Difference between revisions of "Metabolic disease" - New World Encyclopedia

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A metabolic disorder is a medical disorder which affects the production of energy within individual human (or animal) cells. Most metabolic disorders are genetic, though a few are "acquired" as a result of diet, toxins, infections, etc. Genetic metabolic disorders are also known as inborn errors of metabolism.

In general, the genetic metabolic disorders are caused by genetic defects that result in missing or improperly constructed enzymes necessary for some step in the metabolic process of the cell.

The genetics of metabolic disorders

From genes to proteins

Types of inheritance

Lipid storage diseases are inherited from one or both parents who carry a defective gene that regulates a particular protein in a class of the body’s cells. They can be inherited two ways:

Autosomal recessive inheritance: Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent is affected by the disorder. Each child born to these parents has a 25 % chance of inheriting both copies of the defective gene, a 50 % chance of being a carrier, and a 25 % chance of not inheriting either copy of the defective gene. Children of either gender can be affected by an autosomal recessive this pattern of inheritance.

X-linked inheritance: X-linked (or sex-linked) recessive inheritance occurs when the mother carries the affected gene on the X chromosome that determines the child’s gender and passes it to her son. Sons of carriers have a 50 % chance of inheriting the disorder. Daughters have a 50 % chance of inheriting the X-linked chromosome but usually are not severely affected by the disorder. Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.

Mitochondrial inheritance: Mitochondrial inheritance behaves differently from autosomal and sex-linked inheritance. Nuclear DNA has two copies per cell (except for sperm and egg cells). One copy is inherited from the father and the other from the mother. Mitochondria, however, contain their own DNA, and contain typically from five to ten copies, all inherited from the mother (for more detailed inheritance patterns, see mitochondrial genetics). When mitochondria divide, the copies of DNA present are divided randomly between the two new mitochondria, and then those new mitochondria make more copies. As a result, if only a few of the DNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria. Mitochondrial disease begins to become apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called 'threshold expression'.

Not all of the enzymes and other components necessary for proper mitochondrial function are encoded in the mitochondrial DNA. Most mitochondrial function is controlled by nuclear DNA instead.

Mutations to mitochondrial DNA occur frequently, due to the lack of the error checking capability that nuclear DNA has. This means that mitochondrial disorders often occur spontaneously and relatively often. Sometimes the enzymes that control mitochondrial DNA duplication (and which are encoded for by genes in the nuclear DNA) are defective, causing mitochondrial DNA mutations to occur at a rapid rate.

Disorders that give rise to toxic substances

intermediary metabolism errors that lead to acute or progressive intoxication from accumulation of toxic compounds proximal to the metabolic block; clinical similarities—symptom-free period followed by “intoxication” that is acute (vomit, lethargy coma, liver failure) or chronic (progressive developmental decay; cardiomyopathy); expression is often late in onset and intermittent; diagnosis relies on plasma and urine amino-acid or organic-acid chromatography; treatment requires removal of the toxin by special diets, exchange transfusion, peritoneal dialysis, or hemodialysis (to decrease the blood ammonia level)

Disorders of amino acid metabolism

Amino acids are organic molecules that function in the synthesis of proteins; they also function as or participate in the synthesis of other crucial biological molecules such as neurotransmitters and hormones.

Phenylketonuria (PKU) results from the decreased activity of phenylalanine hydroxylase, an enzyme that converts the amino acid phenylalanine into tyrosine, a precursor of several important hormones as well as skin, hair, and eye pigments. This enzyme deficiency results in the build-up of phenylalanine in the blood, which in turn results in progressive developmental delay, behavioral disturbances, and seizures. Due to decreased amounts of the pigment melanin, persons with PKU tend to have lighter features than other family members who do not have the disease. Other examples of disorders of amino metabolism that also involve elevated levels of an amino acid or its metabolites, include classic (heypatorenal or type 1) tyrosemia, homocystinuria, and non-ketonic hyperglycinemia.

Urea-cycle defects

Amino acids can be degraded into ammonia, carbon dioxide, and water. During the urea cycle, the ammonia nitrogen component of the amino acid is broken off, incorporated into the urea (the primary solid component of urine) and excreted in the urine. A defect in any of the enzymes of the urea cycle leads to a toxic accumulation of ammonia in the blood, which in turn can lead to poor feeding, vomiting, lethargy, and possibly coma in a newborn, and, after long-term, untreated episodes, to mental retardation and developmental impairment.

Organic acidemias

Organic acids are carbon-based compounds that appear at abnormally elevated levels when metabolic pathways involving specific enzymes are blocked. Organic acidemias are conditions characterized by the accumulation of organic acids in body tissues and fluids. Maple syrup urine disease (MSUD), a disorder common in the Mennonites of Pennsylvania, involves the accumulation of the amino acids leucine, isoleucine, and valine in body fluids, especially urine, leading to progressive neurological deterioration characterized by seizures and comas. Other examples of organic acidemias include propionic academia and methylmalonic academia (MMA).

Sugar intolerances

In addition to disorders involving organic acids and their metabolites, accumulation of simple sugars such as galactose and fructose, whose metabolism plays a role in many different pathways, may also occur due to enzyme deficiencies:

Galactosemia, which often manifests when milk feeding is started on infants, involves a breakdown in the metabolism of galactose, a sugar in milk, resulting in an accumulation of galactose-1-phosphate that leads to lethargy, progressive liver dysfunction, kidney disease, and weight loss; if left untreated or treated belatedly, mental retardation occurs.
Hereditary fructose intolerance (HFI) is caused by a deficiency in a liver enzyme that helps in the ingestion of fructose, a sugar common in fruits, table sugar (sucrose), and infant formulas.

Disorders involving energy metabolism

intermediary metabolism errors w/ symptoms partly due to a deficiency in energy production or utilization resulting from defect in liver, myocardium, muscle, or brain; symptoms include hypoglycemia, hyperlactacidemia, severe generalized hypotonia, myopathy, cardiomyopathy (heart failure), circulatory collapse, sids, and malformations

Glycogen storage disorders

Glycogen is the storage form of glucose, kept at the ready so that the brain, red blood cells, and the adrenal gland, which are fueled by glucose, can depend on a constant supply for their functioning. Glycogen is often stored in the liver and in muscle tissue; during normal functioning, glycogen is broken down to glucose and released into the blood to be transported to the glucose-hungry part of the body. Glycogen storage disorders (GSDs) occur when enzymes involves in glycogen breakdown are blocked, so that the supply of glycogen remains in the liver and muscle. For example, in GSD type I (von Gierke disease), the last step in glucose release from the liver is defective, leading to hypoglycemia (low blood sugar), which can be treated by continuous drip feedings of glucose to the digestive tract in childhood or liver transplants in a small number who do not respond to treatment. Other types of GSDs are listed in the table below.

Fatty acid oxidation defects

The oxidation (or breakdown) of fatty acids for energy occurs in the mitochondria of liver cells. The first step of degradation requires the transport of blank from the cytoplasm of the cell into the mitochondrion, a process that involves a carrier molecule, carnitine, which is synthesized in the body and may also be obtained from animal products such as meat, milk, and eggs. Some fatty acid oxidation disorders arise through the dysfunction of carnitine transport enzymes. Other examples include CoA dehydrogenase deficiency (MCHAD) and long-chain 3-hydroxyl-acyl CoA dehydrogenase deficiency (LCHAD). Fatty acid oxidation disorders may account for approximately 5-10 percent of cases of sudden infant death syndrome (SIDS). Some of the more common fatty acid oxidation diseases are listed in the table below.

Mitochondrial disease

Mitochondrial diseases are a group of disorders relating to the mitochondria, the organelles that are the "powerhouses" of the eukaryotic cells that comprise higher-order lifeforms (including humans). The mitochondria convert the energy of food molecules into the ATP that powers most cell functions.

Mitochondrial diseases comprise those disorders that in one way or another affect the function of the mitochondria and/or are due to mitochondrial DNA. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease symptoms are often referred to as a mitochondrial myopathy.

The effects of mitochondrial disease can be quite varied. Since the distribution of defective DNA may vary from organ to organ within the body, the mutation that in one person may cause liver disease might in another person cause a brain disorder. In addition, the severity of the defect may be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Other defects can more severely affect the operation of the mitochondria and can cause severe body-wide impacts. As a general rule, mitochondrial diseases are worst when the defective mitochondria are present in the muscles or nerves, because these are the most energy-hungry cells of the body.

However, even though mitochondrial disease varies greatly in presentation from person to person, several major categories of the disease have been defined, based on the most common symptoms and the particular mutations that tend to cause them:

Disorders involving complex molecules

diseases that disturb the synthesis or catabolism of complex molecules; symptoms permanent, progressive, and not related to food intake

Cholesterol synthesis

Cholesterol is a type of lipid. As a result of such defects, lipids may become deposited in the walls of blood vessels, which can lead to [[atherosclerosis], an abnormal thickening and hardening of the walls of the arteries.

Familial hypercholesterolemia is caused by a deficiency of the LDL receptor on the surface of cells in the liver and other organs, so that cholesterol remains in the blood rather than being moved into the cells. In addition, the enzymes involved in cholesterol synthesis do not receive feedback inhibition signaling them to cease synthesis, so that production of more cholesterol is induced. The disease is characterized by early coronary vascular disease, strokes, and fatty deposits on the tendons. Blood cholesterol levels are high from birth, and LDL cholesterol is also elevated.

Lysosomal disorders

Lysosomes are organelles within the cell where the breakdown of various biological molecules, such as lipids and proteins occur. In lysosomal storage disorders, enzyme deficiencies or faulty activity of enzymes result in the accumulation of biological molecules that are normally degraded, causing the abnormal storage of complex molecules such as glycolipids, oligosaccharides, and glycoproteins. Symptoms vary depending on where in the body the storage occurs, though characteristics of many lysosomal storage disorders include coarsening of facial features, eye abnormalities, enlarged liver and spleen, and bone disease as well as neurological impairments. Most of these diseases do not have effective treatments. See the table below for some types of lysosomal disorders.

Glycosylation syndrome

Diagnosis and treatment of metabolic disorders

Diagnosis is made through clinical examination, biopsy, genetic testing, molecular analysis of cells or tissue to identify inherited metabolic disorders and enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency). In some forms of the disorder, a urine analysis can identify the presence of stored material. Some tests can also determine if a person carries the defective gene that can be passed on to her or his children. This process is known as genotyping.

Biopsy for lipid storage disease involves removing a small sample of the liver or other tissue and studying it under a microscope. In this procedure, a physician will administer a local anesthetic and then remove a small piece of tissue either surgically or by needle biopsy (a small piece of tissue is removed by inserting a thin, hollow needle through the skin). The biopsy is usually performed at an outpatient testing facility.

Genetic testing can help individuals who have a family history of lipid storage disease determine if they are carrying a mutated gene that causes the disorder. Other genetic tests can determine if a fetus has the disorder or is a carrier of the defective gene. Prenatal testing is usually done by chorionic villus sampling, in which a very small sample of the placenta is removed and tested during early pregnancy. The sample, which contains the same DNA as the fetus, is removed by catheter or fine needle inserted through the cervix or by a fine needle inserted through the [abdomen]]. Results are usually available within 2 weeks.

Currently there is no specific treatment available for most of the lipid storage disorders but highly effective enzyme replacement therapy is available for patients with type 1 Gaucher disease, some patients with type 3 Gaucher disease, and Fabry disease. Ongoing research is in place to provide enzyme replacement for other lipidoses as well as gene therapy. Patients with anemia may require blood transfusions. In some patients, the enlarged spleen must be removed to improve cardiopulmonary function. The drugs phenytoin and carbamazepine may be prescribed to help treat pain (including bone pain) for patients with Fabry disease. Restricting one’s diet does not prevent lipid buildup in cells and tissues.

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@@ Line 10: / Line 10: @@
 Lipid storage diseases are [[heredity|inherited]] from one or both parents who carry a defective [[gene]] that regulates a particular protein in a class of the body’s cells.  They can be [[Mendelian inheritance|inherited]] two ways:
-====Autosomal recessive inheritance====
+*Autosomal recessive inheritance: [[Autosome|Autosomal]] [[Recessive gene|recessive]] inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent is affected by the [[genetic disorder|disorder]].  Each child born to these parents has a 25 % chance of inheriting both copies of the defective gene, a 50 % chance of being a carrier, and a 25 % chance of not inheriting either copy of the defective gene.  Children of either gender can be affected by an autosomal recessive this pattern of inheritance.
-[[Autosome|Autosomal]] [[Recessive gene|recessive]] inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent is affected by the [[genetic disorder|disorder]].  Each child born to these parents has a 25 % chance of inheriting both copies of the defective gene, a 50 % chance of being a carrier, and a 25 % chance of not inheriting either copy of the defective gene.  Children of either gender can be affected by an autosomal recessive this pattern of inheritance.
-====X-linked inheritance====
+*X-linked inheritance: X-linked (or [[sex]]-linked) recessive inheritance occurs when the mother carries the affected gene on the X [[chromosome]] that determines the child’s gender and passes it to her son.  Sons of carriers have a 50 % chance of inheriting the disorder.  Daughters have a 50 % chance of inheriting the X-linked chromosome but usually are not severely affected by the disorder.  Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.
-X-linked (or [[sex]]-linked) recessive inheritance occurs when the mother carries the affected gene on the X [[chromosome]] that determines the child’s gender and passes it to her son.  Sons of carriers have a 50 % chance of inheriting the disorder.  Daughters have a 50 % chance of inheriting the X-linked chromosome but usually are not severely affected by the disorder.  Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.
-====Mitochondrial inheritance====
+*Mitochondrial inheritance: Mitochondrial inheritance behaves differently from autosomal and sex-linked inheritance.  [[Nuclear DNA]] has two copies per cell (except for sperm and egg cells).  One copy is inherited from the father and the other from the mother.  Mitochondria, however, contain their own DNA, and contain typically from five to ten copies, all inherited from the mother (for more detailed inheritance patterns, see [[mitochondrial genetics]]).  When mitochondria divide, the copies of DNA present are divided randomly between the two new mitochondria, and then those new mitochondria make more copies.  As a result, if only a few of the DNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria.  Mitochondrial disease begins to become apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called '[[Threshold expression|threshold expression]]'.
-Mitochondrial inheritance behaves differently from autosomal and sex-linked inheritance.  [[Nuclear DNA]] has two copies per cell (except for sperm and egg cells).  One copy is inherited from the father and the other from the mother.  Mitochondria, however, contain their own DNA, and contain typically from five to ten copies, all inherited from the mother (for more detailed inheritance patterns, see [[mitochondrial genetics]]).  When mitochondria divide, the copies of DNA present are divided randomly between the two new mitochondria, and then those new mitochondria make more copies.  As a result, if only a few of the DNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria.  Mitochondrial disease begins to become apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called '[[Threshold expression|threshold expression]]'.
 Not all of the enzymes and other components necessary for proper mitochondrial function are encoded in the mitochondrial DNA.  Most mitochondrial function is controlled by nuclear DNA instead.
@@ Line 23: / Line 20: @@
 Mutations to mitochondrial DNA occur frequently, due to the lack of the error checking capability that nuclear DNA has.  This means that mitochondrial disorders often occur spontaneously and relatively often.  Sometimes the enzymes that control mitochondrial DNA duplication (and which are encoded for by genes in the nuclear DNA) are defective, causing mitochondrial DNA mutations to occur at a rapid rate.
-==Disorders of amino acid metabolism==
+==Disorders that give rise to toxic substances==
-==Disorders of carbohydrate metabolism==
+intermediary metabolism errors that lead to acute or progressive intoxication from accumulation of toxic compounds proximal to the metabolic block; clinical similarities—symptom-free period followed by “intoxication” that is acute (vomit, lethargy coma, liver failure) or chronic (progressive developmental decay; cardiomyopathy); expression is often late in onset and intermittent; diagnosis relies on plasma and urine amino-acid or organic-acid chromatography; treatment requires removal of the toxin by special diets, exchange transfusion, peritoneal dialysis, or hemodialysis (to decrease the blood ammonia level)
-definition of carbs
-===Glycogen storage diseases===
+===Disorders of amino acid metabolism===
-'''Glycogen storage disease''' (synonyms: '''glycogenosis''', '''dextrinosis''') is any one of several [[inborn error of metabolism|inborn errors of metabolism]] that result from [[enzyme]] defects that affect the processing of [[glycogen]] synthesis or breakdown within [[muscle|muscles]], [[liver]], and other cell types.
+[[Amino acids]] are organic molecules that function in the synthesis of proteins; they also function as or participate in the synthesis of other crucial biological molecules such as neurotransmitters and hormones.
-There are nine diseases that are commonly considered to be glycogen storage diseases:
+[[Phenylketonuria (PKU)]] results from the decreased activity of phenylalanine hydroxylase, an enzyme that converts the amino acid phenylalanine into tyrosine, a precursor of several important hormones as well as skin, hair, and eye pigments. This enzyme deficiency results in the build-up of phenylalanine in the blood, which in turn results in progressive developmental delay, behavioral disturbances, and seizures. Due to decreased amounts of the pigment melanin, persons with PKU tend to have lighter features than other family members who do not have the disease. Other examples of disorders of amino metabolism that also involve elevated levels of an amino acid or its metabolites, include classic (heypatorenal or type 1) tyrosemia, homocystinuria, and non-ketonic hyperglycinemia.
-*[[Glycogen storage disease type I|GSD type I]]: glucose-6-phosphatase deficiency, von Gierke's disease
+===Urea-cycle defects===
-*[[Glycogen storage disease type II|GSD type II]]: acid maltase deficiency, Pompe's disease
+Amino acids can be degraded into ammonia, carbon dioxide, and water. During the [[urea cycle]], the ammonia nitrogen component of the amino acid is broken off, incorporated into the urea (the primary solid component of urine) and excreted in the urine. A defect in any of the enzymes of the urea cycle leads to a toxic accumulation of ammonia in the blood, which in turn can lead to poor feeding, vomiting, lethargy, and possibly coma in a newborn, and, after long-term, untreated episodes, to mental retardation and developmental impairment.
-*[[Glycogen storage disease type III|GSD type III]]: glycogen debrancher deficiency, Cori's disease or Forbe's disease
-*[[Glycogen storage disease type IV|GSD type IV]]: [[glycogen branching enzyme deficiency]], Andersen disease
-*[[Glycogen storage disease type V|GSD type V]]: muscle glycogen phosphorylase deficiency, McArdle disease
-*[[Glycogen storage disease type VI|GSD type VI]]: [[liver phosphorylase deficiency]], [[Hers's disease]]
-*[[Glycogen storage disease type VII|GSD type VII]]: [[muscle phosphofructokinase deficiency]], [[Tarui's disease]]
-*[[Glycogen storage disease type IX|GSD type IX]]: [[phosphorylase kinase deficiency]]
-*[[Glycogen storage disease type XI|GSD type XI]]: [[glucose transporter deficiency]], [[Fanconi-Bickel disease]]
-Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs because it is another defect of glycogen storage and can cause similar problems:
+===Organic acidemias===
+Organic acids are carbon-based compounds that appear at abnormally elevated levels when metabolic pathways involving specific enzymes are blocked. Organic acidemias are conditions characterized by the accumulation of organic acids in body tissues and fluids. [[Maple syrup urine disease (MSUD)]], a disorder common in the Mennonites of Pennsylvania, involves the accumulation of the amino acids leucine, isoleucine, and valine in body fluids, especially urine, leading to progressive neurological deterioration characterized by seizures and comas. Other examples of organic acidemias include propionic academia and methylmalonic academia (MMA).
-===Fructose and galactose disorders===
+===Sugar intolerances===
-explain
+In addition to disorders involving organic acids and their metabolites, accumulation of simple sugars such as [[galactose]] and [[fructose]], whose metabolism plays a role in many different pathways, may also occur due to enzyme deficiencies:
-==Disorders of lipid metabolism==
+*Galactosemia, which often manifests when milk feeding is started on infants, involves a breakdown in the metabolism of galactose, a sugar in milk, resulting in an accumulation of galactose-1-phosphate that leads to lethargy, progressive liver dysfunction, kidney disease, and weight loss; if left untreated or treated belatedly, mental retardation occurs.
-Lipids are fat-like substances that are important parts of the membranes found within and between each cell and in the [[myelin sheath]] that coats and protects the [[nerve]]s.  Lipids include [[oil]]s, [[fatty acid]]s, [[wax]]es, [[steroid]]s (such as [[cholesterol]] and [[estrogen]]), and other related compounds.
+*Hereditary fructose intolerance (HFI) is caused by a deficiency in a liver enzyme that helps in the ingestion of fructose, a sugar common in fruits, table sugar (sucrose), and infant formulas.
-These fatty materials are stored naturally in the body’s cells, organs, and tissues.  Minute bodies within the cells called [[lysosome]]s regularly convert, or metabolize, the lipids and [[protein]]s into smaller components to provide energy for the body.  Disorders that store this intracellular material are called lysosomal storage diseases.  In addition to lipid storage diseases, other lysosomal storage diseases include the [[mucolipidoses]], in which excessive amounts of lipids and [[sugar]] molecules are stored in the cells and tissues, and the [[mucopolysaccharidoses]], in which excessive amounts of sugar molecules are stored.
+==Disorders involving energy metabolism==
+intermediary metabolism errors w/ symptoms partly due to a deficiency in energy production or utilization resulting from defect in liver, myocardium, muscle, or brain; symptoms include hypoglycemia, hyperlactacidemia, severe generalized hypotonia, myopathy, cardiomyopathy (heart failure), circulatory collapse, sids, and malformations
-===Lipoprotein disorders===
+===Glycogen storage disorders===
-'''Lipid storage disorders''' (or '''lipidoses''') are a group of inherited [[metabolism|metabolic]] disorders in which harmful amounts [[lipid]]s (fats) accumulate in some of the body’s [[cell (biology)|cell]]s and tissues.  People with these disorders either do not produce enough of one of the [[enzyme]]s needed to metabolize lipids or they produce enzymes that do not work properly.  Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the [[brain]], [[peripheral nervous system]], [[liver]], [[spleen]] and [[bone marrow]].
+[[Glycogen]] is the storage form of [[glucose]], kept at the ready so that the brain, red blood cells, and the adrenal gland, which are fueled by glucose, can depend on a constant supply for their functioning. Glycogen is often stored in the liver and in muscle tissue; during normal functioning, glycogen is broken down to glucose and released into the blood to be transported to the glucose-hungry part of the body. Glycogen storage disorders (GSDs) occur when enzymes involves in glycogen breakdown are blocked, so that the supply of glycogen remains in the liver and muscle. For example, in GSD type I (von Gierke disease), the last step in glucose release from the liver is defective, leading to hypoglycemia (low blood sugar), which can be treated by continuous drip feedings of glucose to the digestive tract in childhood or liver transplants in a small number who do not respond to treatment. Other types of GSDs are listed in the table below.
 ===Fatty acid oxidation defects===
-Numerous [[genetic disorders]] are caused by errors in '''fatty acid metabolism'''. These disorders may be described as '''fatty oxidation disorders''' or as a ''[[lipid storage disorder]]s'', and are any one of several [[inborn errors of metabolism]] that result from enzyme defects affecting the ability of the body to [[oxidize]] [[fatty acid]]s in order to produce energy within muscles, liver, and other [[cell (biology)|cell]] types.
+The oxidation (or breakdown) of fatty acids for energy occurs in the mitochondria of liver cells. The first step of degradation requires the transport of blank from the cytoplasm of the cell into the mitochondrion, a process that involves a carrier molecule, carnitine, which is synthesized in the body and may also be obtained from animal products such as meat, milk, and eggs. Some fatty acid oxidation disorders arise through the dysfunction of carnitine transport enzymes. Other examples include CoA dehydrogenase deficiency (MCHAD) and long-chain 3-hydroxyl-acyl CoA dehydrogenase deficiency (LCHAD). Fatty acid oxidation disorders may account for approximately 5-10 percent of cases of sudden infant death syndrome (SIDS). Some of the more common fatty acid oxidation diseases are listed in the table below.
-Some of the more common fatty acid metabolism disorders are:
+===Mitochondrial disease===
-Coenzyme A dehydrogenase deficiencies
-* [[Very long-chain acyl-coenzyme A dehydrogenase deficiency]] (VLCAD)
-* [[Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency]] (LCHAD)
-* [[Medium-chain acyl-coenzyme A dehydrogenase deficiency]] (MCAD)
-* [[Short-chain acyl-coenzyme A dehydrogenase deficiency]] (SCAD)
-* [[Short chain L-3-hydroxyacyl-coA dehydrogenase deficiency]] (SCHAD)
-Other Coenzyme A enzyme deficiencies
-* [[2,4 Dienoyl-CoA reductase deficiency]]
-* [[3-hydroxy-3-methylglutaryl-CoA lyase deficiency]]
-* [[Malonyl-CoA decarboxylase deficiency]]
-Carnitine related
-* [[Primary carnitine deficiency]]
-* [[Carnitine-acylcarnitine translocase deficiency]]
-* [[Carnitine palmitoyltransferase I deficiency]] (CPT)
-* [[Carnitine palmitoyltransferase II deficiency]] (CPT)
-Other
-* [[Mitochondrial trifunctional protein deficiency]]
-* [[Electron transfer flavoprotein dehydrogenase deficiency|Electron transfer flavoprotein (ETF) dehydrogenase deficiency]] (GAII & MADD)
-*[[Tangier disease]]
-==Mitochondrial disease==
 '''Mitochondrial diseases''' are a group of disorders relating to the [[mitochondrion|mitochondria]], the [[organelle|organelles]] that are the "powerhouses" of the [[Eukaryote|eukaryotic cells]] that comprise higher-order lifeforms (including humans).  The mitochondria convert the energy of food molecules into the [[Adenosine triphosphate|ATP]] that powers most cell functions.
@@ Line 92: / Line 58: @@
 However, even though mitochondrial disease varies greatly in presentation from person to person, several major categories of the disease have been defined, based on the most common symptoms and the particular mutations that tend to cause them:
-* {{OMIM|157640}} [[Progressive external ophthalmoplegia]] ([[PEO]])
+==Disorders involving complex molecules==
-** progressive [[ophthalmoparesis]] is the cardinal feature
+diseases that disturb the synthesis or catabolism of complex molecules; symptoms permanent, progressive, and not related to food intake
-** symptomatic overlap with many of the illnesses described below
-* {{OMIM|520000}} [[Diabetes mellitus and deafness]] ([[DAD]])
-**  this combination at an early age can be due to mitochondrial disease
-**  [[Diabetes mellitus]] and [[deafness]] can be found together for other reasons as well
-* {{OMIM|535000}} [[Leber hereditary optic neuropathy]] ([[LHON]])
-** visual loss beginning in young adulthood
-** [[Wolff-Parkinson-White syndrome]]
-** [[multiple sclerosis]]-type disease
-* {{OMIM|540000}} [[Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome]] ([[MELAS]])
-** varying degrees of cognitive impairment and dementia
-** lactic acidosis
-** [[stroke]]s
-** [[transient ischemic attack]]s
-** hearing loss
-** dysmotility
-** weight loss
-* {{OMIM|545000}} [[Myoclonic epilepsy and ragged-red fibers]] ([[MERRF]])
-** progressive myoclonic epilepsy
-** clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "ragged-red fibers" when muscle is stained with modified Gomori trichrome stain
-** short stature
-* {{OMIM|256000}} [[Leigh syndrome]], subacute sclerosing encephalopathy
-** after normal development the disease usually begins late in the first year of life, but the onset may occur in adulthood
-** a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure
-* {{OMIM|551500}} [[Neuropathy, ataxia, retinitis pigmentosa, and ptosis]] ([[NARP]])
-** progressive symptoms as described in the acronym
-** [[dementia]]
-* {{OMIM|530000}} [[Kearns-Sayre syndrome]] (KSS)
-** external [[ophthalmoplegia]]
-** cardiac conduction defects
-** sensory-neural hearing loss
-* {{OMIM|603041}} [[Myoneurogenic gastrointestinal encephalopathy]] ([[MNGIE]])
-** gastrointestinal pseudo-obstruction
-** [[neuropathy]]
-==Other types of metabolic disease==
-Gaucher disease (E75.22)
-[[Gaucher disease]] is the most common of the lipid storage diseases.  It is caused by a deficiency of the enzyme [[glucocerebrosidase]]. Fatty material can collect in the [[spleen]], liver, [[kidney]]s, [[lung]]s, [[brain]], and bone marrow. Symptoms may include enlarged spleen and liver, liver malfunction, [[List of skeletal disorders|skeletal disorders]] and bone lesions that may cause pain, severe [[Neurology|neurologic]] complications, swelling of [[lymph node]]s and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, [[anemia]], low blood [[platelet]]s, and yellow spots in the eyes.  Persons affected most seriously may also be more susceptible to infection. The disease affects males and females equally.
-Gaucher disease has three common clinical subtypes.  Type 1 (or nonneuropathic type) is the most common form of the disease. It occurs most often among persons of [[Ashkenazi Jews|Ashkenazi Jewish]] heritage.  Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen, which can rupture and cause additional complications.  Skeletal weakness and bone disease may be extensive.  The brain is not affected, but there may be lung and, rarely, kidney impairment.  Patients in this group usually [[bruise]] easily and experience fatigue due to low blood platelets.  Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms.  Type 2 (or acute infantile neuropathic Gaucher disease) typically begins within 3 months of birth.  Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, [[spasticity]], [[seizure]]s, limb rigidity, and a poor ability to suck and swallow.  Affected children usually die by age 2.  Type 3 (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood.  It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version.  Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems.  Patients often live to their early teen years and often into adulthood.
-For type 1 and most type 3 patients, enzyme replacement treatment given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations.  Successful bone marrow transplantation cures the non-neurological manifestations of the disease.  However, this procedure carries significant risk and is rarely performed in Gaucher patients.  Surgery to remove the spleen may be required on rare occasions (if the patient is anemic or when the enlarged organ affects the patient’s comfort).  [[Blood transfusion]] may benefit some anemic patients.  Other patients may require [[Replacement joint|joint replacement]] surgery to improve mobility and quality of life.  There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.
-Niemann-Pick disease (E75.23)
-[[Niemann-Pick disease]] is actually a group of autosomal recessive disorders caused by an accumulation of fat and cholesterol in cells of the liver, spleen, bone marrow, lungs, and, in some patients, brain.  Neurological complications may include [[ataxia]], eye [[paralysis]], brain degeneration, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity to touch, and some [[Cornea|corneal]] clouding.  A characteristic cherry-red halo develops around the center of the [[retina]] in 50 % of patients.
-Niemann-Pick disease is currently subdivided into four categories.  Onset of type A, the most severe form, is in early infancy.  Infants appear normal at birth but develop an enlarged liver and spleen, swollen lymph nodes, nodes under the skin ([[xanthema]]s), and profound brain damage by 6 months of age.  The spleen may enlarge to as much as 10 times its normal size and can rupture.  These children become progressively weaker, lose motor function, may become anemic, and are susceptible to recurring infection.  They rarely live beyond 18 months.  This form of the disease occurs most often in [[Jew|Jewish]] families.  In the second group, called type B (or juvenile onset), enlargement of the liver and spleen characteristically occurs in the pre-teen years.  Most patients also develop ataxia, peripheral neuropathy, and pulmonary difficulties that progress with age, but the brain is generally not affected.  Type B patients may live a comparatively long time but many require supplemental [[oxygen]] because of lung involvement.  Niemann-Pick types A and B result from accumulation of the fatty substance called [[sphingomyelin]], due to deficiency of acid [[sphingomyelinase]].
-Niemann-Pick disease also includes two other variant forms called types C and D.  These may appear early in life or develop in the teen or even adult years.  Niemann-Pick disease types C and D are not caused by a deficiency of sphlingomyelinase but by a lack of the NPC1 or NPC2 proteins.  As a result, various lipids and cholesterol accumulate inside nerve cells and cause them to malfunction.  Patients with types C and D have only moderate enlargement of their spleens and livers.  Brain involvement may be extensive, leading to inability to look up and down, difficulty in walking and swallowing, and progressive loss of vision and hearing.  Type D patients typically develop neurologic symptoms later than those with type C and have a progressively slower rate of loss of nerve function.  Most type D patients share a common ancestral background in [[Nova Scotia]].  The life expectancies of patients with types C and D vary considerably.  Some patients die in childhood while others who appear to be less severely affected live into adulthood.
-There is currently no cure for Niemann-Pick disease.  Treatment is supportive.  Children usually die from infection or progressive neurological loss.  Bone marrow transplantation has been attempted in a few patients with type B.  Patients with types C and D are frequently placed on a low-cholesterol diet and/or cholesterol lowering drugs, although research has not shown these interventions to change cholesterol metabolism or halt disease progression.
-Fabry disease (E75.25)
-[[Fabry disease]], also known as [[Galactose|alpha-galactosidase-A]] deficiency, causes a buildup of fatty material in the autonomic nervous system, eyes, kidneys, and cardiovascular system.  Fabry disease is the only x-linked lipid storage disease.  Males are primarily affected although a milder form is common in females, some of whom may have severe manifestations similar to those seen in affected males.  Onset of symptoms is usually during childhood or adolescence.  Neurological symptoms include burning pain in the arms and legs, which worsens in hot weather or following exercise, and the buildup of excess material in the clear layers of the cornea (resulting in clouding but no change in vision).  Fatty storage in blood vessel walls may impair circulation, putting the patient at risk for [[stroke]] or [[heart attack]].  Other symptoms include heart enlargement, progressive kidney impairment leading to [[renal failure]], [[Gastrointestinal tract|gastrointestinal]] difficulties, decreased [[sweat|sweating]], and [[fever]].  [[Angiokeratomas]] (small, non-cancerous, reddish-purple elevated spots on the skin) may develop on the lower part of the trunk of the body and become more numerous with age.
-Patients with Fabry disease often die prematurely of complications from heart disease, renal failure, or stroke.  Drugs such as [[phenytoin]] and [[carbamazepine]] are often prescribed to treat pain that accompanies Fabry disease.  [[Metoclopramide]] or [[Lipisorb]] (a nutritional supplement) can ease gastrointestinal distress that often occurs in Fabry patients, and some individuals may require kidney transplant or [[dialysis]].  Recent experiments indicate that enzyme replacement can reduce storage, ease pain, and improve organ function in patients with Fabry disease.
-Farber’s disease (E75.24)
-[[Farber’s disease]], also known as Farber’s lipogranulomatosis or [[ceramidase]] deficiency, describes a group of rare autosomal recessive disorders that cause an accumulation of fatty material in the joints, tissues, and central nervous system.  The disorder affects both males and females.  Disease onset is typically in early infancy but may occur later in life.  Children who have the classic form of Farber’s disease develop neurological symptoms within the first few weeks of life.  These symptoms may include moderately impaired mental ability and problems with swallowing.  The liver, heart, and kidneys may also be affected.  Other symptoms may include [[vomiting]], [[arthritis]], swollen lymph nodes, swollen joints, joint contractures (chronic shortening of muscles or tendons around joints), hoarseness, and xanthemas which thicken around joints as the disease progresses.  Patients with breathing difficulty may require insertion of a breathing tube.  Most children with the disease die by age 2, usually from lung disease.  In one of the most severe forms of the disease, an enlarged liver and spleen ([[hepatosplenomegaly]]) can be diagnosed soon after birth.  Children born with this form of the disease usually die within 6 months.
-There is no specific treatment for Farber’s disease.  [[Corticosteroid]]s may be prescribed to relieve pain.  Bone marrow transplants may improve [[granuloma]]s (small masses of inflamed tissue) on patients with little or no lung or nervous system complications.  Older patients may have granulomas surgically reduced or removed.
-Krabbé disease (E75.2)
+===Cholesterol synthesis===
-[[Krabbé disease]] (also known as [[globoid]] cell leukodystrophy and [[galactosylceramide]] lipidosis) is an autosomal recessive disorder caused by deficiency of the enzyme [[galactosylceramidase]].  The disease most often affects infants, with onset before age 6 months, but can occur in adolescence or adulthood.  The buildup of undigested fats affects the growth of the nerve’s protective myelin sheath and causes severe degeneration of mental and motor skills.  Other symptoms include muscle weakness, [[hypertonia]] (reduced ability of a muscle to stretch), myoclonic seizures (sudden, shock-like contractions of the limbs), spasticity, irritability, unexplained fever, deafness, optic atrophy and blindness, paralysis, and difficulty when swallowing.  Prolonged weight loss may also occur.  The disease may be diagnosed by its characteristic grouping of certain cells, nerve demyelination and degeneration, and destruction of brain cells.  In infants, the disease is generally fatal before age 2.  Patients with a later onset form of the disease have a milder course of the disease and live significantly longer.  No specific treatment for Krabbé disease has been developed, although early bone marrow transplantation may help some patients.
+Cholesterol is a type of lipid. As a result of such defects, lipids may become deposited in the walls of blood vessels, which can lead to [[atherosclerosis], an abnormal thickening and hardening of the walls of the arteries.
-Metachromatic leukodystrophy (E75.2)
+[[Familial hypercholesterolemia]] is caused by a deficiency of the LDL receptor on the surface of cells in the liver and other organs, so that cholesterol remains in the blood rather than being moved into the cells. In addition, the enzymes involved in cholesterol synthesis do not receive feedback inhibition signaling them to cease synthesis, so that production of more cholesterol is induced. The disease is characterized by early coronary vascular disease, strokes, and fatty deposits on the tendons. Blood cholesterol levels are high from birth, and LDL cholesterol is also elevated.
-[[Metachromatic leukodystrophy]], or MLD, is a group of disorders marked by storage buildup in the white matter of the central nervous system and in the peripheral nerves and to some extent in the kidneys.  Similar to Krabbé disease, MLD affects the myelin that covers and protects the nerves.  This autosomal recessive disorder is caused by a deficiency of the enzyme [[arylsufatase A]].  Both males and females are affected by this disorder.
-MLD has three characteristic phenotypes:  late infantile, juvenile, and adult.  The most common form of the disease is late infantile, with onset typically between 12 and 20 months following birth.  Infants may appear normal at first but develop difficulty in walking and a tendency to fall, followed by intermittent pain in the arms and legs, progressive loss of vision leading to blindness, developmental delays, impaired swallowing, convulsions, and dementia before age 2.  Children also develop gradual muscle wasting and weakness and eventually lose the ability to walk.  Most children with this form of the disorder die by age 5.  Symptoms of the juvenile form typically begin between ages 3 and 10.  Symptoms include impaired school performance, mental deterioration, ataxia, seizures, and dementia.  Symptoms are progressive with death occurring 10 to 20 years following onset.  In the adult form, symptoms begin after age 16 and may include impaired concentration, depression, psychiatric disturbances, ataxia, seizures, tremor, and dementia.  Death generally occurs within 6 to 14 years after onset of symptoms.
+===Lysosomal disorders===
+Lysosomes are organelles  within the cell where the breakdown of various biological molecules, such as lipids and proteins occur. In lysosomal storage disorders, enzyme deficiencies or faulty activity of enzymes result in the accumulation of biological molecules that are normally degraded, causing the abnormal storage of complex molecules such as glycolipids, oligosaccharides, and glycoproteins. Symptoms vary depending on where in the body the storage occurs, though characteristics of many lysosomal storage disorders include coarsening of facial features, eye abnormalities, enlarged liver and spleen, and bone disease as well as neurological impairments. Most of these diseases do not have effective treatments. See the table below for some types of lysosomal disorders.
-There is no cure for MLD.  Treatment is symptomatic and supportive.  Bone marrow transplantation may delay progression of the disease in some cases.
+===Glycosylation syndrome===
-Wolman’s disease (E75.5)
-[[Wolman’s disease]], also known as acid [[lipase]] deficiency, is a severe lipid storage disease that is usually fatal by age 1.  This autosomal recessive disorder is marked by accumulation of [[cholesteryl ester]]s (normally a transport form of cholesterol) and [[triglyceride]]s (a chemical form in which fats exist in the body) that can build up significantly and cause damage in the cells and tissues.  Both males and females are affected by this severe disorder.  Infants are normal and active at birth but quickly develop progressive mental deterioration, enlarged liver and grossly enlarged spleen, distended abdomen, gastrointestinal problems including [[steatorrhea]] (excessive amounts of fats in the stools), [[jaundice]], anemia, vomiting, and calcium deposits in the [[adrenal gland]]s, causing them to harden.
-Another type of acid lipase deficiency is [[cholesteryl ester storage disease]]. This extremely rare disorder results from storage of cholesteryl esters and triglycerides in cells in the blood and lymph and lymphoid tissue. Children develop an enlarged liver leading to [[cirrhosis]] and chronic liver failure before adulthood. Children may also have calcium deposits in the adrenal glands and may develop jaundice late in the disorder.
-There is no specific treatment for Wolman’s disease or cholesteryl ester storage disease.
 ==Diagnosis and treatment of metabolic disorders==
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 Currently there is no specific treatment available for most of the lipid storage disorders but highly effective enzyme replacement therapy is available for patients with type 1 Gaucher disease, some patients with type 3 Gaucher disease, and Fabry disease.  Ongoing research is in place to provide enzyme replacement for other lipidoses as well as gene therapy.  Patients with anemia may require blood transfusions.  In some patients, the enlarged spleen must be removed to improve cardiopulmonary function.  The drugs [[phenytoin]] and [[carbamazepine]] may be prescribed to help treat pain (including bone pain) for patients with Fabry disease.  Restricting one’s diet does not prevent lipid buildup in cells and tissues.
 {{credit5|Metabolic_disorder|59028062|Glycogen_storage-disease|62684843|List_of_fatty_acid_metabolism_disorders|60163888|Lipid_storage_disorder|59442850|Mitochondrial-disease|61998443}}
 [[Category:Life sciences]]