Genetics- Autosomal Recessive Single gene disorder

Autosomal recessive single gene disorder occurs in individuals having two mutant alleles of the disease associated gene. As a person inherits one allele from the father and one from the mother, individuals with autosomal recessive gene disorder inherit one of the mutant allele of the diseased gene from each of the parent.  The following examples explain autosomal recessive inheritance.

Sickle Cell Anemia-

Hemoglobin is the main oxygen transporting molecule present in the red blood corpuscles of chordate animals. It’s essential function is to transport oxygen from the lungs to all the tissues of the body. Two major types of hemoglobin occur in humans at different stage of development: fetal hemoglobin  ( hemoglobin F) and adult hemoglobin( hemoglobin A). Each molecule of hemoglobin contains two identical alpha chains and two identical beta chains. Each polypeptide chain is encoded by specific gene. The alpha chain contain 141 amino acids and beta chain contains 146 amino acids.  Many different variants of hemoglobin have been identified in the human population, most of them being variants of hemoglobin A.

Sickle cell hemoglobin is one such variant . Individuals homozygous for the hemoglobin S allele develop severe hemolytic anemia .Hemoglobin S molecules precipitate when deoxygenated , forming crystalloid aggregates that distort the morphology of RBCs. The erythrocytes elongate and form sickle shaped cells. These sickle shaped cells clog small blood vessels and cut off oxygen transport to various tissues.  This disorder occurs when there is a change in one amino acid in a polypeptide chain. The amino acid sequence of the beta chains of hemoglobin A and hemoglobin S are different. It was found that the sixth amino acid from the amino terminal end of the beta chain of hemoglobin is valine instead of glutamic acid as in case of hemoglobin A. The substitution of valine for glutamic acid at the sixth position in the beta chain allows a new bond formation that changes the its conformation and leads to molecular stacking or aggregation of hemoglobin molecules.

Phenyltketonuria(PKU)

This is another classic example of autosomal recessive dissorer. Individuals with PKU have a defect in the gene encoding the enzyme phenylalanine hydroxylase. This enzyme catalyzes the conversion of the amino acid phenyalanine to related amino acid tyrosine.  The important reaction is the first step that occurs in the catabolism of phenylalanine, which is produced by the hydrolysis of the proteins. This reaction is blocked due to mutation in the gene encoding for phenylalanine hydroxylase. Hence causes no enzume or non functional enzyme to be produced due to which large quantities of phenylalanine will build up in the blood stream . some of the excess phenyalanine is converted to phenylpyruvic acidwhich is highly toxic to the central nervous system causing brain damage and mental retardation.

Phenylalanine plays an important role in the production of melanin, the pigment responsible for skin and hair colour. Individuals suffering from PKU have lighter skin, hair, and eyes.

Symptoms include

·         Delayed mental and social skills

·         Head size significantly below normal

·         Mental retardation

·         Seizures

·         Skin rashes

·         Tremors

Autosomal dominant-

In this situation only one mutated copy of the gene will be necessary for a person to be affected by an autosomal domiant disorder.each affected individual has one affected parent. The chance of the child inheriting the disease is 50%.

Huntington’s disease-

This is a rare adult onset autosomal dominant progressive neurogegenerative disorder. George Huntington was the first person to provide a comprehensive description. The symptoms are manifested by the age between age of 30-45. So majority of the patients already will have children before they grt diagnosed. The gene responsible for this disease is mutant HTT gene.  There is a 50% chance of passing this allele to each of their children.

Huntingtin was the first disease associated gene to be molecularly mapped on to human chromosome. The HTT gene contains a region where the triplet nucleotide CAG is repeated several times. The number of these triplet repeats determines whether an individual has the disease. Generally individuals with 6-35 CAG repeats are unaffected; individuals with 36-39 repeats will be at increased risk and individuals more than 40 will definitely manifest the disease.

The huntingin locus is large spanning 180kb and consist of 67 exons. The gene is expressed is expressed in 2 alternative polydenylated forms different relative abundance in variousfetal and adult tissues. The larger transcript is approximately 13.7kb and is expressed predominantly in adults whereas the smaller transcript of approximately 10.3kb  is more widely expressed.

X linked disorders-

The X linked disorders are of two types i.e. dominant and recessive.

X linked dominant- the disorders in which mutation in the genes of X chromosome fall in this category.  In this both male and females are affected, males typically are affected more . the best example of X linked dominant disorder is Klinefelter syndrome. In this an extra X chromosome is present to the usual male chromosome(XY) . Hence the males affected with this syndrome have (47XXY) . it was first described by H.F. Klinefelter. It is estimated that 1 in every 500 live male births suffer with this syndrome.  Individuals with this syndrome are phenetypiccaly males but with some tandncy towards femaleness, particularly in secondary sex characters.  They have enlarged breasts,underdeveloped body hair, small testes and prostate gland. The XXY constitution originates when by fertilization of an exceptional XX egg and Y sperm or vice versa.  The most common karyotype for klinefelter syndrome is 47,XXY, but the symptoms of te syndrome will usually occur whenever more than one X chromosome is present along with a Y chromosome. More complex karyotypes include XXYY, XXXY, XXXYY, XXXXY, XXXXXY. All patients with this syndrome have one or more X chromatin bodies in their cell. Mental retardation is usually found when there are more than two X chromosome.  The patients are associated with less physical and reproductive anomalies.

X linked recessive-

Muscular dustrophy is a group of unrelated disease that may be defined and distinguished from all other neuromuscular diseases by four distinct characters

·         Primary myopathy

·         Genetic determination

·         Progressive course

·         Degredation of myofibers

Duchenne Muscular dystrophy

DMD is a genetic disorder characterized by progressive muscle degeneration and weakness. It is caused due to absence of a certain muscle protein called as “dystrophin.” This protein helps keep muscle cells intact. Symptoms are seen in early childhood, usually between the ages 3 and 5.

History-

DMD was first described by French neurologist Guillaume Benjamin Amand Duchenne in the 1860s, but until the then little was known about the cause of any kind of muscular dystrophy.  In 1986 , the gene responsible for DMD was identified . This defected gene is present on the X chromosome. This gene codes for the muscle protein dystrophin . Due to the mutation to this gene, the synthesis of dystrophin is affected. Hence the muscle cells become fragile and are easily damaged.

Symptoms-

Children with DMD are often late walkers. It is generally seen that the calf muscles enlarge. This enlargement is known as pseudohypertrophy or false enlargement. This occurs because the muscle cellas are abnormal and may contain scar tissue. In the early stages it seen that the kids are clumsy and fall often. Children also walk on their toes or or on the balls of their feet. In the later stages the mechanical support is required. The deterioration of muscle cells in DMD is not painful because, DMD does not affect the nerves directly. Touch and other senses are norma , as is control over smooth or involuntary muscles of the bladder, bowel and sexual functions.

Lack of dystrophin can weaken the muscle layer in the hear i.e. myocardium, resulting in a condition called “cardiomyopathy.” Sometimes as early as teen years, the damage caused by DMD to the heart becomes life threatening.

At around the age of 10, the diaphragm and the other muscles that operate the lungs weaken, making the lungs less effective. Inhalation and exhalation becomes difficult. Due to this frequent headach , mental dullness, difficulty in concentration , staying awake are seen. Males usually die by the age of 20.

About a third of the boys have difficulty in learning, although few have severe mental retardation. It is believed that the dystrophin abnormalities in the brain have subtle effects on cognition and behavior. Learning problems in DMD occurs in three main areas

·         Attention focusing

·         Verbal learning and memory

·         Emotional interaction

Diagnosis-

                CK level-

                                Initially the blood samples of the patient are tested. This test is called a CK level. CK stands for ‘creatine kinases”, an enzyme that leaks out of damaged muscle. When elevated level CK levels are seen, it means that the muscles are destroyed by some abnormal process such as DMD or inflammation. Extreme high CK level suggests that the muscle themselves are the likely cause of weakness, but it does not tell what the muscle disorder actually is may be. Ck levels elevate upto several thousand IU/L.

                Genetic testing-

                                                Genetic testing involves analyzing the DNA of any cell to see whether there is a mutation in the dystrophin geneand if so, the exact location of mutation.

                Muscle biopsy- 

                                                This method involves the surgical removal of a small muscle from the patient and examining the sample collected. Biopsy differentiates muscular dystrophies from inflammation and other disorders. It also differentiates between different forms of muscular dystrophies. The dystrophin abnormality is studied in myofibers by immunocytochemical studies or immune florescence of biopsy tissue and different portions of the protein may be studied individually.

Inheritance-

In 1986 the defective gene on the X chromosome was discovered. This defective gene causes DMD. The gene was later identified to code for a protein called as dystrophin.  Dmd occurs because the mutated gene fails to produce dystrophin and hence causes muscle weakness. The dystrophin is composed of 2.5 million base pairs. In normal condition transcription and subsequent processing of the dystrophin initial transcript results in a mRna containing only about 14,000 base pairs. This is translated into the dystrophin protein which consists of 3685 amino acids. In males suffering DMD, premature termination of transalation occurs; hence this leads to degradation of improperly transalated dystrophin transcript and nearly completes the absence of dystrophin protein.

DMD is inherited in an X linked pattern, because the gene that can carry DMD- causing mutation is on the X chromosome. The male child inherits an X chromosome from the mother and a Y chromosome from the father and females have two X chromosomes. It has an incidence of 1:3000 amongst male infants. The defective gene at the Xp21.2 locus is the largest known gene.

Each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50% chance of inheriting the flawed gene having DMD. Each of her daughter has 50% of inheriting the mutation and being a carrier. Carriers may not have the symptoms of DMD but can have a child with mutation or disease.DMD mutation change the reading frame of the dystrophin gene. About two thirds of the mutation leading to DMD is due to deletions and insertions. One thirds is dueto point mutation. DMD carriers are at risk for cardiomyopathy.

   Although DMD often runs through in a family, it’s possible for a family with no history of DMD to suddenly have a son with the disease.  There are two explanations

·          The genetic mutation leading to DMD may have existed in the females of a family for some generations without anyone knowing it.

·         Secondly the child having DMD has a new genetic mutation that arouse in one of the mother’s egg cell. Since this mutation isn’t in the mother’s blood cell, it is impossible to detect by standard carrier testing.

If a mother gives birth to achild with DMD, there is always the possibility that more than one of her egg cells has a dystrophin gene mutation, putting her at higher risk of passing the mutation another child. Once the new mutation is passed to the child, he or she can pass it to another generation. A man with DMD cannot pass the defective mutation to his son because the son inherits the Y chromosomefrom the father where as DMD is an X linked dissorder,but the father can pass the mutation to his daughter, the daughters will be carriers and each of the sons will have 50% chance of developing the disease and so on.

Y linked disorders-

These are caused due to mutation on the Y chromosome. Because males inherit a chromosome from their father, every son of an affected father will be affected. Femaleeys are never affected because t inherit only a X chromosome from their father and never a Y chromosome. Hence females are not affected.  The Y chromosome is relatively small and contains very few genes, hence there are relatively few Y linked disorders.  The symptoms often include infertility, which may be circumvented with help of some fertility treatment.

                                               

Multifactorial chromosomal abnormalities-

Genetic disorders in which multiple genes in combination with the environment play a crucial role are categorized as multifactorial disorders. There are several pairs of additive genes involved. These traits are referred to as polygenic i.e. several pairs of genes at different loci with additive effects are involved in this type of inheritance. There is no clear pattern of inheritance in this case thus making it tough to determine a person’s risk of inheriting or passing on the disorders.  As far as pedigree analysis is concerned, multifactorial dissordrs run in the family but inheritance do not follow a specific pattern.

Some multifactorial traits are often expressed more frequently in one or the other sex. For example, cleft lip palate is more common in male. In this, the upper lip is divided by a vertical  fissure. The roof of the mouth is split by a longitudinal fissure.  Cleft lip occurs due to incomplete fusion of the components that form the lip and mouth during fetal development.

Another example is spina bafida where the closure of the bony vertebral column. This is then accompanied by paralysis. Abnormalities in the skin and tufts of hair overlaying the spine in the lower back  are the indications. During pregnancy, spina bafida in the fetus can be diagnose by means of ultrasound and detection of elevated levels of a substance called alpha- fetoprotein in the mother’s blood and in the amniotic fluid that bathes the fetus.