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Phosphofructokinase Deficiency

What is Phosphofructokinase Deficiency?

Human cells need the energy to function. Glucose is the simplest sugar and the main source of energy in human cells. However, cells need to break down glucose to utilize the energy stored in it. This is a multistep and complex process involving multiple enzymes. Enzymes are chemicals in the body that speed up the rate of chemical reactions. Glycolysis is the initial step of the glucose breakdown process. Phosphofructokinase (PFK) is an important enzyme that regulates glycolysis. In PFK deficiency, the ability of the muscle cells to breakdown glucose and utilize its energy is impaired. The cells are not able to obtain the energy required to carry out their functions.

 

PFK deficiency is a genetic disorder that impairs the ability of muscle cells to breakdown glucose to obtain energy. Symptoms include muscle weakness and cramping, fatigue, nausea, and vomiting after exercise. PFK deficiency symptoms most commonly develop during childhood but in rare cases, symptoms present during infancy or adulthood.

 

 

Human cells need the energy to function. Glucose is the simplest sugar and the main source of energy in human cells. However, cells need to break down glucose to utilize the energy stored in it. This is a multistep and complex process involving multiple enzymes. Enzymes are chemicals in the body that speed up the rate of chemical reactions. Glycolysis is the initial step of the glucose breakdown process. Phosphofructokinase (PFK) is an important enzyme that regulates glycolysis. In PFK deficiency, the ability of the muscle cells to breakdown glucose and utilize its energy is impaired. The cells are not able to obtain the energy required to carry out their functions.

 

PFK deficiency is a genetic disorder that impairs the ability of muscle cells to breakdown glucose to obtain energy. Symptoms include muscle weakness and cramping, fatigue, nausea, and vomiting after exercise. PFK deficiency symptoms most commonly develop during childhood but in rare cases, symptoms present during infancy or adulthood.

 

Acknowledgement of Phosphofructokinase Deficiency has not been added yet.

Approximately 100 cases of PFK deficiency have been reported presently. PFK deficiency is more common among the Japanese and Jewish populations.

 

Synonyms for Phosphofructokinase Deficiency has not been added yet.

PFK deficiency is an autosomal recessive inherited disorder. This means that in each cell, both copies of the corresponding gene are defective. Both parents of an individual affected by PFK deficiency have at least one copy of the defective gene but may not exhibits any symptoms.

 

PFK is a protein with a complex structure. It is made of three parts: the muscle subunit, the liver subunit, and the platelet subunit. These subtypes combine in different way to create a functional enzyme depending on the cell type. For example, muscle cells only have the muscle subunit while red blood cells have both the muscle subunit and the liver subunit.

Each of the three subunits are encoded by a different gene. PFKM is the gene that encodes the muscle subunit of PFK. In individuals affected by PFK deficiency, PFKM is defective and produces a dysfunctional protein, leading to reduced PFK activity.

 

Because muscle cells only rely on the muscle subunit, this defect means that PFK is completely dysfunctional in muscle cells. Red blood cells have both the muscle and the liver subunit. Thus, PFK is partially dysfunctional. In other cell types, other subunits can compensate for the defective muscle subunit. Therefore, PFK primarily affects muscle cells. Red blood cells are affected partially.

 

PFK is the regulating enzyme in the breakdown of glucose. This is an important process that allows cells to release and utilize the energy store in this molecule. Glucose can be obtained from food or can be produced in the body. Humans store excess glucose in the liver and muscle cells as a complex molecule called glycogen. When blood glucose levels are low, the body liver and muscle cells break down glycogen into glucose that can be utilized by the cells. In PFK deficiency, muscle cells are not able to break down glucose and do not receive sufficient energy leading to muscle weakness and cramps. When the affected individual exercises, the muscles need more energy to keep up and symptoms worsen.

 

In PFK-deficient muscle cells, the cells can not break down glucose. Thus, muscle cells are saturated with sugar which inhibits the breakdown of glycogen which produces more glucose. As a result, glycogen builds up in the muscle cells which further damages the muscle cells.

 

PFK deficiency can be classified into four types based on the time of onset of symptoms. Each of these types have different signs and symptoms.

 

The classical type is the most common and begins in childhood. Symptoms include muscle pain, muscle cramps, muscle weakness and fatigue after moderate exercise. Strenuous physical activity may lead to nausea and vomiting. Muscle fatigue often settles with rest but other symptoms may persist for days.

 

Due to glycogen build up and a lack of supply of energy, muscle cells begin to break down in PFK-deficient individuals. With the breakdown of muscles, a protein that is normally found inside muscle cells enters the bloodstream. As the kidneys filter the blood to produce urine, myoglobin is removed from the blood as waste and enters the urine (myoglobinuria). In the presence of myoglobin, the urine appears red. This occurs, particularly after strenuous exercise. High levels of myoglobin in the blood are harmful to the kidneys and can lead to kidney failure if untreated. In some individuals affected by the classic type of PFK deficiency, the skin and the white of the eye may develop a yellow appearance (jaundice).

PFK deficiency is classified as infantile when the symptoms present in a newborn. Health muscles do not completely relax and maintain a low basal stiffness and resistance to movement. This is absent in infants with infantile PFK deficiency (hypotonia). Affected infants also have muscle weakness (myopathy) that worsens over time.  They may have difficulty breathing and an enlarged heart (cardiomyopathy).

In rare cases, PFK deficiency may present during adulthood. This is classified as late-onset OFK deficiency. In affected individuals, progressive muscle weakness begins in adulthood although they often have difficulty sustaining exercise from childhood.

In hemolytic PFK deficiency, red blood cells are broken down prematurely. Thus, the number of red blood cells in blood is less than normal (hemolytic anemia). Affected individuals often do not exhibit any symptoms associated with muscles.

 

Diagnosis is made based on clinical symptoms and laboratory testing. When muscle cells cannot meet their energy demands using glycolysis, they resort to alternative pathways. These pathways produce a chemical called uric acid as a byproduct. As a result affected individuals have higher levels of blood uric acid than normal. The blood concentration of a protein called creatine kinase also increases when muscle cells are damaged. As a result of the break down of red blood cells, another chemical called bilirubin also increases in blood. The levels of these chemicals can be detected using blood tests. To confirm the diagnosis, the accumulation of glycogen in muscle cells can be detected. In addition, tests can be done to show that PFK enzyme activity is below normal.

 

A blood test can detect elevated levels of uric acid, bilirubin, and creatine kinase in the blood. However, this is not sufficient to make a diagnosis. A muscle biopsy is a procedure performed to obtain a muscle sample using a needle or a small incision. The sample can then be examined under a microscope. If the muscles are PFK-deficient, the accumulated glycogen will be observable under the microscope. The sample can also be used to assess the enzymatic activity of PFK using biochemical techniques. In PFK deficiency, PFK enzymatic activity will be lower than normal.

 

Genetic testing is also available to determine whether a defective PFKM gene is present.

 

Treatment is often supportive and manages the symptoms. For example, severe anemia may require red blood cell transfusion. Treatment usually involves avoiding heavy exercise. In some cases, limiting carbohydrate intake may also be helpful. There is some evidence that a ketogenic diet may provide symptom relief. The ketogenic diet recommends high fat intake and low carbohydrate intake. This diet forces the body to use fat as its primary energy source instead of sugar. PFK is not involved in break down of fat and this diet reduced the demand for PFK. However, more studies are required to establish the ketogenic diet as effective management for PFK deficiency.

 

Prognosis depends on the onset of symptoms and the extent of the deficiency. Affected individuals with the infantile form of the disorder often do not live past their first year of life. On the other hand, many individuals affected by the classic form never seek treatment because they experience very mild symptoms. Thus, the prognosis varies significantly among different individuals.
 

Tips or Suggestions of Phosphofructokinase Deficiency has not been added yet.

Genetics Home Reference. Glycogen storage disease type VII. 2019. Available from https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-vii#resources

 

Genetic and Rare Disease Information Center.  Glycogen storage disease type 7. 2015. Available from https://rarediseases.info.nih.gov/diseases/5686/glycogen-storage-disease-type-7

 

Piirilä P, Similä M, Palmio J, Wuorimaaet T, Ylikallio E, Sandell S et al. Unique Exercise Lactate Profile in Muscle Phosphofructokinase Deficiency (Tarui Disease); Difference Compared with McArdle Disease. Front Neurol. 2016;7:82. Published 2016 May 30. doi:10.3389/fneur.2016.00082

 

Davidson M, Miranda A, Bender A, Dimauro S, Vora S. Muscle Phosphofructokinase Deficiency

Biochemical and Immunological Studies of Phosphofructokinase isozymes in muscle culture. Journal of Clinical Investigations. 1983; 72:545-550.

 

Olimpia Musumeci a,⇑ , Claudio Bruno b , Tiziana Mongini c , Carmelo Rodolico a , M’hammed Aguennouz a , Emanuele Barca et al. Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII). Neuromuscular Disorders. 2012; 22: 325–330. doi:10.1016/j.nmd.2011.10.022


Vives-Corrons J, Koralkova P, Grau J, Mañú Pereira M, Van Wijk R. First description of phosphofructokinase deficiency in spain: identification of a novel homozygous missense mutation in the PFKM gene. Frontiers in Physiology. 2013; 4:393. doi:10.3389/fphys.2013.00393

Hello Created by sweetbttrfly68
Last updated 21 Mar 2009, 04:13 AM

Posted by VideoProVA
21 Mar 2009, 04:13 AM

I would be happy to discuss my PFK deficiency with you...we can do it here or at my direct email address which I would provide upon request. Dan

Posted by sweetbttrfly68
20 Mar 2009, 05:43 PM

Trying to find others who have Tauri. I would love to hear from others.

Research Created by VideoProVA
Last updated 18 Feb 2009, 05:02 PM

Posted by VideoProVA
18 Feb 2009, 05:02 PM

I was just wondering if anyone knew of other research being done in this field other than that of Dr. Ron Haller Neuromuscular Center Institute for Exercise and Environmental Medicine Presbyterian Hospital of Dallas

Reserach Created by VideoProVA
Last updated 18 Feb 2009, 05:01 PM

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Created by sweetbttrfly68 | Last updated 21 Mar 2009, 04:13 AM

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