Autosomal recessive disorders

The mutant gene present in the homozygous state leads to the expression of the trait. Autosomal recessive inheritance, therefore, requires the mutant allele in a double dose. A heterozygous individual becomes a carrier for passing on the trait to the next generation. Consider a mating between two heterozygous individuals. Each of them carries a mutant gene. Hence, the offspring inherits the disorder since he or she receives both the mutant alleles.

Examples of autosomal recessive disorders:

Disorder	Gene mutation	Clinical features
PKU	Gene located on the 12th chromosome gets mutated.	The excessive pile-up of phenylalanine in the blood, and excretion of phenylpyruvic acid in the urine. Leads to intellectual, developmental, and behavioral problems.
Spinal muscular atrophy	Gene located on the chromosome 5 gets mutated.	Progressive muscle weakness affects the movements.
Cystic fibrosis	Gene located on the 7th chromosome gets mutated.	Sticky mucus formation leading to the blockage of the airways.
Hurler’s syndrome	Gene responsible for coding beta-polypeptide gets mutated.	Glycosaminoglycans do not get degraded. Instead, get accumulated and lead to various complications.
Albinism (Oculocutaneous albinism type-2)	Gene present on the 15th chromosome gets mutated.	Whitish skin and hair coloration due to lack of pigment melanin.

The review article mainly includes four examples of autosomal recessive disorders in detail.

Phenylketonuria:

About 1 in 10,000 individuals suffer from this inborn error of metabolism. Phenylketonuria involves a complete pile-up of an amino acid known as phenylalanine. It is an essential amino acid. It is usually considered as a precursor of another amino acid known as tyrosine. The blood samples of the individuals suffering from PKU show the elevated levels of phenylalanine. This disorder has a background of both genetic and biochemical imbalance. Meaning, the gene responsible for synthesizing an enzyme gets mutated, leading to the deficiency of the enzyme. Hence, the enzyme deficiency leads to an increase in the level of an intermediate compound. In the case of PKU, the intermediate compound is phenylalanine. The enzyme known as phenylalanine hydroxylase becomes deficient. This enzyme mainly helps in the conversion of phenylalanine to tyrosine. However, the deficiency of this enzyme leads to an unconverted phenylalanine which gets accumulated in the blood stream. Also, the accumulated phenylalanine gets converted into phenylpyruvic acid and gets excreted through urine. Hence, the urine samples of the individuals suffering from phenylketonuria show the presence of phenylpyruvic acid through a biochemical test known as the ferric chloride test.

This metabolic disorder leads to serious health conditions including intellectual and developmental problems. The individuals with PKU have a typical body odor resembling that of a mouse. The skin of these individuals is lighter than normal. They have itchy skin accompanied by eczema. There exist variants of PKU. Mild, severe, variant PKU and non-PKU hyperphenylalaninemia forms of PKU commonly occur depending upon the extent of enzyme deficiency. The severe form of PKU, known as classic PKU, permanently affects the intelligence of a person. The permanent intellectual disability gets accompanied by seizures and other developmental problems. Infants suffer from microcephaly (small head), low birth weight, heart defects, epilepsy, arthritis, intellectual disability, and behavioral problems. Individuals with PKU get advised to completely avoid the intake of foodstuffs rich in phenylalanine amino acid.

·        Genetics

PKU or phenylketonuria is an autosomal recessive disorder, requiring two recessive alleles for manifestation. Most of the times, the affected individual receives two mutated genes from both the parents. Both the father and the mother contribute mutated genes to the offspring.

                                Image: Phenylalanine pathway and disorders associated with the same

Albinism:

An important pigment in the skin known as melanin helps in maintaining the skin and hair coloration. However, a deficiency of this pigment melanin leads to a disorder known as albinism. The individuals suffering from this condition show complete whitish pigmentation of the skin. The hair, eyebrows, eyelids, and the overall skin coloration looks whitish. You might know about albino mice. These mice have a white color coat. Similarly, in humans, the skin coloration looks whitish due to the improper synthesis of a pigment known as melanin. This condition leads to sensitivity to sunlight. Hence, these individuals get advised to reduce sun exposure. They also have a very high risk of developing cancer. There is no cure for this condition.

There exist three main types of albinism in humans such as oculocutaneous albinism, oculocutaneous albinism type-1, and oculocutaneous albinism type-2. Oculocutaneos albinism affects the skin as well as the eyes and the hair of the individuals. The affected individual shows a deficiency of pigment melanin in the eyes, skin, hair, eyelids, eyebrows, iris, and the ocular fundus. They have a very poor vision and their eyes appear bluish to brown color. Sometimes they look reddish in the dim light or darkness. They also suffer from an uncontrolled pendular eye movement known as nystagmus. A series of steps lead to the production of the pigment melanin. Phenylalanine amino acid gets converted into tyrosine. This tyrosine further gets converted into DOPA. The conversion of DOPA to melanin requires a key enzyme known as tyrosinase. This enzyme helps in the production of adequate melanin from the DOPA. However, this enzyme deficiency leads to less production of melanin. Mainly the gene responsible for the synthesis of enzyme tyrosinase gets mutated.

·        Genetics

The gene responsible for the synthesis of enzyme tyrosinase is present on the 11^th chromosome. Albinism is an autosomal recessive disorder as it requires two mutated alleles. Both the parents contribute one mutated allele to the child. Hence, the child has two mutated alleles. This is the situation associated with oculocutaneous albinism type I. However, it is not autosomal recessive but X-linked disorder.  In another type of albinism known as oculocutaneous albinism type-II, the gene present on the 15^th chromosome gets mutated. It follows autosomal recessive mutation.

Galactosemia:

A monosaccharide known as galactose is a sugar or a carbohydrate that helps in supplying energy to the cells. However, in a condition known as galactosemia, this sugar does not get utilized by the body for synthesizing energy. So, an excess of galactose gets accumulated and excreted through urine. Hence, individuals show high levels of this sugar. People suffering from this condition get advised to avoid galactose and lactose-rich foods. Why lactose? The sugar, known as lactose gets converted into galactose. The severe form of galactosemia, known as classic galactosemia affects the feeding ability of the infant, diminishes the energy, and affects the growth and the development of the infant. It occurs due to the deficiency of an enzyme known as galactose-1-phosphate uridyl transferase. Increased galactose levels give a nausea sensation, sometimes accompanied by vomiting, and jaundice. Untreated individuals get affected with cataracts, liver cirrhosis, and complete mental retardation. It affects 1 in 30, 000 individuals or 1 in 60,000 individuals. Early diagnosis and treatment help to control the condition.

·        Genetics:

Three gene mutations have been reported to date. These include GALT, GALK1, and GALE gene mutations and show autosomal recessive inheritance. These genes encode the enzyme known as galactose-1-phosphate uridyl transferase. However, the mutations in one or all of the above genes lead to the deficiency of the enzyme.

Hurler’s syndrome:

It involves a deficiency of an enzyme known as Alpha-L-iduronidase. It is a lysosomal enzyme. It plays an important role in the degradation of complex macromolecules such as glycosaminoglycans or the sulfated polysaccharides. The syndrome affects 1 in 2,00,000 individuals in Europe. The affected infants show a typical corneal clouding, retarded growth, and an affected lower spine. Later on, they also develop hepatosplenomegaly, coarse facial features, hearing loss, joint stiffness, and other problems. They die mostly in the teenage. Individuals suffering from Hurler’s syndrome excrete dermatan and heparan sulfate in the urine. Bone marrow transplantation may be recommended in some of the cases.
Genetics:

This kind of autosomal recessive disorder occurs due to a mutant gene encoding the enzyme Alpha-L-iduronidase. Deficiency of this enzyme leads to the accumulation of complex macromolecules in the body leading to complications. 

References:
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter

© Copyright, 2018 All Rights Reserved.

Autosomal recessive inheritance

An autosomal recessive gene or the mutant allele is present in the double dose (homozygous state). A heterozygous individual does not express the gene. A heterozygous individual with an autosomal recessive trait is known as a carrier. Consider a mating between an affected individual and a carrier individual. 50% of the progeny get affected with the trait. The remaining 50% become carriers. An unaffected individual exhibits a normal phenotype. Both the copies of the gene are normal and functional. However, if an individual shows one normal gene and one mutated gene, the individual exhibits a normal phenotype but becomes a carrier. Individuals showing both the mutated gene copies get affected with the condition.

Consider the following characteristics of autosomal recessive inheritance:

1.     The trait may involve skipping of generations.

2.     It affects both males and females equally.

3.     Pseudo-dominant inheritance: 50% of the progeny gets affected.

      Image: Autosomal recessive inheritance 

Spinal muscular atrophy:

It arises due to degeneration of spinal motor neurons. These individuals suffer from hypotonia. The mutated gene is present on the long arm of chromosome 5. Mainly the SMN1 gene gets mutated. The SMN1 gene encodes a protein known as SMN protein. It helps in motor neuron function. Hence, in the spinal muscular atrophy, an SMN1 gene mutation leads to the degenerated function of motor neurons. The voluntary muscle movements get affected. The word atrophy indicates small muscle size due to lack of activity. SMA affects 1 in 10,000 people. A Musculo-genetic disorder affecting the muscle power of an individual is known as spinal muscular atrophy. It affects the muscle movement and nerve function. Motor neurons get affected leading to difficulty in walking, sitting, standing, and other movements. The word atrophy indicates weakness and wasting of the muscles. These individuals also have breathing and swallowing difficulties. There are three types of spinal muscular atrophies as follows:

Type I spinal muscular atrophy: These individuals show developmental defects, breathing difficulties, and problems associated with swallowing. Infants show difficulty in sitting.

Type II spinal muscular atrophy: These individuals show muscle weakness. It affects the children between ages 6 and 12 months. These children do not have sitting problems. However, they need help in balancing their body. Hence, these children are unable to walk properly.  

Type III spinal muscular atrophy: These individuals cannot walk or stand properly. They require a wheelchair for the entire lifetime.

·        Genetics:

Multiple gene mutations result in spinal muscular atrophies. Genes such as SMN1, SMN2, UBA1, and many other gene mutations cause the atrophy. SMN genes encode a protein for the neuronal health. It is known as survival motor neurons (SMN) protein and plays an important role in the maintenance of motor neurons. The spinal cord and brain stem require motor neurons coordinating the muscle movements. The SMN1 and SMN2 gene play a crucial role in synthesizing SMN protein product. Mutated genes give rise to faulty protein products. SMN gene mutations lead to different types of spinal muscular atrophies depending on the molecular situation. SMN gene mutations leading to the shortage of SMN protein result in the death of the neurons, nerve impulses, and muscle weakness.

Cystic fibrosis:

Mucus helps in trapping the microbes and foreign particles. The linings of the airways, stomach, intestine, and other body systems possess mucous membranes. Mucous protects our body from microbial infections. It helps in protecting the stomach from high acidity. Respiratory and digestive systems get affected by the mucus build-up. Individuals with cystic fibrosis suffer from a chronic cough and lung infection. It may also lead to permanent lung damage and fibrosis (scar tissue) accompanying cysts. Children with cystic fibrosis also experience digestive problems. A condition known as meconium ileus involves blockage of the intestine. It is common in the newborn babies. The sticky mucus also builds up in the pancreas and harms the glucose-insulin cycle. Individuals with cystic fibrosis also experience poor growth, malnutrition, weight loss, and gastric disturbances. Imbalanced insulin hormone leads to cystic fibrosis-related diabetes mellitus (CFRDM).

Cystic fibrosis is a fatal childhood disease. Mens affected with cystic fibrosis show an absence of vas deferens. Hence, they are infertile. Women experience complications in the pregnancy.

·        Genetics:

Cystic fibrosis shows an autosomal recessive mutation. The gene known as CFTR gets mutated. The mutant gene is present on the long arm of the 7th chromosome. 1 in 2000 individuals gets affected by the disease. The CFTR gene encodes for CFTR protein. It indicates the cystic fibrosis transmembrane conductance regulator (CFTR). The protein has two hydrophobic segments spanning the plasma membrane. It has an ATP binding site. Patients with severe cystic fibrosis show three nucleotide pair deletion in the gene. The mutated gene results in abnormal CFTR protein. CFTR gene also provides instructions for making ion channels. Chloride ions help in flowing the mucus. Mutated gene disrupts the chloride channel functioning. Thus, it impairs the ion transport across the membrane. It leads to an abnormal mucus secretion.

Sickle cell anemia:

It is a hemoglobinopathy arising due to an autosomal recessive inheritance. Individuals with sickle cell anemia have sickle-shaped RBCs. The hemoglobin of these individuals is different from that of the normal individuals. Hemoglobin of these individuals is known as HbS. The solubility of the hemoglobin of the individuals suffering from sickle cell anemia is very less. Under deoxygenated conditions, HbS gets crystallized. Sickling of RBCs leads to anemia and arterial obstruction. The clinical features of the sickle cell anemia include splenomegaly, weakness, bone marrow hypertrophy, heart defects, spleen infarct, and hematuria. Splenomegaly occurs due to the destruction of the sickle-shaped RBCs in the spleen. The oxygen-carrying capacity of the blood gets reduced. Hence, it results in anemia.

·        Genetics:

It involves a mutation in the gene encoding beta-polypeptide chain. It is 146 amino acid long. The glutamic acid, which is a sixth amino acid changes to valine. A heterozygous individual for the trait becomes a carrier. The condition is known as a sickle-cell trait. 

References:
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter,

© Copyright, 2018 All Rights Reserved.