Glycogen storage disease type VI
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Synonyms and keywords:Her's disease; phosphorylase deficiency glycogen-storage disease of liver; glycogen storage disease type 6; GSD IV; GSD type 6

# Overview
Glycogen storage type disease VI  is caused by the deficiency of phosphorylase B kinase. In 1959, Dr. Hers first discovered glycogen storage type VI disease in the patients with liver phosphorylase deficiency. Glycogen storage type disease VI is an autosomal recessive disease and some forms are X-linked recessive. Glycogen storage disease type VI is classified according to the pattern of inheritance associated with the enzyme deficiency into 2 subtypes, autosomal recessive liver phosphorylase kinase deficiency and x-linked recessive liver phosphorylase kinase deficiency. Glycogen storage disease type VI presents at the age of 1-5 years. A positive history of the protuberant abdomen, growth retardation and the slight delay in motor milestones is suggestive of glycogen storage disease type VI and some children have the history of mild fasting hypoglycemia and hypotonia.Patient with the glycogen storage disease type VI presents with the symptoms of hypoglycemia on fasting, such as faintness, weakness,  and nervousness. On physical examination, the increased liver span is present. The mainstay of treatment is the dietary therapy which includes frequent meals, high carbohydrate diet, high protein diet and supplementation of unsaturated fats.

# Historical Perspective
- In 1959, Dr. Hers first discovered glycogen storage type disease VI in the patients with liver phosphorylase deficiency.
- In 1960, Stetten & Stetten described glycogen storage type disease VI disease after its initial discovery.
- In 1987, gene mutations encoding liver phosphorylase present on chromosome 14q21-q22 became known to be associated with the pathogenesis of glycogen storage type disease VI disease.

# Classification
Glycogen storage disease type VI is classified according to the pattern of inheritance associated with the enzyme deficiency into 2 subtypes:
- Autosomal recessive liver phosphorylase kinase deficiency
- X-linked recessive liver phosphorylase kinase deficiency
- It is further classified into two types:
X-linked recessive liver phosphorylase kinase deficiency classical type (type I)
X-linked recessive liver phosphorylase kinase deficiency variant type (type II)
- X-linked recessive liver phosphorylase kinase deficiency classical type (type I)
- X-linked recessive liver phosphorylase kinase deficiency variant type (type II)

# Pathophysiology

## Pathogenesis
- Glycogen storage disease type VI is caused by the deficiency of liver phosphorylase B kinase.
- The rate-limiting enzyme of glycogen breakdown is phosphorylase, which is activated by a series of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent protein kinase.
- Enzyme deficiency leads to the impaired breakdown of glycogen into glucose.
- In most patients, the enzyme deficiency is incomplete, and gluconeogenesis remains intact.
- Due to impaired functioning of liver phosphorylase, there is difficulty to maintain glucose level at fasting, leading to hypoglycemia at fasting.
- There is also associated hyperketosis and increased levels of urinary ketones and serum ketone bodies.
- There is  mild-moderate hyperlipidemia and increased levels of transaminases.

## Metabolic Pathway

# Causes
- The most common cause of glycogen storage disease type VI is the deficiency of liver phosphorylase b kinase, an enzyme that activates phosphorylase by phosphorylation.
- Phosphorylase b kinase has 4 subunits, each is encoded by different genes present on different chromosomes.
- Mutations in three subunits (PHKA2, PHKB, and PHKG2) is most commonly seen in patients with phosphorylase b kinase deficiency.
- If there is the mutation only in PHKG2, then the patient has significant liver fibrosis and cirrhosis.

# Differentiating Glycogen storage disease type VI from Other Diseases

# Epidemiology and Demographics
- The prevalence of glycogen storage type disease VI is approximately 1 per 100,000 individuals worldwide.
- In the Mennonite population, the prevalence of  glycogen storage type VI is 1 per 1000 individuals due to defect in founder variant.
- Glycogen storage type disease VI usually develops in early childhood.
- Glycogen storage type disease VI affects individuals of the Mennonite religious group.
- One of the forms of liver phosphorylase B  kinase deficiency is X-linked recessive present in affected males, although asymptomatic males and heterozygous (carrier) females  presents with mild symptoms. All other types of glycogen storage type disease VI is autosomal recessive affects men and women equally.

# Risk Factors
The most potent risk factor in the development of glycogen storage disease type VI is a family member with glycogen storage disease type VI.

# Screening
- Glycogen storage disease type VI is an autosomal recessive disease and some forms are X-linked recessive.
- Carrier screening of at-risk relatives may be done.
- Screening requires prior PYGL identification of variants in the family.
- Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies may be done.

# Natural History, Complications, and Prognosis
- If left untreated, 1% of patients with glycogen storage disease type VI may progress to hepatocellular carcinoma.
- Other complications include cardiomyopathy.
- Prognosis is generally excellent if symptoms are controlled with diet.

# Diagnosis

## Diagnostic Study of Choice
There are no established criteria for the diagnosis of glycogen storage disease type VI.

## History and Symptoms
- Glycogen storage disease type VI presents at the age of 1-5 years.
- A positive history of the protuberant abdomen, growth retardation and the slight delay in motor milestones is suggestive of glycogen storage disease type VI.
- Some children have the history of mild fasting hypoglycemia and hypotonia.
- Common symptoms of glycogen storage disease type VI include:
- Symptoms of hypoglycemia on fasting such as faintness, weakness, and nervousness.
- Symptoms of hypoglycemia on fasting such as faintness, weakness, and nervousness.

## Physical Examination
- Patients with glycogen storage disease type VI usually appear normal.
- Physical examination of patients with glycogen storage disease type VI is usually remarkable for hepatomegaly.
- In a young child, delay in motor milestones, mild hypotonia and muscle weakness.

## Laboratory Findings
- Laboratory findings consistent with the diagnosis of glycogen storage disease type VI include:
Serum triglycerides, cholesterol, and liver transaminases are slightly increased.
Creatine kinase is normal.
Uric acid and lactic acid is normal.
Glucose does not increase following glucagon administration confirms hypoglycemia.
- Serum triglycerides, cholesterol, and liver transaminases are slightly increased.
- Creatine kinase is normal.
- Uric acid and lactic acid is normal.
- Glucose does not increase following glucagon administration confirms hypoglycemia.
Fasting test:
- The blood glucose level is assessed after 3-5 hour of fasting, mild hypoglycemia is noticed.
- The urine ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) after few hours of fasting is raised.

## Electrocardiogram
There are no ECG findings associated with glycogen storage disease type VI.

## X-ray
There are no X-ray findings associated with glycogen storage type VI disease.

## Ultrasound
Ultrasound may be helpful in the diagnosis of glycogen storage disease type VI. Findings on an ultrasound suggestive of glycogen storage disease type VI  include hepatomegaly.

## CT scan
CT scan may be helpful in the diagnosis of glycogen storage disease type VI. Findings on CT scan suggestive of glycogen storage disease type VI is hepatomegaly.

## MRI
MRI may be helpful in the diagnosis of glycogen storage disease type VI. Findings on MRI suggestive of glycogen storage disease type VI is hepatomegaly.

## Other Imaging Findings
- Other imaging studies can be  in glycogen storage disease type VI is Bone scan

## Other Diagnostic Studies

### Molecular genetic testing
Molecular genetic testing is done under the following conditions :
- Children with hepatomegaly and ketotic hypoglycemia.
- Children with unexplained hepatomegaly with a mild-moderate elevation of transaminase.
Liver biopsy is reserved for those in whom the diagnosis cannot be confirmed by molecular genetic techniques.

### Enzyme activity assay
- Assay of hepatic glycogen phosphorylase enzyme activity can be performed on red blood cells, leukocytes, and liver cells.

### Liver biopsy
The liver biopsy is helpful in the diagnosis of glycogen storage disease type VI.
Findings suggestive of glycogen storage disease type VI include:
- Glycogen distended liver cells are seen.
- Glycogen content is increased to four times in liver cells than muscle cells.
- The accumulated glycogen ( alpha particles, rosette form) looks frayed or burst.
- Interlobular fibrous septa and low-grade inflammatory changes are seen.

# Treatment

## Medical Therapy
- The mainstay of treatment is dietary therapy.
- Most of the patient has better growth with therapy but some doesn't require therapy.
- Dietary therapy includes frequent meals, high carbohydrate diet, high protein diet and supplementation of unsaturated fats.
- Therapy depends on the symptoms of the patient:
Before starting therapy, it is always better to measure blood glucose level.
For the hypoglycemic patient, frequent small meals and uncooked cornstarch 1.5-2 g/kg TID normalize blood glucose concentration and avoid ketosis.
For children and adults with no hypoglycemic episodes, a bedtime dose of cornstarch 1.5-2 g/kg is given to normalize blood glucose.
For infants (<6 months), cornstarch causes gastrointestinal distress, it should be avoided.
- Before starting therapy, it is always better to measure blood glucose level.
- For the hypoglycemic patient, frequent small meals and uncooked cornstarch 1.5-2 g/kg TID normalize blood glucose concentration and avoid ketosis.
- For children and adults with no hypoglycemic episodes, a bedtime dose of cornstarch 1.5-2 g/kg is given to normalize blood glucose.
- For infants (<6 months), cornstarch causes gastrointestinal distress, it should be avoided.

## Surgery
Surgical intervention is not recommended for the management of glycogen storage disease type VI.

## Primary Prevention
Effective measures for primary prevention of glycogen storage disease type VI include:
- Genetic counseling: Genetic counseling should be offered to all parents with a child with GSD type VI.
- Prenatal diagnosis: The preferred method for prenatal diagnosis is molecular testing when PGYL mutation is known. Mutation analysis is performed either on cultured chorionic villus samples or amniocytes.
- Screening: The proband's PGYL mutations should be determined for diagnosis and direct further testing for family members.

# Secondary Prevention
Effective measures for the secondary prevention of Her's disease include:
- Osteoporosis is common in glycogen storage disease type VI. Treatment includes:
Complex carbohydrates or cornstarch improves bone density.
- Complex carbohydrates or cornstarch improves bone density.
- Short stature and delayed puberty occurs due to chronic ketosis, may improve with better metabolic control.

## Surveillance:
- Routine monitoring of blood glucose concentration and blood ketones is recommended especially for increased activity and illness.
- Monitoring of blood ketones every morning and several times per month using a portable blood ketone meter is recommended. The goal is to maintain blood beta-hydroxybutyrate concentrations lower than 0.3 mmol/L.
- Monitoring of blood glucose concentrations at 2 AM to 4 AM can predict the time of suboptimal control.
- Height and weight should be measured to monitor growth every year.
- Liver ultrasound examinations are recommended starts at age five years should be done every year.
- Bone density measurement are recommended after growth is complete.
Agents to avoid:
- To prevent excessive hepatic glycogen deposition, amounts of simple sugars should be limited.
- Glucagon administration as a rescue therapy for hypoglycemia.
- Growth hormone usually exacerbates ketosis.
- When hepatomegaly is present, contact sports are avoided.