Inherited Metabolic Disorders

Written by Matt McMillen, Matthew Hoffman, MD
Medically Reviewed by Shruthi N, MD on March 24, 2025
9 min read

Inherited metabolic disorders are genetic conditions that result in metabolism problems. Most people with inherited metabolic disorders have a defective gene that results in lack of an enzyme. According to the latest count, 1,564 of these disorders have been identified. There are hundreds of different genetic metabolic disorders, also known as “inborn errors of metabolism.”

“The impact of the disorders can vary markedly from very severe to mild depending on the type of disorder that one inherits,” says Timothy Tramontana, MD, a specialist in medical genetics at the Cleveland Clinic Center for Personalized Genetic Healthcare in Cleveland, OH.

Each of these inherited metabolic disorders is individually very rare. However, when considered together, they’re not so uncommon. Christina Tise, MD, PhD, an assistant professor of medical genetics at Stanford Medicine in Stanford, CA, estimates that about 1 in 100 babies are born with some type of inherited metabolic disorder. But the exact number remains unknown, she adds.

“It is hard to really know the prevalence of these conditions because newborn screening only screens for a small handful of the conditions we know about,” Tise says. “It is for sure a group of genetic conditions that are underrecognized. Also the definition is not clear, and many inherited metabolic disorders are yet to be identified, are under-diagnosed, and have considerable variation in age of onset from fetus/neonate to adult.”

Other factors also make it hard to get a correct count. For example, many fetuses, infants, and children with such disorders will die before they are diagnosed, Tise says. And if a disorder doesn’t cause symptoms until adulthood, she adds, it may not be correctly diagnosed. Why? “They are seen as pediatric disorders even though they affect people at all ages,” Tise says.

Metabolism refers to all the chemical reactions taking place in the body to convert or use energy. A few major examples of metabolism include:

  • Breaking down the carbohydrates, proteins, and fats in food to release energy.
  • Transforming excess nitrogen into waste products excreted in urine.
  • Breaking down or converting chemicals into other substances and transporting them inside cells.

Metabolism is an organized but chaotic chemical assembly line. Raw materials, half-finished products, and waste materials are constantly being used, produced, transported, and excreted. The “workers” on the assembly line are enzymes and other proteins that make chemical reactions happen.

An inherited metabolic disorder messes up the works, disrupting the assembly line. The consequences can be very bad.

These disorders affect “the breakdown or synthesis of proteins, lipids and sugars essential for the normal function of our body,” says Eva Morava, MD, PhD, the director of the Inherited Metabolic Diseases Program at the Icahn School of Medicine at Mount Sinai in New York City, NY. “Untreated, these disorders can lead to multiorgan failure and death.”

In most inherited metabolic disorders, a single enzyme is either not produced by the body at all or is produced in a form that doesn’t work. The missing enzyme is like an absentee worker on the assembly line. Depending on that enzyme’s job, its absence means toxic chemicals may build up or an essential product may not be produced.

The code or blueprint to produce an enzyme is usually contained on a pair of genes. Most people with inherited metabolic disorders inherit two defective copies of the gene — one from each parent. Both parents are “carriers” of the bad gene, meaning they carry one defective copy and one normal copy.

In the parents, the normal gene copy compensates for the bad copy. Their enzyme levels are usually enough, so they may have no symptoms of a genetic metabolic disorder. But the child who inherits two defective gene copies cannot produce enough effective enzymes and develops the genetic metabolic disorder. This form of genetic transmission is called autosomal recessive inheritance.

The original cause of most genetic metabolic disorders is a gene mutation that occurred many generations ago. The gene mutation is passed along through the generations, ensuring its preservation.

Each inherited metabolic disorder is very rare in the general population. But considered together, inherited metabolic disorders may affect about 1 in 1,000 to 2,500 newborns. In certain ethnic populations, such as in Ashkenazi Jews with central and eastern European ancestry, the rate of inherited metabolic disorders is higher.

Hundreds of inherited metabolic disorders have been identified, and new ones continue to be discovered. Some of the more common and important genetic metabolic disorders include:

Lysosomal storage disorders . Lysosomes are spaces inside cells that break down waste products of metabolism. Various enzyme deficiencies inside lysosomes can result in buildup of toxic substances, causing metabolic disorders including:

  • Hurler syndrome (abnormal bone structure and developmental delay)
  • Niemann-Pick disease (babies develop liver enlargement, difficulty feeding, and nerve damage)
  • Tay-Sachs disease (progressive weakness in months-old children, progressing to severe nerve damage; the child usually lives only until age 4 or 5)
  • Gaucher disease (bone pain, enlarged liver, and low platelet counts, often mild, in children or adults)
  • Fabry disease (pain in the extremities in childhood, with kidney and heart disease and strokes in adulthood; only males are affected)
  • Krabbe disease (progressive nerve damage, developmental delay in young children; occasionally adults are affected)

Galactosemia. Impaired breakdown of the sugar galactose leads to jaundice, vomiting, and liver enlargement after breast or formula feeding in a newborn.

Maple syrup urine disease . Deficiency of an enzyme called BCKD causes buildup of amino acids in the body. This results in nerve damage, and the urine smells like syrup.

Phenylketonuria (PKU). Deficiency of the enzyme PAH results in high levels of phenylalanine in the blood. Intellectual disability results if the condition is not recognized.

Glycogen storage diseases. Problems with sugar storage lead to low blood sugar levels, muscle pain, and weakness.

Mitochondrial disorders. Problems inside mitochondria, the powerhouses of cells, lead to muscle damage.

Friedreich ataxia. Problems related to a protein called frataxin cause nerve damage and often heart problems. Inability to walk usually results by young adulthood.

Peroxisomal disorders. Similar to lysosomes, peroxisomes are tiny spaces filled with enzymes inside cells. Poor enzyme function inside peroxisomes can lead to buildup of toxic products of metabolism. Peroxisomal disorders include:

  • Zellweger syndrome (abnormal facial features, enlarged liver, and nerve damage in infants)
  • Adrenoleukodystrophy (symptoms of nerve damage can develop in childhood or early adulthood, depending on the form)

Metal metabolism disorders. Levels of trace metals in the blood are controlled by special proteins. Inherited metabolic disorders can result in protein malfunction and toxic accumulation of metals in the body. Metal metabolic disorders include:

Organic acidemias. Examples include methylmalonic acidemia and propionic acidemia.

Urea cycle disorders. Examples includeornithine transcarbamylase deficiency and citrullinemia.

The symptoms of genetic metabolic disorders vary widely depending on the metabolism problem present. Some symptoms of inherited metabolic disorders include:

The symptoms may come on suddenly or progress slowly. Symptoms may be brought on by foods, medications, dehydration, minor illnesses, or other factors. Symptoms appear within a few weeks after birth in many conditions. Other inherited metabolic disorders may take years to develop symptoms.

Inherited metabolic disorders are present at birth, and some are detected by routine screening. All 50 states screen newborns for phenylketonuria. Most states also test newborns for galactosemia. But no state tests babies for all known inherited metabolic disorders.

Improved testing technology has led many states to expand newborn screening for genetic metabolic disorders. The National Newborn Screening and Genetics Resources Center provides information on each state’s screening practices.

If an inherited metabolic disorder is not detected at birth, it's often not diagnosed until symptoms appear. Once symptoms develop, specific blood or DNA tests are available to diagnose most genetic metabolic disorders. Being referred to a specialized center (usually at a university) increases your chances of a correct diagnosis.

But as Tise points out, these disorders are often thought of as affecting children, so they may not be on your doctor’s list of possible suspects if you don’t show symptoms until adulthood.

Limited treatments are available for inherited metabolic disorders. The essential genetic defect causing the condition can’t be corrected with the technology we have right now. Instead, treatments try to work around the problem with metabolism.

“There are presently therapies used for some of the inherited metabolic disorders that are quite efficacious, including medications and dietary therapy, and can help to varying degrees of effect depending on the particular disorder,” Tramontana says.

But, he continues, many of these disorders have no treatment, and for those that do, such treatments may not have much evidence to support their use.

Treatments for genetic metabolic disorders follow a few general principles:

  • Reduce or eliminate intake of any food or drug that can’t be metabolized properly.
  • Replace the enzyme or other chemical that is missing or inactive to restore metabolism to as close to normal as possible.
  • Remove toxic products of metabolism that build up due to the metabolic disorder.

Treatment may include such measures as:

  • Following special diets that cut out certain nutrients
  • Taking enzyme replacements or other supplements that support metabolism
  • Treating the blood with chemicals to detoxify dangerous metabolic by-products

Whenever possible, a person with an inherited metabolic disorder should get care at a medical center experienced with these rare conditions.

Children and adults with inherited metabolic disorders can become very ill, requiring hospitalization and sometimes life support. Treatment during these episodes focuses on emergency care and improving organ function.

Experts continue to search for effective ways to treat these disorders.

“There are new and promising therapies coming out in the realm of gene therapy, enzyme replacement therapy, and prenatal therapies in fetuses with a known diagnosis,” Tise says.

Inherited metabolic disorders are individually very rare, but taken together, they affect many people. Their impact on people’s health varies widely. While some may cause only mild symptoms, others are fatal. How treatable these disorders are also varies, but there’s hope that future therapies will effectively treat a growing number of these disorders and, perhaps, provide a cure.

How rare are inherited metabolic disorders?

Each disorder is very rare on its own. Taken together, they add up, though to what number remains uncertain. Studies published over the last two decades suggest they’re less common, ranging from 1 in 800 to 1 in 2,000 in live births. But Tise estimates that as many as 1 in 100 babies may be born with an inherited metabolic disorder. Why? For many reasons, she says, including that many of these disorders go unrecognized or undiagnosed.

Is Crohn’s disease an inherited metabolic disorder?

No, Tramontana says. While certain genes have been linked to Crohn’s, the disease has no known cause. It's considered an autoimmune inflammatory disease, not an inherited metabolic disorder.

What are the most common inherited metabolic disorders?

The most common include:

  • Lysomal storage disorders, such as Hurler syndrome, Gaucher disease and Tay-Sachs disease
  • Maple syrup urine disease
  • Glycogen storage disease
  • Mitochondrial diseases
  • Peroxisomal disorder 

What inherited metabolic disorders cause weight gain?

Metabolic disorders are more likely to cause weight loss or make it difficult to gain weight. But in some disorders you need to eat frequently in order to prevent complications such as hypoglycemic crisis, or dangerously low blood sugar levels, Tramontana says. This can lead to weight gain. He points to one such disorder: medium chain acyl-CoA dehydrogenase deficiency (MCADD). This disorder prevents your body from converting certain fats into energy. “[It] requires frequent feeding early in life that could result in overindulgence in calories and weight gain,” Tramontana says.

Can inherited metabolic disorders be cured?

Not yet, though finding cures is the eventual goal, Tramontana says.