الوراثة والطفرة الجينية

Genetic Diseases

• Hereditary disorders are derived from one parent, transmitted through gametes, and are familial.
• Congenital diseases are present at birth.
• Not all genetic diseases are congenital, and not all congenital diseases are genetic (e.g., congenital syphilis).
• Mutations are permanent changes in DNA.
• Germ cell mutations are transmitted to offspring, causing inherited diseases.
• Somatic cell mutations are not transmitted to offspring but can cause cancers and some congenital malformations.

Types of Mutations

• Point mutations result from substituting one nucleotide base with a different base.
• This substitution can replace one amino acid in the protein product (e.g., sickle cell anemia).
• In sickle cell anemia, the nucleotide triplet CTC (or GAG in mRNA), which encodes glutamic acid, is changed to CAC (or GUG in mRNA), which encodes valine. This is called a missense mutation.
• Nonsense mutations change an amino acid codon to a chain termination codon (stop codon), causing rapid degradation of the resultant protein.
• A point mutation affecting the codon for glutamine (CAG) creates a stop codon (UAG) if U is substituted for C, resulting in premature termination of the β-globin gene translation, and the short peptide is rapidly degraded. This causes deficiency of β-globin chains and a severe form of anemia called β0-thalassemia.
• Frameshift mutations occur when the insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.

Other Types of Mutations

• Three-base deletion in the common cystic fibrosis (CF) allele results in synthesis of a protein lacking amino acid 508 (phenylalanine). This is not a frameshift mutation.
• A four-base insertion in the hexosaminidase A gene leads to a frameshift mutation, causing Tay-Sachs disease in Ashkenazi Jews.
• A single-base deletion at the ABO (glycosyltransferase) locus leads to a frameshift mutation that is responsible for the O allele.
• Trinucleotide repeat mutations are characterized by the amplification of a sequence of three nucleotides. For example, in fragile X syndrome, there are 250-4000 repeats of the sequence CGG within the gene called FMR-1. In the normal population, the number of repeats is typically small (29).

Four Types of Genetic Diseases

• Those resulting from mutation in a single gene (Mendelian disorders).
• Complex disorders involving multiple genes and environmental influences (multifactorial inheritance), e.g., diabetes mellitus.
• Chromosomal disorders, arising from structural or numerical alterations in autosomes and sex chromosomes.
• Heterogeneous group involving single genes but not following Mendelian inheritance rules.

Diseases Caused by Single Gene Defects

• Approximately 1% of all adult and 6-8% of pediatric hospital admissions.
• Mutations follow patterns of inheritance: autosomal dominant, autosomal recessive, and X-linked.

Single Gene Mutations May Lead To Multiple Phenotypic Effects

• A single gene mutation can lead to multiple phenotypic effects (pleiotropy), e.g., Marfan syndrome. A defect in connective tissue that affects the skeleton, eyes, and cardiovascular systems.
• Conversely, multiple mutations can contribute to the same trait (genetic heterogeneity), e.g., retinitis pigmentosa.

Autosomal Dominant Disorders

• At least one parent of an affected individual is affected (in heterozygous state).
• Both males and females are affected.
• Affected individuals marrying unaffected ones have a 50% chance of having an affected child. New mutations can also occur.

Autosomal Recessive Disorders

• Affected individuals are homozygous for the mutated gene.
• The parents may be carriers (heterozygous) yet unaffected.
• Affected siblings have a 25% chance with each birth.
• Low frequency of mutation in the population suggests a possible consanguineous marriage.
• In heterozygotes, equal amounts of normal and defective enzymes are synthesized, allowing normal enzyme function with a 50% reduction. Clinical symptoms are rarely associated.

X-Linked Disorders

• Mostly recessive; only males are affected.
• Inherited from heterozygous females to sons, as males are hemizygous for the X chromosome.
• Heterozygous females are usually silent carriers.
• Affected males do not transmit the disease to their sons, but all daughters are carriers.
• Sons of heterozygous mothers have a 50% chance of being affected.
• Only few X-linked dominant diseases exist; characterized by transmission to 50% of offspring.

Examples of Autosomal Dominant Disorders

• Marfan syndrome
• Hypercholesterolemia
• Polycystic kidney disease
• Hereditary spherocytosis
• Familial polyposis coli

Examples of Autosomal Recessive Disorders

• Sickle cell anemia
• Thalassemia
• Glycogen storage disease
• Cystic fibrosis
• Phenylketonuria
• Wilson disease

Examples of X-Linked Disorders

• Hemophilia A and B
• Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)
• Agammaglobulinemia
• Duchenne muscular dystrophy

diseases Caused by Structural Proteins

• Marfan syndrome, an autosomal dominant disease. Connective tissue protein (fibrillin) has defects. Skeleton, eyes and cardiovascular systems are primarily affected.
• Clinical characteristics include:
  • Skeletal abnormalities (slender build, long legs and arms, high-arched palate, hyper-extensibility of joints, pectus excavatum or pigeon chest).
  • Eye abnormalities (bilateral dislocation or subluxation of the lens, due to weakness of the suspensory ligament, known as ectopia lentis)
  • Cardiovascular symptoms (fragmentation of elastic fibers in the aorta (aneurysmal dilation), aortic dissection, aortic valve ring dilation, mitrial and tricuspid valve regurgitation, leading to congestive heart failure).
• Death may occur from aortic rupture at any age. Variable expressions of features.

Diseases Caused by Receptor Proteins

• Familial hypercholesterolemia. Autosomal dominant disease resulting in elevation of plasma cholesterol levels. Individuals remain asymptomatic until adulthood with the development of xanthomas along tendon sheaths, premature coronary artery disease. Homozygotes are more severely affected with cutaneous xanthomas in childhood and frequently die from myocardial infarction in their teens. Mutation in LDL receptor gene causes the accumulation of LDL cholesterol in the plasma; absence of LDL receptors on the liver impairs transport of IDL to the liver.

Diseases Caused by Mutation in Enzymes

• Phenylketonuria (PKU). Inborn error of metabolism; autosomal recessive disorder. Characterized by a severe lack of phenylalanine hydroxylase. This leads to hyperphenylalaninemia, reducing formation of myelin, epinephrine, norepinephrine, myelin, dopamine, thyroxin and melanin in the body. Affected infants display a strong musty or mousy odor. Often accompanied by mental retardation, inability to walk or talk, seizures, decreased skin&hair pigmentation, eczema. Treated with restriction of phenylalanine intake early in life.

Glycogen Storage Disorders (Glycogenosis)

• Inherited deficiency of enzymes involved in glycogen synthesis or degradation, leading to excessive glycogen accumulation or abnormal glycogen forms in tissues.
• Hepatic forms involve liver enlargement, glycogen storage, and hypoglycemia due to defective glucose production. e.g. von Gierke disease (Glucose-6-phosphatase deficiency).
• Myopathic forms involve striated muscle glycogen storage and weakness. Individuals have muscle cramps after exercise and failure of exercise to elevate blood lactate levels. (e.g McArdle disease (Phosphorylase deficiency)).

Diseases Caused By Mutation In Protein That Regulate Cell Growth

• Protooncogenes and cancer suppressor genes
• Mutations in these genes can lead to tumor formation
• About 5% of all cancers are associated with mutations in tumor suppressor genes, which appear in germ cells and can be passed on

Cytogenetic Disorders

• Normal chromosome count is 46, a multiple of haploid number (2n=46).
• Any number not an exact multiple of n is called aneuploid.
• Aneuploidy is frequently caused by non-disjunction during meiosis I or II. Failure of homologous chromosomes or sister chromatids to separate.

Other Disorders

• Fragile X Syndrome (X-linked)
• Neurofibromatoses (autosomal dominant)
• Prader Willi Syndrome (imprinting, deletion in paternal 15q11)
• Angleman Syndrome (imprinting, deletion in maternal 15q11)
• Mitochondrial diseases

Genetic Analysis Techniques

• Karyotyping
• Fluorescence in situ hybridization (FISH), and Polymerase chain reaction (PCR)

Genetic Analysis - Prenatal and Postnatal

• Prenatal genetic analysis is performed on cells obtained from amniotic fluid, chorionic villi, or umbilical cord blood.
• Indications for prenatal testing include maternal age over 35, previous chromosomal abnormality in a child, and identified carriers of genetic disorders.
• Postnatal testing uses peripheral blood lymphocytes (e.g. in the case of suspected aneuploidy, sex chromosome abnormalities, or multiple congenital anomalies).
• In postnatal analysis, genetic testing can be used for undiagnosed developmental delay, infertility to rule out sex chromosome abnormalities, or multiple spontaneous abortions.

Scientific Breakthroughs

• Increased understanding of disease processes.
• Potential cures and preventative measures.
• Insights on human evolutionary origins.

Gene Therapy

• Techniques for genetic alteration of somatic cells.
• Involves injecting modified genes targeted for a specific disorder into the patient's blood stream, which then find their way to the defective site and trigger treatment.

Genetic Counseling

• Provides valuable information for couples regarding their genetic makeup and associated risks.
• Involves studying parental medical records and family history to build a pedigree.