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Inborn Errors of Metabolism BCH 451 Dr. Amina ElGezeery Continuous Assessment Tests (CAT) • Two Tests --------------------------40 Marks • Two Quiz --------------------------10 Marks • Final----------------------------------50 Marks • Dates for CAT: – 1st CAT: …… Sat. 10-4-1433 – 2nd CAT: ……… Sat.29-5-1433 Time: 11-12 Lecture Room: Ref. Books : • Inborn Metabolic Diseases . J. Fernandes , J. Saudubary , G. van den Berghe . • Genetic in Medicine. Nussbaum R L , Mclnnes R and Willard H . Course Outline 1- Definition and classification of genetic disorders 2-Mode of inheritance 3- Gene structure , genetic code and gene mutation 4- Major histocompatibility genes 5- Disorders of carbohydrate metabolism 6- Disorders of amino acids and urea cycle enzymes 7- Disorders of lipoprotein metabolism 8- Lipid storage diseases 9- Disorders of purine and pyrimidine metabolism 4 Inborn errors of metabolism Inborn errors of metabolism (IEM) or inherited metabolic diseases are inherited disorders for a heterogeneous group of more than 500 pathologies originated from mutation of genes resulting in deficiency or absence of a protein, generally an enzyme, and loss of its metabolic function. • Inborn errors of metabolism ( IEM) or metabolic disorders are genetic disorders resulting from mutation in a gene , mainly encoding enzyme , which produce a block in normal course of metabolism . • IRM are monogenic diseases . • IEM mainly affect the biochemical pathways in body . • They result from deficient activity of enzymes , cofactors , activators or defective transport of compounds . Classification of Genetic Diseases • • • • • Single Gene Disorders ( monogenic ) . Chromosomal Disorders . Multifactorial Diorders . Mitochondrial disorders . Acquired Somatic Genetic Disorders (eg.cancer ). Definitions • Chromosome is the carrier of the genetic element . • Gene is ( the genetic element ) a sequence of • • • • chromosomal DNA that is required for the production of functional product (mRNA , polypeptide chain , rRNA , tRNA) Alleles are different forms, or variants, of a gene. Genotype is the particular set of alleles for all the genes carried by an individual. Wild type is the normal, non mutant allele. Phenotype is the observable expression of the genotype . Human Chromosomes • Chromosomes are double chromatide during cell division BUT it’s a single chromatide in the rest of cell cycle . So Genes are present in pairs • If the two alleles are simillar→ Homozygous • If the two alleles are different → Heterozygous • Somatic human cell has 46 chromosomes i.e 23 pairs . • 22 pairs are autosomes ( from No 1 to 22 ) . • One pair is sex chromosomes : XY in males XX in females . Genes on sex chromosomes are said to be sex – linked genes , X- linked and Y – linked . Genes on autosomes are said to be autosomal genes . Human Chromosomes • Autosomes = chromosomes 1-22 • Sex chromosomes = X and/or Y • Autosomes carry genes for all functions • Sex genes carry mostly genes for sex determination Single Gene Disorders •Caused by mutation in or around a gene. •Lead to critical errors in the genetic information. •Exhibit characteristic pedigree pattern of inheritance (Mendelian Inheritance) . •Occur at a variable frequency ranging from 1/500 to 1/200,000. •Over 7,000 single gene disorders have been identified . •May be: -Autosomal - Sex linked Ex . For Single Gene Disorders • Sickle cell anemia . • Thalassemia . • Familial hypercholesterolemia . Mode of inheritance of single gene disorders Sex Linked Autosomal Dominant Recessive X- Linked Y- Linked Codominant Dominant Recessive Autosomal Inheritance -This is the inheritance of the gene present on the Autosomes ( chr. 1-22). -Both sexes have equal chance of inheriting the disorder. -Three types: Autosomal dominant inheritance, if the gene gives its phenotype in heterozygous state. Autosomal recessive inheritance, if the gene gives its phenotype in homozygous state only . Codominant inheritance , if the two alleles are equally expressed in heterozygot . Autosomal Dominant Inheritance -The trait ( character , disease) occurs in heterozygous . -The trait (character, disease) appears in every generation. -The trait is transmitted by an affected parent to half the children. - The occurrence and transmission of the trait is not affected by sex. - Both males and females affected, and can pass on the trait with equal probability Examples of Autosomal dominant disorders - Familial hypercholesterolemia - Adult polycystic kidney disease - Dominant blindness Autosomal Recessive Inheritance -The trait expresses itself only in homozygous state -Unaffected persons (heterozygotes) may have affected childrens. -The parents of the affected child may be consanguineous. -Males and female are equally affected. - Not found in multiple generations Punnetts quare showing autosomal recessive inheritance (1) Both Parents Heterozygous: 25% offspring affected “Homozygous” 50% Trait “Heterozygous normal but carrier” 25% Norml Examples of Autosomal Recessive Diorders • • • • Phenylketonuria . Galactosemia . Alkaptonuria . Congenital deafness . Sex –Linked Inheritance -This is the inheritance of a gene present on the sex chromosomes. -The Inheritance Pattern is different from the autosomal inheritance. -Inheritance is different in the males and females. Y –Linked Inheritance -The gene is on the Y chromosomes. -Shows Holandric inheritance. i.e. The gene is passed from fathers to sons only. -Daughters are not affected. e.g. Hairy ears in India. -Since male are Hemizygous, the condition exhibits itself whether dominant or recessive. Y-Linked Inheritance • Traits on the Y chromosome are only found in males, never in females. • The father’s traits are passed to all sons. • Dominance is irrelevant: there is only 1 copy of each Y-linked gene (hemizygous). X –Linked Inheritance • The gene is present on the X -chromosome. • Each son has a 50% chance of receiving the mutant gene from the mother • Daughters also have a 50% chance, but will also inherit a normal X from the father . • Variable phenotype in carrier daughters, because of random X inactivation • Since males have one X chromosome, and are hemizygous. ( heterozygot only ) Females have 2 X chromosomes, they may be homozygous or heterozygous. • These disorders may be : recessive or dominant. X –Linked Recessive Inheritance X –Linked Recessive Inheritance -The incidence of the X-linked disorders is higher in male than in female. -The trait is passed from an affected man through all his daughters to half their sons. -The trait is never transmitted directly from father to sons. -An affected women has all affected sons and carrier daughters - Ex . Glucose 6-phosphate dehydrogenase deficiency . Albinism (Ocular). Lesch–Nyhansyndrome. Hemophilia A. Hemophilia B. E.g. Glucose -6- phosphate dehydrogenase deficiency Normal female, affected male All daughters carriers “not affected, pass the disease to 50% of their sons”. X-Linked Dominant Disorders • -The gene is on X Chromosome and is dominant. • Affected females are about twice as common as affected males ( homo. And heterozygotes), but affected females typically have milder (although variable) expression of the phenotype. • Hemizygous male and heterozygous females express the disease. Punnett square showing X –linked dominant type of Inheritance: (1) Affected male and normal female: All daughters affected, all sons normal. • What are the percentage of normal and affected children in the following matting ? 1- Normal father and Affected (Homozygous ) mother with recessive autosomal disease . 2- affected father with dominant X-linked disorder and normal mother. 3- Affected father with Y-linked disease and a normal mother . Mitochondrial Disorders * The defective gene is present on the mitochondrial chromosomes. * Effect generally energy metabolism. * Effect those tissues more which require constant supply of energy e.g muscles. * Shows maternal inheritance:-affected mothers transmit the disorder equally to all their children. * affected fathers do not transmit the disease to their children. Mitochondrial DNA • In the human mitochondria the chromosomes are present as 10 circular double helices of DNA. • They are self replicative. • Contain: 16,596bp, genes for 22tRNAsand 2 types of ribosomal RNA required for mitochondrial protein synthesis. • They also have genes for 13 polypeptides, involved in cellular oxidative phosphorylation. • Both strands of DNA are transcribed and translated. Mitochondrial DNA cont…. • The mitochondrion divides by simple division during cytokinesis , the mitochondria are randomly distributed to the 2 daughter cells . • When the cell containing a mixture of normal and mutated mtDNA divides , its daughter cells may contain only normal mtDNA , only mutant mtDNA or a mixture of both. • The phenotypic expression of a mutation in mtDNA depends on the relative proportions of normal and mutant mtDNA , so the variability of expression is a feature of mitochondrial disorders . Mitochondrial DNA cont…. • The unique feature of mtDNA is its maternal inheritance because the ovum is well supplied with mitochondria , but the sperm contains few , and even those few do not persist in offspring . • So the mother transmits her mtDNA to all her offspring . Mitochondrial Genes • Mitochondria are only inherited from the mother. • If a female has a mitochondrial trait, all of her offspring inherit it. • If a male has a mitochondrial trait, none of his offspring inherit it. • Note that only 1 allele is present in each individual, so dominance is not an issue. • Ex. Lebers hereditary optic neuropathy . Multifactorial inheritance • Inheritance controlled by many genes with small additive effects (polygenic) plus the effects of the environment • Clinical clue: One organ system affected Multifactorial Disorders • •Result from interaction between environmental and genetic factors. •Often polygenic in nature, no single error in the genetic information.( sum of the effects of many genes , each gene has a small effect ) • •Environmental factors play a significant role in precipitating the disorder in genetically susceptible individuals. •Tend to cluster in families. •Do not show characteristic pedigree pattern of inheritance. • Are not inherited in Mendelian fashion Examples of Multifactorial disorders • • • • Diabetes Mellitus . Coronary heart disease . Cancer . Cleft lip/ cleft palate . Risk factors for coronary artery disease Uncontrollable (but identifiable) Family history (genetics) Age Male sex Potentially controllable or treatable Fatty diet Hypertension Smoking High serum cholesterol Low serum HDL High serum LDL Stress Insufficient exercise Obesity Diabetes Multifactorial Disorders Cleft lip and palate Caused by a combination of genetic predisposition and environmental influences Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X-linked inheritance patterns Chromosomal Disorders •The first chromosomal disorder was Trisomy 21 (Downs syndrome)and was recognized in 1959. •These disorders are quite common and affect about 7/1000 live born infants. •Account for almost half of all spontaneous firsttrimester abortions. •Do not follow a Pedigree pattern of inheritance. Chromosomal Abnormalities I - Numerical abnormalities ;change in chromsome number : 1- Aneupliody ; increase or decrease in one or more of chr. 2n+1 or 2n-1 … 2-Polypliody : increase in a whole set of chr. 3n ,4n,….. II - Structural abnormalities ; change in chromosome structure . Aneuploidy • The variation in chromosome number not involved the whole set . • Most commonly involve increase or decrease in one chromosome . • May be in autosomes or sex chr . • The main cause is non disjunction during gametogenesis . • Trisomy : increase in one chr. (47 chr.) • Monosmy : decrease in one chr. (45 chr.) • Tetrasomy : increase in two chr.(48 chr) Aneuploidy • Trisomy: results from fertilization between one normal gamete & one gamete that contains an extra chromosome. • In Humans: Autosomal Trisomy usually results in spontaneous abortion. • The only autosomal trisomies seen in live births are trisomy 13, 18 and 21. • Trisomosy 21 (Down Syndrome) is the only autosomal trisomy that allows survival until adult hood. 24 23 47 Causes of Aneuploidy • The main cause of aneuploidy is non-disjunction . • Non-disjunction ( ND ) : is the failure of a pair of chromosomes to separate ( or associate ) during cell division resulting in unequal distribution of the chromosomes between the two daughter cells . • The most common cause of aneuploidy is ND in meiosis in females . Common Sex Chromosome Anuploidy • Turner Syndrome (female) 45,XO • Trisomy X 47, XXX (female) • Klinefelter Syndrome 47,XXY (male) • Extra “Y” chromosome 47,XYY (male) Polyploidy • Presence of additional set of chromosomes ; 3n ,4n , 5n … • Origin – Failure of the spindle mechanism after the chromosomes have been duplicated which result in 2n gamete . – Multiple sperm fertilize an egg • Polyploidy is present in certain cells of the body, some liver cells , and frequently seen in the chromosomes of tumor tissues . Triploidy • • • • Complete extra set of chromosomes ,3n; 69 chromosomes . Most common form of human polyploidy . Mostly miscarriages, 15-18% of spontaneuos abortions Approximately 75% have two sets of paternal chromosomes, probably due to polyspermy , fertilization by two sperms . • Two types: - Digynic ; the extra chromosomal set is maternal. - Diandric ; the extra set is paternal . • Fetal wastage skeleton more than cephalic, 2% survive to be recognized • Genital and CNS abnormalities Types of Structural Chromosomal abnormalities • Structural abnormalities either : * Balanced (usually normal phenotype) : - Translocations - Inversions * Unbalanced (abnormal phenotype) : – Deletions – Duplications – Insertions – Rings – Isochromosomes Crossing Over • Crossing over is the exchange of genetic material between homologous chromosomes leading to increased genetic variations . • During miosis , the pair of homologous chromosomes should be paired exactly so that each gene should face the homologous gene in the other chromosome , so the exchanged material is equal . Unequal Crossing Over Deletions Isochromosome Ring chromosome Duplications Robertsonian translocation Inversions