2024_11_25_inborn_errors_of_metabolism_I

Introduction to Inborn Errors of Metabolism

Overview

Inborn errors of metabolism (IEM) represent a significant class of genetic diseases defined as congenital disorders due to enzyme activity failures resulting from single gene defects. These defects lead to the accumulation of toxic substances and disturbances in normal metabolism. Other terminologies include congenital metabolic diseases, inherited metabolic disorders, and enzymopathy. Such conditions are present from birth, regardless of cause.

Monogenic Diseases and Genetic Inheritance

Approximately 16,000 known monogenic diseases exist, including sickle cell anaemia, cystic fibrosis, phenylketonuria (PKU), and muscular dystrophy. These diseases highlight the importance of understanding genetic inheritance patterns. Conversely, polygenic diseases involve multiple genes and interactions with environmental factors. Examples of polygenic diseases include coronary heart disease, cancer, type 2 diabetes, asthma, gout, and osteoporosis. Genetic liability and environmental liability play critical roles in influencing disease expression.

Genetic Diversity

Key factors contributing to genetic diversity include random errors during DNA replication and random gene swapping (crossing over) during meiosis. Genetic diversity encompasses Single Nucleotide Polymorphisms (SNPs) and mutations. This diversity is essential as variations between siblings arise due to these processes.

Genome Understanding

Fundamental genetic concepts include the genome, genotype, chromosome, gene, and DNA, comprising four nucleotide bases. The human karyotype is defined as the visual representation of an individual's complete set of chromosomes, totaling 46 chromosomes. Females possess 23 homologous pairs, while males have 22 homologous pairs and one heterologous pair. Homologous chromosomes contain the same genes, which can have different versions called alleles. These alleles can be recessive or dominant.

Inheritance Patterns

Every individual carries two alleles per gene, inherited from both parents. Types of inheritance include autosomal recessive, where diseases occur from the absence of an intact gene (e.g., sickle cell anaemia), and autosomal dominant, where diseases are present with just one faulty gene. Gregor Mendel's contributions to Mendelian genetics underscore key observations on inheritance, including the law of segregation, dominance, and independent assortment.

Genetic Diversity in Siblings

Siblings display different genotypes primarily due to random segregation of alleles during gamete formation and independent assortment of genes contributing to variations.

Phenylketonuria (PKU)

Phenylketonuria (PKU) is a significant inborn error of amino acid metabolism caused by an error in the phenylalanine hydroxylase gene. This condition results in the accumulation of phenylalanine in blood and tissues, leading to severe mental retardation if untreated. PKU is both genotypically and phenotypically heterogeneous, with over 300 distinct variants identified. Early diagnosis is crucial, as untreated PKU leads to irreversible cognitive disabilities, with a current global incidence of approximately 1 in 24,000 births. Dietary management includes the restriction of phenylalanine intake and supplementation with low-phenylalanine amino acids and other nutrients such as tyrosine, B12, calcium, and vitamin D.

Genetic Mutations and Errors

Errors during DNA replication can lead to mutations, including substitutions, insertions, and deletions affecting protein synthesis. Understanding these mechanisms is essential in the study of genetic diseases. Mitosis produces normal daughter cells, but mutations may spread if errors occur. During meiosis, mutations could potentially affect offspring, highlighting the importance of understanding SNPs in genetic diversity studies.