Genetic Basis of Diseases 4(1) PDF

GENETIC AND PAEDIATRIC DISEASES. 1. Developmental defects 2. Cytogenetic defects. 3. Single gene defects. 4. Multifactorial inheritance disorders. 5. Other diseases.  Developmental defects. Due to errors in morphogenesis during foetal life. The science dealing with t...

GENETIC AND PAEDIATRIC DISEASES. 1. Developmental defects 2. Cytogenetic defects. 3. Single gene defects. 4. Multifactorial inheritance disorders. 5. Other diseases.  Developmental defects. Due to errors in morphogenesis during foetal life. The science dealing with these anomalies is known as teratology. Certain chemicals, drugs, physical and biological agents implicated (teratogens). The defect is known as malformation.  Pathogenesis. Outcome may be:  Intrauterine foetal death.  Intrauterine growth retardation.  Functional defects.  Malformations. Effects of teratogens related to: Variable individual susceptibility to teratogen. Intrauterine stage at exposure- 1st trimester. Dose of teratogen. Specificity of developmental defect for specific teratogen  Classification i. Agenesis- complete absence of an organ. ii. Aplasia- absence of development of an organ with presence of rudiment or anlage. iii. Hypoplasia- incomplete development of organ. iv. Atresia- incomplete formation of lumen.  Examples: 1. Anencephaly-spina bifida complex. 2. Thalidomide malformations (phocomelia, seal limbs). 3. Foetal hydantoin syndrome. 4. Foetal alcohol syndrome. 5. TORCH complex( toxoplasma, rubella, cytomegalovirus and herpes simplex) during pregnancy 6. Congenital syphilis- Hutchison’s triad. Anencephaly Thalidomide malformations Baby with congenital CMV infection causing microencephaly Purpuric skin rash at birth from congenital Rubella infection  Malformations Polydactyly & Cleft Lip Severe Lethal Malformation syndactyly  Cytogenetic (karyotypic) abnormalities. Ova and sperms contain 23 chromosomes (haploid). All nucleated cells contain 23 pairs of chromosomes. Lymphocytes source for the study of chromosomes. Karyotyping is done by arresting the dividing cells in metaphase by colchicine.  ct Then cells spread on glass slide and staining them with Giemsa stain. Chromosomes classified according to the location of centromere:  metacentric  Submetacentric  Acrocentric  Chromosomal banding  Employed for the study of chromosomes.  Unique alternate dark and light bands. o G-banding ( Giemsa stain) o Q-banding ( quinacrine fluorescent stain). o R-banding- ( reverse Giemsa staining) o C- banding ( constitutive heterochromatin demonstration).  SPECTRAL KARYOTYPING  Numerical abnormalities of chromosomes 1. Haploid - a single set of each of the chromosomes characteristic of a species (23 in human). 2. Diploid - a double set (2n)= 46 chromosomes. 3. Euploid- any multiple (from n to 8n) of haploid number of chromosomes 4. Polyploidy- number of chromosomes which is a multiple of haploid number eg triploid or 3N ( 69 chromosomes). tetraploid (4N= 92 chromosomes). : occurs normally in megakaryocytes and dividing liver cells. : if in somatic cells of conceptus results in spontaneous abortion.  ct 5. Aneuploidy- number of chromosomes not an exact multiple of haploid number eg : hypodiploid or 2N-1 ( 45 chromosomes) = monosomy; : hyperdiploid or 2N+ 1 ( 47 chromosomes)= trisomy. Most common mechanism is nondisjunction (failure of separation in mitosis or meiosis).  ct – Non-disjunction during 1st meiotic division results into no chromosomes (nullisomic) – During 2nd meiotic division, one gamate with 2 identical chromosomes, 1 nullisomic, and 2 with normal chromosome number. – If during mitosis, mosaicism occurs – Anaphase lag- one chromosome lags behind.  Syndrome arising from chromosomal aberrations 1. Down’s syndrome (Trisomy 21). – 95 % of cases due to nondisjunction during meiosis. – Commonest chromosomal disorder and cause of mental retardation. – Incidence higher in mothers over 35 years. – Commonest cause is meiotic nondisjunction. – In 4 % of cases a translocation ( chrom. 21 to 22 or 14) Such cases are familial; inherited from one parent, a carrier of Robertsonian translocation. Clinical findings Severe mental retardation Mongoloid facial features (flat face,low- bridged nose, and epicanthal folds) Brushfield spots-speckled appearance of the iris Muscular hypotonia Broad short neck Palmar (simian) crease  Congenital heart defects Duodenal atresia ("double-bubble" sign) Edward syndrome (trisomy 18) Karyotype:47 XX or XY+ 18 Risk increases with maternal age Caused by nondisjunction Clinical findings Mental retardation Low set ears and micrognathia Congenital heart defects Overlapping flexed fingers Rocker-bottom feet  Klinifelter’s syndrome( 47XXY). Most common sex chromosome trisomy. Patients have testicular dysgenesis. Caused by meiotic nondisjunction Common cause of male hypogonadism Lab investigations i. Elevated FSH and LH ii. Low levels of testosterone Clinical findings Testicular atrophy Infertility due to azoospermia Eunuchoid body habitus High-pitched voice Female distribution of hair Gynecomastia Turner’s syndrome ( monosomy, X0, 45). Due to loss of X chromosome in paternal meiosis Common cause of female hypogonadism The second X chromosome is necessary for oogenesis and normal development of the ovary No Barr body present Clinical features Failure to develop secondary sex characteristics Short stature Atrophic "streaked" ovaries Primary amenorrhea & Infertility Webbing of the neck Congenital heart diseases  Structural abnormalities  During cell division, structural abnormalities of chromosomes may occur.  If during gametogenesis, transmitted to progeny (hereditary).  May produce mutation of somatic cells with no effect to some forms of cancer.  ct Structural abnormalities may be balanced or unbalanced. Balanced : no change in total number of genes or genetic material. Unbalanced: gene rearrangement with loss or gain of genetic material.  Translocations. Crossing over or exchange of fragment of chromosome. May occur between homologous or non- homologous chromosomes. 2 types: Reciprocal in 2/3 of cases: Robertsonian in 1/3.  Reciprocal translocation. Exchange of genetic material between 2 heterologous chromosomes. – Centromere not involved (acentric) – Occurs due to single breaks in both chromosomes. Exchange detected by banding technique. May be balanced (without loss of genetic material) or unbalanced.  ct Balanced reciprocal translocation :  more common.  Individuals phenotypically normal eg Philadelphia chromosome (46 XX, t(9;22). Unbalanced:  less common.  causes repeated abortions/malformations  Robertsonian translocation Less common. There is fusion of 2 acrocentric chromosomes at centromere with loss of short arms. Result is one very large and one very small chromosome. Phenotype may be normal but infertility or higher risk of malformed children.  Deletions. Loss of genetic material. May be terminal or middle portion of chromosome. Examples:  cri du chat syndrome( short arm of chromosome 5).  Several cancers  eg retinoblastoma(chr. 13),  Wilm’s tumour (chr. 11)  Inversion. A rearrangement involving breaks of single chromosome at 2 points. May be peri or para-centric. Not associated with any abnormality.  0000000000000000000000000 0000000000000000000000000 0000000000000000000000000 0000000000000000000000000 Others : 000000 Ring chromosomes Isochromosomes  SINGLE GENE DEFECTS Also called Mendelian disorders. Are a result of mutation of a single gene of large effects. Mutation in germ cells leads to inherited diseases to next progeny. Mutation of somatic cells a cause of cancer and congenital malformations.  Types of mutation i. Point mutation:  Substitution of a single nucleotide base by different base.  Results in replacement of one amino acid by another eg sickle cell anaemia. ii. Stop codon or nonsense mutation.  The protein chain is prematurely terminated or truncated.  The resulting protein is rapidly degraded.  ct iii. Frame shift mutation.  Insertion or deletion of 1 or 2 base pairs in DNA sequences.  Example in cystic fibrosis of pancreas. iv. Trinucleotide repeat mutations- amplification of sequence of 3 nucleotides.  Mendelian disorders. Diseases caused by single gene defect. Mutations may be:  Autosomal dominant.  Autosomal recessive  Sex linked. A single gene mutation may lead to phenotypic effects( pleiotropy). Conversely mutations at several genetic loci may produce same trait (heterogeneity).  Autosomal dominant disorders. Are manifested in the heterozygote state. One parent of index is usually affected. Both males and females are affected. Both can transmit the condition. When an affected person marries an unaffected one, every child has one chance in two of having the disease.  ct Some patients do not have affected parents. – Such patients owe their disorder to new mutations involving egg or sperm from which they were derived. – Their siblings are neither affected nor at increased risk of developing the disease. – Clinical features can be modified by reduced penetrance and variable expressivity. In many cases age of onset delayed.  Examples of autosomal dominant disorders. 1. Familial hypercholesterolaemia. 2. Adult Polycystic kidney disease. 3. Huntington’s disease. 4. Familial polyposis coli 5. Hereditary spherocytosis. 6. Marfan’s syndrome  Examples of Autosomal Dominant diseases 1.Connective tissue disease –e.g. Marfan’s syndrome 2. Adult polycystic kidney disease 3. Haemoglobinopathies – e.g. sickle cell anaemia, thalassemia 4. Familial hypercholesterolaemia – impared metabolism of cholesterol 5. Familial tumours –e.g. Familial polyposis coli, Neurofibromatosis Examples of autosomal Recessive diseases:- 1. Inborn errors of metabolism:-  Phenylketonuria  Alkaptonuria  Albinism 2. Lysosomal storage diseases:-  Glycogenosis  Lipidoses  ct iii. Endocrine;  Congenital adrenal hyperplasia. iv. Nervous system:  Neurogenic muscular atrophies  Friedreich ataxia.  Spinal muscular atrophy.  Sex (X) linked disorders All are X-linked. To date, no Y-linked disease known. Most are X-linked recessive. Are transmitted by heterozygous female carriers only to sons who are hemizygous for x-chromosome.  Examples of sex linked recessive disorders i. Musculoskeletal: Duchenne muscular dystrophy. ii. Blood: Haemophilia A and B. Chronic granulomatous disease. Glucose 6 dehydrogenase deficiency iii. Immune; agammaglobulinaemia iv. Metabolic: diabetes mellitus. Examples of X-linked diseases: 1. Haemophilia A (Factor VIIIC, classic haemophilia) 2. G-6PD deficiency 3. Diabetes insipidus 4. Red/Green colour blindness etc  Diseases with multifactorial inheritance Combined effect of genetic and environmental influences. Examples:  Cleft lip and cleft palate.  Pyloric stenosis.  Diabetes mellitus.  Hypertension  Congenital heart disease.  Peptic ulcer. MULTIFACTORIAL INHERITANCE These are inherited NEITHER as dominant NOR as recessive mendelian characteristics It is a combination of many genetic and non genetic factors:-  Systemic hypertension  Diabetes mellitus  Cleft lip and palate  Congenital pyloric stenosis. END