Inborn errors of metabolism: Definition and examples

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IEMs are a group of conditions that disrupt a metabolic pathway. These disorders typically occur due to problems with specific enzymes that help to metabolize or store macronutrients, such as carbohydrates, fats, and proteins. Problems with these biochemical reactions can result in a buildup of toxic substances, which can have significant health complications.

As there are many different metabolic pathways, health experts may categorize IEMs depending on the biochemical reaction they affect. Some examples include the following:

Urea cycle disorders

As the name implies, these conditions describe a problem with one of the enzymes or transporter molecules in the urea cycle.

The urea cycle is the waste-removal process where the body eliminates urea. If there is a problem with the urea cycle, ammonia can accumulate and cause health problems. After a person consumes protein, the body breaks it down into amino acids. Ammonia is a byproduct of leftover amino acids that the body does not need.

Typically, enzymes and transporter molecules turn nitrogen from amino acids into urea, which the body then removes through urine. However, problems with this process can cause a buildup of ammonia in the blood, which can travel to the brain and can cause coma and brain damage.

Examples of urea cycle disorders include:

• N-acetylglutamate synthase deficiency
• carbamoylphosphate synthetase I deficiency
• ornithine transcarbamylase deficiency

Organic acidemias

These conditions describe when problems with certain enzymes result in the accumulation of organic acids in the blood and urine. This often results in a concentration of toxic chemicals and a shortage of other chemicals that are essential for normal functioning.

Symptoms of organic acidemias often present in newborns and can have serious complications. As such, it is common for newborn screening to check for these conditions. Some general symptoms of organic acidemias may include vomiting, failure to thrive, seizures, and an unusual odor.

Examples of organic acidemias include:

• methylmalonic aciduria
• propionic acidemia
• isovaleric acidemia

Amino acidopathies

Similar to organic acidemias, these conditions also result in the accumulation of harmful acids. However, in these cases, problems with metabolism result in high levels of toxic amino acids. As these amino acids can travel to the brain, they can cause brain damage and may lead to learning disabilities.

Examples of amino acidopathies include:

• phenylketonuria (PKU)
• tyrosinemia
• maple syrup urine disease (MSUD)

Fatty acid oxidation defects

Usually, enzymes help the body convert fat into fatty acids and then into energy. However, with fatty acid oxidation defects, problems with enzymes mean that a person may experience a deficiency in energy production. This problem with enzymes can also cause fatty acids to build up in the heart, liver, and other organs, which may cause severe health problems.

Children with fatty acid oxidation defects may experience symptoms such as drowsiness, vomiting, and poor feeding. If they do not eat often and follow a special diet, they can have seizures and go into a coma.

Examples of fatty acid oxidation defects include:

• carnitine uptake deficiency (CUD)
• long-chain L-3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency
• medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Carbohydrate disorders

Typically, enzymes are able to break carbohydrates down into glucose, which is the body’s main source of energy. However, when problems with these enzymes occur, it can result in a harmful accumulation of sugars in the body.

As glucose is the primary energy source, hypoglycemia, or low blood sugar, is a common symptom of these conditions. Additionally, as the body stores excess glucose in the muscles and liver, people may also experience liver enlargement and muscle weakness.

Examples of carbohydrate disorders include:

• galactosemia
• glycogen storage diseases
• Hurler syndrome

Mitochondrial disorders

These conditions refer to problems with mitochondria. These are organelles that provide the energy cells require to function. As such, issues with mitochondria mean that cells cannot function properly. These conditions most often affect areas with the highest energy demands, such as the brain, muscle, liver, heart, and kidney.

Depending on which cells have ineffective mitochondria, different symptoms can occur. This can result in a variety of health concerns, such as heart problems, developmental disabilities, and seizures.

Examples of mitochondrial disorders include:

• Alpers syndrome
• Leigh syndrome
• mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

IEMs typically occur due to genetic alterations in the genes responsible for producing certain enzymes and other proteins. Problems with the production of these substances affect metabolic pathways, which can cause a variety of health problems.

While spontaneous gene changes can cause an IEM, a person will usually inherit the genes for an IEM from their parents. The risk of developing an IEM also depends on the inheritance pattern of the condition. Most people inherit IEM in an autosomal recessive manner. This means they need to inherit one copy of the genetic variation from both parents.

In some cases, newborn screening may be able to diagnose IEMs. However, different states and hospitals have differing screening panels. As there are many possible conditions, and IEMs are often rare, it may not always be possible to identify an IEM.

Newborn screening involves taking a blood sample after birth to check for rare but serious health conditions. This involves pricking the baby’s heel to get a few drops of blood. This sample will then undergo laboratory testing, and the caregiver will typically receive the results a few days later.

However, in many cases, an infant may not present with noticeable symptoms of a metabolic condition in the first few days of life. This can be due to it being too early for the harmful substances to accumulate to a measurable level.

As such, some people may not receive a diagnosis for an IEM until a later stage. While diagnosing IEMs can be difficult, improvements in genetic testing are helping to enhance the speed and effectiveness of diagnoses.

Treatment options will vary depending on the specific condition.

In general, treatment will aim to minimize or prevent the buildup of toxic substances that occur due to problems with metabolism. Typically, this will involve a combination of special diets, supplements, and removal of the harmful toxins.

A person will also require regular appointments with a doctor who specializes in metabolic disorders.

Inborn errors of metabolism (IEMs) are conditions that involve problems with metabolism. Metabolic reactions are biochemical processes that occur in the body and are vital for supporting life.

There are many different IEMs that vary depending on the metabolic pathway they disrupt. IEMs occur due to genetic variations that affect metabolic reactions. Symptoms vary but may result in severe complications. Treatments typically involve a variety of dietary changes and options to remove or reduce toxins.