Metabolic disease

A metabolic disorder is any diseases or disorder that affects the production or utilization of chemical energy from food (such as carbohydrates, proteins, and fats) within individual human (or animal) cells. Most metabolic disorders are genetic; thus, they are also known as inborn errors of metabolism.

Cellular metabolism consists of numerous interconnected pathways that are catalyzed by enzymes in a series of biochemical reactions. Metabolic disorders typically result when an enzyme necessary for some step in the metabolic process of the cell is missing or improperly constructed due to a genetic defect. Depending on the enzyme’s function within the body, one of three major types of metabolic disorders may result:

• The substrate typically catalyzed by the enzyme might accumulate to toxic levels, leading in some disorders to neurological problems.
• An enzyme defective within a particular organ, such as the liver, myocardium, muscle, or brain, might lead to low energy production or prevent transport to the part of the body requiring energy.
• The abnormal or unregulated synthesis of complex molecules might result due to the absence of a particular enzyme. For example, in familial hypercholesterolemia, enzymes do not receive the signals that typically inhibit cholesterol synthesis, so that excessive production of cholesterol occurs, resulting in early coronary vascular disease and strokes in patients.

Given the number of metabolic disorders recognized (3?? In 2000?), there are a range of symptoms, diagnostic methods, and treatments (variable severity even within the same disorder, depending on the age of onset and other factors). Prenatal testing for some metabolic disorders is available, and is typically administered to families who are in a defined ethnic group in which the disorder has a relatively high incidence. Late onset of a metabolic disease is often triggered by acute metabolic stresses, such as infection, fasting, or consumption of a nutrient for which a metabolic intolerance exists. Some common therapies include a restrictive diet and toxin-removal procedures; however, some severe diseases, such as many of the lipid storage diseases, currently have no effective therapy.

The genetics of metabolic disorders

From genes to proteins

In 1908, physician Sir Archibald Garrod coined the term “inborn errors of metabolism” to suggest that defects in specific biochemical pathways were due to an inadequate supply or a lack of a given enzyme. His phrase suggests a link between genes (the molecular blueprint, stored as DNA, that directs the body on how to construct proteins such as enzymes) and the enzymes involved in metabolism, which was elaborated in 1945 by geneticists George Beadle and Edward Tatum:

1. All biochemical processes in all organisms are under genetic control. 2. These biochemical processes can be broken down into a series of individual stepwise reactions. 3. Each biochemical reaction is under the ultimate control of a different single gene. 4. The mutation of a single gene results in an alternation in the ability of the cell to carry out a single primary chemical reaction.

Although this “one gene-one enzyme” principle has since been refined (not all gene products are enzymes, and some enzymes are composed of multiple units coded by different genes), it does capture the basic relationship between genetics and metabolic disorders: inborn errors of metabolism are caused by mutant genes that produce abnormal proteins whose function is altered.

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.

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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