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Genetic Disorders

Genetic Disorders. Etiolgy of Mental Retardation Syndromes with Mental Retardation. Mental Retardation.

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Genetic Disorders

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  1. Genetic Disorders Etiolgy of Mental Retardation Syndromes with Mental Retardation

  2. Mental Retardation Mental retardation is a particular state of functioning that begins in childhood and is characterized by limitation in both intelligence and adaptive skills (daily living, communication, social).

  3. Classification of MR

  4. Specific Causes of Mental Retardation

  5. The Diagnostic Process:Clinical Evaluation • Clinical history, prenatal and birth history • birth measurements extremely important • Family pedigree • 3-generation, learning problems, psychiatric disorders, autism, mental retardation • Physical and neurological examination • assess minor anomalies, growth, development

  6. Major categories of genetic disorders include; • Chromosomal-Aneuploidy,Deletions, Duplications/Insertions • Single Gene-Autosomal Dominant, Recessive, X-linked -Nonmedelian inheritance ( Triplet repeat disorders, Imprinting, Mitochondrial ) • Multifactorial – central nervous system abnormalities

  7. Diagnostic Tests • Chromosome analysis • Molecular analysis

  8. Normal Female Karyotype

  9. Normal MaleKaryotype

  10. Down Syndrome

  11. Trisomy 21—Down Syndrome • Most common chromosomal abnormality • Most common cause of mental retardation • 1:700 • Associated with maternal age • 1/625 at 33 • 1/30 at 45

  12. Trisomy 21—Down Syndrome Clinical Features • Typical facial features • Flat face, upslanting palpebral fissures, epicanthus, • Smian crease (%45) – sandal gap (%50) • Atrioventricular septal defect (Endocardial Cushion Defect) most common !!! • VSD, PDA • Growth and Mental Retardation • Hypotonia

  13. Trisomy 21—Down Syndrome • Hearing problems • Duodenal Atresia • Acute Lymphoblastic Leukemia • Hypothyroidy • Diabetes • Immune Deficency • Early Alzheimer Dz

  14. Trisomy 21—Down Syndrome • 94% Trisomy 21 (regular type) 47,XX,+21 • 4% Robertsonian Translocation (inherited form) 46,XX,rob(14;21),+21 • 1-2% Trisomy 21 Mosaicism 46,XX/47,XX,+21 Attention !!!Mosaic froms don’t mean mild MR. Mosaic trisomy 21 can be more severe than other forms.

  15. Regular type

  16. Robertsonian translocation (inherited type)

  17. Mosaic type

  18. Trisomy 21—Down Syndrome • Down Syndrome can be diagnosed 95% at clinical level. • Karyotype analysis is important for genetic counseling of recurrence risk. • Recurrence risks for regular type and mosaic forms are lower than 1 %. • Recurrence risk for Down syndrome due to robertsonian translocation is much higher. (10-15 %)

  19. Edward’s Syndrome

  20. Trisomy 18-Edward’s Syndrome • Incidende 3/1000 • Head and Face • Microcephaly, prominentocciput, micrognathia, cleft lip and palate • Chest • Congenital Heart Disease, Narrow chest and Short Sternum, Small and widely spaced nipples • Extremities • Limited hip abduction, overlapping fingers, rocker bottom feet. • General • Severe developmental delay and growth retardation. • Only 5% live beyond 1 year.

  21. Patau Syndrome

  22. Trisomy 13-PatauSyndrome • Incidence 1/5000 • Head and Face • Scalp defects, microcephaly • Microphthalmia, • Cleft lip and palate (60-80%), • Holoprosencephaly • Chest • Congenital Heart Disease 80% (VSD, PDA, and ASD) • Abdomen • Omphalocele • Extremites • Overlapping fingers and toes, polydactyly • General • Severe developmental delay and mental retardation, only 5% live longer than 6 months.

  23. Prenatal Diagnosis • Screening tests for common aneuploidies ; 1-First trimester screening: Nuchal translucency + biochemical parameters (hCG+PAPP-A) 2-Second trimester screening (triple test ) Only biochemical parameters (hCG,AFP,E3) • If the risk above the cut-off value (>1/250) , we can offer invasive prenatal diagnosis such as chorion villus biopsy or amniocenthsis or cordocenthesis.

  24. Chromosomal deletion

  25. Chromosomal Deletions (and microdeletions)

  26. 5p deletion Syndrome • Best known deletion is at 5p-, Cri du Chat • Characteristic cry, hypotonia, microcephaly, round face, hypertelorism, high and flat nasal bridge, high arched palate and mental retardation. • Prognosis- 10% mortality in first year of life then a normal life span. • Other common deletions; • 1p-,4p-, 5p-, 9p-, 11p-, 13p-, 18p-, 21q-

  27. Chromosomal Microdeletion Microdeletions are small chromosomal deletions which can not be detected by convetional karyotype analysis. (only high resolution banding procedures or FISH) These deletions produce syndromes that are usually clinically recognizible.

  28. Williams Syndrome • Chromosome 7q11.23 • Round face with full checks, • Thick lips • strabismus, • supravalvular aortic stenosis, • friendly personality, • hyperactivity • varying degrees of • mental retardation (IQ 41-80)

  29. Velocardiofacial-DiGeorge Syndrome- Chromosome22q11.2 • conotruncal anomalies (tertrology of fallot), • hypoplasia or agenesis of the thymus and parathyroid gland resulting in frequent infections and hypocalcemia, • hypoplasia of the auricle and external auditory canal, • cleft palate, short stature, • behavior problems.

  30. Miller-Dieker Syndrome Chromosome 17p13.3 • Lissencephaly • Microcephaly • Severe mental retardation and developmental delay • Hypotonia

  31. Prader-Willi Syndrome Paternaldeletion of Chromosome15q11q13 • Mental retardation • Obesity • short stature • small hands and feet • Typical facial features • Round face • Almond shape eyes • Small chin

  32. Angelman Syndrome Maternal deletion of chromosome 15q11q13 behaviourlike excessive laughter, apparent happiness with tremulous movements gait ataxia (lack of coordination of muscle movement)

  33. Genomic Imprinting Two copies of most genes are functionally equivalent but in a small number only one the pair is transcribed. Therefore, the active gene will be inherited from a specific parent and the other copy is silenced by methylation- this is Genomic imprinting

  34. Fragile X • Most common form of inherited MR • 1 in 1,200 males • Single gene disorder but nonmendelianinheritance • Caused by increased CGG repeats of FMR1 gene on X chromosome(triplenucleotiderepeatdisorder) • Premutation50-200 repeats (not affected) • >200 are affected individuals • 50% of carrier females have some developmentaldelay

  35. Fragile X • Males affected more severely • Males have moderate MR, • characteristic face; • Elongated face • Flattened Nasal Bridge • Protruding Ears large testicles, joint mobility • Girls may have mild MR

  36. Behavior in Fragile X Hyperactivity, impulsivity Social anxiety Poor eye contact Self-injury, usually hand-biting in response to anxiety or excitement Delayed imitative and social play Stereotyped and repetitive behaviors 1 in 3 with Fragile X syndrome have autism

  37. Rett syndrome • Neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. • Hypotonia is usually the first symptom. • As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact.

  38. Rett syndrome • Caused by change in MECP2 gene on X chromosome - insufficient amounts or structurally abnormal forms of the protein are formed – Mutation found in about 80% • X-linked dominant • Affects females almost exclusively. • 1% of children with autism have MECP2 gene change.

  39. Mitochondrial Inherited Diseases • Mitochondrial diseases are a clinically heterogeneous group of disorders that can be caused by mutationsof nuclear or mitochondrial DNA (mtDNA). Often present with prominent neurologic and myopathic features. MELAS- Myopathy, Encephalopathy, Lactic Acidosis, and Stroke like episodes. LHON - Subacute bilateral visual failure, Dystonia, Cardiac pre-excitation syndromes MERRF- Myoclonic epilepsy associated with ragged red fibers. Kearns-Sayre Syndrome- ophthalmoplegia, pigmentary retinopathy, and cardiomyopathy.

  40. Neurocutaneous Syndromes • Familial/ primitive ectoderm • All AUTOSOMAL DOMINANT • Neurofibromatosis I/II • Tuberous Sclerosis • Sturge-Weber • Von Hippel-Lindau • Ataxia Telengiectesia • Linear Nevus Syndrome • Hypomelanosis of Ito • Incontinentia Pigmenti

  41. Environmental factors • Infectious agents • Radiation • Chemical Agents • Hormones • Maternal Disease • Nutritional Deficiencies • Hypoxia

  42. Infectious Agents Rubella • Malformations of the eye • Cataract (6th week) • Microphthalmia • Malformations of the ear (9th week) • Congenital deafness • Due to destruction of cochlea • Malformations of the heart (5th -10th week) • Patent ductusarteriosis • Atrialseptal defects • Ventricular septal defects • May be responsible for some brain abnormalities • Mental retardation • Intrauterine growth retardation • Myocardial damage • Vascular abnormalites • Incidence • 47%- during 1st four weeks • 22% - 5th – 8th weeks • 13% - 9th – 16th week

  43. Infectious Agents Cytomegalovirus • Malformations • Microcephaly • Cerebral calcifications • Blindness • Chorioretinitis • Kernicterus (a form of jaundice) • multiple petechiae of skin • Hepatosplenomegaly • Mother asymptomatic

  44. Radiation • Teratogenic effect of ionizing radiation well established • Microcephaly • Skull defects • Spina bifida • Blindness cleft palate • Extremity defects • Direct effects on fetus or indirect effects on germ cells • May effect succeeding generations • Avoid X-raying pregnant women

  45. Drugs Thalidomide • Antinauseant & sleeping pill • Found to cause amelia & meromelia • Total or partial absence of theextremities • Intestinal atresia • Cardiac abnormalities • Many women had taken thalidomide early in pregnancy (in Germany in 1961) Anticonvulsants • Diphenylhydantoin (phenytoin) • Craniofacial defects • Nail & digital hypoplasia • Growth abnormalities • Mental retardarion • The above pattern is know as “fetal hydantoin syndrome” • Valproic acid • Neural tube defects • Heart defects • Craniofacial & limb anomalies

  46. Alcohol Relationship between alcohol consumption & congenital abnormalities • Growth deficiency Disproportional low weight to height • Craniofacial abnormalities • Short palpebral fissures • Hypoplasia of the maxilla • Limb deformities • Cardiovascular defects • Ventricular septalabnormalites • Structural brain abnormalities • Head circumference < 10% (microcephaly) • Mental retardation

  47. Fetal Alcohol Syndrome

  48. Cigarette Smoking • Has not been linked to major birth defects • Smoking does contribute to intrauterine growth retardation & premature delivery • Some evidence that is causes behavioral disturbances

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