Metabolic Disorders

Although most metabolic disorders are also genetic disorders, not all genetic disorders are metabolic. About 1 in 1,000 babies is born with a genetically based inborn error of metabolism (IEM). There are about 200 known IEMs that range in their severity of mental and physical symptoms. Most symptoms are apparent at or soon after birth. The more severe IEMs may cause failure to thrive or develop properly, abnormally small or large body parts, bone deformities, or general lethargy. Most hereditary metabolic disorders are inherited in a recessive fash ion—meaning that a copy of the defective gene was inherited from both parents. For this reason, individual IEMs tend to be rare, most occurring at a frequency of about 1 in every 10,000 births. Some of the best understood IEMs include alkaptonuria, phenylketonuria (PKU), thalassemias, porphyrias, Tay-Sachs disease, Hurler's syndrome, Gaucher's disease, abetalipoproteinemia, and galactosemia.

Alkaptonuria was the first condition known to be caused by a metabolic enzyme deficiency. In 1902, Sir Archibald Garrod studied newborns whose urine turned black shortly after urination. The black color was due to oxidation in the urine of homogenistic acid, which accumulates because of a deficiency of the enzyme homogentisate dioxygenase. Fortunately, the urine discoloration is not detrimental to people with this IEM; however, alkaptonurics do tend to develop arthritis later in life.

PKU is a serious IEM caused by a liver enzyme deficiency. In PKU, phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, is defective. Several different mutations are responsible for altering or reducing the activity of the phenylalanine hydroxylase gene. Because PKU patients cannot make the pigment melanin, 90% of PKU patients are blond-haired with blue eyes. Other clinical features include seizures, a mousy body odor, and eczema. Left untreated, accumulated phenylalanine can cause severe mental retardation. If detected early enough, however, PKU can be controlled by restricting the intake of foods rich in phenylalanine, such as meat and milk. For this reason, newborns are routinely screened for this disorder. The benefits of early detection of PKU to prevent mental retardation are enormous in terms of both health and cost.

Thalassemias are a group of metabolic disorders that affect hemoglobin synthesis. They can be caused by mutations in several locations in either the alpha or beta hemoglobin genes. The most severe thalassemia, Cooley's anemia, is a recessively transmitted disorder caused by the mutant beta hemoglobin gene. These children appear normal at birth, but symptoms of vomiting, paling complexion, poor sleeping, and anorexia appear from 3-18 months of age. Death usually occurs before age eight. Children who inherit a mutated alpha hemoglobin gene from both parents are either stillborn or die shortly after birth.

Porphyrias are characterized by the dysfunctional metabolism of various pigments in several tissues, particularly the liver and bone marrow cells. Afflicted individuals are highly sensitive to light and are usually quite mentally disturbed. Avoiding sunlight can reduce the symptoms. Unlike most other IEMs, porphyrias are dominantly inherited traits. King George III of England suffered from porphyria although, at the time, he was diagnosed as having manic depression by some and madness by others. This disorder has been well documented in the descendants of Mary Queen of Scots. Because of its link to the royal houses of Stuart, Hanover, and Prussia, it has been called the "Royal Malady."

Other IEMs include Tay-Sachs disease, Hurler's syndrome, and Gaucher's disease. Tay-Sachs is a disease that occurs in one out of about 3,600 pregnancies in Jews of Eastern European descent. Although the disease is usually not detectable until about six months after birth, it is usually apparent by one year of age. Tay-Sachs is triggered by abnormal brain chemistry due to a deficiency of hexosaminidase A, which is required for the catabolism of a class of fats, the sphingolipids. These lipids accumulate in the brain and cause severe problems including blindness, deafness, apathy, and death usually before age of five years. Hurler's syndrome is also usually detected between 6-12 months of age and is caused by a defect in or loss of the enzyme alpha L-iduronidase. Without this enzyme, Hurler's patients accumulate high levels of mucopolysaccharides. Hurler's victims have skeletal abnormalities including short stature, enlarged tongue and liver, distended stomachs, blindness and deafness, and cardiac abnormalities. Children with Hurler's usually die before age 10. Gaucher's disease is a rare disorder that also involves fat metabolism and leads to enlargement of the spleen and liver. Childhood mortality is high for those afflicted with Gaucher's but people who survive childhood can live many years into adulthood. The Gaucher defective gene is carried by about one in 600 Jews of Eastern European descent.

Abetalipoproteinemia is a rare IEM involving lipid dysfunction. Also called Bassen-Kornzweig syndrome, it is characterized by extremely low cholesterol due to deficient or absent beta lipoproteins, which are an important component of the cholesterol molecular complex. Symptoms include growth retardation, neurological dysfunction, retinal pigment degeneration, and upper intestinal malabsorption.

Galactosemia is a metabolic disorder marked by the inability to metabolize lactose, the primary sugar in milk. At an early evolutionary stage, most humans lost the ability to digest large quantities of milk after about age six. However, adults in Northern European populations developed the ability to digest milk sugar because of its prevalence in their diets. In adulthood, people of other ancestries are more susceptible to this condition, sometimes called lactose intolerance. If present and untreated in infancy, galactosemia can lead to mental retardation.