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LIFE CYCLE MODULE STUDENT GUIDANCE Contributors : dr Rita Rosita, MKes Safrina Dewi, Msi.Med dr Siti Lintang Kawuryan, SpA(K) dr Eko Sulistijono,SpA(K) dr Brigitta RVC,MKes,SpA Dr dr Mardhani Yosoprawoto, dr., SpA(K) dr Ariani,MKes,SpA dr Haryudi AC, SpA(K) dr M.Ridwan, SpKFR dr Eko Nugroho,SpKFR dr Sri Sunarti, SpPD dr Hidayat Sujuti, PhD, SpM dr Bambang Prijadi, MS dr Anik Puryatni, SpA(K) dr Laksmi S, SpPD FACULTY OF MEDICINE UNIVERSITY OF BRAWIJAYA Page | 1 1

Submodule 1 Prenatal Dev Student Guidance

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Page 1: Submodule 1 Prenatal Dev Student Guidance

LIFE CYCLEMODULE

STUDENT GUIDANCE

Contributors :

dr Rita Rosita, MKesSafrina Dewi, Msi.Med

dr Siti Lintang Kawuryan, SpA(K)dr Eko Sulistijono,SpA(K)dr Brigitta RVC,MKes,SpA

Dr dr Mardhani Yosoprawoto, dr., SpA(K)dr Ariani,MKes,SpA

dr Haryudi AC, SpA(K)dr M.Ridwan, SpKFR

dr Eko Nugroho,SpKFRdr Sri Sunarti, SpPD

dr Hidayat Sujuti, PhD, SpMdr Bambang Prijadi, MSdr Anik Puryatni, SpA(K)

dr Laksmi S, SpPD

FACULTY OF MEDICINE UNIVERSITY OF BRAWIJAYA

MALANG2012

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MODULE CONTENTS:

TOPICS AUTHORSSub Module I: PRENATAL DEVELOPMENTSub Module 1a : Prenatal Growth & Changes(Embriogenesis)Sub Module 1b : Development of FetusSub Module 1c : Medical Genetic

Sub Module 1a,b: dr Rita Rosita, MKesSub Module 1c: Safrina Dewi,Msi.Med

Sub Module 2: INFANCYSubModule 2a : Neonatal IntroductionSubModule 2b : Neonatal AdaptationSubmodule 2c : Neonatal Physical ExaminationSubModule 2d : Breastfeeding Management

Sub Module 2a,b,c,d: dr Siti Lintang Kawuryan, SpA(K) dr Eko Sulistijono, SpA(K) dr Brigitta Corebima, MKes, SpA

Sub Module 3: CHILDREN & ADOLESCENCESub Module 3a : Growth & Development in childrenSub Module 3b : Growth & Development in adolescent Sub Module 3c : ImmunizationSub Module 3d : Growth & Development Examination

Sub Module 3a: Dr dr Mardhani Y, SpA(K) dr Ariani,MKes, SpA

Sub Module 3b: Dr dr Mardhani Y,SpA(K) dr Ariani,MKes, SpA dr Haryudi,SpA

Sub Module 3c,d: Dr dr Mardhani Y,SpA(K) dr Ariani,MKes, SpA

Sub Module 4: ADULTHOODSub Module 4a : Physical Development & the Sense in Early AdulthoodSub Module 4b : Social & Personality Development in Early AdulthoodSub Module 4c : Physical Development & the Sense in Middle AdulthoodSub Module 4d : Social & Personality Development in Middle AdulthoodSub Module 4e : Physical Development & the Sense in Late AdulthoodSub Module 4f : Social & Personality Development in Late Adulthood

Sub Module 4a-f : dr Sri Sunarti, SpPD

SubModule 5:RehabilitationSub Module 5a : Rehabilitation in special casesSub Module 5b : Exercise in Elderly

Sub Module 5a,b : dr M.Ridwan,SpRM

Sub Module 6 : NUTRITION in LIFE CYCLESub Module 6a : Nutrigenomics & Metabolism of MicronutrientSub Module 6b : Nutrition in infant Sub Module 6c : Nutrition in children Sub Module 6d : Nutrition in adulthoodSubModule 6e : Nutrition in Elderly

Sub Module5a: dr Hidayat Sujuti, PhD, SpM dr Bambang Prijadi,MSSubModule 5b,c: dr Anik Puryatni, SpA(K)SubModule 5d,e: dr Laksmi S,SpPD

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SUBMODULE 1:

PRENATAL DEVELOPMENT

Contributors :

dr Rita Rosita, MKesSafrina Dewi, Msi.Med

FACULTY OF MEDICINE UNIVERSITY OF BRAWIJAYA

MALANG2012

PRENATAL DEVELOPMENT

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IntroductionThis topic is part of Life Cycle block which is concerning to Prenatal development as the first stage of individual life.

The topic will be distributed into two subtopics exploring on Embryology and Medical genetics. Sub topic of Embryology presents an overview of early development of human being which will be started from gametogenesis process through embryonic period. Attention will be devoted to placental and fetal development. Any clinical appearance which might follow all those processes will also be introduced. Due to birth defects as the leading cause of infant mortality and a major contributor to disabilities, there is a need for prospective doctors to generate a tentative prenatal diagnosis and birth defects. Thus, basic concept and principles of embryology as well as new prevention strategies will be addressed in this topic. In order to build cellular and molecular basic understanding of perinatal development, a fundamental process of medical genetic become a necessary part of this topic. Thereore, the second subtopic offers exploration to medical genetic which occupies the principles of hereditary material, how it is transmitted and the pattern of inheritance until its relevance to clinical genetics. The concerning issues are genetic structure and regulation, the central dogma, pathology process (mutation) and its inheritance mode. Covering all these material, medical doctors are expected to contribute in a genetic counseling process which might require an understanding about technical laboratory finding to support screening intention and a diagnosis of birth defect.

Recent advances in medical genetics, developmental biology, and maternal-fetal medicine may lead to a comprehensive understanding to the pathogenesis of a disease. Therefore, this topic has tight relation with some previous blocks such as blok Structure, Function and General Patology, and block Biocemical, Biomollecular and Biocellular. In addition, Embryology and genetic build a fundamental processes for each organ formation and function; thus, prenatal development should be related to all block systems on further semesters.

Learning objectives:Completing this topics, students are expected to have comprehensive understanding to such key concepts of prenatal development below :

1. The stage of embryonic and fetal development 2. The implantation and placentation3. The clinical entities related to embryologic concepts4. The cellular and molecular basis of inheritance, its impact to genetic diseases and its application during

genetic counseling.Furthermore, we promote students to use technology of information extensively in exploring the concerning topic to enrich their understanding for current and further use of their knowledge.

Competency area:Area of competences addressed in this topic are

a. Scientific base of medical knowledgeb. Management of Health Problemsc. Management of Informationd. Self-awareness and Self-development

Since this topic is intended for students learning in second semester and look up the feature of concerning medical knowledge, level of competence of area scientific base of medical knowledge is to be reached on 1 st – 2nd of the Standard of Competencies for Doctors from Indonesian Medical Council

Competency component:In regard to above areas competencies, students are expected to

1. Generate a clinical diagnosis of congenital defect based on physical examination and laboratory finding2. Explain about pathomechanism of congenital defect cases during a genetic counseling3. Using various learning resources to enrich their understanding of prenatal development

Develop their understanding of prenatal development for further learning

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Topic tree:

Fig. 1 Basic concept of prenatal development

Figure 1 shows a diagram in which a basic concept of prenatal development is visualized. In order to present a working diagnose of any birth defect, we must consider the possible pathomechanism and its pattern or traits to any individu having birth defect. Close interaction between mother and the embryo along with the feature of embryo himself might influence the process of pathology of birth defect. Anyhow, medical genetic might become the underlying factor. Therefore, medical doctor should be supplied with a technical knowledge to do screening and diagnosis of birth defects. Although they will not participate in subsequent management of theraphy for birth defect (that they should deliver the patient to specialist), doctors may give some information regarding to gene contribution and gene theraphy to the disease.

Educational Format :Prenatal development will be delivered using a modul task which will be discussed under a small group discussion. In addition, some expert lectures will also be available in order to present basic explanation about some topics which are not covered in small group discussion and can function to clarify any lack of understang and misconception which might occur in small group discussion.

AssessmentIn order to measure students’ understanding on topic of prenatal development, we measure it by using a summative assessment of MCQ (multiple-choice question) method. In light of the feature of knowledge of prenatal development, we introduce to apply some cases questions along with current use of factual knowledge questions. Since assessment should also be functioning in improving students’ learning, we will try to develop some formative assessment to identify lack of understanding and any misconception during students’ small group discussion.

References/ Learning resources :

Our extensive resources in providing topic of prenatal development will be available on some lietratures below :Carlson, B. (2004). Human Embryolgy and Developmental Biology, 3rd ed, Elsivier MosbyCorey, J. & White, B. (2004). Medical genetics, 3rd ed., Elsevier, Missouri.Kingston, H.M. (2002). ABC of clinical genetics, 3rd ed., Chennai, India.Mueller, R.F. & Young, I.D. (2001). Emery’s elements of medical genetics, 11th ed. Churchill Livingstone, London.Passarge, E. (2007). Thieme: color atlas of genetics, 3rd ed., Thieme, New York.Pasternak, J.J. (2005). An introduction to human molecular genetics: mechanisms of inherited diseases, 2 nd ed., John

Willey & Sons, New Jersey.

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Medical embryology

Medical genetics

Feto-maternal interaction

Pathomechanism of birth defect

The pattern/traits of birth defect

Diagnosis of birth defect

Genetics counseling

Technical knowledge supporting screening and diagnosis of birth defect

Knowledge of gene therapy

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Sadler, T.W. (). Langman’s Medical Embryology, Lippicott Williams&W, pp. 1-114Williams, (). Obestetrics, 23rd ed, The McGraw-Hill companies, chapter 3-4

PRENATAL DEVELOPMENTFrom Gametogenesis to Histogenesis….

Human development is a continuous process that begins when an oocyte (ovum) from a female is fertilized by a sperm (spermatozoon) from a male. Cell division, cell migration, programmed cell death, differentiation, growth, and cell

rearrangement transform the fertilized oocyte, a highly specialized, totipotent cell, a zygote, into a multicellular human being.

Human development is a continuous process that begins when an oocyte (ovum) from a female is fertilized by a sperm (spermatozoon) from a male. Cell division, cell migration, programmed cell death, differentiation, growth, and cell rearrangement transform the fertilized oocyte, a highly specialized, totipotent cell, a zygote, into a multicellular human being. Although most developmental changes occur during the embryonic and fetal periods, important changes occur during later periods of development: infancy, childhood, adolescence, and early adulthood Development does not stop at birth. Important changes, in addition to growth, occur after birth (e.g., development of teeth and female breasts). It is customary to divide human development into prenatal (before birth) and postnatal (after birth) periods. Knowledge that physicians have of normal development and of the causes of anomalies is necessary for giving the embryo and fetus the greatest possible chance of developing normally. Much of the modern practice of obstetrics involves applied embryology. Embryologic topics of special interest to obstetricians are ovulation, oocyte and sperm transport, fertilization, implantation, fetal-maternal relations, fetal circulation, critical periods of development, and causes of birth defects. In addition tocaring for the mother, physicians guard the health of the embryo and fetus. The significance of embryology is readily apparent to pediatricians because some of theirpatients have birth defects resulting from maldevelopment, e.g., diaphragmatic hernia, spina bifida, and congenital heart disease.I. GAMETOGENESIS

The sperm and oocyte, the male and female gametes, are highly specialized sex cells.Each of these cells contains half the number of chromosomes (haploid number) that are present in somatic (body) cells. The number of chromosomes is reduced during meiosis, a special type of cell division that occurs during gametogenesis. Gamete maturation is called spermatogenesis in males and oogenesis in females.The sequence of gametogenesis is the same, but the timing of events during meiosis differs in the two sexes. Gametogenesis is typically divided into four phases :1. The extraembryonic origin of the germ cells and their migration into the gonad

Primordial germ cell(PGCs), precursor of gametes, arise outside the gonads during early embryonic development. Human PGCs first become recognizable at 24 hours after fertilization in endodermal layer of the yolk sac by their large size and high content of alkaline phosphatase. During the fourth week these cells begin to migrate from the yolk sac toward the developing gonad, where they arrive by the end of fifth week.

2. An increase in the number of germ cells by mitosis

Mitotic division increase their number during their they migration and also when they arrive in the gonad. The patterns of mitotic proliferation differs markedly between male and female.

3. A reduction in chromosomal number by meiosis

Germ cells divide to reduce the number of their chromosomes by half, from a diploid to haploid set. Meiosis involves two sets of divisions. In the first meiotic division occurs crossover, the interchange of chromatid segments between paired homologous chromosomes. The second meiotic division is similar to an ordinary mitotic division, except that before division the cell is haploid.Meiotic promotes genetic variation, helps to establish homozygous mutant alleles, and eliminates bad genes.

4. Structural and functional maturation of the eggs and spermatozoa.

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The process that prepare the grown oocyte for fertilization are collectively called oocyte maturation. The maturation process that transform the spermatid into spermatozoon is called spermiogenesis.

Modul Task 1 :

1. The patterns of mitotic proliferation differs markedly between male and female. Could you explain the statement, and describe tthe implications?

2. Meiosis is a specialized process of cell division that occurs only in the production of gameteswithin the female ovary or male testes. It consists of two divisions (meiosis I and meiosis II). Describe the phases of meiosis and the major characteristic of each step !

3. The incidence of trisomy 21 (Down syndrome) increases with advanced age of the mother, Why?

4. During evaluation of male fertility, an analysis of semen is made. Explain how it used, when is it ordered, and what the result is mean?

II. TRANSPORT GAMETES AND FERTILIZATION

Explains the way the egg and sperm cells come together in the female reproductive tract so that fertilization can occur.

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Ovulation :

Toward the midpoint of the menstrual cycle, under the influence of FSH and LH. Coincident with final development of the secondary follicle, there is an abrupt increase in LH that causes the primary oocyte to complete meiosis I and the follicle to enter the pre-ovulatory stage.

Meiosis II is also initiated, but the oocyte is arrested in metaphase approximately 3 hours before ovulation. In the meantime, the surface of the ovary begins to bulge locally, and at the apex, an avascular spot, the stigma, appears. The collagenase activity increases resulting in digestion of collagen fibers surrounding the foliccle, and local muscular in the ovarian wall contract give rise oocyte breaks free and floats out of the ovary.

Oocyte transport :

Before ovulation, fimbriae of the oviduct sweep over the ovary, and tube contract rhytmically. Oocyte is carried into the tube by motion of cilia on the epithelial lining.

Sperm transport :

Seminiferous tubule move toward to epididymis and go through biochemistry maturation,coverred by glycoprotein and get the external energy source from prostate gland & seminal vesicles during ejaculation (2-6 ml, 100 million cell/ml) environment condusive to independent motion.

1% sperm deposited in vagina enter cervix go to oviduct (by sperm propulsion & fluids +cilia) but in isthmus, sperm become less motile. At ovulation, cumulus cell that surrounding oocyte produce chemoattractrans that cause sperm become motile again swim to ampulla

Spermatozoa are not abble to fertilizise the oocyte, before undergo :

•Capasitation :–A period conditioning in the female reprod tract. –Interaction between sperm-mucosal surface–The glycoprotein coating of sperm removed

•Acrosome reaction :–Occurs after binding zona pellucida(zp)–Release of enzymes (acrosin & trypsin like substance ) needed to penetrate zp

Fertilization : =the process by which male and female gametes fuse. Occurs in the ampullary region of the oviductFertilization divided into 3 phase :–Phase 1 : Penetration of the Corona Radiata–Phase 2 : Penetration of Zona Pellucida–Phase 3 : Fusion of the oocyte and sperm cell membrane

Modul task 2 :1. How is the viability of both gametes before they undergo fertilization?2. Because X and Y sperms are formed in equal numbers, the expectation is that the sex ratio at fertilization

(primary sex ratio) would be 1.00 (100 boys per 100 girls). It is well known, the preselection of embryo’s sex (gender selection). How it could happen?

3. In vitro fertilization (IVF) of oocytes and transfer of the cleaving zygotes into the uterus have provided an opportunity for many women who are sterile (e.g., owing to tubal occlusion) to bear children. Describe the step of IVF!

4. There are more than one spermatozoa that penetrate the egg in fertilization process. What is polyspermy, and how is it prevented after a spermatozoon enters the egg?

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5. The zygote is genetically unique because half of its chromosomes came from the mother and half from the father. The maternal immune system reacts towards the foreign tissue, but instead of triggering rejection, it tolerates, supports and regulates its development. Explain this phenomenone, please!

III. CLEAVAGE AND IMPLANTATIONCleavage is a series of mitotic divisions of the zygote. 1. Zygote cytoplasm is successively partitioned (cleaved) to form a blastula consisting of increasingly smaller

blastomeres (2-cell, 4-cell, 8-cell, and so on). Blastomeres are considered totipotent (capable of forming a complete embryo) up to the 4- to 8-cell stage (important when considering monozygotic twinning).

2. Blastomeres form a morula by undergoing compaction, that is, tight junctions are formed between the cells in the outer cell mass, thereby sealing off the inner cell mass. Uvomorulin, a glycoprotein found on the surface of blastomeres, is involved in compaction.

Blastocyst formation involves fluid secreted within the morula that forms the blastocyst cavity. The conceptus is now called a blastocyst.1. The inner cell mass is now called the embryoblast (becomes the embryo).2. The outer cell mass is now called the trophoblast (becomes the fetal portion of the placenta).Zona pellucida degeneration occurs by day 4 after conception. The zona pellucida mustdegenerate for implantation to occur.

Implantation :

Implantation is the first physical and physiological contact between blastocyst and the mucosa of the uterus, its divided into 3 phase :– Preparation of the uterus for adhesion and implantation– Trophoblast-uterus adhesion– Blastocyst movement into the uterusAt the time of implantation, the mucosa of the uterus is in the secretory phase. Normally the human blastocyst implants in the endometrium along the anterior or posterior wall of the body of the uterus, where it becomes embedded between the openings of the glands.

If the oocyte is not fertilized, the menstrual phase begins, blood escapes from superficial arteries, and small pieces of stroma and glands break away.

Modul Task 3:1. During in vitro cleavage of a zygote, all blastomeres of a morula were found to have an extra set of

chromosomes. Explain how this could happen. Can such a morula develop into a viable fetus?2. A 20-year-old woman presents at the emergency department with severe abdominal pain on the right side

with signs of internal bleeding. She indicated that she has been sexuall active without contraception and miss her last menstrual period. Based on this information what is the diagnosis?

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3. What the function of zona pellucida after fertilization to implantation stage ?

IV. GENERERATE MULTIPLE CELL LAYERS

Formation of Bilaminar Germ Disc ;Second week of developmentDuring this time period, the embryoblast differentiates into two distinct cellular layers: the dorsal epiblast layer (columnar cells) and the ventral hypoblast layer (cuboidal cells). The epiblast and hypoblast together form a flat, ovoid-shaped disk known as the bilaminar embryonic disk. Within the epiblast, clefts begin to develop and eventually coalesce to form the amniotic cavity. Hypoblast cells begin to migrate and line the inner surface of the cytotrophoblast, forming the exocoelomic membrane,which delimits a space called the exocoelomic cavity (or primitive yolk sac ). This space is later called the definitive yolk sac when a portion of the exocoelomic cavity is pinched off as an exo-coelomic cyst. At the future site of the mouth, hypoblast cells become columnar shaped and fuse with epiblast cells to form a circular, midline thickening called the prochordal plate.

Formation of Trilaminar Germ Disc; Third week of developmentThe third week of embryonic development coincides with the week following the firstmissed menstrual period; that is, 5 weeks after the first day of the last normalmenstrual period. Cessation of menstruation is often the first indication that a womanmay be pregnant. Approximately 3 weeks after conception, approximately 5 weeksafter the last normal menstrual period, a normal pregnancy can be detectedwith ultrasonography.Gastrulation is the formative process by which the three germ layers, which areprecursors of all embryonic tissues, and axial orientation are established in embryos.During gastrulation, the bilaminar embryonic disc is converted into a trilaminarembryonic disc, ectoderm, mesoderm, and endoderm. Extensive cell shape changes, rearrangement, movement, and changes in adhesive properties contribute to the process of gastrulation. Gastrulation is the beginning of morphogenesis (development of body form) and is the significant event occurring during the third week.

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Fourth to eight week of development (organogenesis)

All major external and internal structures are established during the fourth to eighth weeks. By the end of this period, the main organ systems have begun to develop; however, the function of most of them is minimal except for the cardiovascular system. As the tissues and organs form, the shape of the embryo changes, and by the eighth week, it has a distinctly human appearance. Because the tissues and organs are differentiating rapidly during the fourth to eighth weeks, exposure of embryos to teratogens during this period may cause major congenital anomalies.

Modul task 4 :1. During week 2 of development, what process is happened in trophoblast?2. Describe changes involving the three layer of germ disc during fourth to eight week of development!

3. A female infant was born with a large tumor situated between her anus and sacrum. A diagnosis of sacrococcygeal teratoma was made and the mass was surgically removed.

a. What is the probable embryologic origin of this tumor?b. Explain why these tumors often contain various types of tissue derived from all three germ layers.

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V. DIFFERENTIATION OF FUNCTIONING TISSUE/ FETAL DEVELOPMENTThe period from beginning of the ninth week to birth is kown as fetal period. Its characterized by maturation of tissues and rapid growth of the body. The transformation of an embryo to a fetus is gradual, but the name change is meaningful because it signifies that the embryo has developed into a recognizable human being and that the primordia of all major systems have formed. Development during the fetal period is primarily concerned with rapid body growth and differentiation of tissues, organs, and systems. A notable change occurring during the fetal period is the relative slowdown in the growth of the head compared with the rest of the body.The rate of body growth during the fetal period is very rapid, and fetal weight gain is phenomenal during the terminal weeks. Periods of normal continuous growth alternate with prolonged intervals of absent growth. The length of fetus is usually indicated as the crown-rump length (CRL) is the sitting height. This measurement, expressed in centimeters, are correlated with the age of the fetus in weeks or month.•Monthly changes :

– Third month : face more like human, primary ossification, intestine withdraw into abdominal cavity– Fourth to fifth week : the fetus lengthens rapidly, movement of the fetus can be felt by the mother– Sixth month :50% full term weight is added, the respiratory system and CNS have not differentiated sufficiently– Seventh to ninth month :deposition of subcutananeous fat. At the end of ninth month : the skull has largest circumference, weight normal fetus is 3000-3400g, its CRL is about 36 cm, Sexual characteristics are pronounced, and the testes shoul be in the scrotum.Time of Birth

– The length of pregnancy is considered to be 280 days or 40 weeks after the onset of last normal menstrual period or more accurately 266 days or 38 weeks after fertilization. If they are born much earlier called as premature; if born later is postmature

– The age of embryo or small fetus determined by combining data of the onset last menstrual period with fetal length, weight, and morphological characteristic

Valuable tool for assisting determination is ultrasound CRL and biparietal diameterModul task 5 :1. Various measurements and external characteristics are useful for estimating fetal age. In

the second and third trimesters, several structures can be identified and measuredultrasonographically, but the basic measurements are................

2. Describe the highlight of fetal development beginning 9th until 12th week3. How about fetal movement?4. Some infants in such pregnancies develop the postmaturity syndrome and have an increased risk of mortality.

Could you explain those statement, please!

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SUB MODULE 1b FETAL DEVELOPMENT

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Learning objectives:Students should familiar with the cellular and molecular basis of inheritance, and its impact to genetic diseases.

Introduction:Medical genetics occupies the principles of hereditary material, how it is transmitted and the pattern of

inheritance until its relevance to clinical genetics. The aspect in this study will include genetic structure and regulation, the central dogma, pathology process (mutation) and its inheritance mode.

The hereditary material is called DNA present in the nucleus of the cell, while protein synthesis takes place in the cytoplasm. The molecular link between the DNA code of genes and the amino acid code of protein is RNA. The informational relationship among DNA, RNA, and protein are called Central Dogma of molecular biology. DNA directs the synthesis and sequence of RNA, RNA directs the synthesis and sequence of polypeptides, and specific proteins are involved in the synthesis and metabolism of DNA and RNA by transcription and translation processes. During synthesis phase (S-phase) of cell division, DNA replicate to transmit genetic information to the next generation. However, the copy error could happened along replication, transcription and translation process. the change in the genetic material is called mutation, which can affect on autosome or sex chromosome. Mutation can occur on base level or chromosomal level.

According to the mutation occur, there are three main categories of genetic disorders, single gene, chromosomal, and multifactorial. The patterns of transmission of single gene disorders are often called Mendelian. Genes at the certain locus are called allele. The genotype person is genetic constitution at a single locus and the phenotype is the expression of genotype as a morphological, biochemical, or molecular trait which may be normal or abnormal. Single gene disorder is determined by a specific allele at a single locus on one or both of a chromosome pair because human has a pair of chromosome homolog (same number). When a person has a pair of identical alleles, it condition is called homozygous; when the allele are different, it called heterozygous or carrier. Single gene disorders are characterized by their patterns of transmission in families. The step to establish the pattern is to obtain information about the family history of the patient and to summarize the details in the form of a pedigree using standard symbols. The patterns of single gene disorders in pedigree depend on two factors:

1. The chromosomal location of the gene locus: autosomal or sex linked (in sex linked cases mostly the genes are on x chromosome)

2. The expression of the phenotype: a. Dominant, expressed even when only one chromosome of a pair carried the variant alleleb. Recessive, expressed only when both chromosome of a pair carry a variant allele

Thus there are four basic pattern of single gene inheritance: Autosomal dominant, autosomal recessive, x-linked dominant, x-linked recessive.

A number of disorders do not follow basic pattern of Mendelian inheritance. The several different mechanisms have been recognized are the following:

1. New mutation, the sudden unexpected appearance of a condition arising as a result of a mistake occuring in the transmission of a gene. New dominant mutation have been associated with an increased age of the father. This condition could be bias with non-penetrance which affected person’s parents are heterozygous for the mutant allele but so mildly and has not been detected. Other explanation for new mutation is that the stated father is not the child’s biological father or non-paternity. e.g. achondroplasia, Duchenne muscular dystrophy

2. Anticipation, the tendency for some diseases to manifest at an earlier age and/or to increase in severity with each succeeding generation. Usually refers to unstable mutation like triple repeate.g. myotonic dystrophy, Huntington’s disease, fragile-X syndrome

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SUB MODULE 1c MEDICAL GENETICS

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3. Reduced penetrance, usully refers to dominant traits in heterozygotes. If a condition is expressed is less than 100% of persons who carry the mutant allele.

4. Variable expressivity, when the manifestation of a phenotype differs in people who have the same genotype. 5. Mosaicism, an individual or particular tissue of the body can consist of more than one cell type or cell line through

an error occuring during mitosis at any stage after conception.a. Somatic mosaicism, not inheritedb. Gonadal mosaicism, may be transmitted to the next generation and could recurrence condition in

offspring from unaffected parents. 6. Uniparental disomy, an individual who inherit both chromosome homologues pair from only one of their parents.

e.g. father with hemophilia having an affected son7. Genomic imprinting, differing expression of genetic material dependent on the sex of the transmitting parent.

e.g. Prader Willi syndrome, Angelmann syndrome8. Mitochondrial inheritance/matrilineal inheritance, transmission of mutant allele in the mitochondrial DNA from

affected mother to all children, none of the children from affected male will inherit the disease.

Abnormalities in chromosome structure follow a chromosome break and the reunion of the wrong segments of the chromosome. If there is a loss or gain of chromosomal material (an unbalanced rearrangement) there can be significant clinical consequences. If there is no loss or gain of chromosomal material (a balanced rearrangement), then the individual is mentally and physically normal. However, there is an increased risk of having chromosomally abnormal offspring because individuals who carry balanced chromosome rearrangements may produce chromosomally unbalanced gametes. Chromosome studies on parents should be ordered if a child is found to have a structural chromosome abnormality (e.g., translocation, deletion, inversion, etc.) to rule out carrier status. However, aneuploidy such as trisomy 21 and monosomy X (Turner syndrome), mostly is caused by nondisjunction related to advantage maternal age and cause children carry 47 chromosome which written as 47,xx/xy (+21). As nondisjunction occurs sporadically at the time the egg or sperm is formed, it is assumed that the parents of these children have a normal chromosome complement.

Each types of genetic disorders needs the difference tools for analysis. Principally, there are two main way to detect the origin of abnormality. Single-gene disorders are analyzed by molecular testing, although suspected chromosome disorders are establised by chromosome analysis (karyotype).

In genetic diseases, there is special consideration in treating genetic diseases. The need for long-term assessment of treatment could appear some unexpected problems. For example, clotting factor infusion in hemophilia sometimes result in the formation of antibodies to the infused protein, and blood transfusion in thalassemia can produces iron overload, which can be managed but with difficulty.

Genetic disease can be treated at many levels as shown below. Treatment at the level of the clinical phenotype include all the types of medical or surgical intervention, for example some surgically correctable malformations (cleft lip/palate, vaginoplasty in androgen insensitivity syndrome/AIS, clitoridectomy in congenital adrenal hyperplasia/CAH or female virilisation), besides educating the patient and family to achieve understanding of the disease, its genetic implications, and the treatment that may be inconvenient and lifelong.

Level of intervention Treatment strategy ExamplesMutant gene Modification of the somatic

genotype (transplantation; gene transfer therapy)

Bone marrow transplantation in thalassemia

Pharmacologic modulation of gene expression

Hydroxyurea to stimulate g-globin synthesis in sickle cell disease

Mutant mRNAMutant protein Protein/enzyme replacement Factor VIII in hemophilia AMetabolic or other biochemical dysfunction

Dietary or pharmacologic PKU~dietary of phenylalanine Galactosemia~dietary of galactoseCAH~hydrocortisonCongenital hypothyroidism~thyroxine Fragile-x~minocycline

Clinical phenotype Medical or surgical intervention

Cleft lip/palate, CAH, AIS

The family Genetic counseling; carrier screening; presymptomatic

All genetic disorders

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diagnosis

Based on the technology used, treatment of genetic diseases is divided into two ways:1. Conventional approaches; protein/enzyme, drug treatment, tissue removal/transplant2. Using DNA recombinant; insulin synthesize from human insulin gene by microorganism3. Gene therapy, the replacement of a deficient gene product or correction of an abnormal gene which can be done

either in vitro by treatment of cells or tissue from an affected individual in culture with reintroduction into the affected individual, or in vivo if cells cannot be cultured or be replaced in the affected individual.

References: Kingston HM. ABC of clinical genetics, 3rd ed., Chennai, India, 2002.Mueller RF & Young ID. 2001. Emery’s elements of medical genetics, 11th ed. Churchill Livingstone, London.Pasternak JJ. An introduction to human molecular genetics: mechanisms of inherited diseases, 2nd ed., John Willey & Sons, New Jersey, 2005.

Modul task:1. A partial gene sequence from the database reads:

5’-CAG CTG GAG GAA CTG GAG CGT GCT TTT GAG-3’Write the sequence of the template strand and the mRNA.What is the amino acid sequence produced by translation of the mRNA sequence? What kind of mutation will occur if the sixth guanine changes into adenine (G7A)?

2. Does the mutation on base level change the chomosome structure? Explain your answer.3. The disease in the pedigree below is inherited in what manner? Mention the characteristic and sample of

diseases for this manner.

4. Why is it important to know your patient's ethnic background? Why should you ask about consanguinity?

5. From the pedigree, it was known that individual II:1 and III:3 have severe hemophilia A. a. What is the mode of inheritance of this disease? Give a reason for your answer!

b. Give the mark of the possibility genotype status below each individual!c. The affected individual got the mutant allele from .......... explain your answer! d. Based on the pedigree, the female who obligatory has mutant allele or carrier are…….., then they are

called an obligate carrier.e. What is the chance for individual III:2 to be a carrier for haemophilia A? f. The possibility of the pregnancy (IV:1) to be affected hemophilia if his mother (III:2) is carrier is ….g. Give another samples of trait or disease on X-linked recessive manner.

6. What should you do if you have a patient with suspect Down Syndrome?

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7. A newborn child with Down syndrome, when karyotyped, is found to have two cell lines: 70% of her cells have the typical 47,XX,+21 karyotype, and 30% are nomal 46,XX. When did the nondisjunctional event probably occur? What is the prognosis for this child?

8. Discuss possible reasons why the recurrence risk of Down syndrome is higher for mothers under 30 years of age than for mothers over 35 years of age.

9. What will you do to determine the sex status of suspected patient with development sex disorder in case ambiguous genitalia?

10. Buccal smear is not recommended to do as a sexual determination in case ambigous genitalis, why?

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