Mendelian Disorders

A few decades ago, precise diagnosis in the field of genetics could not be done by analyzing the chromosomes or conducting biochemical studies. However, as the scope of genetics has rapidly expanded, direct analysis of gene defects has become possible, and so has the probability of correcting the defects. As the knowledge regarding the molecular patterns for various diseases has grown exponentially, new patterns of inheritance have also come up which challenge the accepted principles of inheritance.

Principles of Mendelian Disorders

Mendel, Johann Gregor (1822-1884)

Genetics' Father Gregor Mendel uncovered the fundamental laws of inheritance through his research on pea plants. He came to the conclusion that genes are passed down in pairs and as independent entities, one from each parent. Mendel looked at the segregation of parental genes and how they manifested themselves in the offspring as dominant or recessive traits. He was well-versed in the mathematical patterns of heredity passed down through the generations.

The studies performed by Mendel on pea plants for knowing inheritance patterns provide a solid base for our current understanding of single-gene diseases in humans. Mendelian or monogenic diseases are caused by mutations in one gene. They run in families sometimes. Mendelian disorders are a result of a mutation at a single genetic locus. This locus could be present on an autosome or a sex chromosome. It can manifest itself in either a dominant or recessive model. By performing pedigree analysis of large families that have many affected individuals, we can find out if a disease-associated gene is present on an autosome or on a sex chromosome. It is also used to know whether the related phenotype is dominant or recessive.

Mendel's Law of Segregation

The law of segregation states that at the time of formation of gametes, each gene gets separated so that every gamete will carry only one allele for each gene.

Mendel's Law of Independence

This law states that at the time of formation of the gametes, the segregation of each gene pair takes place independently of the other pairs. In other words, the allele received by a gamete for one gene is independent of the allele received for another gene. 

Mendelian Disorders in Humans

Genetic disorders are consequences of genome abnormality or mutations in a single gene. These disorders are visible since the birth of a child and can be predicted on the basis of family history. This is called pedigree analysis. Genetic disorders are highly uncommon and affect one out of a thousand or a million individuals. They could be heritable or non-heritable. Usually, inheritable genetic disorders occur in the germline and the defects are a result of new mutations. 

Types of Mendelian Disorders

The different types of Mendelian Disorders according to Mendel's laws of inheritance are as follows:

• Autosomal dominant

• Autosomal recessive

• X-linked dominant

• X-linked recessive

• Mitochondrial

Examples of Mendelian Disorders in Humans

• Sickle cell anemia

• Thalassemia

• Cystic fibrosis

• Colour blindness

• Haemophilia

• Skeletal dysplasia

• Muscular dystrophy

• Phenylketonuria

• Cystic Fibrosis

Cystic fibrosis is a disease that mainly affects the lungs and the digestive system. A person suffering from this disease produces an abnormal amount of sticky mucus which can act as a blockage to the lungs and the pancreas. Cystic fibrosis (CF) is one of the most common life-shortening recessive diseases, with a wide range of clinical symptoms and prognosis. In clarifying the role of genetic and nongenetic variables in CF, significant progress has been made. Some elements of the disease are linked to allelic variation in CFTR, the gene that causes CF.

However, CFTR has no effect on lung function, newborn intestinal obstruction, diabetes, or anthropometry, although candidate gene investigations have discovered genetic modifiers underpinning these features. The use of genome-wide methods offers a lot of potential for identifying unique genetic variants that cause CF's heritable characteristics and consequences. Patients with this disease usually have a very short lifespan. It is an example of autosomal recessive disorder.

• Thalassemia

Thalassemia is an example of X-linked recessive disease. In this disorder, the body produces an abnormal amount of the protein, hemoglobin. Thalassemia is a Mendelian disorder because it is caused by a single allele mutation in the HBA1 and HBA2 genes, which are inherited in a Mendelian recessive manner. Symptoms: Thalassaemia patients produce less haemoglobin and circulating red blood cells than healthy people, resulting in mild to severe anaemia. Cause: Autosomal recessive inheritance is common in both and -thalassemias, though this is not always the case.

Thalassaemias are a series of illnesses caused by errors in globin polypeptide production. An overabundance of one of the globin chains derives from the absence or decreased synthesis of the other. This results in a huge number of red blood cells being destroyed, therefore leading to anemia. The symptoms of thalassemia include dark urine, swelling in the abdomen, deformities of facial bones, etc.

• Sickle Cell Anemia

Sickle cell anemia is caused when the glutamic acid present in the sixth position of the beta-globin chain of hemoglobin is replaced by valine. The hemoglobin molecule changes physically. Its biconcave shape transforms into a sickle shape, thereby reducing the oxygen-carrying capacity of hemoglobin.

Anemia can develop when red blood cells sickle and break down early. Shortness of breath, weariness, and slowed growth and development are all symptoms of anemia in children. Yellowing of the eyes and skin, which are symptoms of jaundice, can be caused by the fast breakdown of red blood cells. Sickled red blood cells, which are stiff and inflexible, can become caught in narrow blood vessels, resulting in painful episodes. It is an example of a recessive genetic disorder. 

• Haemophilia

Haemophilia is also called the royal disease because it was first observed in a royal family. It is an example of X-linked recessive disorder. This disorder is passed by an unaffected carrier mother, as she passes the hemophilic genes to sons. It is quite rare for females to suffer from this disorder because to get the disease, the mother should either be a carrier of hemophilia or the father should be hemophilic.

In this disorder, the clotting of the blood does not happen in a normal way because it affects the protein that helps in clotting. So, a person suffering from this disease can lose excessive blood from cuts and injuries. Males are more frequently affected because the mutant gene is located on the X chromosome. 

• Phenylketonuria

This disorder is called because of the low metabolism level of the amino acid phenylalanine. A person suffering from phenylketonuria does not have the enzyme to convert phenylalanine to tyrosine. This leads to the accumulation of phenylalanine. It changes into many derivatives and leads to mental retardation. PKU manifests itself in a variety of ways, from moderate to severe. Classic PKU is the most severe form of this illness. Until they are a few months old, infants with classic PKU appear normal. These youngsters will develop a persistent intellectual handicap if they are not treated. Seizures, developmental delays, behavioral issues, and psychiatric illnesses are all frequent. Excess phenylalanine in the body can cause a musty or mouse-like stench in untreated persons. It is an example of autosomal recessive disorder.