Human Genetic Disorders

Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that affect the germ cells are transmitted to the progeny and may give rise to inherited diseases. Mutations affecting somatic cells do not cause hereditary disease, but are important factors in the development of cancer and some congenital malformations.

Mutations are classified into three categories Genome mutations: these involve loss or gain of a whole chromosome. Thus genome mutations affect the number of chromosomes Chromosomes mutations: structural changes within a chromosome due to re-arrangement of genetic material Gene mutations: affecting individual genes within a chromosome

MENDELIAN DISORDERS They are caused by mutations affecting single genes. More than 4500 disorder were listed. These disorders are inherited either as autosomal dominant, autosomal recessive or X-linked inheritance. It has to be remembered that each gene is represented as a pair (alleles) on a specific gene locus on the corresponding chromosomes.

MENDIALIAN DISORDERS AUTOSOMAL DOMINANT AUTOSOMAL RECESSIVE X-LINKED DISORDERS

AUTOSOMAL DOMINANT DISORDERS Definition: These are disorders manifested in the heterozygous state i.e. resulting from mutations affecting one of a paired allele and the other is not necessarily affected.

Examples of autosomal dominant diseases: Nervous disorders such as neurofibromatosis Renal disorders such as adult type polycystic kidney Gastrointestinal disorders as familial polyposis Skeletal disorders such as Marfan syndrome Haemopeotic disorders such as hereditary spherocytosis Metabolic disorders such as familial hypercholesterolemia Bone disorder such as multiple exostosis

NEUROFIBROMATOSIS

Polycystic Kidney Disease

Marfan's Syndrome Dominant Disorder Connective Tissue defects 1/20,000 people Connective Tissue defects Dislocation of lens in eye Rupture of aorta (weak vessel walls) “Spider fingers” Elongated body, face Caved-in chest

Marfan's Syndrome Abraham Lincoln? Lincoln could have had a mild form of Marfan’s

AUTOSOMAL RECESSIVE DISORDERS Definition: These are disorders manifested in the homozygous state i.e. resulting from mutation affecting both of a paired allele. Abnormality of one allele without its corresponding allele results in a heterozygous carrier state without clinical manifestations

Examples of autosomal recessive diseases: Nervous disorders such as spinal muscular atrophy Renal disorder such as infantile type of polycystic kidney Haematopoeitic disorders such as sickle cell anemia and thalassaemias Metabolic disorders such as cystic fibrosis, phenylketonuria, galactosaemia, alpha one anti-trypsin deficiency and haemochromatosis.

Sickle Cell Anemia Recessive Defective Haemoglobin yn RBCs Anemia (loss of blood cells) Damage to brain, heart, lungs Primarily in African Americans; 1/10 in US is a carrier

X-LINKED DISORDERS Definition: Types: Disorders resulting from a mutant gene existing in the X chromosome Types: May be recessive or rarely dominant:

X-linked recessive disorders: The abnormal (mutant) gene is of a recessive nature. Thus females are carriers and do not suffer from a clinical disease since the other allele is normal, while males suffer from a disease since the abnormal gene has no corresponding allele on the Y chromosome

Examples of X-linked recessive disorders: Skeletal disorders as Duchenne muscular dystrophy Haempoeitic disorders as hemophilia A&B Ocular disorders as color blindness Immune disorders as agammaglobuniemia Metabolic disorders as diabetes insipidus

Duchenne Muscular Dystrophy X-linked recessive Most Common in males 1/3500 Muscle Enlargement Dystrophin Protein that provides support for the cell; without it the cell enlarges and explodes

Haemophilia X-linked recessive Most Common in males “Bleeder’s Disease” Missing clotting factor Bleeding spontaneously and in joints Queen Victoria: descendents affected with hemophilia

X-linked dominant disorders (rare) The mutant gene is of a dominant nature, i.e. only one abnormal gene of the allele pair is sufficient to cause disease; therefore the disease affects both males and females Example: Vitamin D resistant rickets

CYTOGENETIC (CHROMOSOMAL) DISORDERS The normal human karyotype of somatic cells is 46 chromosomes including 44 (22 pairs) of autosomes and two sex chromosomes either XY (male) or XX (female) The normal human karyotype (44 XY or 44XX) is symbolized as 2n- diploid. The normal gamete (sperm or ovum) karyotype is symbolized as in 1n-haploid (22X or 22Y)

NORMAL KARYOTYPING

Chromosomal abnormalities include: Structural abnormalities Numerical (number) abnormalities

Numerical (number) abnormalities of chromosomes

Numerical (number) abnormalities: Euploidy: Euploidy refers to the normal number of chromosomes within the cell; for example the euploid number of chromosomes in a human cell is 46. Aneuploidy: Aneuploidy is defined as an abnormal number of chromosomes. Syndromes caused by an extra or missing chromosome are among the most widely recognized genetic disorders in humans.

Examples of syndromes with chromosome number abnormalities: Abnormal number of sex chromosomes: Klinefelter's syndrome: Male with karyotype 47XXY, characterized by atrophic testis, infertility and gynaecomastia Turner's syndrome: Female with karyotype 45X, characterized by atrophic ovaries, infantile external genitalia, underdeveloped breast, amaenorrhea, infertility, normal or subnormal mentality and may be congenital heart diseases

Klinefelter Syndrome Longer fingers and arms Scarce beard Sterile 1 in 1,100 births 47 chromosomes XXY only #23 Trisomy Nondisjunction Longer fingers and arms Scarce beard Sterile Delicate skin Low mental ability Normal lifespan

Klinefelter's Syndrome George Washington? No Children – Sterile? Dental Problems Height – Very tall for generation Still Inconclusive

Turners Syndrome 96-98% do not survive to birth No menstruation 1 in 5,000 births 45 chromosomes X only 96-98% do not survive to birth No menstruation No breast development Narrow hips Broad shoulders and neck

Turner's Syndrome Monosomy of Sex Chromosomes; XO female Infertile Dwarfism Some mental retardation Webbed Neck

Abnormal number of autosomes: Trisomy 21 ( Down syndrome): Karyotype: 47 XX or XY +21 Most common type of chromosomal disorders Incidence: 1:700 births Risk usually increases with maternal age

Down Syndrome Short, broad hands Stubby fingers Rough skin Impotency in males Mentally retarded Small round face Protruding tongue Short lifespan

Down's Syndrome Trisomy 21 Mild to severe mental retardation Distinct Facial Features Heart Defects Fingerprints – Sworl Most Common Birth Defect – 1/700 births Mother’s Age over 40 – 1/80 Problems during Oogenesis

Downs Syndrome - Trisomy-21 Simian Crease

Edwards syndrome: Karyotype: 47 XX or XY +18 Risk also increase with maternal age

Edward's Syndrome Trisomy 18 Elfin Appearance Low set ears Malformation of many organs – specifically heart/lungs “Blue Babies” due to lack of oxygen 90% die within first 6 months

Patau syndrome: Karyotype; 47XX or XY +13 Risk increase with maternal age

Patau's Syndrome Trisomy 13 Cleft Lip and Palate Polydactyl – more than ten fingers/toes 1/6000 births Most die within first year

Patau’s Trisomy Syndrome 1 in 14,000 births 47 chromosomes XY or XX #13 Trisomy Nondisjunction Small head Small or missing eyes Heart defects Extra fingers Abnormal genitalia Mentally retarded Most die a few weeks after birth Cleft palate

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