Genetics in medicine, genetic counselling, prevention and

treatment of hereditary diseases

MUDr. S. Sytařová

Lecture No. 442

Course: Heredity

Genetic counselling

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

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

Indicationfor 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

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

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.

Hereditary diseases

- monogenic – mendelian heredity

- polygenic – multifactorial

- chromosomal aberrations

- mitochondrial

- cancer diseases – somatic mutations

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

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)

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)

Cause of inborn defects

Malformation, dysplasia – monogenic, chromosomal and multifactorial

Disruption – sporadic, environmental factor

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)

Potter sequence

Teratogenesis

= disturbances in prenatal development leading to origin of

inborn defects

TeratogenesisEmbryotoxic effect

death

malformation

growth retardation

disorder in function

Sensitivity to teratogenes:

genotype of mother + embryo

type of teratogene and dose

permeability through placenta (do 800-1000 daltons)

period of impact

Teratogenes:

Physical

Chemical

Biological

Maternal factors

Physical: Diagnostic irradiation RTG untill 10th day after conception with more than

100mSV – letal effectLater more than 100mSv – PMR, inborn defectsBelly examination Outside uterus less than 20mSv – no effectMore than 20 mSV – consultation with radiologistMore 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

SONO, MRI – safe methodsCT – not recomanded

Hypertermia (first six weeks of gravidity)Hot bath, sauna – 3x higher risk of inborn defectsFever >38.5oC > 1 daySA, IUGR, defects of CNS, MR, facial dysmorphia hypotonia, hypertonia, NTD

Mechanical causes:Uterus myomatosusAmnional bands

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

Proved teratogenes in Ist trimester:

Thalidomid (1956-62)

Anti-emetic, sedative, hypnotic

Reductional limb deformities

21.-36. day (12 000 cases)

1998 permited again:

malignities, leprosy, Crohn disease, skin TBC, AIDS

A vitamine and its analogs:

defects of CNS, craniofacial structures, auditory apparate, hearth, limbs

Warfarinbone deformities, chondrodysplasia punctata,CNS defects

Diethylstilbestrol

Years 1938-70., 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

Other risky medicaments

Anticonvulsives:

Fetal hydantoine syndrome mental retardation hypoplasia of middle face cleft face defects limb defects

Fetal valproate syndrom

craniofacial anomalies

cleft face defects

disturbanes in neural tube development

inborn hearth defects

ACE inhibitors:I. trimester: risk of inborn hearth defects 3,7x higher,

other defects 2,7x higherII. 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

Tetracycline ( after 20th week):

distubance in development of bones and teeth

Drugs:Caffeine:> 4 cups a day –

Lower birth weight

Premature childbirth

Cigarettes:

SA, IUGR

Cocaine:

SA, hearth defects, urogenital defects

LSD: SA, IUGR

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)

Fetal alcohol syndrome:

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

RubeollaVaccination!

mikrocephalia, MR, hearth defects, cataracta, deafness

CMV infectionmicrocephalia, deafness, poliomyelitis,

chorioretinitis, hepatosplenomegalia

2. bacteria: Treponema pallidum: IUGR, chorioretinitisbone and teeth deformities

3. protozoa: Toxoplasma gondii:

hydrocephalus, microcephalus,

chorioretinitis, blindness, MR

Plasmodium malarie : IUGR

Maternal factors:

A. Nourishment:Folic acid : NTD ( 0,4-4mg/den )

Calcium, vitamin D : rachitis, hypocalcemia, tetania

Iodine : struma, MR

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

Prevention of genetic disorders

Prevention

Primary prevention

– prevention of disease origin

Secondary prevention

– prevention of birth of affected child

(Tertiary prevention

– prevention of disease complications)

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

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

Secondary prevention

= prevention of birth of child with serious genetic defect or disease – care for mother during pregnancy

- prenatal screening

- invasive methods

- interruption

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

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

Nuchal translucency Ultrasound examination done between 11+0 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

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

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

Affection risk assesment

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

Maternal age and risk of trisomy 21

Invasive prenatal methods

• AMC amniotic fluid cells examination 16 -18 week

• CVS chorionic villi cells examination 10 -12 week

• Fetal blood from umbilical cord after 20 week

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

http://www.forumzdravi.cz

Amniotic cells colony

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)

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 %)

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

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

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)

Other screening possibilities

Detectin of individuals in risk

- screening of carriers (AR diseases)

- e.g. thalassemia in Sardinia

- screening of CF heterozygots in CZ?

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)

Thank you for your attention.