What are 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.
FAQs on Mendelian Disorders
1. What are Mendelian disorders?
Mendelian disorders are a type of genetic disorder caused by a mutation or alteration in a single gene. These disorders follow the patterns of inheritance first described by Gregor Mendel. They can be traced through families using pedigree analysis and are classified based on whether the gene is on an autosome or a sex chromosome, and whether the trait is dominant or recessive.
2. What are some common examples of Mendelian disorders explained in the CBSE Class 12 syllabus?
Common examples of Mendelian disorders include:
- Cystic Fibrosis: An autosomal recessive disorder affecting mucus and sweat glands.
- Sickle-cell Anaemia: An autosomal recessive blood disorder caused by a point mutation.
- Phenylketonuria (PKU): An autosomal recessive metabolic disorder.
- Haemophilia: An X-linked recessive blood clotting disorder.
- Thalassemia: An autosomal recessive blood disorder affecting haemoglobin production.
- Colour blindness: An X-linked recessive disorder affecting the ability to distinguish colours.
3. What is the key difference between Mendelian disorders and Chromosomal disorders?
The key difference lies in the scale of the genetic defect. Mendelian disorders are caused by mutations in a single gene (a small segment of a chromosome). In contrast, Chromosomal disorders are caused by an abnormality in the number or structure of entire chromosomes, such as the absence of a chromosome, the presence of an extra one (e.g., Trisomy 21 or Down Syndrome), or a large-scale structural change.
4. How is a pedigree analysis used to identify the inheritance pattern of a Mendelian disorder?
Pedigree analysis is a crucial tool in human genetics that involves creating a family tree to track a specific trait or disorder over several generations. By observing how the trait appears in males and females across generations, one can deduce its inheritance pattern. For instance:
- An autosomal recessive disorder often skips generations and affects males and females equally.
- An autosomal dominant disorder appears in every generation and affects both sexes.
- An X-linked recessive disorder affects more males than females and is never passed from father to son.
5. Why are males more frequently affected by X-linked recessive disorders like Haemophilia?
Males are more frequently affected because they have only one X chromosome (XY). If they inherit a single recessive allele for the disorder on their X chromosome (from their mother), they will express the trait. Females, having two X chromosomes (XX), must inherit the recessive allele on both of their X chromosomes to be affected. A female with one recessive allele is typically an unaffected carrier.
6. What determines if a Mendelian disorder is dominant or recessive?
The distinction depends on how many copies of the mutated gene are needed to express the disorder. A dominant disorder manifests even if only one copy of the mutated gene is inherited (heterozygous state). A recessive disorder requires two copies of the mutated gene to be inherited (homozygous state) for the disorder to be expressed. An individual with just one copy of the recessive gene is an unaffected carrier.
7. How does the single gene mutation in Sickle-cell Anaemia cause such a severe disease?
Sickle-cell anaemia is caused by a point mutation in the beta-globin gene. This single change replaces the amino acid glutamic acid with valine at the sixth position of the haemoglobin's beta-globin chain. Under low oxygen conditions, this altered haemoglobin polymerises, causing the normally biconcave red blood cells to deform into a rigid, sickle shape. These sickled cells can block blood flow and have a much shorter lifespan, leading to anaemia, pain, and organ damage.
8. What is Phenylketonuria (PKU) and how does it cause mental retardation if left untreated?
Phenylketonuria (PKU) is an inborn error of metabolism inherited as an autosomal recessive trait. Affected individuals lack an enzyme that converts the amino acid phenylalanine into tyrosine. This causes phenylalanine to accumulate in the body and get converted into phenylpyruvic acid and other derivatives. The toxic buildup of these substances in the brain interferes with normal development, leading to severe mental retardation.
9. Can two unaffected parents have a child with an autosomal recessive Mendelian disorder?
Yes, this is a classic inheritance pattern for recessive disorders. If two unaffected parents have a child with an autosomal recessive disorder, it means both parents must be heterozygous carriers. Each parent carries one normal allele and one mutated recessive allele but does not show symptoms. For each child they have, there is a 25% chance of inheriting two recessive alleles (one from each parent) and being affected by the disorder.
