Glycerol kinase deficiency

Last updated
Glycerol kinase deficiency
Other namesGKD

Glycerol kinase deficiency (GKD) is an X-linked recessive enzyme defect that is heterozygous in nature. Three clinically distinct forms of this deficiency have been proposed, namely infantile, juvenile, and adult. National Institutes of Health and its Office of Rare Diseases Research branch classifies GKD as a rare disease, known to affect fewer than 200,000 individuals in the United States. The responsible gene lies in a region containing genes in which deletions can cause Duchenne muscular dystrophy and adrenal hypoplasia congenita. Combinations of these three genetic defects including GKD are addressed medically as Complex GKD. [1]

Contents

Signs and symptoms

Glycerol Kinase Deficiency causes the condition known as hyperglycerolemia, [2] an accumulation of glycerol in the blood and urine. This excess of glycerol in bodily fluids can lead to many more potentially dangerous symptoms. Common symptoms include vomiting and lethargy. [3] These tend to be the only symptoms, if any, present in adult GKD which has been found to present with fewer symptoms than infant or juvenile GKD. [4] When GKD is accompanied by Duchenne muscular dystrophy and Adrenal Hypoplasia Congenita, also caused by mutations on the Xp21 chromosome, [5] the symptoms can become much more severe. Symptoms visible at or shortly after birth include:

Some other symptoms that become more noticeable with time would be:

Many of the physically visible symptoms, such as cryptorchidism, strabismus, learning disabilities, [5] and myopathy, tend to have an added psychological effect on the subject due to the fact that they can set him or her apart from those without GKD. Cryptorchidism, the failure of one or both of the testes to descend to the scrotum, has been known to lead to sexual identity confusion amongst young boys because it is such a major physiological anomaly. [7] Strabismus is the misalignment of one's eyes. Typically, one is focused but the other is “lazy” and is directed inward or out ward (up and down is less common but does occur).

Causes

Glycerol kinase deficiency has two main causes.

Effect on glycolysis

The metabolic pathway of glycolysis releases energy by converting glucose to pyruvate by via a series of intermediate metabolites. Each chemical modification (red box) is performed by a different enzyme. Glycolysis metabolic pathway 3 annotated.svg
The metabolic pathway of glycolysis releases energy by converting glucose to pyruvate by via a series of intermediate metabolites. Each chemical modification (red box) is performed by a different enzyme.

In order to understand how this condition affects a person you must first have a basic understanding of the process called glycolysis. This fundamental metabolic pathway is found in all known organisms. The process provides energy for our cells to carry out their daily functions. The overall reaction involves a cell taking in the sugar glucose and converting it into the energy rich molecule pyruvate. Inside the overall reaction there lie many steps that need to be followed in order for the original glucose molecule to be transformed into pyruvate. The glucose first gathers a phosphate group from an ATP molecule in order to become glucose-6-phosphate. It is then changed into fructose 6-phosphate, with the assistance of phosphoglucose isomerase, which is then changed into fructose 1,6-biphosphate when the fructose molecule receives a phosphate group from another ATP. The next step in the chain is crucial for cells in order to make more energy than they expend through the process of glycolysis; this step is when the fructose 1,6-bisphosphate molecule breaks down into two molecules of dihydroxyacetone phosphate (DHAP), so from this point on whenever ATP is being generated from ADP there are really two ATP molecules generated because there are two molecules undergoing the same reaction. [13] One molecule that takes advantage of this second part of the metabolic process is the fatty molecule glycerol. This is unfortunately prevented if someone is experiencing Glycerol Kinase Deficiency.

When a human's body needs to use stored fat for energy it will release glycerol and other fatty acids into the bloodstream. However, these glycerol molecules must contribute to the process of glycolysis before they can provide energy to the body, as they do not hold the necessary energy within themselves. So before glycerol can enter the pathway of glycolysis it must be converted into an intermediate molecule, which in this case is dihydroxyacetone phosphate (DHAP). This is where glycerol kinase comes into the picture. The enzyme is used in the first step in turning glycerol into dihydroxyacetone phosphate (DHAP). It catalyzes the transfer of a phosphate group from an ATP to a glycerol molecule forming glycerol (3) phosphate. Then glycerol 3-phosphate, with the assistance of glycerol 3-phosphate dehydrogenase, can be dehydrogenated into DHAP. This molecule can then enter the metabolic pathway of glycolysis and provide more energy for the cell. [14] Looking at the entire glycolysis pathway this conversion would yield an extra ATP for each glycerol molecule that eventually made its way into a DHAP molecule, which demonstrates the benefit of releasing glycerol into the bloodstream. However, when suffering from a glycerol kinase deficiency many of the glycerol molecules released into the bloodstream end up not being converted to dihydroxyacetone phosphate (DHAP), because the host does not have enough of the enzyme to catalyze all of the reactions waiting to occur. These extra molecules of glycerol are left floating around in the cell and can cause serious damage if left untreated.

Diagnosis

Classification

GKD can be divided into three distinct forms: infantile, juvenile, and adult. Out of all of these the infantile form is the most clinically relevant because it leads to developmental delay and adrenal insufficiency. [11]

Treatment

Treatments for Glycerol Kinase Deficiency are targeted to treat the symptoms because there are no permanent treatments for this disease. The main way to treat these symptoms is by using corticosteroids, glucose infusion, or mineralocorticoids. Corticosteroids are steroid hormones that are naturally produced in the adrenal glands. These hormones regulate stress responses, carbohydrate metabolism, blood electrolyte levels, as well as other uses. The mineralocorticoids, such as aldosterone control many electrolyte levels and allow the kidneys to retain sodium. Glucose infusion is coupled with insulin infusion to monitor blood glucose levels and keep them stable. [15]

Due to the multitude of varying symptoms of this disease, there is no specific treatment that will cure this disease altogether. The symptoms can be treated with many different treatments and combinations of medicines to try to find the correct combination to offset the specific symptoms. Everyone with Glycerol Kinase Deficiency has varying degrees of symptoms and thereby requires different medicines to be used in combination to treat the symptoms; however, this disease is not curable and the symptoms can only be managed, not treated fully. [16]

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.

<span class="mw-page-title-main">Phosphoglucomutase</span> Metabolic enzyme

Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction.

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way.

<span class="mw-page-title-main">Glyceraldehyde 3-phosphate</span> Chemical compound

Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms. With the chemical formula H(O)CCH(OH)CH2OPO32-, this anion is a monophosphate ester of glyceraldehyde.

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

Aldolase A, also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.

Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis. It is the phosphate ester of dihydroxyacetone.

sn-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of two stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of bacterial and eukaryotic glycerophospholipids. From a historical reason, it is also known as L-glycerol 3-phosphate, D-glycerol 1-phosphate, L-α-glycerophosphoric acid.

<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">Glycerol kinase</span> Enzyme

Glycerol kinase, encoded by the gene GK, is a phosphotransferase enzyme involved in triglycerides and glycerophospholipids synthesis.

<span class="mw-page-title-main">Aldolase A deficiency</span> Medical condition

Aldolase A deficiency is an autosomal recessive metabolic disorder resulting in a deficiency of the enzyme aldolase A; the enzyme is found predominantly in red blood cells and muscle tissue. The deficiency may lead to hemolytic anaemia as well as myopathy associated with exercise intolerance and rhabdomyolysis in some cases.

<span class="mw-page-title-main">Glycerol-3-phosphate dehydrogenase</span> Class of enzymes

Glycerol-3-phosphate dehydrogenase (GPDH) is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate to sn-glycerol 3-phosphate.

The methylglyoxal pathway is an offshoot of glycolysis found in some prokaryotes, which converts glucose into methylglyoxal and then into pyruvate. However unlike glycolysis the methylglyoxal pathway does not produce adenosine triphosphate, ATP. The pathway is named after the substrate methylglyoxal which has three carbons and two carbonyl groups located on the 1st carbon and one on the 2nd carbon. Methylglyoxal is, however, a reactive aldehyde that is very toxic to cells, it can inhibit growth in E. coli at milimolar concentrations. The excessive intake of glucose by a cell is the most important process for the activation of the methylglyoxal pathway.

<span class="mw-page-title-main">DAX1</span> Protein-coding gene in humans

DAX1 is a nuclear receptor protein that in humans is encoded by the NR0B1 gene. The NR0B1 gene is located on the short (p) arm of the X chromosome between bands Xp21.3 and Xp21.2, from base pair 30,082,120 to base pair 30,087,136.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Fructolysis refers to the metabolism of fructose from dietary sources. Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body.

A contiguous gene syndrome (CGS), also known as a contiguous gene deletion syndrome, is a clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome. The combined phenotype of the patient is a combination of what is seen when any individual has disease-causing mutations in any of the individual genes involved in the deletion. While it can be caused by deleted material on a chromosome, it is not, strictly speaking, the same entity as a segmental aneuploidy syndrome. A segmental aneuploidy syndrome is a subtype of CGS that regularly recur, usually due to non-allelic homologous recombination between low copy repeats in the region. Most CGS involve the X chromosome and affect male individuals.

Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate from precursors other than glucose. Usually, glycerol 3-phosphate is generated from glucose by glycolysis, in the liquid of the cell's cytoplasm. Glyceroneogenesis is used when the concentrations of glucose in the cytosol are low, and typically uses pyruvate as the precursor, but can also use alanine, glutamine, or any substances from the TCA cycle. The main regulator enzyme for this pathway is an enzyme called phosphoenolpyruvate carboxykinase (PEPC-K), which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. Glyceroneogenesis is observed mainly in adipose tissue, and in the liver. A significant biochemical pathway regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorders such as type 2 diabetes.

Hyperglycerolemia, also known as glycerol kinase deficiency (GKD), is a genetic disorder where the enzyme glycerol kinase is deficient resulting in a build-up of glycerol in the body. Glycerol kinase is responsible for synthesizing triglycerides and glycerophospholipids in the body. Excess amounts of glycerol can be found in the blood and/ or urine. Hyperglycerolmia occurs more frequently in males. Hyperglycerolemia is listed as a "rare disease", which means it affects less than 200,000 people in the US population, or less than about 1 in 1500 people.

References

  1. 1 2 Office of Rare Diseases, National Institutes of Health (25 January 2005). "Annual Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1997". Archived from the original (pdf) on 30 July 2012. Retrieved 21 December 2012.
  2. ↑ Sjarif, D. R.; Hellerud, C.; Van Amstel, J. K. P. V.; Kleijer, W. J.; Sperl, W.; Lacombe, D.; Sass, J. R. O.; Beemer, F. A.; Duran, M.; Poll-The, B. T. (2004). "Glycerol kinase deficiency: Residual activity explained by reduced transcription and enzyme conformation". European Journal of Human Genetics. 12 (6): 424–432. doi: 10.1038/sj.ejhg.5201172 . PMID   15026783.
  3. 1 2 Wishart, David (6 March 2010). "Glycerol Kinase Deficiency". Small Molecule Pathway Database. Archived from the original on 2 July 2012. Retrieved 21 December 2012.
  4. ↑ "Hyperglycerolemia". Online Mendelian Inheritance in Man. National Center for Biotechnology Information. 29 June 2010. Retrieved 21 December 2012.
  5. 1 2 "Chromosome Xp21 Deletion Syndrome". Online Mendelian Inheritance in Man. National Center for Biotechnology Information. 8 December 2010. Retrieved 21 December 2012.
  6. ↑ Seltzer, W. K.; Firminger, H.; Klein, J.; Pike, A.; Fennessey, P.; McCabe, E. R. B. (1985). "Adrenal dysfunction in glycerol kinase deficiency". Biochemical Medicine. 33 (2): 189–199. doi:10.1016/0006-2944(85)90027-4. PMID   2988520.
  7. ↑ Galifer, R. B.; Kalfa, N.; Guibal, M. P. (2004). "What a hidden testicle can hide?...or the clinical traps of cryptorchidism". Archives de Pédiatrie. 11 (4): 350–359. doi:10.1016/j.arcped.2003.11.015. PMID   15139321.
  8. ↑ Mahbubul Huq, A. H. M.; Lovell, R. S.; Ou, C. -N.; Beaudet, A. L.; Craigen, W. J. (1997). "X-Linked Glycerol Kinase Deficiency in the Mouse Leads to Growth Retardation, Altered Fat Metabolism, Autonomous Glucocorticoid Secretion and Neonatal Death". Human Molecular Genetics. 6 (11): 1803–1809. doi: 10.1093/hmg/6.11.1803 . PMID   9302256.
  9. ↑ Rahib, L.; MacLennan, N. K.; Horvath, S.; Liao, J. C.; Dipple, K. M. (2007). "Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling". European Journal of Human Genetics. 15 (6): 646–657. doi: 10.1038/sj.ejhg.5201801 . PMID   17406644.
  10. ↑ National Library of Medicine (17 December 2012). "Genotype-Phenotype Correlation". Genetics Home Reference. Retrieved 21 December 2012.
  11. 1 2 3 Francke, U.; Harper, J. F.; Darras, B. T.; Cowan, J. M.; McCabe, E. R.; Kohlschütter, A.; Seltzer, W. K.; Saito, F.; Goto, J.; Harpey, J. P.; Wise, J. E. (1987). "Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: Molecular genetic evidence for deletions". American Journal of Human Genetics. 40 (3): 212–227. PMC   1684111 . PMID   2883886.
  12. ↑ Richards, Julia E.; Hawley, R. Scott (2010). The Human Genome: A User's Guide. Academic Press. ISBN   978-0-12-333445-9.
  13. ↑ Benson, Darik (14 August 2012). "Glycolysis". UC Davis ChemWiki. Retrieved 21 December 2012., . "." . University California Davis, 2 Nov. 2010. Web. <>
  14. ↑ Medh, Jheem D. (August 2006). "Glycolysis" (PDF). Retrieved 21 December 2012.
  15. ↑ Blau, Nenad; Hoffmann, Georg F.; Leonard, James; Clarke, Joe T.R. (2005). Physician's Guide to the Treatment and Follow-Up of Metabolic Diseases. Springer. ISBN   978-3540229544.
  16. ↑ "Glycerol Kinase Deficiency". MIC - Metabolic & Genetic Information Centre. 17 October 2010. Archived from the original on 23 March 2012. Retrieved 21 December 2012.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.