Phosphofructokinase deficiency

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Phosphofructokinase deficiency
Other namesGlycogen storage disease type VII or Tarui's disease [1] [2]
PFKM Image.png
A rendering of the human muscular form of phosphofructokinase. Mutations in the production of this enzyme are the cause of Tarui's disease. [3] The symmetry of the enzyme is a result of its tetrameric structure.
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Phosphofructokinase deficiency is a rare muscular metabolic disorder, with an autosomal recessive inheritance pattern.

Contents

It may affect humans as well as other mammals (especially dogs). [4] It was named after the Japanese physician Seiichiro Tarui (b. 1927), who first observed the condition in 1965. [5]

Presentation

In humans

Human PFK deficiency is categorized into four types: classic, late-onset, infantile and hemolytic. These types are differentiated by age at which symptoms are observed and which symptoms present. [6]

Classic form

Classic phosphofructokinase deficiency is the most common type of this disorder. This type presents with exercise-induced muscle cramps and weakness (sometimes rhabdomyolysis), myoglobinuria, as well as with haemolytic anaemia causing dark urine a few hours later. [7] Hyperuricemia is common, due to the kidneys' inability to process uric acid following damage resulting from processing myoglobin. Nausea and vomiting following strenuous exercise is another common indicator of classic PFK deficiency. Many patients will also display high levels of bilirubin, which can lead to a jaundiced appearance. Symptoms for this type of PFK deficiency usually appear in early childhood.[ citation needed ]

Late-onset form

Late-onset PFK deficiency, as the name suggests, is a form of the disease that presents later in life. Common symptoms associated with late-onset phosphofructokinase deficiency are myopathy, weakness and fatigue. Many of the more severe symptoms found in the classic type of this disease are absent in the late-onset form.[ citation needed ]

Infantile form

Phosphofructokinase deficiency also presents in a rare infantile form. Infants with this deficiency often display floppy infant syndrome (hypotonia), arthrogryposis, encephalopathy and cardiomyopathy. The disorder can also manifest itself in the central nervous system, usually in the form of seizures. PFK deficient infants also often have some type of respiratory issue. Survival rate for the infantile form of PFK deficiency is low, and the cause of death is often due to respiratory failure.[ citation needed ]

Hemolytic form

The defining characteristic of this form of the disorder is hemolytic anemia, in which red blood cells break down prematurely. Muscle weakness and pain are not as common in patients with hemolytic PFK deficiency.[ citation needed ]

In dogs

Presentation of the canine form of the disease is similar to that of the human form. Most notably, PFK deficient dogs have mild, but persistent, anemia with hemolytic episodes, exercise intolerance, hemoglobinuria, and pale or jaundiced mucous membranes. [8] Muscle weakness and cramping are not uncommon symptoms, but they are not as common as they are in human PFKM deficiency.[ citation needed ]

Risk factors

In humans

In order to get Tarui's disease, both parents must be carriers of the genetic defect so that the child is born with the full form of the recessive trait. The best indicator of risk is a family member with PFK deficiency. [9]

In dogs

Canine phosphofructokinase deficiency is found mostly in English Springer Spaniels and American Cocker Spaniels, but has also been reported in Whippets and Wachtelhunds. [10] [11] Mixed-breed dogs descended from any of these breeds are also at risk to inherit PFK deficiency.[ citation needed ]

Pathophysiology

Phosphofructokinase is a tetrameric enzyme that consists of three types of subunits: PFKL (liver), PFKM (muscle), and PFKP (platelet). The combination of these subunits varies depending on the tissue in question. [12] In this condition, a deficiency of the M subunit (PFKM) of the phosphofructokinase enzyme impairs the ability of cells such as erythrocytes and rhabdomyocytes (skeletal muscle cells) to use carbohydrates (such as glucose) for energy. Unlike most other glycogen storage diseases, it directly affects glycolysis. [13] The mutation impairs the ability of phosphofructokinase to phosphorylate fructose-6-phosphate prior to its cleavage into glyceraldehyde-3-phosphate which is the rate limiting step in the glycolysis pathway. Inhibition of this step prevents the formation of adenosine triphosphate (ATP) from adenosine diphosphate (ADP), which results in a lack of available energy for muscles during heavy exercise. This results in the muscle cramping and pain that are common symptoms of the disease. [14]

In humans

Genetic mutation is the cause of phosphofructokinase deficiency. Several different mutations in the gene that encodes for PFKM have been reported in humans, but the result is production of PFKM subunits with little to no function. [15] As a result, affected individuals display only about 50–65% of total normal phosphofructokinase enzyme function. [16]

In dogs

PFK deficiency is believed to be the result of a nonsense mutation in the gene that encodes for PFKM. This results in an unstable, truncated protein that lacks normal function. This results in a near complete loss of PFKM activity in the skeletal muscle. Dogs with the mutation display 10–20% of normal PFK activity in their erythrocytes, due to a higher proportion of PFKM in those cells. [17]

Diagnosis

Symptoms of phosphofructokinase deficiency can closely resemble those of other metabolic diseases, include deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, beta-enolase and aldolase A. [7] Thus, proper diagnosis is important to determine a treatment plan.[ citation needed ]

Glycogen deposits in the muscle of a human patient, shown by electron microscopy. The presence of this excess glycogen in muscle tissue is a result of phosphofructokinase deficiency. Glycogen Buildup.jpeg
Glycogen deposits in the muscle of a human patient, shown by electron microscopy. The presence of this excess glycogen in muscle tissue is a result of phosphofructokinase deficiency.

A diagnosis can be made through a muscle biopsy that shows excess glycogen accumulation. Glycogen deposits in the muscle are a result of the interruption of normal glucose breakdown that regulates the breakdown of glycogen. Blood tests are conducted to measure the activity of phosphofructokinase, which would be lower in a patient with this condition. [19] Patients also commonly display elevated levels of creatine kinase. [7]

Management

Treatment usually entails that the patient refrain from strenuous exercise to prevent muscle pain and cramping. Avoiding carbohydrates is also recommended. [20]

A ketogenic diet also improved the symptoms of an infant with PFK deficiency. The logic behind this treatment is that the low-carb high fat diet forces the body to use fatty acids as a primary energy source instead of glucose. This bypasses the enzymatic defect in glycolysis, lessening the impact of the mutated PFKM enzymes. This has not been widely studied enough to prove if it is a viable treatment, but testing is continuing to explore this option. [21]

Genetic testing to determine whether or not a person is a carrier of the mutated gene is also available.

In dogs

Diagnosis of canine phosphofructokinase deficiency is similar to the blood tests used in diagnosis of humans. Blood tests measuring the total erythrocyte PFK activity are used for definitive diagnosis in most cases. [22] DNA testing for presence of the condition is also available. [23]

Treatment mostly takes the form of supportive care. Owners are advised to keep their dogs out of stressful or exciting situations, avoid high temperature environments and strenuous exercise. It is also important for the owner to be alert for any signs of a hemolytic episode. Dogs carrying the mutated form of the gene should be removed from the breeding population, in order to reduce incidence of the condition.

Related Research Articles

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<span class="mw-page-title-main">Glycogen storage disease type V</span> Human disease caused by deficiency of a muscle enzyme

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<span class="mw-page-title-main">Glycogen storage disease</span> Medical condition

A glycogen storage disease is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.

<span class="mw-page-title-main">Phosphofructokinase 1</span> Class of enzymes

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell's energy requirements. For example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

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<span class="mw-page-title-main">Glycogen storage disease type II</span> Medical condition

Glycogen storage disease type II, also called Pompe disease, and formerly known as GSD-IIa. It is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. GSD-II and Danon disease are the only glycogen storage diseases with a defect in lysosomal metabolism, and Pompe disease was the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

Seiichiro Tarui is a Japanese physician and metabolic disorder researcher. He received the Uehara Award in 1990 while working as a professor at the University of Osaka. He also received the Takeda Medical Science Prize in 1995.

<span class="mw-page-title-main">Sandhoff disease</span> Medical condition

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<span class="mw-page-title-main">Glycogen storage disease type IV</span> Human disease

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<span class="mw-page-title-main">Myophosphorylase</span> Muscle enzyme involved in glycogen breakdown

Myophosphorylase or glycogen phosphorylase, muscle associated (PYGM) is the muscle isoform of the enzyme glycogen phosphorylase and is encoded by the PYGM gene. This enzyme helps break down glycogen into glucose-1-phosphate, so it can be used within the muscle cell. Mutations in this gene are associated with McArdle disease, a glycogen storage disease of muscle.

<span class="mw-page-title-main">Phosphofructokinase</span> Enzyme in glycolysis

Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.

<span class="mw-page-title-main">PFKM</span> Mammalian protein found in Homo sapiens

6-phosphofructokinase, muscle type is an enzyme that in humans is encoded by the PFKM gene on chromosome 12. Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

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<span class="mw-page-title-main">Schindler disease</span> Medical condition

Schindler disease, also known as Kanzaki disease and alpha-N-acetylgalactosaminidase deficiency, is a rare disease found in humans. This lysosomal storage disorder is caused by a deficiency in the enzyme alpha-NAGA (alpha-N-acetylgalactosaminidase), attributable to mutations in the NAGA gene on chromosome 22, which leads to excessive lysosomal accumulation of glycoproteins. A deficiency of the alpha-NAGA enzyme leads to an accumulation of glycosphingolipids throughout the body. This accumulation of sugars gives rise to the clinical features associated with this disorder. Schindler disease is an autosomal recessive disorder, meaning that one must inherit an abnormal allele from both parents in order to have the disease.

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