Inborn Errors of Metabolism

What are Inborn Errors of Metabolism?

Metabolism is a biochemical process by which our body converts nutrients from food to energy. Inborn errors of metabolism are a group of inherited congenital disorders in which the body cannot properly break down the nutrients from food. This results in the accumulation of food substrates in the cells of the body, leading to clinically significant consequences.

If inborn errors of metabolism are not clinically managed, they can lead to developmental delays and other severe health conditions.

What are the Causes of Inborn Errors of Metabolism?

Certain chemicals known as enzymes facilitate the biochemical processes of the metabolic pathways. A defect in a gene, also called mutation, that controls the production of a particular enzyme can result in a faulty enzyme or reduced quantity of the enzyme. The body’s metabolic pathway can thus be affected.

Each gene has two copies and we inherit one copy from each parent. Mutations can arise in the individual for the first time or may be inherited from parents. The inheritance can occur in various patterns – autosomal or sex-linked, dominant or recessive. Individuals who have an inherited metabolic disorder usually inherit the condition in an autosomal recessive pattern. They need to inherit two copies (one from each parent) of the mutated gene to manifest the condition. These individuals will not have adequate normal enzyme in their body to carry out the metabolic reaction and will be affected with the metabolic disorder. Carriers of the mutation, which means those that have one mutated copy and one normal copy of the gene do not develop the condition because the enzyme made by the normal copy compensates for the missing or faulty enzyme due to the mutated copy.

Patterns of autosomal dominant inheritance, where only one defective gene is necessary to produce the condition, as well as sex-linked inheritance, where the defect is on the X or Y sex chromosome are also, though less commonly, associated with inborn errors or metabolism.

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What are the Different Types of Inborn Errors of Metabolism?

Inborn errors of metabolism are quite rare in the general population and have been estimated to affect 1 in every 1,500 individuals. Due to the significant health implications of these conditions, it is important to understand these disorders to provide the required care at the right time and prevent severe complications. There are hundreds of known inherited metabolic diseases and each disorder is associated with a different gene. Some of the commonly known inherited metabolic disorders include:

Lysosomal storage disorders: Lysosomes are a specialized subunits within cells that breakdown waste products. Deficiency of lysosomal enzymes leads to build-up of toxic waste in cells leading to disorders including:

• Hurler syndrome is caused due to the deficiency of the enzyme called lysosomal alpha-L-iduronidase, which helps the breakdown of large sugar molecules known as glycosaminoglycans. Accumulation of glycosaminoglycans affects the joints, the heart and other organs leading to abnormal bone structure and developmental delay.
• Niemann-Pick disease (NPD) types A and B are caused due to the deficiency of the enzyme called acid sphingomyelinase. Sphingomyelinase help breakdown lipids in the body. Accumulation of lipids is damaging to the spleen, liver and brain; therefore babies with NPD have an enlarged liver, nerve damage and difficulty with feeding.
• Tay-Sachs disease (TSD) is a fatal inherited metabolic disorder, caused due to a deficiency of the enzyme called hexosaminidase-A. Hexosaminidase-A is involved in the breakdown of GM2 ganglioside, a type of lipid, that accumulates in the nerve cells of the brain in the absence of the enzyme. Children with TSD have progressive weakness and severe nerve damage from birth. The nervous system in children with TSD is so badly affected that many succumb to the disease by the age of 5 years.
• Gaucher disease is caused due to a deficiency of the enzyme glucocerebrosidase that is essential to breakdown the lipid – glucocerebroside. In the absence of the enzyme, glucocerebroside molecules accumulate in the liver, spleen, bone marrow and the nervous system affecting their normal function. Individuals with Gaucher diseases have liver enlargement, pain in their bones and low platelet counts. Most children or adults with Gaucher disease have a mild disease.

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Classic Galactosemia is a metabolic condition in which the body cannot breakdown galactose (a sugar found in milk) due to the deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT). If infants with galactosemia are given milk (human or animal), galactose gets accumulated in their system and damages the kidney, liver, brain and eyes. This causes jaundice, vomiting, growth failure and other complications including liver failure resulting in death in infancy.

Phenylketonuria (PKU) is caused due to the deficiency of the enzyme phenylalanine hydroxylase (PAH), which is essential for the breakdown of the amino acid phenylalanine. If children with PKU consume foods high in protein content, phenylalanine accumulates in their body, which causes severe intellectual disability, and neurological and behavioral problems.

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Glycogen storage diseases (GSD) are a group of metabolic disorders that have defects in enzymes responsible for the breakdown of glycogen or storage of glucose in the form of glycogen in our body. If the enzymes required to process glycogen are deficient, glycogen accumulates in the liver and muscles causing weakness and muscle pain. The inability to break down glycogen into glucose can result in situations of low blood sugar levels.

What are the Symptoms and Signs of Inborn Errors of Metabolism?

Most inherited metabolic disorders will manifest at infancy or childhood and some mild conditions can manifest in adulthood. Symptoms may be triggered by certain foods, medications or other factors. The symptoms and signs depend on the underlying metabolic problem associated with the condition. Some common symptoms of inherited metabolic conditions include:

• Lethargy
• Vomiting
• Breathing problems - apnea or tachypnea
• Poor appetite
• Weight loss
• Failure to gain weight
• Failure to thrive
• Jaundice
• Seizures
• Developmental delay
• Abnormal odor of urine, breath, saliva or sweat
• Coma

How do you Diagnose Inborn Errors of Metabolism?

Inborn errors of metabolism are usually diagnosed by biochemical analysis and/or other laboratory tests on the blood, skin or sweat sample. These biochemical tests analyze enzyme activity by measuring the levels of metabolic substrates in the body that is, the substance that has to be broken down by the enzyme. Abnormal levels of metabolic substrates in the body is indicative of an inherited metabolic disorder. Sometimes further testing is required, specific to a condition, to confirm the diagnosis. Inborn errors of metabolism can be diagnosed prior to the manifestation of symptoms through newborn screening or after the manifestation of symptoms.

Newborn screening is a protocol devised to diagnose inborn errors of metabolism in asymptomatic infants to prevent severe damage to the child’s organs. To screen for inherited metabolic disorders, a small blood sample is taken from the child and is tested for a number of inherited metabolic disorders. This is done through biochemical analysis and/or DNA testing.

If an inborn error of metabolism is not detected at birth, it is usually diagnosed only after symptoms appear. When an individual develops symptoms of an inherited metabolic condition, biochemical tests are used to diagnose the condition.

How do you Treat Inborn Errors of Metabolism?

The treatment of inborn errors of metabolism aims at limiting the toxicity of substrates in cells. If this is done at an early stage of the condition, major complications, such a developmental delay, can be prevented. The following methods help treat inherited metabolic disorders:

• Incorporating special diets to eliminate the intake of food that cannot be metabolized.
• Replacing the missing or inactive enzymes with an enzyme supplement or other supplements to restore the body’s metabolism.
• Removal of toxic chemicals accumulated in the body by treating the blood with purifying chemicals.

Gene therapy also has a role in the treatment of these disorders, where the mutated gene can be supplemented by normal genes that can produce the enzyme.

Health Tips

Know your symptoms: The key to diagnosis of inborn errors of metabolism is through the symptoms. Therefore know the symptoms of inherited metabolic conditions and if you notice anything unusual in yourself or your child, see a specialist.

Earlier the diagnosis, better the prognosis: For a positive prognosis or outcome, it is important that you have an accurate diagnosis of the condition, as early as possible. Therefore, it is important that you see a specialist and get the required tests done, in order to diagnose the condition.