Glycerol kinase deficiency
Encyclopedia
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 (ORDR) branch classifies GKD as a rare disease, known to affect less 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.
. 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. 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 glycloysis and provide more energy for the cell. 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.
in the blood
and urine
. This excess of glycerol in bodily fluids can lead to many more potentially dangerous symptom
s. Common symptoms include vomiting and lethargy. 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. When GKD is accompanied by Duchenne Muscular Dystrophy
and Adrenal Hypoplasia Congenita, also caused by mutation
s on the Xp21 chromosome
, 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, 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. 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).
s, glucose infusion
, or mineralocorticoid
s. Corticosteroids are steroid hormones that are naturally produced in the adrenal glands. These hormone
s 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. .
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. .
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
and its Office of Rare Diseases Research (ORDR) branch classifies GKD as a rare disease, known to affect less 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
Duchenne muscular dystrophy
Duchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...
and adrenal hypoplasia congenita. Combinations of these three genetic defects including GKD are addressed medically as Complex GKD.
Causes
Glycerol Kinase Deficiency has two main causes associated with it.- The first cause is isolated enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
deficiency. The enzyme glycerol kinaseGlycerol kinaseGlycerol kinase is a phosphotransferase enzyme involved in triglycerides and glycerophospholipids synthesis.Glycerol kinase catalyzes the transfer of a phosphate from ATP to glycerol thus forming glycerol phosphate . Adipocytes lack glycerol kinase so they cannot metabolize the glycerol produced...
is encoded by the X-chromosomeX chromosomeThe X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
in humans. It acts as a catalyst in the phosphorylationPhosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of glycerolGlycerolGlycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
to glycerol-3-phosphate which plays a key role in formation of triacylglycerol (TAG) and fat storage. There is no genotypeGenotypeThe genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
–phenotypePhenotypeA phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
correlation in isolated GKD and it can be either symptomatic or asymptomatic. Symptomatic means that GKD shows symptoms when it persists in the body and asymptomatic means that the no symptoms appear in the body. In this deficiency the genotype is not associated with the phenotype. The presence of certain mutations in genes has no relation with the phenotype i.e. any resulting physical traits or abnormality. - The second cause is a deletion or mutation of a single gene. GKD is described by mendelian inheritance and is an X-linked recessive trait due to which it occurs mainly in males and occasionally in females. GKD results when the glycerol kinase gene present on the locus Xp21 of the X chromosome is either deleted or mutated. Females have two X chromosomes and males have one X and one Y chromosome .The expression of recessive genes on the X chromosome is different in males and females. This is due to the fact that genes present on the Y chromosome do not pair up with genes on the X chromosome in males. In females the disorder is expressed only when there are two copies of the affected gene present on each X chromosome but since the glycerol kinase gene is present only on one X chromosome the disorder is not expressed in women. Women have a second good copy that can compensate for the defect on the first copy. On the other hand males only need a single copy of the recessive gene for the disorder to be expressed. They do not have a second copy that can protect against any defect on the first copy.
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.- The infantile form is referred to as complex GKD because the defect in the gene for the glycerol kinase enzyme is interconnected with defects in one or both of its affected genes that are responsible for Duchenne muscular dystrophyDuchenne muscular dystrophyDuchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...
and adrenal hypoplasia congenita.The cause of this form is deletion of the Xp21 gene on the X chromosome. Patients have increased levels of serum creatine phosphokinase(CPK) which leads to myopathic changes in muscle biopsies resembling Duchenne muscular dystrophy. - The juvenile form does not show myopathy and patients have normal adrenal function.The main cause leading to this form of GKD is isolated enzyme deficiency.
- The adult form is also caused by an isolated enzyme deficiency. Patients having this form of the disorder are clinically normal.
Effect on glycolysis
In order to understand how this condition affects a person you must first have a basic understanding of the process called glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. This fundamental metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
is found in all known organisms. The process provides energy for our cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
to carry out their daily functions. The overall reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
involves a cell taking in the sugar glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
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
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
molecule in order to become glucose-6-phosphate. It is then changed into fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
, 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
Fructose 1,6-bisphosphate
Fructose 1,6-bisphosphate is fructose sugar phosphorylated on carbons 1 and 6 . The β-D-form of this compound is very common in cells...
molecule breaks down into two molecules of dihydroxyacetone phosphate (DHAP), so from this point on whenever ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
is being generated from ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
there are really two ATP molecules generated because there are two molecules undergoing the same reaction. One molecule that takes advantage of this second part of the metabolic process is the fatty molecule glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
. This is unfortunately prevented if someone is experiencing Glycerol Kinase Deficiency.
When a human’s body needs to use stored fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
for energy it will release glycerol and other fatty acids into the bloodstream. However, these glycerol molecules must contribute to the process of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
before they can provide energy to the body, as they do not hold the necessary energy within themselves. So before glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
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
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
of glycloysis and provide more energy for the cell. 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.
Symptoms
Glycerol Kinase Deficiency causes the condition known as hyperglycerolemia, an accumulation of glycerolGlycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
. This excess of glycerol in bodily fluids can lead to many more potentially dangerous symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s. Common symptoms include vomiting and lethargy. 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. When GKD is accompanied by Duchenne Muscular Dystrophy
Duchenne muscular dystrophy
Duchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...
and Adrenal Hypoplasia Congenita, also caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s on the Xp21 chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
, the symptoms can become much more severe. Symptoms visible at or shortly after birth include:
- cryptorchidismCryptorchidismCryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
- strabismusStrabismusStrabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
- seizures.
Some other symptoms that become more noticeable with time would be:
- metabolic acidosisMetabolic acidosisIn medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
- adrenal cortexAdrenal cortexSituated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
insufficiency - learning disabilities
- osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
- myopathyMyopathyIn medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
Many of the physically visible symptoms, such as cryptorchidism, strabismus, learning disabilities, 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
Sexual identity
Sexual identity is a term that, like sex, has two distinctively different meanings. One describes an identity roughly based on sexual orientation, the other an identity based on sexual characteristics, which is not socially based but based on biology, a concept related to, but different from,...
confusion amongst young boys because it is such a major physiological anomaly. 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).
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 corticosteroidCorticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, glucose infusion
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
, or mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
s. Corticosteroids are steroid hormones that are naturally produced in the adrenal glands. These hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s regulate stress responses, carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, blood electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
levels, as well as other uses. The mineralocorticoids, such as aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
control many electrolyte levels and allow the kidneys to retain sodium. Glucose infusion is coupled with insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
infusion to monitor blood glucose levels and keep them stable. .
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
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
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. .