficiency - Although liver PhK insufficiency has traditionally been regarded as a benign illness, more severe involvement has been observed. The three subtypes, caused by pathogenic mutations in three distinct genes (PHKA2, PHKB, and PHKG2), cannot be identified by their clinical characteristics because the severity of these features can vary greatly.

   1. Hepatomegaly - Hepatomegaly is one of the most typical manifestations of liver PhK deficiency. The size of the enlarged liver might range from modest to massive. Age often causes a reduction in hepatomegaly. Following therapy with cornstarch and a high-protein diet, it has been reported that the size of the liver shrank, and the liver enzymes returned to normal.

   2. Liver Fibrosis - When PHKG2 pathogenic variations produce liver PhK insufficiency, liver fibrosis can develop and, in some cases, lead to cirrhosis. It has also been documented in some people with PHKA2 pathogenic variants. It has not yet been linked to PHKB variations, but it might happen, given the results of studies on other liver PhK deficient illnesses.

   3. Liver Adenoma - Although it has been recorded, it seems highly uncommon and primarily connected to the PHKG2-related subtype.

   4. Growth Restriction - Childhood growth limitation is the most prominent, and after that, catch-up growth and normal sexual development occur; most people achieve a normal height.

   5. Hyperketotic Hypoglycemia - With or without hypoglycemia, hyperketosis can develop during extended fasting intervals, reduced calorie intake, or vomiting and diarrhea during an illness. Blood 3-hydroxybutyrate (OHB) greater than 1.0 mmol/L (normal 0.3 mmol/L) is hyperketonemia.

      1. Ketotic hypoglycemia can range from being occasional to recurring in some people.

      2. Chronic ketosis indicates poor metabolic regulation and can impact development and general health.

   6. Muscular Concerns - Some people have been seen to exhibit hypotonia and muscle weakness.

      1. Mild delays in gross motor development are typically seen in young children.

      2. Cardiac symptoms are uncommon, but a patient with PHKB-associated liver PhK deficit was found to have asymptomatic interventricular septal hypertrophy.

   7. Genitourinary Findings

      1. Females with liver PhK insufficiency have been reported to develop polycystic ovaries. Dysmenorrhea, irregular menstruation, and oligomenorrhea have all been recorded, although the frequency of fertility problems has not been thoroughly researched.

      2. There have been rare cases of renal tubular acidosis recorded.

2. Muscle PhK Deficiency - The PHKA1 mutation leads to muscle-specific phosphorylase kinase deficiency. However, pathogenic mutations in PHKB and (rarely) PHKG2 are also responsible for muscle PhK deficiency. A wide range of symptoms, including exercise intolerance, muscle cramps, myalgia, myoglobinuria, and increasing muscle weakness, can be present in this phenotype between childhood and maturity. It generally appears in youngsters as a modest gross motor delay.

   1. Muscular Involvement

      1. There have been reports of minor muscular involvement in some affected people, especially concerning muscle PhK insufficiency caused by PHKG2.

      2. Fatigue, soreness, and cramping brought on by exercise.

      3. Weakness in the proximal limb girdles, particularly the pelvic girdle.

      4. Atrophy of the muscles as a result of progressively weaker muscles.

      5. Rhabdomyolysis.

      6. Increase of plasma CK in some people without any symptoms.

   2. Liver Involvement - Some people with pathogenic mutations in PHKB have hepatomegaly and hypoglycemia.

   3. Cardiac involvement - An individual with a PHKB variation has been documented to have interventricular septal hypertrophy.

How Is GSD IX Diagnosed?

The diagnosis of GSD IX is based on clinical and laboratory findings and positive family history of storage diseases.

1. Clinical Findings - Presence of signs and symptoms of possible muscle and liver PhK deficiency.

2. Laboratory Findings

   1. Increased liver transaminases.

   2. Increased triglycerides and cholesterol.

   3. Normal uric acid and lactic acid concentrations.

   4. Increased serum concentrations of creatine kinase.

3. Molecular Genetic Testing - To assess the mutation in the PhK gene.

4. Liver Biopsy

   1. Histological Findings

      1. Hepatocytes that have accumulated too much glycogen typically display distension in histology. Steatosis, low-grade inflammatory alterations, and bridging portal fibrosis may also be present. Adenomas and liver cirrhosis have both been documented.

      2. Biochemical analysis of liver biopsy tissue that has been frozen reveals an astonishingly high glycogen concentration with normal glycogen structure.

   2. Enzyme Testing - The liver, erythrocytes, and leukocytes of most (not all) people with liver PhK deficiency have lower levels of phosphorylase B kinase (PhK).

      1. Normal PhK activity is 1.0 mol/min/g hemoglobin in erythrocytes and 0.1 mol/min/mg protein in the liver.

      2. The abnormal range is lesser than 10 % of the normal level in the tissue being tested.

5. Muscle Biopsy

   1. Histological Findings

      1. On histology, there is an abnormal buildup of subsarcolemmal glycogen.

      2. Muscle biochemical testing reveals a higher-than-normal glycogen level and normal glycogen structure.

   2. Enzyme Testing

      1. In contrast to the liver, blood cells, and fibroblasts, the activity of the PhK enzyme is significantly reduced in muscle.

      2. In people with muscle PhK deficiency, the activity of glycogen myophosphorylase (phosphorylase-a) in the muscle may be decreased because the PhK enzyme activates glycogen phosphorylase in the liver and muscle.

How Is GSD IX Treated?

The various treatments, according to the manifestations, are

1. Liver PhK Deficiency - Maintaining blood sugar levels between 70 and 100 mg/dL is the treatment's aim.

   1. Hypoglycemia - It can be avoided with regular daytime feedings rich in complex carbohydrates and protein.

      1. Depending on the clinical signs, the dose of cornstarch might range from 0.6 to 2.5 g/kg every six hours. Glycosade, a waxy maize extended-release cornstarch, enables steady glucose release, sometimes even throughout an entire night.

      2. As long as renal function is intact, protein should be supplied as 15 % to 25 % of total calories or two to three grams of protein/kg body weight/day (adapted to the patient's age). Protein offers a different source of glucose thanks to gluconeogenesis, which is still active.

      3. Around 30 % of total calories should come from fats. Cholesterol intake should be kept to 300 mg daily and saturated fats to no more than 10 % of total calories.

      4. Since excessive cornstarch consumption might result in diarrhea, weight gain, and insulin resistance, it should be avoided.

   2. Signs of Hypoglycemia or Ketosis

      1. If oral intake is acceptable, Polycose or fruit juice should be administered before a protein- and complex carbohydrate-rich snack. To ensure that blood glucose and ketone levels return to normal, periodic monitoring is advised. An IV (intravenous) should be administered if oral consumption is not tolerated.

      2. When intravenous dextrose support is necessary, a 10 % dextrose concentration should be utilized at a rate that is 1 to 1.25 % of the maintenance rate, along with the proper electrolytes. Depending on the blood glucose level, the rate might be raised.

   3. Symptomatic Treatment - It is appropriate to treat hepatic symptoms such as cirrhosis, liver failure, and portal hypertension on a symptomatic basis.

2. Muscle PhK Deficiency - The management of signs and symptoms should be similar to other muscle GSDs, like GSD III.

   1. Evaluation and treatment in physical therapy based on physical condition and function.

   2. Coordination with a metabolic nutritionist to regulate and enhance blood glucose levels dependent on activity and exercise.

What Are the Agents to Avoid With GSD IX Disease?

The agents to avoid in persons having GSD IX are

1. Liver PhK Deficiency

   1. Large amounts of simple sugars may increase the glycogen stored by the liver and cause rapid changes in blood sugar and insulin levels.

   2. Extended fasting.

   3. Suppose severe (moderate to enormous) hepatomegaly and high-impact contact sports exist. Clinical judgment informs the final choice.

   4. Drugs known to mask hypoglycemia symptoms, such as beta-blockers, and cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas).

   5. Alcohol - may increase the risk of hypoglycemia.

   6. Because Augmentin includes clavulanic acid, which is linked to idiopathic liver disease and can cause malabsorption.

   7. Growth hormone therapy should not be used unless there is a known deficiency since it can cause hepatic adenomas and induce ketosis.

2. Muscle PhK Deficiency

   1. Vigorous activity.

   2. Drugs that may result in rhabdomyolysis (e.g., Succinylcholine).

   3. Statins (must be used with caution, as they can cause rhabdomyolysis).

Conclusion:

The disorder known as glycogen storage disease type IX (GSD IX) is brought on by a problem with the breakdown of a complex sugar called glycogen. The condition's various manifestations may impair the breakdown of glycogen in muscle or liver cells or occasionally both. Lack of glycogen breakdown impairs the affected tissue's ability to operate normally. Early diagnosis followed by appropriate treatment and precautions improves the quality of life of people with GSD IX.