Because enzymes are so important in all metabolic processes, when they malfunction, it can create big problems for the organism. Here are some examples of genetic disorders that are caused by an enzyme that is not working correctly:

Maple syrup urine disease

Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants’ urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death.

Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease. Each of these three genes provides the instructions to make one protein. The proteins work together as part of an enzyme complex. The enzyme complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs.

Mutations in any of these three genes reduce or eliminate the function of the enzyme complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease.

Tay Sachs Disease

Tay-Sachs disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord.

The most common form of Tay-Sachs disease becomes apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Tay-Sachs disease experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with this severe infantile form of Tay-Sachs disease usually live only into early childhood.

Mutations in the HEXA gene cause Tay-Sachs disease. The HEXA gene provides instructions for making part of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord. This enzyme is located in lysosomes (remember that these are the organelles that break down toxic substances and act as recycling centers). Within lysosomes, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside.

Mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, which prevents the enzyme from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in neurons in the brain and spinal cord. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these neurons, which causes the signs and symptoms of Tay-Sachs disease. Because Tay-Sachs disease impairs the function of a lysosomal enzyme, this condition is sometimes referred to as a lysosomal storage disorder.

Phenylketonuria

Phenylketonuria (commonly known as PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. Phenylalanine is an amino acid that is obtained through the diet. It is found in all proteins and in some artificial sweeteners (aspartame – found in Nutrasweet and Equal) . If PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems.

The signs and symptoms of PKU vary from mild to severe. The most severe form of this disorder is known as classic PKU. Infants with classic PKU appear normal until they are a few months old. Without treatment, these children develop permanent intellectual disability. Seizures, delayed development, behavioral problems, and psychiatric disorders are also common. Untreated individuals may have a musty or mouse-like odor as a side effect of excess phenylalanine in the body. Children with classic PKU tend to have lighter skin and hair than unaffected family members and are also likely to have skin disorders such as eczema.

Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia, have a smaller risk of brain damage. People with very mild cases may not require treatment with a low-phenylalanine diet.

Mutations in the PAH gene cause phenylketonuria. The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme converts the amino acid phenylalanine to other important compounds in the body. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage.

Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase enzyme activity is severely reduced or absent. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious health problems. Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia.

References

Genetics Home Reference; National Library of Medicine. August 10, 2019. Public Domain. From: https://ghr.nlm.nih.gov/condition