What are metabolic disorders?

Causes and Symptoms

Metabolic disorders of all types are usually inherited from one or both parents who carry a defective gene; the gene is one that codes for an enzyme responsible for a part of the metabolic pathway (either anabolic or catabolic). Much like an assembly line that takes raw material and produces a final product through multiple steps, the metabolism of proteins, lipids, and carbohydrates in the human body requires multiple steps, each with its own enzyme. In some cases, there are multiple pathways to metabolize a particular starting product. In this case, lack of one enzyme may not have a dramatic effect. Other pathways are exclusive, however, and any disruption of an enzyme will lead to disease. In addition to loss of a particular product, some enzyme defects lead to the accumulation of precursor molecules that may be toxic or may interfere with normal function of the cell.

When the deoxyribonucleic acid (DNA) coding for a particular gene is altered, one of three outcomes may be seen: no change (silent mutation), partial loss of ability of the enzyme to do its job (mild disease), or complete loss of enzyme function (mild to severe disease). Diseases in the human are not known for all enzymes that could potentially be lost; this is most likely because disruption of an enzyme that is absolutely necessary in early development of the fetus will lead to early (and undetected) loss of the fetus.

Disorders of metabolism may be classified according to the pathways that are disrupted. Disorders associated with protein/amino acid metabolism may be seen when amino acids cannot be effectively broken down or when they cannot be transported into the cells of the body for use in building new proteins. Most of these disorders are seen early in life, since many proteins are essential for growth and development of the body. Examples of amino acid metabolism disorders are Phenylketonuria (PKU)
and Maple syrup urine disease (MSUD). Other amino acid/protein disorders are homocystinuria, citrullinemia, alkaptonuria, and tyrosinemia.

Phenylalanine is an essential amino acid involved in the production of tyrosine, which in turn is converted to dopamine and serotonin. In PKU, the absence of this conversion means that phenylalanine accumulates in the body, causing toxic reactions within the brain and other organs. Mental retardation is the most obvious effect of this toxicity; other symptoms may include seizures, skin rashes, nausea and vomiting, and aggressive behavior. Phenylacetate (a by-product of excess phenylalanine) is secreted in sweat and urine, giving a distinctive odor to the child.

Leucine, isoleucine, and valine are amino acids that have a branched side chain. As a result of the presence of this special shape, an enzyme that can convert these enzymes is needed in order to metabolize food containing them. In MSUD, that enzyme is absent or deficient and these amino acids accumulate in the urine, giving a distinctive smell for which the disorder is named. If left untreated, this can lead to vomiting, staggering, confusion, coma, and eventual death from degeneration of the developing nerves early in life. A total of six different genes are responsible for production of the branched-chain alpha-ketoacid dehydrogenase enzyme complex, thus leading to some variation in the severity of the disease. While this disease is rare in the general population, the Mennonite community of Pennsylvania has a high rate of carriers for these mutations and thus is particularly affected.

Lipids (fats) are used in numerous ways in the human body, including for energy, temperature regulation, cell membrane structure, and nerve function. A variety of enzymes are responsible for breaking down and processing both stored and dietary lipids. In the absence of efficient processing of lipids, accumulations occur that can be extremely harmful to the organs of the body. Examples of lipid metabolism disorders are fatty acid oxidation disorders and Tay-Sachs disease. Other lipid metabolism disorders include Gaucher’s disease, Refsum disease, Niemann-Pick disease, Tangier disease, carnitine uptake defect, and trifunctional protein deficiency.

Several enzymes are involved in pathways that help stored lipids to be broken down and turned into energy. In the most common fatty acid oxidation disorder the enzyme deficient in this pathway is medium-chain acyl-coenzyme A dehydrogenase (MCAD). This is one of the most common errors of metabolism among people of northern European descent. A buildup of acyl-coenzyme A leads to delayed development, heart muscle weakness, and enlarged liver; death may occur. Symptoms develop shortly after birth and are most severe if the child goes without food for a prolonged period of time, or following exercise and the need for more energy to the cells (thus triggering the lipid breakdown pathways).

Perhaps the best known of the lipid metabolism disorders, Tay-Sachs disease results from errors in the enzyme β-hexosaminidase, which is responsible for breaking down the lipid GM2 ganglioside. The gene for this enzyme is known to reside on chromosome 15, and the absence of this enzyme allows large amounts of the ganglioside to accumulate in neurons. This accumulation leads to neurodegeneration that often results in floppy muscle tone, then paralysis, dementia, blindness, and death by age three or four. Less severe forms lead to long-term problems in the nervous system that progress throughout life. Tay-Sachs disease is most commonly seen in the Ashkenazi Jewish community but is also seen in the French Canadian population of Quebec and the Cajun population of Louisiana.

Carbohydrates
(especially glucose) are the principal fuels for the body on a daily basis. Carbohydrate metabolism requires a variety of intracellular enzymes, as well as those responsible for transport and entry into the cell. Diseases or disorders of carbohydrate metabolism can be quite severe. Examples of carbohydrate metabolism disorders are type 1 diabetes mellitus
and glycogen storage diseases.

The ability to get glucose (the primary carbohydrate) into the cells of the body requires the hormone insulin. A lack in the production of insulin in the pancreas (type 1 diabetes) leads to hyperglycemia (high blood levels of glucose) and a lack of glucose for energy within the cells. In addition to lack of cellular energy, this can lead to increased risk of blindness, heart disease, kidney failure, neurological diseases, and problems with circulation in the extremities. Type 1 diabetes may result from any one of several known mutations in DNA, the most common of which has been tracked to chromosome 6. In some forms of type 1 diabetes, the body attacks either the insulin or the pancreatic cells that produce it, making this an autoimmune disease.

Glycogen is the branched-chain storage form of glucose in the liver and muscles of the body. Glycogen storage diseases are actually a group of eleven similar diseases that result in the inability of the body to produce sufficient glucose for the bloodstream to be used by cells of the body to produce energy. In addition to low blood sugar levels, children with these diseases often have enlarged livers, swollen abdomens, and weak muscles. Elevated levels of lipids in the blood (taking the place of glucose as an energy source), may lead to acidosis and stress on the heart and kidneys.

In addition to the transport, storage, and breakdown of proteins, lipids, and carbohydrates, metabolism involves alterations in the use of elements such as iron and copper and the synthesis, storage, and use of the components of DNA and ribonucleic acid (RNA). Diseases and disorders in each of these areas are known as well. Examples include Wilson disease, Menkes disease, hereditary hemochromatosis, and Lesch-Nyhan syndrome.

Copper is necessary in cells for energy metabolism, bone production, and nerve maturation. Wilson disease and Menkes disease are disorders of copper transport and absorption that lead to a buildup of copper to toxic levels in the liver and the brain. Both liver disease and neurological damage can be present if they are not diagnosed early on; eventually, toxicity can be seen in many other organs as well. Menkes disease is usually fatal during infancy. Both diseases have been mapped to chromosome 13 and appear to be the result of proteins that are part of a transmembrane pump system. Menkes disease is transmitted as an X-linked recessive trait, while Wilson’s disease is autosomal recessive.

Hereditary hemochromatosis is a disorder of iron metabolism seen predominantly in those of Northern European, Caucasian descent and traceable to a mutation on chromosome 6. Because iron is not adequately metabolized, the levels stored in the body grow over time, leading to symptoms that include cirrhosis of the liver, cardiomyopathy (heart muscle disease), alterations in skin pigmentation, joint damage, and decreased functioning of the gonads. Because men generally retain iron better than women do, symptoms often occur earlier in men. Symptoms also occur early in alcoholics, as alcohol consumption affects uptake of dietary iron.

Both DNA and RNA are constructed in part from nitrogen-containing bases; these bases are chemically grouped as purines and pyrimidines. The body can both make and recycle these bases. One of the genes involved in the recycling of purines (HPRT1) is located on the X chromosome. In Lesch-Nyhan syndrome, several known mutations result in low levels of the enzyme, and thus a lack of purine recycling. The resulting disease is seen almost exclusively in males and causes accumulation of uric acid (the starting point in purine synthesis). Uric acid leads to gout
(painful deposits in the skin and joints) and kidney stones. For unknown reasons, this enzyme deficiency also leads to self-mutilation (biting of the fingers and tongue). Severe muscle weakness and mental retardation generally occur.

Treatment and Therapy

The most important diagnostic tool available for metabolic disorders is routine neonatal genetic screening. In 2005, a report by the American College of Medical Genetics recommended a core panel of twenty-eight metabolic disorders that should be screened for in all newborn children. This list includes disorders of protein metabolism, carbohydrate metabolism, and lipid metabolism, as well as a few multisystem disorders. Such screening does not prevent disorders but does allow early detection and therefore early intervention with diet, drugs, and other regimens that allow extended life spans for those afflicted. As of 2013, newborn screening in the United States varies from state to state, with most states testing for more than thirty disorders.

Once detected, treatment of metabolic disorders is quite varied and is related to the underlying cause of the disorder. For protein/amino acid disorders, dietary restrictions are a key element in treatment. For instance, in PKU, phenylalanine intake must be restricted starting in the first few weeks of life. This means elimination of most forms of natural protein and substitution with phenylalanine-free foods. Patients with homocysteinuria often improve with vitamin B6 (pyridoxine) or vitamin B12 (cobalamin). In maple syrup urine disease, restricting the dietary intake of the three branched-chain amino acids to the minimal amount required for growth and development allows for the best improvement. Vitamin B1 (thiamine) is helpful in those with mild disease; dialysis is used in those with severe disease. Gene therapy is a possibility in the future.

In lipid disorders, control of diet is also essential. With fatty acid oxidation disorders
it is important that patients eat often, never skip meals, and consume a diet high in carbohydrates and low in lipids. Treatment with intravenous glucose is helpful during attacks. The long-term outcome is very good in those who follow a strict dietary regimen. Likewise, in Refsum disease, a diet with little or no phytanic acid (carefully controlled plant products that contain no chlorophyll) is the key; plasmapheresis may be also be helpful. Other lipid disorders, including Gaucher’s and Tay-Sachs, require drug intervention. Gaucher’s type I patients (especially those without nervous system damage) can be treated with enzyme replacement therapy; the modified enzyme is given intravenously every two weeks. Enzyme therapy
has been shown to stop, and even reverse, many of the symptoms of this disease. The late-onset (less severe) form of Tay-Sachs has seen some promise from treatment with a ganglioside synthesis inhibitor. Treatment of the infantile form has shown little promise, since much of the neurological damage occurs prior to birth and reversing neurological damage that has already occurred has proven to be extremely difficult.

Type 1 diabetes can usually be controlled well with daily insulin (artificial) and control of diet (to match the amount of energy needed for daily activities). Although islet cell transplantation or immunosuppression has been on the drawing board for several years, no real success has yet been obtained.

Other metabolic disorders run the gamut from easy to impossible to treat. Hereditary hemochromatosis, for instance, is easy to control, with therapeutic phlebotomy (blood-letting) to remove excess iron that has built up. Early diagnosis and treatment leads to a normal life span. By contrast, there is no cure for Niemann-Pick disease, and these children generally die of infection or degeneration of the central nervous system. For Menkes disease, administration of copper histidinate has shown promise, but it increases the patient’s life span only by a few years (less than ten). In Lesch-Nyhan syndrome, medications are used to decrease the levels of uric acid; restraint against self-mutilation is commonly needed. Advances in gene therapy look promising for several of these conditions as well.

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