Acknowledgement of Glycogen Storage Disease Type 7, PFKM Deficiency has not been added yet.

Only about 100 cases have been reported worldwide, with the condition estimated to occur in less than 1:1,000,000 individuals. This rare disease is seen most often in those of Japanese or Ashkenazi Jewish descent.

Name	Abbreviation
Glycogen Storage Disease Type 7	GSD7
Glycogen Storage Disease Type VII	GSDVII
Tarui Disease	TD
Phosphofructokinase Deficiency	PFKM Deficiency
Muscle Phosphofructokinase Deficiency	MPD
Glycogenosis Type 7
Glycogenosis Type VII

Genetic basis

Chromosomes are bundles of genetic material, or DNA, that children inherit from their parents. Typically, each person has 23 pairs of chromosomes, with one of each pair inherited from the mother (maternal copy) and the other inherited from the father (paternal copy). Each chromosome has a long (q) and short (p) arm, along which different genes and gene-regulating elements are located. Genes encode for proteins, which execute functions and act as the building blocks of the cell.

GSD7 is a glycogen storage disorder caused by autosomal recessive mutations in the PFKM gene, which is located on chromosome 12. When a condition is inherited in an autosomal recessive manner, those with two defective copies of the responsible gene will be affected, while those with only one defective copy are asymptomatic carriers who do not present the disease but can pass on the mutation to their children. If both parents are carriers, the chance of having an affected child is 25% with each pregnancy, while the chance of having a child who is a carrier themself is 50%.

Cellular and molecular basis

Glycogen is composed of branched glucose (simple sugar) subunits and is stored mainly in the liver and skeletal muscle. In response to fasting or exercise, it is normally broken down to release glucose into the blood or muscles, respectively. Glucose can be further broken down to release adenosine triphosphate (ATP), which is an energy-carrying molecule. 

The PFKM gene encodes a subunit of phosphofructokinase, one of the enzymes involved in glycolysis, or the breakdown of glucose released from glycogen to generate energy. This particular subunit is found in muscle cells and erythrocytes (red blood cells). When an individual inherits one mutated copy of PFKM from their father and another mutated copy from their mother, the breakdown of glycogen into glucose and, ultimately, energy becomes impaired.

Phosphofructokinase deficiency leads to decreased energy availability during activity or exercise, as well as excessive buildup of partially broken down glycogen in the muscles. Cramping, muscle weakness, pain, and stiffness result, with possible nausea and vomiting from excessive exercise. In some cases, the muscles may actually begin to break down in a process known as rhabdomyolysis. In severe cases of rhabdomyolysis, a protein called myoglobin is released from degenerating muscle tissue, filtered through the kidneys, and excreted in the urine (myoglobinuria). Myoglobinuria can damage the kidneys, leading to life-threatening renal failure. Because this subtype of the phosphofructokinase enzyme is also expressed in red blood cells, when there is a lack of energy from ATP, these cells can become dehydrated and destroyed in a process called hemolytic anemia, which causes its own set of symptoms.

There are four types of GSD7:

Childhood (Classic) GSD7
Classic GSD7 is the most common form. It begins early in life with the following symptoms after exercise or exertion:

• Skeletal muscle weakness

• Pain and stiffness

• Nausea

• Vomiting

• Dark-colored urine (myoglobinuria)

• Yellowing of skin and eyes (jaundice)

• Low red blood cells (anemia)

• Glycogen buildup in muscles

• Breakdown of muscle tissue (rhabdomyolysis)

• High uric acid in blood (hyperuricemia)

 

Infant GSD7
This form is rare and characterized by infantile onset of the following severe symptoms:

• Loss of muscle tone (hypotonia)

• Skeletal muscle weakness

• Heart muscle weakness (cardiomyopathy)

• Breathing problems

• Curving of the joints (arthrogryposis)

• Intellectual disability

 

Late-onset (adult) GSD7
This less-severe form of GSD7 occurs in adults with the following symptoms:

• Skeletal muscle weakness

• Pain

 

Hemolytic GSD7
The hemolytic form of GSD7 occurs in individuals without muscle symptoms but who have hemolytic anemia from breakdown of erythrocytes (red blood cells). This causes the following symptoms:

• Pale skin

• Yellowing of skin and eyes (jaundice)

• Dark-colored urine (myoglobinuria)

• Fever

• Weakness

• Dizziness

• Confusion

• Increased heart rate (tachycardia)

Name	Description
Weakness and Stiffness	Gradual, progressive weakness and stiffness of the legs
Muscle pain	Muscle pain

GSD7 can be diagnosed by muscle biopsy, bloodwork, and/or genetic testing. Patients will have diminished levels of phosphofructokinase enzyme in muscle tissue or blood. A muscle biopsy will also reveal elevated ammonia but irregularly reduced lactate levels following anaerobic (short, high-intensity) exercise, as lactate is also generated from the breakdown of glucose. Patients may have high levels of bilirubin (due to hemolysis), creatine kinase (due to muscle degeneration), lactate dehydrogenase (involved in glucose breakdown to lactate), and aspartate transaminase (generally a sign of liver and/or muscle damage) in the blood. Increased reticulocytes (newly generated, immature red blood cells) may be present in the case of hemolytic anemia, which destroys mature red blood cells. Non-invasive molecular genetic testing can confirm mutations present in the PFKM gene.

Muscle biopsy - removal of a small sample of tissue for analysis in the laboratory

Forearm exercise test - bloodwork from the forearm before and after performance of an exercise activity

Molecular genetic testing - sequence analysis of the PFKM gene

Though there is no cure or therapy for GSD7, it is generally recommended that patients avoid heavy exercise and a carbohydrate-heavy diet, which may exacerbate symptoms.

Many individuals are able to manage symptoms and live productive lives, and there are even some adult-onset patients whose symptoms are very mild. However, a common complication of myoglobinuria caused by GSD7 is renal (kidney) failure, which may shorten life expectancy. 

The infantile form of GSD7 is generally severe and often fatal by 1 year of age.

Tips or Suggestions of Glycogen Storage Disease Type 7, PFKM Deficiency has not been added yet.

1. https://rarediseases.info.nih.gov/diseases/5686/glycogen-storage-disease-type-7

2. https://www.omim.org/entry/232800?search=glycogen%20storage%20disease%20vii&highlight=%28glycogen%7Cglycogenic%29%20disease%20storage%20vii

3. https://medlineplus.gov/genetics/condition/glycogen-storage-disease-type-vii/

4. https://rarediseases.org/rare-diseases/glycogen-storage-disease-type-vii/

5. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=19&Disease_Disease_Search_diseaseType=ORPHA&Disease_Disease_Search_diseaseGroup=371&Disease(s)/group%20of%20diseases=GSD-type-7&title=GSD-type-7&search=Disease_Search_Simple

6. https://www.socialstyrelsen.se/stod-i-arbetet/sallsynta-halsotillstand/taruis-sjukdom/

7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802397

8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331362/