1. Genetics in medicine, genetic counselling, prevention and treatment of hereditary diseases
MUDr. S. Sytařová
Lecture No. 442
Course: Heredity

2. Genetic counselling

3. Clinical genetics
- diagnostics, complex care, ev. treatment of patients with hereditary disease
- focus not only on individual patient, but on whole family
- main goal: prevention of genetic diseases

4. Genetic counselling
= process of communication with whole family focused on problems of occurence or reccurence risk of genetic disease in family
Tasks: diagnosis, prognosis for patient, risks for other family members, treatment possibilities, prevention

5. Indication for genetic couselling
- known or suspected genetic disease in patient or his family
- occurence of inborn defect or mental retardation
- advanced maternal age (over 35 years)
- atypical results of prenatal screening
- familial occurence or early onset of cancer
- repeated spontaneous abortions, infertility
- exposition of teratogene during pregnancy
- chronic disease in woman planing gravidity
- consanguinity

6. Genetic counselling
- detailed anamnesis including family and clinical information
- forming pedigree
- indication of genetic diagnostic examination, prenatal dg.
- other possibilities of examination, care and treatment
- examination of other persons in risk in family
- providing sufficient amount of information, careful explanation of problematics, psychology

7. Nondirective counselling Geneticist just advices further procedures, patient himself decides for undergoing the examination, ev. alternative method. Patient´s informed agreement is required for examination of his genetic material.

8. Hereditary diseases - monogenic – mendelian heredity
- polygenic – multifactorial
- chromosomal aberrations
- mitochondrial
- cancer diseases – somatic mutations

9. Methods of diagnosis and prognosis assesment
Genealogic (pedigrees) – monogenic heredity type assesment, correct diagnosis, risk calculation for other family members, presymptomatic diagnosis, possibilities of treatment and prevention
Population (epidemiologic) – empiric risks of polygenic diseases, disease frekvencies in population, sex ratio of affected, age of disease onset, frekvency of heterozygots
Dysmorphologic examination – isolated inborn defect or multiple defects

10. Examination Cytogenetical – karyotype, chromosomal aberrations
Postnatal – chromosomes of peripheral blood lymphocytes
Prenatal – AMC, CVS, fetal blood
Biochemical – assesment of metabolites, concentration of metabolites, hormons, enzyme activities – from blood, urine
Prenatal, postnatal screening
Molecular genetic – detection of mutations, prenatal, postnatal (RFLP, PCR)

11. Inborn defects
Malformation- morphologic defect resulting from abnormal
development ( cleft lip)
Disruption - breakdown or interference with originally normal developmental process by trauma, teratogen … (deformity of extremities caused by thalidomide)
Deformation - abnormal form, shape, position caused by
mechanical forces (compression of fetus in
oligohydramnion)
Dysplasia abnormal organisation of cells into tissues
(achondroplasia)

12. Cause of inborn defects
Malformation, dysplasia – monogenic, chromosomal and multifactorial
Disruption – sporadic, environmental factor

13. Multiple anomalies
Sequence = multiple anomalies derived from single anomaly
(e.g. Potter sequence = renal agenesis → oligohydramnion → fetol compression → flattened face, abnormality of extremities, pulmonary hypoplasia)
Syndrome = multiple anomalies independent, pathogenically related
(e.g. phenylketonuria)

14. Potter sequence

15. Teratogenesis
= disturbances in prenatal development leading to origin of inborn defects

16. Teratogenesis Embryotoxic effect death malformation growth retardation
disorder in function
Sensitivity to teratogenes:
genotype of mother + embryo
type of teratogene and dose
permeability through placenta (do daltons)
period of impact

17. Teratogenes:
Physical
Chemical
Biological
Maternal factors

18. Physical: Diagnostic irradiation
RTG untill 10th day after conception with more than 100mSV – letal effect
Later more than 100mSv – PMR, inborn defects
Belly examination
Outside uterus less than 20mSv – no effect
More than 20 mSV – consultation with radiologist
More than 100 mSV- reason for ending gravidity, risk of inborn defects more than 50%
Examination with radioisotops I 121
SA, IUGR, defects of CNS and eyes

19. SONO, MRI – safe methods
CT – not recomanded
Hypertermia (first six weeks of gravidity)
Hot bath, sauna – 3x higher risk of inborn defects
Fever >38.5oC > 1 day
SA, IUGR, defects of CNS, MR, facial dysmorphia
hypotonia, hypertonia, NTD
Mechanical causes:
Uterus myomatosus
Amnional bands

20. Food, medicines, drugs A not likely (clinical studies negative)
B less likely
(no risk in animals, not known in people)
(risk in animals, not proved in people)
C (risk in animals or not known, not known in people)
D proved risk, reconsider indication
X contraindication

21. Proved teratogenes in Ist trimester:
Thalidomid ( )
Anti-emetic, sedative, hypnotic
Reductional limb deformities
day ( cases)
1998 permited again:
malignities, leprosy, Crohn disease, skin TBC, AIDS

22. A vitamine and its analogs:
defects of CNS, craniofacial structures, auditory apparate, hearth, limbs

23. Warfarin bone deformities, chondrodysplasia punctata, CNS defects

24. Diethylstilbestrol
Years , prevention of SA
Risk of breast ca 40% higher in users
Daughters: ca of vagina and cervix uteri, reduced fertility, 2-3x higher risk of premature climacterium
Sons: infertility and genital defects
Cytostatics - (fluoruracil, methotrexate, cyclophosphamide): cardiopathia, osteopathia, spina bifida and other defects

25. Other risky medicaments

26. Anticonvulsives:
Fetal hydantoine syndrome
mental retardation
hypoplasia of middle face
cleft face defects
limb defects

27. Fetal valproate syndrom
craniofacial anomalies
cleft face defects
disturbanes in neural tube development
inborn hearth defects

28. ACE inhibitors:
trimester: risk of inborn hearth defects 3,7x higher, other defects 2,7x higher
II. and III. trimester: hypotension, reduced renal flow, oligouria,renal dysgenesis, oligohydramnion, pulmonal hypolasia, craniofacial deformation, IUGR
Wet-nursing – caution in first weeks especially with premature babies - hypotension
Antagonists of angiotensinu II (sartans) – not recomanded
salicylates: higher risk of bleeding and SA (breaks effect of prostaglandines), elongation of gravidity, hearth defects, NTD, limb defects

29. Tetracycline ( after 20th week):
distubance in development of bones and teeth

30. Drugs: Caffeine: Cigarettes: SA, IUGR Cocaine:
> 4 cups a day –
Lower birth weight
Premature childbirth
Cigarettes:
SA, IUGR
Cocaine:
SA, hearth defects, urogenital defects
LSD: SA, IUGR

31. Fetal alcohol syndrome:
Alcohol: 3/4 women, 1/3 till 3rd month of gravidity, 16% even later
Slower metabolism!
Lower birth weight
Fusion of gyri, MR ( IQ 50 – 80 )
Short eyelids, epicantus, microphtalmia
Wide nose root
Long philtrum
Narrow upper lip
Hearth defects
(dose lower than 28g – low risk)

32. Fetal alcohol syndrome:

33. Biologic: 1. viruses: Varicela zoster:
microcephalia, MR, cataracta, chorioretinitis,
Reduction limb deformities, muscular atrofphy
Herpes: SP, IUGR, eye defects
Influenza viruses: NTD
Hepatitis viruses: biliar atresia, chronic hepatitis
Coxackie: pancarditis, memingoencefalitis
HIV : imunodeficiency, dysmorphia

34. Rubeolla
Vaccination!
mikrocephalia, MR, hearth defects, cataracta, deafness

35. CMV infection microcephalia, deafness, poliomyelitis,
chorioretinitis, hepatosplenomegalia

36. 2. bacteria:
Treponema pallidum:
IUGR, chorioretinitis
bone and teeth deformities

37. 3. protozoa: Toxoplasma gondii: hydrocephalus, microcephalus,
chorioretinitis, blindness, MR
Plasmodium malarie : IUGR

38. Maternal factors: A. Nourishment: Folic acid : NTD ( 0,4-4mg/den )
Calcium, vitamin D : rachitis, hypocalcemia, tetania
Iodine : struma, MR

39. B. Maternal diseases: Diabetes mellitus
SA, IUGR, hearth defects(3x), renal and limb defects, sy. of caudal regresion, NTD, holoprosencephalia
Phenylketonuria
SA, IUGR, microcephalia , MR, hearth defects, facial dysmorphia
Hypo(hyper)thyreosis
SA, growth retardation

40. Prevention of genetic disorders

41. Prevention Primary prevention Secondary prevention
– prevention of disease origin
Secondary prevention
– prevention of birth of affected child
(Tertiary prevention
– prevention of disease complications)

42. Primary prevention
= set of arrangements, that shall prevent genetic disease origin or multifactorial inborn defect
Methods:
- family planning, reproduction in optimal age
- restriction of reproduction (anticonception, sterilisation)
- preconceptional care

43. Preconceptional care - gynecologic care
- adjustment of healthy state and hormonal dysbalance
- healthy lifestyle
- healthy food with enough vitamines (folic acid)
- protection against teratogenes, mutagenes, infections
= influencing of environmental factors, prevention of multifactorial defects or diseases

44. Secondary prevention
= prevention of birth of child with serious genetic defect or disease – care for mother during pregnancy
- prenatal screening
- invasive methods
- interruption

45. Screening in medicine
Screening method = inexpensive, suitably reliable method useful for examination of larger populations
– selection of subpopulations for further diagnostics only (orientational examination)
Goal – early diagnossis of disease with possiible treatment, prevention, ev. influencing of reproductional behavior

46. Prenatal screening Combined screening in I. trimester (11 – 13 week)
- biochemical markers: hCG, PAPP-A
- ultrasound markers: nuchal translucency (NT), nasal bone, omphalocoele, megavesica, abnormalities in ductus venosus flow measure, tricuspidal regurgitation

47. Healthy child Increased backhead thickness
Nuchal translucency
Ultrasound examination done between and 13+6 week of gravidity /in first trimester/, thickness of liquid in backhead area of child is measured /NT/.
Healthy child Increased backhead thickness

48. Prenatal screening
Biochemical screening in II. trimester (16 – 18 week)
„triple test“ - AFP, hCG, uE3
AFP = risk of neural tube defects
AFP, hCG, uE3 = risk of DS

49. Ultrasound screening in II. trimestru (18 – 22 week)
Prenatal screening
Ultrasound screening in II. trimestru (18 – 22 week)
- number of foetuses, vitality, biometry, pregnancy duration, proportionality of foetus, indirect marks of inborn defect (growth retardation, growth dysproportionality, various ultrasound markers, amniotic fluid amount, movement activity), direct identification of inborn defects

50. Affection risk assesment → risk 1:250 (350) - invasive examination
Risk according to maternal age, week of pregnancy, biochemical marker values from maternal blood, ultrasound abnormalities, mother´s weight
→ risk 1:250 (350) - invasive examination

51. Maternal age and risk of trisomy 21

52. Invasive prenatal methods
AMC amniotic fluid cells examination week
CVS chorionic villi cells examination week
Fetal blood from umbilical cord after 20 week

53. Amniocentesis (AMC) - examination of foetal cells from amniotic fluid
- long-term cultivation (14 days), cells grow in colonies on bottom of special bottle, cytogenetical analysis
- safe, reliable investigation, as a day case
(risk 0,5-1 %)
- early AMC (7 – 12 week) – higher risk (2 – 5 %)
- possibility of detection of most frequent trisomies and gonosomal abnormalities in 3 days

55. Amniotic cells colony

56. Chorionic villi samples (CVS)
- early method
- biopsy of vilous chorionic tissue (foetal membranes)
- direct method – villi surface cells
indirect method – log-term cultivation of internal villi cells
- risk cca 1%
- cca 2 % ambiquous results (extraembryonal tissue) – necessary to prove with other method (AMC)

57. Cordocentesis - umbilical cord punction, foetal blood taking
- short-time cultivation (2 days)
- possibility of examination of other parametres (biochemical, moleculary genetical etc.)
- higher risk (2 – 5 %)

58. Indication of invasive prenatal examination:
advanced maternal age ≥ 35let
abnormal biochemical screening
abnormality on ultrasound
parent – carrier of balanced CHA
psychologic
molecular diagnostics of disease

59. Neonatal screening - examinaton of dry blood drop from child´s heel
- 13 diseases in CZ – mostly metabolic
- goal – early detection of disease and possibility of medical influence of complications
- e.g. diet in phenylketonuria

60. Presymptomatic screening
Other screening possibilities
Presymptomatic screening
- detection of disease before its onset
- e.g. breast cancer, colon cancer in individuals with predisposition
- Huntington´s disease – problematic (no possible treatment, onset after reproduction, psychiatric problems in tested individuals)

61. Other screening possibilities
Detectin of individuals in risk
- screening of carriers (AR diseases)
- e.g. thalassemia in Sardinia
- screening of CF heterozygots in CZ?

62. Treatment of genetic diseases:
- restriction of potentionally toxic enviromental agents
- dietary therapy (phenylketonuria, hypercholesterolemia)
- replacement of deficient product
(antihemophilic factor, vitamin D)
- induction of enzyme by medicaments
(barbiturates in nonhaemolytic icterus)
- transplantation of organs (lungs - CF, hepar – Wilson)
- removal of organs (colon – fam. polyposis coli)
- operation (heart disease)

63. Thank you for your attention.