Inborn errors of metabolism are a group of uncommon genetic conditions that disrupt the body’s ability to convert food into energy. These disorders arise from defects in genes that provide instructions for making enzymes, the proteins that facilitate chemical reactions to break down food. When an enzyme is missing or faulty, the metabolic process is interrupted. This leads to a buildup of substances that can be toxic and a deficiency of substances the body needs to function.
The Genetic Origins
The root of an inborn error of metabolism is a mutation in a gene responsible for creating a specific enzyme. This genetic defect results in a non-functional enzyme or prevents its production, leading to the chemical imbalances seen in these disorders.
Most of these disorders are inherited in an autosomal recessive pattern. To have the disorder, an individual must inherit two copies of the mutated gene—one from each parent, who are carriers but do not show symptoms. The disorder manifests only when a child inherits the mutated gene from both parents.
Some metabolic disorders follow an X-linked recessive pattern, where the mutated gene is on the X chromosome, affecting males more frequently. Other less common patterns, such as autosomal dominant inheritance, also exist for certain conditions.
Major Categories and Examples
Inborn errors of metabolism are diverse and are often categorized based on the type of molecule they affect. The major groups include disorders of amino acid, fatty acid, and carbohydrate metabolism.
Amino Acid Disorders
Amino acid disorders interfere with the body’s ability to break down proteins from food. A faulty enzyme needed to process a particular amino acid leads to its accumulation in the blood and tissues, which can be harmful, especially to the brain.
A well-known example is Phenylketonuria (PKU). Individuals with PKU lack a functional enzyme needed to break down the amino acid phenylalanine. If PKU is not treated, high levels of phenylalanine can build up and cause severe intellectual disability and other neurological problems.
Fatty Acid Oxidation Disorders
Fatty acid oxidation disorders disrupt the body’s ability to use fat for energy, especially during fasting or illness. A defect in a required enzyme prevents the body from converting fat into usable energy, leading to low blood sugar (hypoglycemia) and a buildup of fatty acids.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common examples. In MCAD deficiency, the enzyme needed to break down medium-chain fatty acids is defective. Without treatment, individuals can experience metabolic crisis, characterized by vomiting, lethargy, and low blood sugar, which can lead to seizures or coma.
Carbohydrate Metabolism Disorders
Disorders of carbohydrate metabolism affect how the body processes sugars for energy. When an enzyme in this process is defective, the body cannot properly use or store sugars. This can result in dangerously low blood sugar or the accumulation of a specific sugar to toxic levels.
Galactosemia is a classic example, caused by a deficiency in an enzyme needed to process galactose, a sugar in milk. When infants with galactosemia consume milk, galactose builds up in their system. This can lead to severe liver damage, cataracts, and developmental delays if not managed early.
Detection and Diagnosis
The identification of these disorders often begins shortly after birth through routine newborn screening programs. These programs detect serious conditions in infants before symptoms develop, allowing for early intervention to prevent irreversible health problems.
The most common method is the heel prick test, where a healthcare provider collects a few drops of blood from the baby’s heel. This sample is analyzed at a lab, often using tandem mass spectrometry, to screen for dozens of metabolic disorders by measuring the levels of various substances.
An abnormal screening result indicates that further testing is needed to confirm a diagnosis. Follow-up tests may include detailed blood and urine analysis or genetic testing to identify the specific gene mutation.
Therapeutic and Management Strategies
Once diagnosed, a management plan is created to mitigate the disorder’s effects. While these conditions are not curable, lifelong management can prevent or reduce symptoms and long-term complications. Treatments are tailored to the specific metabolic pathway that is disrupted.
A primary approach is dietary management, which involves controlling the intake of the nutrient the body cannot process. For PKU, this means a strict low-protein diet to limit phenylalanine. For galactosemia, all sources of lactose and galactose must be eliminated from the diet.
Medications and supplements are also used in management. Some treatments involve supplementing a product the body cannot produce. Other medications may help remove toxic substances or support a faulty enzyme’s function.
For some disorders, enzyme replacement therapy (ERT) is an option. This treatment involves regular intravenous infusions of the missing enzyme to restore the normal metabolic process. ERT is primarily used for certain lysosomal storage diseases, another category of these disorders.