Overview of Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) is the term for a large and diverse group of genetic diseases. Each specific disease is quite rare. Many of these conditions are very serious, and may even be life-threatening. Others can be managed very well with proper care.

Fortunately, with better treatments and diagnosis, the outlook has improved for many people with these conditions. For patients and loved ones, it can be helpful to learn about similarities in this large group of diseases as well as the specific characteristics of each particular type.

To understand an inborn error of metabolism, it helps to think about metabolism itself. Metabolism is related to the rate at which your body uses calories, but it is much more than that.

The term metabolism refers to a very complex and coordinated series of chemical reactions that take place inside your body’s cells. These reactions are necessary to sustain life. Through these reactions, your body releases the energy found in nutrients like protein and carbohydrates.

Your body breaks down certain compounds and creates others in many different processes. Metabolism is also needed to help remove certain waste products from the cells, where they can ultimately be eliminated from the body.

Many of these metabolic processes take place in a series of steps, with one compound being transformed many different times along the way. Compounds also need to be transported in and out of many specific places inside and outside cells.

If there is a problem with one step of the process, it can cause serious problems. Certain compounds may build up to levels that are too high causing damage to the cell and surrounding organs. Other problems can happen because a necessary compound is deficient.

The chemical reactions that take place in your body require the help of various enzymes. The enzymes ensure that a specific chemical reaction occurs quickly. But if the enzyme doesn’t work properly, it can cause a major block to a metabolic pathway. An IEM refers to a type of medical condition in which one of these enzymes does not work properly because of a genetic defect.

Inborn errors of metabolism are present from birth—though symptoms don’t always begin right away. A person’s genes contain the information needed to make these metabolic enzymes. If there is a problem with one of these genes due to a mutation, the resulting enzyme may not work very well, or it may not work at all.

The mutation ultimately leads to the symptoms of an IEM, because there is a problem with a specific metabolic pathway in the body. Different types of IEM are usually named for the specific enzyme that is not working properly.

There are many different types of IEM. These can be placed into disease subgroups, which include enzymes from closely related processes. Some of the main categories are:

• Carbohydrate metabolism disorders (like galactosemia)
• Amino acid metabolism disorders (like phenylketonuria)
• Fatty acid metabolism disorders (like MCAD deficiency) 
• Urea cycle disorders (such as citrullinemia)
• Organic acidemias (such as maple syrup urine disease)
• Mitochondrial disorders (such as MELAS) 
• Peroxisomal disorders (like Zellweger syndrome)
• Lysosomal disorders (like Gaucher disease)

Members of each subgroup may have somewhat similar symptoms and treatments. However, even within the same group, there can be a wide variation in terms of symptoms and severity.

As a group, inborn errors of metabolism may affect as many as one to three in 3,000 people. More than 1,000 different types of IEM have been described. Certain IEM are more common in particular ethnic groups.

The symptoms of inborn errors vary according to the specific type of IEM and the severity of the mutation. In people with severe mutations, symptoms often begin within a few days of birth. In people with more mild mutations, symptoms may not begin until later childhood or even adulthood. The same disease might cause very different symptoms in an adult than in a child.

Symptoms of an IEM can affect almost any cell type or organ in the body. Often these diseases are multi-systemic, causing problems in multiple parts of the body at once. Some possible symptoms in an infant might include:

• Lethargy
• Problems with feeding
• Low body temperature
• Vomiting
• Quick breathing
• Seizures
• Abnormal muscular rigidity

If not treated, these symptoms can progress to coma, organ failure, respiratory arrest, and death. An IEM can also affect other systems of the body, depending on the specific disease. It’s important to realize that not every IEM will cause all of the following symptoms. Even people with the same type of IEM may have somewhat different symptoms. The following are just some of the possible additional problems that an IEM might cause:

• Failure to grow properly
• Developmental delay
• Muscle cramps
• Problems with nerve pain
• Movement disorders
• Behavioral and psychiatric problems
• Hearing or visual problems
• Recurring vomiting and diarrhea
• Abdominal pain
• Jaundice and liver problems
• Enlarged internal organs
• Heart problems, like cardiomyopathy or heart attack
• Skin rash or abnormal pigmentation
• Unusual or distinctive physical features (dysmorphic features)
• Unusual odor

Sometimes a person will experience repeated bouts of symptoms, as certain types of stress may worsen the condition and may even lead to life-threatening problems. Other symptoms tend to be chronic. Much depends on the specific type of IEM and the severity of the particular mutation.

Doctors consider medical history, medical exam, and various routine blood tests when diagnosing an IEM. Medical imaging tests can also lend clues, as they show affected areas of the body. Family medical history is often very important.

However, genetic testing is almost always needed for definitive diagnosis. A handful of these conditions are tested as part of routine infant screening that all US newborns receive, but many more are not.

Because each individual IEM is quite rare, a non-specialist doctor may not have experience with a particular IEM. These conditions may have similar symptoms to other conditions that are more common.

For example, an IEM may initially be mistaken for sepsis—an overwhelming response to an infection. Or it may be mistaken for some sort of problem with the heart or lungs.

It is important that clinicians consider the possibility that a patient might have an IEM instead, so they can order the necessary genetic or other initial screening tests. However, it can be challenging for doctors to know exactly which genetic tests to recommend. If an IEM is a possibility, it can be helpful to enlist the help of a physician who specializes in treating these types of diseases.

It is important that diagnosis happens as quickly as possible. In some cases, prompt treatment of the IEM can help prevent permanent damage and death.

The treatment for inborn errors of metabolism varies based on the specific gene involved and its particular metabolic pathway. However, there are some general similarities in treatment, including:

• Supplementing metabolic products that are “blocked” because of the defective gene
• Reducing metabolic products that have built up to too high levels
• Preventing situations that exacerbate or trigger symptoms of the IEM (like dehydration)
• Providing symptomatic treatments (e.g., anti-seizure medications)

In some situations, it can help to follow a specific diet that will reduce problems from the IEM. For example, people with phenylketonuria need to follow a low-protein diet.

At various points, people with an IEM may need to be hospitalized so they can receive more intense supportive care. The overall success of treatment varies significantly among the different types of IEM.

For some diseases, the treatment allows individuals to lead normal or near-normal lives. At the other extreme, infants with certain types of IEM may die within a few days of birth, even if they have been properly diagnosed. There are also people who live life with mild to severe symptoms from their IEM.

Fortunately, more and more treatments are becoming available for people with IEMs. All people with an IEM should receive care from a medical professional with experience treating these rare conditions.

Most types of IEM are inherited in an autosomal recessive fashion. That means that a person has to receive an affected gene from both their mother and their father. People who have only one affected copy of the gene usually don’t have any symptoms, and they are called “carriers” of the disease.

Many people who are carriers of a particular IEM will never know it. But if a couple has had one child born with an IEM, they have a 25 percent chance of having another child born with the same condition.

Some IEMs are x-linked recessive. These diseases are more common and more severe in males. Here, a male patient might only receive one affected gene from his mother (who probably wouldn’t have symptoms). Other types of genetic inheritance are less common in these conditions.

It is often helpful to talk to a genetic counselor if you know that an IEM runs in your family. The counselor can help you find out about the risks of having a baby with an IEM. For some types of IEM, genetic testing is available that may be able to test for an IEM prenatally. Some couples at risk may also opt for selective implantation of an embryo known to be without disease.

There is so much to learn when you find out that you or a loved one has been diagnosed with an inborn error of metabolism. It can be isolating and overwhelming but know that it isn’t your fault. A team of medical professionals is available to help. Many people with these rare diseases also choose to connect with other families through the internet. By learning more about the specific condition, you can make better decisions about managing the disease.