11 min readConcept sheet1-mark MCQ, a 3-mark comparison of sickle-cell anaemia and thalassemia, and a 5-mark answer on the base change; also a NEET favourite

Mendelian disorders: sickle-cell anaemia, phenylketonuria and thalassemia

Mendelian disorders come from a change in a single gene. Sickle-cell anaemia changes one amino acid in β-globin; thalassemia lowers globin output; phenylketonuria blocks one enzyme.

Mendelian disorderCaused by a change (mutation) in a single gene; follows Mendel's laws and can be traced in a pedigree

Sickle-cell changeSixth codon of the β-globin gene changes from GAG to GUG; glutamic acid is replaced by valine

Sickle-cell genotypesHbA HbA normal; HbA HbS carrier; HbS HbS affected

Thalassemia genesα: HBA1 and HBA2 on chromosome 16; β: HBB on chromosome 11

What makes a disorder Mendelian

A Mendelian disorder is caused by a change in a single gene. It is passed on by Mendel's rules, so its pattern can be traced with a pedigree. It may be dominant or recessive, and autosomal or sex-linked. Examples are haemophilia, cystic fibrosis, sickle-cell anaemia, colour blindness, phenylketonuria and thalassemia. Sickle-cell anaemia, phenylketonuria and thalassemia are all autosomal recessive: only homozygous people are affected, and heterozygous people are healthy carriers.

Sickle-cell anaemia: from one base to a sickle cell

1
Haemoglobin has four polypeptide chains: two α (alpha) and two β (beta).
2
In the β-globin gene, the sixth codon changes from GAG to GUG (as read in mRNA). This is a single base substitution, a point mutation.
3★
So glutamic acid (Glu) at the sixth position of the β-chain is replaced by valine (Val).
4
The changed haemoglobin (HbS) polymerises when oxygen is low.
5
Red blood cells change from biconcave discs into elongated, sickle-like cells.
6
Only HbS HbS people show the disease. HbA HbS people look healthy but are carriers.

★ key step

Two carriers of the sickle-cell allele

Problem

Both parents are carriers (HbA HbS). What is the chance that a child will (a) have sickle-cell anaemia, (b) be a carrier, (c) be normal?

Working

Each parent makes two kinds of gametes: HbA and HbS, half each.
Punnett square: HbA HbA, HbA HbS, HbS HbA, HbS HbS.
Affected (HbS HbS): 1 box of 4.
Carrier (HbA HbS): 2 boxes of 4.
Normal (HbA HbA): 1 box of 4.

Answer

(a) 1/4 (25%), (b) 1/2 (50%), (c) 1/4 (25%).

Phenylketonuria: an inborn error of metabolism

Phenylketonuria is an autosomal recessive disorder. The affected person lacks the enzyme that converts phenylalanine to tyrosine. So phenylalanine builds up and is changed into phenylpyruvic acid and other products. These collect in the brain and cause mental retardation. Because the kidney absorbs them poorly, they are also passed out in urine.

Thalassemia

Thalassemia is an autosomal recessive blood disease. A child gets it when both parents are healthy carriers. A mutation or deletion slows down how fast one kind of globin chain (α or β) is made. Too little normal haemoglobin forms, so the person has anaemia. In α-thalassemia, the genes involved are HBA1 and HBA2, a closely linked pair on chromosome 16. Each parent passes on one pair, so a person has four α-globin genes; the more of them that are mutated or deleted, the less α-globin is made. In β-thalassemia, the gene involved is HBB on chromosome 11. A person has two copies, one from each parent, and one or both may be mutated.

Sickle-cell anaemia vs thalassemia

Sickle-cell anaemiaA qualitative problem: globin is made, but it is the wrong kind (Glu replaced by Val). Red blood cells become sickle-shaped.

ThalassemiaA quantitative problem: too few globin chains are made because of a mutation or deletion. The blood carries too little working haemoglobin.

Both are autosomal recessive and both cause anaemia.

In real life

A baby with phenylketonuria can develop normally on a low-phenylalanine diet started early, which is why newborn screening matters. Carrier tests for thalassemia before marriage or pregnancy are encouraged in many parts of India.

Exam angle

2 marks: “Why is sickle-cell anaemia called a Mendelian disorder? Give the genotype of a carrier.” It is caused by a change in a single gene (β-globin) and is inherited by Mendel's rules as an autosomal recessive trait. Carrier: HbA HbS.

3 marks: “Explain the cause of sickle-cell anaemia at the molecular level.” Point mutation in the sixth codon of the β-globin gene, GAG to GUG; glutamic acid replaced by valine at position six of the β-chain; HbS polymerises at low oxygen; RBCs become sickle-shaped; only HbS HbS affected.

3 marks: “Differentiate between sickle-cell anaemia and thalassemia.” Sickle-cell: qualitative, wrong globin (Glu to Val), single base substitution. Thalassemia: quantitative, too little globin, mutation or deletion; α (HBA1, HBA2 on chromosome 16) or β (HBB on chromosome 11). Both autosomal recessive.

Remember it

Sickle: sixth codon, Glu goes, Val arrives (GAG → GUG). Thalassemia is too little; sickle is the wrong kind.