Human inherited diseases

• A genetic disorder that is caused by abnormality in an individual's DNA. Abnormalities can range from small mutation in a single gene to the addition or subtraction of a whole chromosome or set of chromosomes.

• Incidence: -

• Nearly 3-5 % of all diseases in general populations have genetic causes.

Classification

Inherited diseases can be classified into 4 main groups:

I. Chromosomal disorders

II. Monogenic disorders

III. Multigenic ( multifactorial) disorders

IV. Mitochondrial disorders

1. Chromosomal disorders

Abnormalities in chromosomal numbers or structure (cytogenetics). Also it is called

chromosome aberrations, which are two types: Numerical and Structural.

Numerical changes are either polyploidy when the changes involves a set number of chromosomes or aneuploidy in which the changes is limited to the number of individual chromosomes.

The incidence of aneuploidy is usually more common than polyploidy.

• Polyploidy occurs in humans as triploidy, with 69 chromosomes (sometimes called 69,XXX), or tetraploidy with 92 chromosomes (sometimes called 92,XXXX).

• Triploidy, is usually responsible for 17 % of spontaneous abortions. The main causes include fertilization with diploid spermatocyte or the fertilization with a single normal egg by two sperms.

• In aneuploidy, an extra or missing chromosome is a common cause of genetic disorders (birth defects). Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division in the form of monosomies or trisomies (disomies is normal), when the chromosomes do not separate properly between the two cells. This generally happens when the cytokinesis occurring properly while the karyokinesis occurring incompletely.

• Usually aneuploidy causes the termination of developing fetus, but there can be cases of live birth incidences. The most frequently extra chromosomes among live births occurring in numbers 13, 18 and 21.

• An example of a chromosomal aneuploidy is Down syndrome, or trisomy 21, which is associated with mental retardation and other birth defects, such as heart problems.

• Another example is Turner syndrome, which is caused by the absence of one sex chromosome (monosomy).

• Although most Turner patients are infertile, there have been few cases of fertility but these women have increased risk of chromosomal errors and high incidence of fetal miscarriage (premature termination of fetus).

1. Chromosome structural changes involve the loss or gain of portions in chromosomes, due to :

deletion,

inversion,

duplication and

translocation

2. Monogenic disorders

A genetic mutation that involves single allele on nuclear chromosome and follows classical Mendelian inheritance.

The primary genetic defect is usually a point or frame shift mutations. Such genetic changes may affect the synthesis of structural or transport protein, receptor, coagulation factor, immunoglobulin, peptide hormone, natural inhibitor, or an enzyme. Also called In born errors of metabolism which means inherited defect involving one of the steps in certain metabolic pathway.

• The severity of mutation depends on the function of protein being affected :

• Some mutations can be harmless like pentosuria & fructosuria (Appearance of pentose and fructose sugars in urine due to defect in their metabolisms).

• Others can be harmful due to decreased formation of an important structural protein like collagen or receptor protein like LDL receptor or regulatory natural inhibitor like α1-antitrypsin or some enzymatic defect in metabolism that causes one of the following metabolic changes:

1. Decrease in the rate of product formation

Deficiency of glucose 6-phosphatase. A liver enzyme in glycogen catabolic pathway leads to reduced formation of glucose from glucose-6-phosphate. The genetic disease is called Von Gierke’s glycogen storage disease in which liver abnormally accumulates glycogen without being able to degrade glycogen into glucose.

2. Decrease in the rate of substrate removal

• The deficiency of phenyl alanine hydroxylase

enzyme leads to accumulation of phenyl alanine substrate as well as its chemically deaminated products phenylketones, which appears in urine due to their excessive formation (Phenylketonuria disease or PKU). Normally this enzyme converts the amino acid phenylalanine to the amino acid tyrosine, therefore patients with PKU have low levels of tyrosine. The high levels of phenylalanine metabolites affect neuronal development, which leads to mental retardation.

• The symptoms associated with this disease can be prevented by proper nutrition. Phenylalanine is an amino acid found in many proteins; therefore, patients affected with PKU can escape the disease by strictly limiting themselves to low protein diets. Providing that PKU be detected early, a proper nutrition lacking phenylalanine will prevent the disease development.

3. Altered feedback control

• Cortisol hormone is synthesized in the adrenal gland from cholesterol in a pathway requires the enzyme 21-hydroxylase.Excessive formation of cortisol can inhibit this pathway by feedback inhibition.

• Deficiency of 21-hydroxylase enzyme causes reduced formation of cortisol which stops the feedback control mechanism and leads to increase secretion of adrenocorticotrophic hormone (ACTH) in a disease called Congenital adrenal hyperplasia.

21-Hydroxylase

Cholesterol Cortisol

CRH=Corticotropin releasing hormone

Pedigree

It is a family of genetic tree which describes the interrelationship between parents & children for a particular trait.

The pedigree not only gives genetic information about the history of the family for certain trait, but also can predict to some extent the segregation of this trait in future generations.

In a pedigree, the following symbols are used:

Squares(□)→ Males

Circles (○) → Females .

Horizontal lines connect male and female→ mating.

Vertical lines extending downward from a couple→ their children.

Dark color → individuals affected by the disease

White color→ healthy individuals.

Mode of inheritance for monogenic disorders:

• The mode of inheritance for monogenic disorders can be either autosomal dominant or autosomal recessive or sex linked.

1-Autosomal dominant disorder

Autosomal ( defective gene is present on one of the 22 somatic( non-sex ) chromosome pairs).The phenotypic properties of the dominant disorder (symptoms) will appear even when the individual has mutation in only one copy of the two gene alleles ( heterozygous) .In fact the homozygous state of this dominant mutation is usually lethal causing spontaneous abortion in pregnant women.

• Males and females are affected with equal frequency, which can occur in each generation. The child of an affected individual has a 50 % risk of inheriting the mutated gene.

• The trait does not skip a generation.

• Where one parent is affected, about half of the progeny will be affected.

Selected examples

• Familial hyperlipidemia: Abnormal increase of all lipid fractions in plasma.

• Familial hypercholesterolemia: Abnormal increase of cholesterol in plasma

• Spherocytosis: Hemolytic type of anemia due to the formation of abnormal spherical RBC shape instead of the normal disc shape.

Pedigree of autosomal dominant trait

• Example. Wooly hair results from a dominant allele; therefore, individuals who are homozygous dominant (WW) or heterozygous (Ww) have this trait. Individuals who are homozygous recessive (ww) for this gene have normal hair. The man at the top of the pedigree has normal hair, so his genotype is ww. His wife has wooly hair, but must be heterozygous (Ww) since three of their six children have normal hair.

Wooly hair

2-Autosomal recessive disorders

• These disorders range in severity from traits that are mild such as Albinism to those very severe like Cystic fibrosis.The heterozygous individual of this mutation is a normal carrier or some times shows mild clinical symptoms (e.g.Thalasemia).Thus recessively autosomal disorder shows up a disease symptoms only in the homozygous individuals who inherit one recessive allele from each parent.

• The majority of individuals affected with recessive disorders are born to normal parents who are both carriers. These individuals carry 25 % risk of disease incidence compared with 25 % chance of normal genotype and 50 % probability of a heterozygous carriers. If one of the parent is a carrier and the other is homozygous for the recessive defect then the probability of disease is increased to 50 % for each child.

• The clinical expression of autosomal recessive disorders is usually more predictable than in autosomal dominant disorders. That is most recessively mutated alleles lead to a complete or partial loss of protein functions. In addition, lethal alleles are more common in recessive than in autosomal dominant inheritance because the effects of lethal allele are masked in the heterozygous state.

Selected examples

• Phenylketonuria

• Thalasemia = Defective hemoglobin due to the formation of short α or β chains resulted from frame shift mutation.

• Sickle cell disease= Abnormal precipitation of hemoglobin due to substitution mutation in β- chains of hemoglobin that change the shape of hemoglobin to curved shape instead of disk shape.

Pedigree for autosomal recessive disorder

• This figure shows the pattern of albinism inheritance that can be observed for a recessive trait. The half-filled symbols indicate carriers (heterozygotes). An individual expressing a recessive trait (homozygous recessive) may not appear in every generation.

3. Sex –linked disorders

• Genes carried either on the y or x sex

chromosomes are said to be sex linked. Disorders, which are transmitted as y- linked, are very rare. In contrast, the x-linked defective alleles can be inherited as x- linked either recessive or dominant disorders similar to that of the autosomal genetic transmittance.

• As females have two x-chromosomes they will be unaffected carriers of x-linked recessive disease, unless they are homozygous for the mutated allele(very rare).However males who have only one copy of the x chromosome will develop the clinical symptoms of the disease from the mutated allele.

Selected examples

• Hemophilia: defect in one of the clotting factors in blood

• Duchenne muscular dystrophy: defect in membrane protein called dystrophine, which is present in muscle cells. The defect leads to muscle weakening.

X-Linked Recessive Pedigree • Completely affected mother can pass the

disease to their sons, but the daughters will remain carriers.

X-Linked dominant

• The x-linked dominant disorder is rare, which

shows the clinical symptoms in the heterozygous female or in a male with single copy of the mutated allele.

• Both Males and Females carrying a single copy of the allele are affected. Females will pass the disease to half of their children in a sex-unspecific manner. Males will pass the disease to all their daughters but none to their sons.

• An X-linked dominant form of the disease hypophosphatemia (a form of rickets) exists. This disease occurs due to an excess excretion of phosphates from the body, which results in bones being unable to properly calcified and having short stature.

• Y-Linked dominant

• Males always affected by the disease because they carry a copy of the mutated allele. All sons inherited the disease from their fathers while daughters are free of the disease.

• Y-linked diseases are generally rare because there are very few genes present on this relatively small chromosome. Only those genes important to spermatogenesis are mainly found on this chromosome, and therefore their defect is linked to male infertility.

• One such condition, Sertoli syndrome, results in the complete absence of the germ cells in the male testis.

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