Inborn Error of Metabolism

Inborn errors of metabolism are a group of rare genetic conditions that prevent the body from properly converting food into energy and removing waste products. While each individual disorder is uncommon, together they affect approximately 1 in every 1,500 to 2,500 births worldwide, making early recognition and proper management essential for improving outcomes.

Table of contents

• What Are Inborn Errors of Metabolism?
• How Common Are These Disorders?
• Types of Inborn Errors of Metabolism
• What Causes These Disorders?
• Signs and Symptoms
• Diagnosis and Testing
• Treatment Options
• Living with an Inborn Error of Metabolism

What Are Inborn Errors of Metabolism?

Inborn errors of metabolism, also known as inherited metabolic disorders or hereditary metabolic disorders, are genetic conditions that affect the body’s ability to break down nutrients and generate energy^[1]. Your metabolism is a series of chemical processes that turn what you eat and drink into energy your body can use. These processes also help remove waste and unhealthy substances from your body.

When someone has an inborn error of metabolism, their body cannot complete these chemical processes as expected. This happens because of a problem with specific proteins called enzymes that help break down parts of food^[3]. When an enzyme is missing or does not work properly, substances that should be broken down can build up in the body and cause a wide range of health problems.

These disorders involve failure of the metabolic pathways involved in either the breakdown or storage of carbohydrates, fatty acids, and proteins^[2]. The effects are due to toxic accumulations of substances before the metabolic block, defects in energy production caused by a deficiency of products beyond the block, or a combination of these metabolic problems^[4].

How Common Are These Disorders?

Although any single inborn error of metabolism is very rare, taken as a group, these conditions occur in approximately 1 out of every 1,500 to 2,500 births^[2][5]. This makes them collectively quite common, even though individual disorders are uncommon.

The frequency of specific disorders varies across different racial and ethnic groups. For example, certain conditions are more common in people of Ashkenazi Jewish descent, including Tay-Sachs disease. Other disorders, such as phenylketonuria and medium-chain acyl-CoA dehydrogenase deficiency, are among the most prevalent, with respective incidences of 1 in 10,000 and 1 in 20,000^[4].

Types of Inborn Errors of Metabolism

There are hundreds of different inborn errors of metabolism. Most conditions receive their names from the enzyme that is not working as it should^[1]. The major categories include:

Lysosomal storage disorders: In these conditions, the body cannot remove or break down waste products, which causes toxins to build up. Examples include Hurler syndrome, Gaucher disease, and Tay-Sachs disease^[1].

Amino acid disorders: These affect how the body processes proteins. Maple syrup urine disease causes amino acids to build up in the body, leading to nerve damage and urine that smells like maple syrup. Phenylketonuria occurs when the body lacks an enzyme needed to break down phenylalanine, an essential amino acid^[1].

Organic acidemias: This group includes conditions like propionic acidemia, methylmalonic aciduria, isovaleric acidemia, and glutaric acidemia^[6].

Urea cycle disorders: The body cannot process ammonia, and it builds up to toxic levels in the blood. Examples include ornithine transcarbamylase deficiency, citrullinemia, and argininosuccinic aciduria^[1][6].

Fatty acid oxidation defects: These disorders affect how the body breaks down fats for energy. Medium chain acyl-CoA dehydrogenase deficiency and carnitine palmitoyl transferase 1 deficiency are examples^[6].

Carbohydrate disorders: These conditions affect how the body processes sugars. Galactosemia prevents the body from breaking down galactose, a sugar found in dairy products. Glycogen storage disease affects the body’s ability to store sugar from food, causing low blood sugar. Hereditary fructose intolerance affects the breakdown of fructose^[1][3].

Mitochondrial diseases: Cells in the body are not able to produce enough energy from the food you eat. This condition affects many organ systems, including the brain, muscles, liver, and kidneys^[1].

Metal metabolism disorders: Small traces of metals in the body build up to toxic levels. These include Wilson disease, where excess copper accumulates, and hemochromatosis, where excess iron builds up^[1].

Peroxisomal disorders: Similar to lysosomal storage disorders, these lead to toxins building up in the body^[1].

What Causes These Disorders?

A genetic mutation that happens when cells divide and replicate during fetal development causes inborn errors of metabolism^[1]. These are inherited disorders caused by mutations in genes that code for proteins functioning in metabolism^[2].

Inborn errors of metabolism can affect anyone because the condition results from a genetic change in DNA. Most are inherited as autosomal recessive, meaning both parents are carriers of the disorder. Rarely, they are autosomal dominant or X-linked^[2]. Each type has a different form of inheritance, and you are at higher risk of having an inborn error of metabolism if someone in your family has the condition^[1].

You have two copies of most genes, with one copy inherited from your mother and one from your father. For autosomal recessive disorders, a person must inherit two copies of the altered gene (one from each parent) to develop the condition. When both parents are carriers, there is a chance that their child will inherit the disorder^[6].

Signs and Symptoms

Symptoms of inborn errors of metabolism vary widely depending on the condition and its severity. They can present at any age, from the newborn period to late adulthood^[4]. In some cases, symptoms may not appear until adolescence or adulthood, when patients have residual enzyme activity that allows for slow accumulation of toxic molecules over time^[5].

Common symptoms include^[1]:

• Developmental delays
• Weight loss
• Growth challenges
• Seizures
• Poor appetite
• Low energy (feeling lethargic)
• Unusual odors of urine, sweat, or breath
• Abdominal pain

Symptoms may involve any system in the body, with neurological and digestive symptoms being most common. Neurological symptoms include diminished energy, coma, seizures, developmental delay or regression, weakness and numbness in the hands and feet, poor muscle tone or lack of muscle control, and psychiatric problems^[14].

Digestive system signs include recurrent episodes of vomiting, poor feeding and failure to thrive, an enlarged liver or spleen, and jaundice^[14].

Other symptoms can include thickening or enlargement of the heart, certain facial or body features, eye problems such as cataracts, skin issues, and strange-smelling urine, breath, sweat, or earwax^[14].

The symptoms range from mild to severe and can be life-threatening if left untreated^[1]. Even apparently stable patients with mild symptoms may deteriorate rapidly, with progression to death within hours^[4].

Diagnosis and Testing

The first opportunity to detect an inborn error of metabolism occurs during preconception counseling, when individuals can undergo carrier screening. For individuals of all ethnic backgrounds, screening includes testing for a variety of these disorders^[5].

All U.S. states conduct newborn screening tests to identify many of these disorders. The test is administered in the hospital after a baby is born by pricking the baby’s heel and taking a few blood drops as samples^[14]. Newborn screening is recommended for 34 disorders, including 25 inborn errors of metabolism^[5]. However, different states and hospitals have different testing panels, and screens may identify 8 to 50 different diseases, though there are thousands of possible conditions^[2].

Some disorders can be detected before birth using ultrasound^[5]. However, some newborns present with symptoms consistent with an inborn error of metabolism before newborn screening results are available, or present with symptoms from a disorder not detectable with screening. Such situations are medical emergencies requiring immediate consultation with a metabolic specialist^[5].

Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. An understanding of the major clinical signs provides the basis for knowing when to consider the diagnosis. A high index of suspicion is most important in making the diagnosis^[4].

Physicians should consult with a metabolic specialist on an emergency basis upon suspecting or diagnosing an inborn error of metabolism in a newborn. Guidelines and action sheets should be used to determine appropriate action after a positive newborn screen, particularly if there is a delay in contacting a metabolic specialist^[5].

Treatment Options

Goals of treatment for patients with an inborn error of metabolism are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites^[11]. With appropriate therapy, patients may completely recover from metabolic crisis without long-term problems^[4].

Treatment of patients with a known disorder should be disease and patient specific. Early recognition and appropriate treatment is critical to optimize outcome^[4]. Start treatment as soon as the diagnosis is considered, even before confirmation^[11].

Dietary management: Since metabolism disorders result from the body’s inability to properly turn food into energy, treatment often consists of lifelong dietary restrictions. Treatment includes changes to your diet or taking medicines to help your body process certain foods^[1]. Some disorders require a low protein diet with low protein medical foods and metabolic formula. Patients work closely with a metabolic dietitian to monitor the effectiveness of dietary restrictions, growth trends, and laboratory tests for needed dietary changes^[20].

For example, people with phenylketonuria must follow a low-phenylalanine diet for life to prevent the amino acid from building up in their bodies and damaging the brain. Children with galactosemia must avoid dairy products and other foods with galactose for life to prevent damage to the brain, eyes, kidneys, and liver^[14].

Emergency treatment: In emergency situations, initial treatment involves discontinuing feeding and providing high-rate glucose infusions to prevent the buildup of toxic substances^[5]. For all patients in whom an inborn error of metabolism cannot be ruled out, glucose should be given intravenously at specific rates to prevent breakdown of body tissues and promote urinary excretion of some toxic metabolites^[11].

Medications: Medical therapy specific for the diagnosed disorder will need to be continued, usually for life. Long-term treatments include enzyme-replacement therapies for some conditions^[5][11].

Other therapies: Strict adherence to dietary and medication regimens is recommended for patients diagnosed with an inborn error of metabolism. Early treatment of symptoms and recognition that physical stressors, including illness, trauma, surgery, and changes in diet, may trigger symptoms is important in avoiding metabolic breakdown^[11].

Living with an Inborn Error of Metabolism

Care for individuals with inborn errors of metabolism will be lifelong. There are professionals specially trained to help anyone living with a rare metabolic disease^[20]. It is important to trust your care teams because they are there to support you through life’s milestones, from infancy and adolescence to adulthood and family planning.

Families and patients should be supported by a team of specialists who provide education and support regarding disease signs, course of disease, medical care, and psychosocial challenges, and offer genetic counseling to discuss recurrence risks, screening of other family members, and prenatal diagnosis^[4]. Professional and peer support groups exist for many of these conditions.

Long-term, routine follow-up screening should be provided for potential disease complications^[11]. Since in most cases, a metabolic disorder is genetic, someone related to you may also be a carrier. A genetic counselor can help with further testing, interpret results, and help you understand how it can affect other family members^[20].

Your diagnosis can help your relatives and loved ones. A genetic counselor can help with further testing and family planning decisions^[20].