Inherited metabolic disorders

Inherited metabolic disorders are genetic diseases that lead to metabolic problems. Most people with inherited metabolic disorders have a defective gene that causes an enzyme deficiency. There are hundreds of different genetic metabolic disorders, and their symptoms, treatments, and prognosis vary greatly.

What is metabolism?

Metabolism refers to all chemical reactions that take place in the body to convert or use energy. Here are some basic examples of metabolism:

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 pipeline. Raw materials, semi-finished products and waste are constantly used, produced, transported and excreted from the body. The “workers” on the conveyor are enzymes and other proteins that cause chemical reactions.

Causes of inherited metabolic disorders

In most inherited metabolic disorders, one enzyme is not produced by the body at all, or is produced in a form that does not work. A missing enzyme is like a missing worker on an assembly line. Depending on how this enzyme works, its absence means that toxic chemicals may build up or a desired product may not be produced.

The code or blueprint for the production of an enzyme is usually contained in a gene pair. 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, which means they carry one defective copy and one normal copy.

In parents, a normal copy of the gene compensates for a bad copy. Their enzyme levels are usually adequate, so they may not show any symptoms of a genetic metabolic disorder. However, a child who inherits two defective copies of the gene cannot produce enough effective enzymes and develops a genetic metabolic disorder. This form of genetic inheritance is called autosomal recessive inheritance.

The main cause of most genetic metabolic disorders are genetic mutations that occurred many generations ago. The mutation of a gene is passed from generation to generation, ensuring its safety.

Each inherited metabolic disorder is quite rare in the general population. Collectively, inherited metabolic disorders can occur in about 1 in 1,000 to 2,500 newborns. In some ethnic groups, such as Ashkenazi Jews (Jews of Central and Eastern European origin), the frequency of inherited metabolic disorders is higher.

Types of inherited metabolic disorders

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

Lysosomal storage disorders: Lysosomes are spaces within cells that break down metabolic waste. Deficiency of various enzymes inside lysosomes can lead to the accumulation of toxic substances, causing metabolic disorders, including:

Hurler syndrome (abnormal bone structure and developmental delay)
Niemann-Pick disease (children have an enlarged liver, feeding difficulties and nerve damage)
Tay-Sachs disease (progressive weakness in a child a few months old, progressing to severe nerve damage; the child usually does not live past 4-5 years)
Gaucher disease (bone pain, liver enlargement, and low platelets, often benign, in children or adults)
Fabry disease (pain in the extremities in childhood, in diseases of the kidneys and heart and strokes in adulthood; only men are affected)
Krabbe disease (progressive nerve damage, developmental delay in young children, sometimes adults are affected)

Galactosemia: Impaired degradation of the sugar galactose results in jaundice, vomiting, and liver enlargement after breastfeeding or artificial feeding of the newborn.

Maple syrup urinary tract disease: A deficiency in an enzyme called BCKD causes a buildup of amino acids in the body. As a result, nerve damage occurs, and the urine smells like syrup.

Phenylketonuria: Deficiency of the enzyme PAH leads to high levels of phenylalanine in the blood. Mental retardation occurs if the condition is not recognized.

Glycogen Storage Diseases: Problems with sugar storage lead to hypoglycemia, muscle pain and weakness.

Mitochondrial Disorders: Problems within the mitochondria, the powerhouses of cells, lead to muscle damage.

Friedreich's Ataxia: Problems with a protein called frataxin cause nerve damage and often heart problems. The inability to walk usually occurs in early adulthood.

Peroxisomal disorders: Like lysosomes, peroxisomes are tiny spaces filled with enzymes within cells. Violation of the enzymatic function within peroxisomes can lead to the accumulation of toxic metabolic products. Peroxisomal disorders include:

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

Metal metabolism disorders: the levels of trace metals in the blood are controlled by special proteins. Inherited metabolic disorders can cause protein dysfunction and accumulation of toxic metals in the body:

Wilson's disease (levels of toxic copper build up in the liver, brain, and other organs)
Hemochromatosis (the intestine absorbs excess iron that accumulates in the liver, pancreas, joints and heart, causing damage)

Organic acidemia: methylmalonic acidemia and propionic acidemia.

Urea cycle disorders: ornithine transcarbamylase deficiency and citrullinemia.

Symptoms of inherited metabolic disorders

The symptoms of genetic metabolic disorders vary greatly depending on the underlying metabolic problem. Some symptoms of inherited metabolic disorders include:

Lethargy
Poor appetite
Abdominal pain
Vomiting
Weight loss
Jaundice
Failure to gain weight or grow
Developmental delay
Seizures
Coma
Abnormal odor of urine, breath, sweat, or saliva

Symptoms may appear suddenly or progress slowly. Symptoms may be caused by food, medications, dehydration, minor illnesses, or other factors. Symptoms appear a few weeks after birth in many conditions. Other inherited metabolic disorders can take years before symptoms develop.

Diagnosis of inherited metabolic disorders

Inherited metabolic disorders are present at birth, and some are found on routine screening.

Improved testing technology is prompting many states to expand newborn screening for genetic metabolic disorders.

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

Treatment of inherited metabolic disorders

Limited therapies are available for the treatment of inherited metabolic disorders. The essential genetic defect underlying the disease cannot be corrected by current technologies. Instead, the treatment attempts to bypass the metabolic problem.

Treatment of genetic metabolic disorders follows several 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 accumulate due to the metabolic disorder.
Treatment may include such measures as:
Special diets that eliminate 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 receive care at a medical center experienced in the treatment of these rare diseases.

Children and adults with inherited metabolic disorders can become seriously ill, requiring hospitalization and sometimes life-saving assistance. Treatment during these episodes is aimed at emergency care and improving organ function.