Inborn Errors of Metabolism- Examples

Phenylketonuria:

Phenylalanine, an essential amino acid, is a precursor of tyrosine. It is one of the building blocks of proteins. An increased pile-up of this amino acid in the blood leads to an inborn error of metabolism known as phenylketonuria and further leads to serious health conditions. There are mild and severe forms of PKU. The severe form of PKU, also known as classic PKU, leads to permanent intellectual disability, seizures, and other developmental problems. The excess pile-up of phenylalanine in the body gives a typical mouse-like odor in the body. They also have lighter skin coloration and hair accompanying eczema and other skin disorders. Other variants of this inborn error of metabolism include variant PKU and non-PKU hyperphenylalaninemia. Infants with very high levels of phenylalanine have low birth weight, microcephaly, heart defects, and other intellectual and behavioral problems.

An enzyme known as phenylalanine hydroxylase helps in the conversion of phenylalanine to tyrosine. The deficiency of this enzyme mainly leads to an accumulation of phenylalanine. Instead of getting converted into tyrosine, now, the phenylalanine gets converted into phenylpyruvic acid. Thus, the urine of the individuals suffering from PKU consists of phenylpyruvic acid. PKU mainly occurs at a frequency of 1 in 10,000 individuals and follows the autosomal recessive type of inheritance. The ferric chloride test helps in detecting the phenylpyruvic acid in the urine. Also, the direct fluorometric assays help to determine the excessive amounts of phenylalanine in the blood. Mutation of a gene encoding the enzyme known as phenylalanine hydroxylase mainly leads to the condition. The only option to control the phenylalanine levels in the blood is to reduce or completely avoid the foods rich in phenylalanine amino acid.

Image: Phenylalanine-tyrosine pathway

Albinism:

An inborn error of metabolism involving little or no production of melanin pigment is known as albinism. Melanin is an important pigment that usually determines the color of the skin, hair, and eyes. This pigment also plays an important role in the optical nerve development. Light skin coloration usually completely whitish skin color is a typical feature of albinism. The hair of these individuals shows a typical white to brown coloration. These individuals have a very light blue to brown eye color. Such individuals also have a very high chance of developing cancer. It is a type of autosomal recessive inheritance and has no cure. They must reduce the sun exposure due to their sensitive skin. A kind of albinism known as oculocutaneous albinism involves the pigment deficiency affecting the eyes, hair, and the skin. An autosomal recessive condition indicates two mutations for the manifestation of the disease phenotype. 
An individual with an autosomal recessive disorder such as albinism has both the parents carrying one functional copy of the mutant gene and one non-functional copy. Such types of parents are known as carriers since they do not get the disease but have genes associated with the disease that gets passed on to the next generation. Hence, both the parents have a defective gene leading to the inheritance of both the genes in the baby leading to albinism. Mainly the mutation in the gene responsible for encoding an enzyme known as tyrosinase leads to this type of inborn error of metabolism. Hence, the DOPA does not get converted to melanin. Hence, there is a genetic block. The long arm of chromosome 11 consists of the affected gene. This type of albinism is known as oculocutaneous albinism type-1. It follows the X-linked pattern of inheritance. Oculocutaneous albinism type 2 occurs due to gene mutation on the long arm of chromosome 15. It follows the autosomal recessive type of inheritance.

Galactosemia:

Metabolism of the sugar known as galactose becomes difficult in galactosemia. The normal body cells use galactose for generation of energy. However, in the case of galactosemia, the cells fail to utilize galactose sugar for getting energy. The severe form of this condition known as classic galactosemia involves feeding difficulties in infants, a lack of energy, and diminished growth. Galactosemia occurs due to the deficiency of an enzyme known as galactose-1-phosphate uridyl transferase and gets manifested due to an autosomal recessive pattern of inheritance. The mutated gene gets passed on to the offspring. Classic galactosemia affects 1 in 30,000 to 1 in 60, 000 newborns and a relatively fewer offsprings get affected in other types of galactosemia. GALT, GALK1, and GALE gene mutations mainly lead to galactosemia.

Hurler’s syndrome:

This autosomal recessive disorder involves a most severe form of mucopolysaccharidosis type 1. It is a rare lysosomal storage disease leading to various health conditions. These individuals have respiratory problems, skeletal problems, cognitive impairment, and many other factors. It affects 1 in 2,00,000 individuals. The deficiency of the lysosomal enzyme known as Alpha-L-iduronidase mainly causes Hurler’s syndrome. This enzyme plays an important role in the degradation of complex macromolecules. Hence, the lack of this enzyme leads to the accumulation of these complex macromolecules. Examples of accumulated macromolecules include glycosaminoglycans or sulfated polysaccharides. These individuals also show corneal clouding and an abnormal curve in the lower spine. These individuals excrete excessive dermatan and heparan sulfate. The IDUA gene present on the 4^th chromosome gets mutated. 

References:
[1] Human Genetics, 3/e, Gangane
[2] Emery's Elements of Medical Genetics, Peter D Turnpenny, Sian Ellard
[3] Medical Genetics, G.P. Pal

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