Genetic Disorders 3: Genetic Disorders 3 Dra. Olga A. Gonzalez R.


Multifactorial Inheritance.: Multifactorial Inheritance. Result from the combined actions of environmental influences and two or more mutant genes having additive effects . The greater the number of inherited deleterious genes , the more severe expression of the disease.


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Multifactorial inheritance.: Multifactorial inheritance. The risk of expressing a multifactorial disorder is conditioned by the number of mutant genes inherited. The greater the number of affected relatives, the higher is the risk for other relatives. The rate of recurrence of the disorder is the same for all first degree of relatives.


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Multifactorial Inheritance. : Multifactorial Inheritance. The likelihood that both identical twins will be affected is significantly less than 100% but is much greater than the chance that both nonidentical twins will be affected. The risk of recurrence of the phenotypic abnormality in subsequent pregnancies depends on the outcome in previous pregnancies.


Multifactorial Inheritance.: Multifactorial Inheritance. Expression of a multifactorial trait may be continuous or discontinuous. Disease expression only when the combined influences of the genes and environment cross a certain threshold.


Cytogenetic Disorders. : Cytogenetic Disorders.


Chromosome Breakage Syndromes.: Chromosome Breakage Syndromes. Translocation:A segment of one chromosome is transferred to another. Balanced or reciprocal translocation Robertsonian Translocation ( Centric fussion) Isochromosomes: One arm of a chromosome is lost and the remaining arm is duplicated, resulting in a chromosome with two short arms or two long arms.


Chromosome breakage syndromes.: Chromosome breakage syndromes. Inversion: Involves two breaks within a single chromosome with inverted reincorporation of the segment. Deletion: Loss of a portion of a chromosome. Ring chromosome: A special form of deletion. When a break occurs at both ends of a chromosome with fusion of the damaged ends.


Disorders Involving an Extra Autosome.Down Syndrome. Trisomy 21.: Disorders Involving an Extra Autosome. Down Syndrome. Trisomy 21. Kariotype 47XX or XY +21. Most common of the chromosomal disorders. Most common cause of inherited mental retardation Incidence: 1 in 700 births. U.S.A. Risk increases with maternal age.


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Down Syndrome. Pathogenesis.: Down Syndrome. Pathogenesis. Meiotic nondisjunction (95%) Robertsonian translocation (4 %) Mosaicism due to mitotic nondisjunction during embryogenesis(1%)


Down Syndrome. Clinical Findings.: Down Syndrome. 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


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Down Syndrome. : Down Syndrome. Congenital Heart defects. Endocardial cushion defect Atriventricular canal Duodenal atresia 'double-bubble' sign Hirchsprung disease. Increased risk ( 15 -20 %) of acute lymphoblastic leukemia( ALL) Alzheimer disease ( by age 40 virtually all will develop Alzheimer disease. )


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Edward Syndrome. ( Trisomy 18): Edward Syndrome. ( Trisomy 18) Karyotype : 47XX or XY+18. Risk increases with maternal age. Caused by nondisjunction


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Edward Syndrome. Trisomy 18.: Edward Syndrome. Trisomy 18. Clinical findings. Mental retardation Low set ears and micrognathia Congenital heart defects. Overlapping flexed fingers Rocker bottom feet Very poor prognosis due to severe congenital malformations.


Patau Syndrome. Trisomy 13.: Patau Syndrome. Trisomy 13. Kariotype: 47XX or XY +13 Risk increases with maternal age. Caused by non disjunction


Patau Syndrome. Trisomy 13.: Patau Syndrome. Trisomy 13. Clinical Findings. Mental retardation Cleft lip and/or palate Cardiac defects Renal abnormalities Microcephaly Polydactily Very poor prognosis due to severe congenital malformations.


Disorders involving Sex Chromosomes.Klinefelter Syndrome.: Disorders involving Sex Chromosomes.Klinefelter Syndrome. Kariotype: 47XXY Caused by meiotic nondisjunction Common cause of male hypogonadism. Lab. Elevated FSH and LH Low levels of testosterone


Klinefelter Syndrome. : Klinefelter Syndrome. Clinical findings: Testicular atrophy Infertility due to azoospermia Eunuchoid body habitus. High-pitched voice Female distribution of hair Gynecomastia.


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Turner Syndrome. : Turner Syndrome. Karyotype 45XO Common cause of female hypogonadism The second X chromosome is necessary for oogenesis and normal development of the ovary. No Barr body present


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Clinical features. Turner Syndrome.: Clinical features. Turner Syndrome. Failure to develop secondary sex characteristics Short stature with widely spaced nipples Atrophic streaked ovaries Primary amenorrhea Infertility Cystic hygroma and webbing of the neck Hypothyroidism Congenital Heart disease Preductal coarction of the aorta Bicuspid aortic valve Hydrops fetalis.


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Hermaphroditism.: Hermaphroditism. DETERMINATION OF SEX. Karyotypic ( genetic) sex presence of a Y chromosome results in testicular development. Gonadal sex: Presence of ovarian or testicular tissue Ductal Sex: Presence of Mullerian (female) or Wolffian (male) duct adult derivatives. Phenotypic ( genital ) sex: external appearance of the genitalia.


True Hermaphrodite.: True Hermaphrodite. Definition: Presence of both ovarian and testicular tissue within an individual Genetic Sex: 46XX, 46XY, 45X/ XY mosaics Gonadal Sex. Ovary on one side and testes on the other. Ovotestes: A gonad with both testicular and ovarian tissue. Ductal Sex: Often mixed Phenotypic sex : Ambigous genitalia Exceptionally rare.


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Female pseudohermaphroditism: Female pseudohermaphroditism Genetic sex: Normal female( 46XX) Gonadal and ductal Sex: Normal female internal organs. Phenotypic sex : Ambigous or virilized external genitalia. Exposure of a female fetus to androgens in utero. Congenital adrenal hyperplasia Androgen producing tumors (ovarian Sertoli-Leydig cell tumors) Exogenous androgens


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Male pseudohermaphroditism.: Male pseudohermaphroditism. Genetic sex: Normal male ( 46 XY) Gonadal and ductal Sex: Testes present Phenotypic Sex: Ambigous or female genitalia Testicular feminization Most common cause Defect: Mutation of the androgen receptor ( Xq 11-12)


Triplet repeat mutations.: Triplet repeat mutations. Fragile X Syndrome Triplet nucleotide repeat mutations : Nucleotide sequence CGG repeats typically hundreds of thousands of times. Mutation occurs in the FMR-1 gene (familial mental retardation -1 gene) on X chromosome Xq 27.3


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Fragile X Syndrome: Fragile X Syndrome Clinical Presentation Mental retardation in affected males and 50% of female carriers. Elongated face with a large jaw Large everted ears Macro-orchidism Diagnosis: DNA probe analysis.


Huntington’s Disease. : Huntington’s Disease. Genetics: Triplet repeat mutation CAG of the Huntington gene produces an abnormal protein (Huntington) which is neurotoxic. Atrophy of caudate nucleus Clinical Presentation Early onset ( age range : 20-50) of progressive dementia. Choreiform movements.


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Mitochondrial Inheritance.: Mitochondrial Inheritance. Rare Many affect the neuromuscular System The expression of disorders is quite variable. Leber hereditary optic neuropathy . Bilateral loss of central vision (15-39 y.) MATERNAL INHERITANCE


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Genomic imprinting : Genomic imprinting Differential expression of genes based on chromosomal inheritance from maternal versus paternal origin Prader-Willi Syndrome. Deletion on paternal chromosome.15.q11,q13 Mental retardation Obesity Hypogonadism Hypotonia


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Angelman Syndrome “happy puppet” syndrome.: Angelman Syndrome 'happy puppet' syndrome. Deletion on maternal chromosome 15 q11,q13. Mental retardation Seizures Ataxia Inappropriiate laughter May play a role in Huntington’s disease,neurofibromatosisand myotonic dystrophy.


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