2024_11_29_inborn_errors_of_metabolism_II

Introduction to Dr. Brigitte A. Graf

Dr. Brigitte A. Graf can be reached via email at b.graf@mmu.ac.uk and is located in office CA C.2.17 in the Cavendish Building. Her topics of interest include inborn errors of metabolism, human biochemistry, DNA damage and cancer, cystic fibrosis, Prader Willi Syndrome, obesity, and cardiovascular disease (CVD).

Genetics and Genetic Disorders

Genetic disorders are defined as errors in the DNA that codes for a protein. They can be categorized into several types: monogenic diseases, which are caused by a single gene mutation; polygenic diseases, which involve multiple genes; and complex multifactorial disorders, which result from the interplay of environmental factors, such as diet, medication, tobacco, alcohol, and toxins, alongside multiple gene mutations. Chromosomal disorders occur when one chromosome is missing or there is an extra chromosome, with examples including phenylketonuria (PKU), Down syndrome, sickle cell disease, cystic fibrosis, cardiovascular disease, diabetes, and cancer.

Cell Biology in Cancer

Cancer cells differ significantly from normal cells; normal cells divide and multiply in a controlled manner, are programmed to die through apoptosis, remain in their environment, and grow slowly. In contrast, cancer cells multiply uncontrollably, ignore apoptotic signals, can metastasize (spread to other parts of the body), and grow rapidly. Cancer arises when mutations occur in one or more genes, leading to tumor formation.

Causes of Genetic Change

Genetic changes can arise due to various factors, including heredity, viruses, ultraviolet (UV) radiation, smoking, chemicals, and improper cell division.

Genetics and Environment

There is a significant interaction between genetics and the environment, influencing the development and outcomes of various conditions. Continued insights into this model are explored in key readings such as Anand et al. (2008) featured in Pharmaceutical Research.

Understanding BRCA1 and BRCA2

BRCA1 and BRCA2 are tumor suppressor genes critical for DNA repair. Mutations in these genes are linked to increased breast cancer risk. Both genes are essential for effective DNA repair, with distinct types of tumor suppressor genes responsible for either DNA repair or preventing cell division (Fang et al., 2020, Frontiers in Cell Developmental Biology).

Genetic Location of BRCA Genes

The BRCA1 gene is located on chromosome 17 (base pair range: 41,196,312 to 41,277,500), while the BRCA2 gene is on chromosome 13 (long arm position: 12.3, 13q12.3). Human cDNA for BRCA2 consists of 10,254 base pairs coding for a protein of 3,418 amino acids.

Inheritance of BRCA Defects

The defects in BRCA1 and BRCA2 are classified as autosomal dominant, indicating that only one mutated copy of the gene is necessary for the condition to manifest. This mode of inheritance is reaffirmed, indicating that these genetic defects are not inherited from parents but rather occur through embryonic development.

Monogenic Inborn Errors of Metabolism

Monogenic inborn errors of metabolism are characterized by specific examples: adrenoleukodystrophy (ALD), which is a fatal nerve disease; muscular dystrophy, resulting in progressive muscle deterioration; Gaucher disease, involving chronic enzyme deficiency; hemophilia A, which showcases clotting deficiencies prevalent among Ashkenazi Jews; and Ehlers-Danlos syndrome, a connective tissue disease. Additionally, conditions such as retinitis pigmentosa, ALS, and Huntington’s disease exhibit considerable clinical manifestations.

Cystic Fibrosis Overview

Cystic fibrosis is caused by a faulty CFTR protein affecting ion transport, leading to the retention of chloride (Cl-) and bicarbonate ions, resulting in thick mucus accumulation in the lungs and other organs. In healthy individuals, CFTR normally transports ions out of cells, primarily found in the epithelial cells of the lungs, pancreas, and gut.

Epidemiology of Cystic Fibrosis

Cystic fibrosis is classified as an autosomal recessive disorder, with data indicating that in Northern Europe, 1 in 25 individuals are carriers of the faulty CFTR gene, and 1 in 3000 actually have cystic fibrosis. The health implications include impaired mucus clearance, which contributes to bacterial infections in the lungs, pancreas, liver, kidney, and gut.

Gastrointestinal Problems in Cystic Fibrosis

The consequences of cystic fibrosis on digestion include impaired bicarbonate secretion that disrupts pancreatic enzyme function, leading to incomplete digestion. Symptoms may include fatty stools and deficiencies in key vitamins (A, E, D, K).

Prader-Willi Syndrome Overview

Prader-Willi syndrome is a rare inborn error of metabolism occurring in 1 in 20,000 births. Key characteristics include poor feeding in infancy and weak muscle tone, which typically transitions into an insatiable appetite between ages 2-6, leading to obesity and developmental delays. This syndrome is genetically caused by defects on chromosome 15.

Genetic Defects in Prader-Willi Syndrome

There are two main types of defects on chromosome 15 related to Prader-Willi syndrome: in 70% of cases, the maternal chromatid is inactive with errors on the paternal chromatid; in 25% of cases, two faulty maternal chromatids are present. These defects are not considered inherited but occur during embryonic development.

Obesity as a Genetic Disease

Data indicates that children with obese parents have an 80% likelihood of being obese themselves, whereas only 10% of children with non-obese parents are obese (Kolata, G., 2007, "Rethinking Thin"). This raises questions about the potential genetic contributions to obesity trends.

Examination of Genes and Obesity Trends

The inquiry into whether our genes have changed since 1975 remains a significant topic within genetic research.

Obesity and Genetics Revisited

Research continues to explore the relationship between genetics and obesity, delving deeper into why certain individuals may be predisposed to obesity regardless of lifestyle choices.

Genes versus Behaviors in Obesity

The ongoing debate surrounding genetics versus lifestyle choices continues to influence the understanding of obesity outcomes.

CVD as a Complex Multifactorial Disorder

Cardiovascular disease (CVD) serves as an example of a complex multifactorial disorder, where factors like clot and plaque formation significantly impact cardiovascular health.

Detailed Mechanisms in CVD

CVD involves intricate interactions, with key factors comprising thrombus formation, platelet activation, leukocyte involvement, and more, which ultimately results in complications such as lesions and thrombosis.

Polygenic Diseases and Threshold Theory

The threshold theory, which relates to polygenic diseases, suggests they are influenced by multiple genetic mutations alongside environmental factors. Examples of polygenic diseases include chronic conditions like coronary heart disease, cancer, diabetes, asthma, and osteoporosis.

T2D Prevalence in the UK

Insights into the prevalence and impact of Type 2 Diabetes (T2D) in the UK offer important data regarding public health concerns.

Human Biochemistry and Metabolism

Key questions in metabolism include understanding how food is converted into energy, the role of enzymes, and challenges related to macronutrient balance. Complex topics also involve nutrigenetics and nutrigenomics, personalized nutrition, and potential impacts on acid-base balance, alongside a diversity of inborn errors of metabolism and their inheritance in monogenic diseases.