Glycogen storage disease type VII
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Synonyms and keywords:Tarui's disease; glycogen storage disease type 7; GSD type VII; phosphofructokinase deficiency; muscle phosphofructokinase deficiency

# Overview
Glycogen storage disease type VII (Tarui's disease) is a rare autosomal recessive disease, clinically characterized by early exercise intolerance which manifests during childhood, with muscle pain and myoglobinuria after exercise or strenuous exercise. In 1965, Tarui first described the phosphofructokinase (PFK) deficiency in 3 siblings with easy fatigability and exercise intolerance. GSD type VII is caused by mutation of phosphofructokinase gene located at 12q13 for the M (muscle isoform) that results in a deficiency of the phosphofructokinase enzyme which converts fructose-6-phosphate to fructose-1,6-diphosphate.

# Historical Perspective
The historical perspective of the glycogen storage disease type VII is as follows:
- In 1965, Tarui first described the phosphofructokinase (PFK) deficiency in 3 siblings with easy fatigability and exercise intolerance.
- In 1967, Layer et al suggested autosomal recessive inheritence of the disease by detecting the disease in a 18 year old male.
- Also in 1967, Satoyoshi and Kowa postulated the role of a inhibitor in the development of disease.
- In 1980, Vora et al studied a patient with myopathy and hemolysis which were assosciated with PFK deficiency.
- In 1983 Tani et al studied two Japanese with congenital non-spherocytic hemolytic anemia and mild myopathy, having erythrocyte PFK deficiency.

# Classification
There is no established classification of glycogen storage disease type VII.

# Pathophysiology

## Pathogenesis
- Mutations in the phosphofructokinase (PFKM) gene cause glycogen storage disease type VII.
- PFKM gene signals to make the PFKM subunit of an enzyme called phosphofructokinase, which plays a key role in the metabolism of the glycogen.
- The phosphofructokinase enzyme is made up of four subunits and is found in a variety of tissues.
- Various tissues have different combinations of these four subunits of phosphofructokinase enzyme.
- In skeletal muscles where the main source of energy is stored glycogen, the phosphofructokinase enzyme is solely composed of the PFKM subunits.
- To maintain normal blood sugar levels between meals or during exercise, glycogen is metabolized rapidly into the when energy is needed.
- Phosphofructokinase is involved in the above-mentioned chain of events that metabolizes glycogen to provide energy to muscle cells.
- The mutations of the PFKM gene results in non-functional or dysfunctional PFKM subunits.
- As a result, no functional phosphofructokinase is formed in skeletal muscles, and glycogen cannot be metabolized completely resulting in the accumulation of the partially metabolized glycogen in the skeletal muscle cells.
- If these skeletal muscles are put to a moderate strain such as exercise, cramping ensues as these muscles do not have access to glycogen as an energy source.
- In other tissues, other subunits that make up the phosphofructokinase enzyme likely compensate for the lack of PFKM subunits, and the enzyme is able to retain some function, this compensation may help explain why other tissues are not affected by PFKM gene mutations.

## Metabolic Pathway

## Genetics
- Glycogen storage disease type VII is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations.
- Disease manifests when there is a mutation in the gene for M (muscle isoform), L (liver isoform) and P (platelet isoform) of phosphofructokinase enzyme.
- A variety of mutations can occur, one of which is alteration of splice site leading to exon skipping and single nucleotide mutation leading to 95% of causes of glycogen storage disease type VII.

## Microscopic findings
The following changes are seen in the muscle on muscle biopsy:
- Muscle fiber necrosis
- Increased variation in the fibre size
- Ring fibers
- Endomyosial fibrosis
- Moderate excess of subsarcolemmal glycogen accumulation on periodic acid-Schiff (PAS) staining
- In 10% of muscle fibers, diastase-resistant, long filamentous inclusions are seen
- Iodine absorption spectra of both the inclusions and a diastase-resistant fraction of isolated glycogen resembled amylopectin
- The abnormal polysaccharide in PFK deficiency may be related to greatly elevated concentration of muscle glucose-6-phosphate, an activator of the chain-elongating enzyme glycogen synthase

# Causes
- Glycogen storage disease type VII is inherited as an autosomal recessive genetic disorder.
- GSD type VII is caused by mutation of phosphofructokinase gene located at 12q13 for the M (muscle isoform) that results in a deficiency of the phosphofructokinase enzyme which converts fructose-6-phosphate to fructose-1,6-diphosphate.
- This is the rate-limiting step in the metabolism of the glucose into available energy, if the phosphofructokinase is deficient, energy is not available to muscles during heavy exercise and hence pain and cramps occur in the muscle.

# Differentiating Glycogen Storage Disease Type VII from Other Diseases

# Epidemiology and Demographics
The epidemiology and demographics of the Glycogen storage disease type VII are as follows:
- Glycogen storage disease type VII is considered a rare condition; however, more than 100 cases have been found in the literature.
- The incidence of glycogen storage disease type VII is 2.3 children per 100,000 births per year.
- Glycogen storage disease type VII commonly affects children, all patients of reported cases died by age 4 years.
- Glycogen storage disease type VII usually affects individuals of the Japanese and Ashkenazi Jewish descent.
- Some disease-causing mutations have been found in the PFK-M gene in Italian, French Canadian, and Swiss patients.
- Glycogen storage disease type VII affects men and women equally.

# Risk Factors
- The most potent risk factor in the development of glycogen storage disease type VII is a sibling with glycogen storage disease type VII.

# Screening
- There is insufficient evidence to recommend routine screening for Tarui's disease.
- The proband's PFK mutations should be determined for diagnosis and direct further testing for family members.

# Natural History, Complications, and Prognosis
Complications:
Common complications of glycogen storage disease type VII disease include:
- Extertional rhabdomyolysis
- Renal failure
- Gout
- Hyperuricemia
- Erythrocyte hemolysis
- Pneumonia
- Respiratory failure
- Gallstones

# Diagnosis

## Diagnostic study of choice
- Biochemical enzyme activity
- Molecular genetics

## History and Symptoms
The hallmark of glycogen storage disease type VII is muscle exercise intolerance.
The specific areas of focus when obtaining patient history include:
- Muscle weakness following a high carbohydrate meal
- Muscle exercise intolerance
- Slowly progressive limb weakness with or without myoglobinuria or cramps
Most common symptoms
The most common symptoms of glycogen storage disease type VII include:
- Muscle cramps
- Muscle tenderness
- Progressive muscle weakness
- Hematuria
- Hypoglycemia
- Vomiting
Less common symptoms
- Cortical blindness
- Erythrocyte hemolysis

## Physical Examination
Physical examination of patients with glycogen storage disease type VII is usually remarkable for:
Neuromuscular
- Muscle atrophy
- Arthrogryposis(congenital joint contracture)
Cardiovascular
- Hypertrophic cardiomyopathy
- Paroxysmal atrial fibrillation
Ophthalmology
- Corneal opacity

## Laboratory Findings
The following laboratory findings are seen in glycogen storage disease type VII:
More common findings
- Elevated serum creatine kinase
- Reduced red blood cell phosphofructokinase activity.
- Reticulocytosis
- Hyperuricemia
- Myoglobinuria
Less common findings
- Hemolytic anemia
- Mild hyperbilirubinemia
Laboratory findings seen after exercise
High concentrations of:
- Ammonia
- Inosine
- Hypoxanthine

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

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

## Ultrasound
Ultrasound abdomen may be helpful in the diagnosis of hepatomegaly.

## CT scan
There are no CT scan findings associated with glycogen storage disease type VII.

## MRI
There are no MRI findings associated with glycogen storage disease type VII.

## Other Imaging Findings
There are no other imaging findings associated with glycogen storage disease type VII.

## Other Diagnostic Studies
- Muscle enzyme assay and DNA testing are helpful in the diagnosis of glycogen storage disease type VII.

# Treatment

## Medical Therapy
- There is no medical treatment for glycogen storage disease type VII.
- The mainstay of therapy is supportive care.

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

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

## Secondary Prevention
Effective measures for the secondary prevention of glycogen storage disease type VII include:
- Avoidance of strenuous exercise
- High carbohydrate meal: Consumption of high carbohydrate meal should be avoided before exercise.
- Ketogenic diet