Inborn Errors of Metabolism BCH 451 Dr. Amina ElGezeery

Continuous Assessment Tests (CAT) Two Tests Marks Two Quiz Marks Final Marks Dates for CAT: – 1st CAT:Wed. …… 26 DhuAl-Qadah 1431 – 2nd CAT: Sat. ……… 7 Muharram 1432 Time: Lecture Room: B8/R 686

Ref. Books : Inborn Metabolic Diseases. By :J. Fernandes, J. Saudubary, G. van den Berghe. Harpers’s Biochemistry. By : Murray et all.

Inborn errors of metabolism (IEM) 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.

IEM mainly affect the biochemical pathways in body. They result from deficient activity of enzymes, cofactors or activators deficiencies or defective transport of compounds. So …

IRM 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.

Classification of Genetic Diseases Single Gene Disorders ( monogenic ). Chromosomal Disorders. Multifactorial Diorders. Mitochondrial disorders. Acquired Somatic Genetic Disorders (eg.cancer ).

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 7,000single gene disorders have been identified. May be: -Autosomal - - Sex linked

Ex. For Single Gene Disorders Sickle cell anemia. Thalassemia. Familial hypercholesterolemia.

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

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 is dominant. * Autosomal recessive inheritance, if the gene is recessive. * Codominant inheritance, if the two alleles are equally expressed in heterozygot.

Autosomal Dominant Inheritance -Autosomal dominant inheritance, if the gene is dominant. -The trait (characteristic, disease) appears in every generation. -The trait is transmitted by an affected person to half the children. -Unaffected persons do not transmit the trait to their children. -The occurrence and transmission of the trait is not affected by sex.

Examples of Autosomal dominant disorders - Familial hypercholesterolemia - Adult polycystic kidney disease - Dominant blindness

Autosomal Recessive Inheritance -The trait (characteristic, disease) is recessive. -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.

Punnetts quares howing 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.

X –Linked Inheritance - The gene is present on the X -chromosome. -The inheritance follows specific pattern. -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 -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

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. -The trait occurs at the same frequency in both males and females. -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 X Affected (Heterozygous ) mother. 2- Normal father X Affected (homozygous ) mother.

Result from defect in the number (i.e. Numerical disorders) or structure (i.e. Structural disorders)of chromosomes. The first chromosomal disorder was Trisomy 21 (Downs syndrome)and was recognized in These disorders are quite common and affect about 7/1000 live born infants. Account for almost half of all spontaneous first- trimester abortions.Do not follow a Pedigree pattern of inheritance. Chromosomal Disorders

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.

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.

Examples of Multifactorial disorders Diabetes Mellitus. Coronary heart disease. Cancer. Cleft lip/ cleft palate.

Multifactorial  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