Congenital Anomali.ppt

Basic Pathology

Congenital Anomalies dr. Gara Samara B., SE, MMR, M.Sc., M.Si.Med.

Congenital vs Genetic diseases Mengenal Kelainan Genetik

Hereditary disorders, familial Mengenal Kelainan Genetik

Basic Pathology

Kromosom Mengenal Kelainan Genetik

Basic Pathology

DNA

Mengenal Kelainan Genetik

Basic Pathology

HEREDITARY, FAMILIAL and CONGENITAL Hereditary disorders are derived from one parents, and are transmitted in the germ line through the generations, and therefore are Familial. The term congenital simply implies BORN WITH. Some congenital diseases ARE NOT GENETIC eq Congenital syphilis. NOT ALL GENETIC DISEASE ARE CONGENITAL. Some diseases begin to manifest their condition only after 3rd or 4th decade of life.

CONGENITAL vs GENETIC DISEASES The term congenital simply implies BORN WITH. Some congenital diseases ARE NOT GENETIC eq Congenital syphilis.

NOT ALL GENETIC DISEASE ARE CONGENITAL. Some diseases begin to manifest their condition only after 3rd or 4th decade of life.

3 Major Categories of GENETIC DISORDERS 1). RELATED TO MUTANT GENES OF LARGE EFFECTS. Most of these follow the classic mendelian pattern of inheritance  MENDELIAN DISORDERS. 2). DISEASES WITH MULTIFACTOR (POLYGENIC) INHERITANCE. Such as hypertension, DM. Multifactorial: influence by both Genetic and Environmental factors. The genetic component involves results of multiple genes of small effect, while the environmental contribution may be small or large. . 3).DISEASES THAT RESULT FROM GENOMIC OR CHROMOSOMAL MUTATIONS, associated with Numerical or Structural Changes in chromosomes

MUTATIONS Define as Permanent Change in the DNA Mutations that affect the GERM CELLS are transmitted  inherited disease Mutations that arise in SOMATIC CELLS do not cause Hereditary diseases, but important for the Genesis of Cancer and some Congenital anomalies

CHROMOSOME MUTATION  involving NUMBER or STRUCTURE of chromosome. Transmitted infrequently because most are incompatible with survival Majority of mutations associated with Hereditary diseases is GENE MUTATION.

GENE MUTATIONS Majority of mutations associated with Hereditary diseases is GENE MUTATION. Partial or complete deletion of a gene or more often affect a single base POINT MUTATION: single nucleotide substitute by a different base (F5.2) FRAMESHIFT MUTATION: one or two base pairs may be inserted into OR deleted from DNA  alteration in the reading frame of the DNA strand. (f5.3-5.4)

GENE MUTATION: point mutations POINT MUTATION WITHIN CODING SEQUENCE: A point mutation (single base substitution) may alter the code in a triplet of bases  replace one amino acid by another in gene product (often term as missense mutation) Ex: sickle mutation affecting the beta globin of Hb ( CTC for glutamic acid is changed to CAC for valine)  alter physicochemical properties of Hb  sickle cell anaemia A point mutation may change amino acid codon to stop codon (nonsense mutation), ex: CAG for glutamine is changed to UAG for stop codon  premature translation of beta globin: short peptide is rapidly degraded. Lack of beta globin chains  Thalassemia

GENE MUTATION: point mutations POINT MUTATION WITHIN NONCODING SEQUENCES: Transcription of DNA is initiated and regulated by promoter and enhancer sequences. Point mutation or deletion involving these regulatory sequences may interfere the total lack of transcription, ex: certain form of hereditary haemolytic anaemia. Point mutation within intron  interfere with normal mRNA transcript, failure to form the mature mRNA  translation can not take place, gene product is not synthesized. DELETIONS AND INSERTIONS involving coding sequence  alteration of the reading frame  frameshift mutations.

CHROMOSOME MUTATIONS CHROMOSOME MUTATION  involving NUMBER or STRUCTURE of chromosome. Transmitted infrequently because most are incompatible with survival

Majority of mutations associated with Hereditary diseases is GENE MUTATION.

3 Major Categories of GENETIC DISORDERS 1). RELATED TO MUTANT GENES OF LARGE EFFECTS. Most of these follow the classic mendelian pattern of inheritance  MENDELIAN DISORDERS. 2). DISEASES WITH MULTIFACTOR (POLYGENIC) INHERITANCE. Such as hypertension, DM. Multifactorial: influence by both Genetic and Environmental factors. The genetic component involves results of multiple genes of small effect, while the environmental contribution may be small or large. . 3).DISEASES THAT RESULT FROM GENOMIC OR CHROMOSOMAL MUTATIONS, associated with Numerical or Structural Changes in chromosomes

Pendahuluan Kromosom, dari bahasa Yunani: χρώμα (chroma, warna) dan σώμα (soma, tubuh) Kromosom merupakan rangkaian utas DNA (dari satu molekul DNA) yang sangat panjang dan kontinyu, berisi banyak gen, elemen regulator dan sekuens nukleotida pengisi lainnya.

DISEASES RELATED TO MUTANT GENES OF LARGE EFFECTS  MENDELIAN DISORDERS Most of these follow Mendelian patterns of Inheritance

Mendelian disorders All mendelian disorders are the result of expressed mutations of single gene of large effect The number of mendelian disorders known has grown, listed more than 4500 disorders. Estimated that every individual is a carrier of 5 to 8 deleterious genes. Fortunately most of these are recessive About 80% of these mutations are familial

Mendelian disorders Genetic defect (mutations)  formation of abnormal protein (gene product)  phenotypic effects Single gene disorders: Enzyme deffect Defect membrane receptor and transport system Alternation in the structure, function, or quantity of non enzyme proteins Mutations resulting in unusual reactions to drugs

Mendelian disorders Mutation  Enzyme deffect: reduced activity, reduced amount of normal enzyme Ex: enz phenylalanine hydroxylase  phenylketonuria Hexosaminidase  Tay-Sachs disease Adenosine deaminase  Severe Combined Immunodeficiency

Mendelian disorders Defect membrane receptor and transport system Many biologically actve substances transported across cell membrane. Ex: reduced synthesis or function of low density lipoprotein (LDL) receptors  defective transport LDL into the cells, secondary excessive cholesterol synthesis by complex mechanism  Familial hypercholesterolaemia Ex: Vit D receptors  vit D resistent rickets Ex: transport oxygen (Hb)  thalassemia (alfa, beta) Ex: ions  cystic fibrosis

Mendelian disorders Alternation in the structure, function, or quantity of non enzyme proteins Ex: defect structure of globin molecule  haemoglobinopathies, sickle cell anaemia. Ex: reduced amount of struturally normal Hb (alfa or beta globin chains)  Thalassemia Ex: collagen  Osteogenesis imperfecta Ex: dystrophin  muscular dystrophia Ex: Fibrilin  marfan syndrome

Mendelian disorders Mutations resulting in unusual reactions to drugs Enzyme defficiencies after exposure of affected individual to certain drugs  Pharmacogenetic Ex:Def enz G6PD. In normal condition, G6PD does not result in disease. On administration of primaquine (antimalaria)  severe haemolytic anaemia

Transmission pattern of singlegene disorders Mutations involving single gene typically follow one of 3 pattern: autosomal dominant, autosomal recessive, and X-linked. AUTOSOMAL DOMINANT DISORDERS AUTOSOMAL RECESSIVE, X-LINKED

Transmission pattern of single-gene disorders:

AUTOSOMAL DOMINANT DISORDERS Manifest in the heterozygote state, at least one parent is usually affected, male or female can affected, both can transmit the condition If an affected person marries unaffected, every child has one change in two of having the disease In addition, the characteristic as follows: Some patients do not have affected parents, their disorder caused by new mutation involving eggs or sperm. Their siblings are neither affected. Many new mutations seem to occur in germ cells of relatively older fathers.

Transmission pattern of single-gene disorders:

AUTOSOMAL DOMINANT DISORDERS Some individual inherit the mutant gene, but phenotypically normal. This is referred as reduced penetrance. This is important for genetic counseling. If a trait is seen in all individuals carrying mutant gene, but expressed differently among individual, it is called variable expressivity. Example: manifestations of neurofibromatosis range from brownish spots to multiple skin tumor and skeletal deformities In many conditions, the age of onset is delayed, symptom and signs do not appear until adult hood Two major categories of nonenzyme proteins are usually affected in autosomal dominant disorders:

Transmission pattern of single-gene disorders:

AUTOSOMAL DOMINANT DISORDERS Some individual inherit the mutant gene, but phenotypically normal. This is referred as reduced penetrance. This is important for genetic counseling. If a trait is seen in all individuals carrying mutant gene, but expressed differently among individual, it is called variable expressivity. Example: manifestations of neurofibromatosis range from brownish spots to multiple skin tumor and skeletal deformities In many conditions, the age of onset is delayed, symptom and signs do not appear until adult hood Two major categories of nonenzyme proteins are usually affected in autosomal dominant disorders:

Transmission pattern of single-gene disorders: AUTOSOMAL RECESSIVE DISORDERS The trait does not affect the parents, siblings may show the disease Onset is frequently early in life

Transmission pattern of singlegene disorders: X-LINKED DISORDERS All sex-linked disorders are X-linked Almost all X-linked recessive

DISEASES WITH MULTIFACTORIAL (POLYGENIC) INHERITANCE Influence by both Genetic and Environmental Factors Included most common diseases in human: hypertension and DM

DISEASES THAT RESULT FROM GENOMIC OR CHROMOSOMAL MUTATIONS associated with Numerical or Structural Changes in chromosomes

Kromosom Kromosom pertama kali diamati pada tanaman oleh ahli botani Swiss Karl Wilhelm von Nageli (1817-1891) tahun 1842. Dan pada cacing Askaris oleh ilmuwan Belgia Edouard Van Beneden (1846-1910). Sifat-sifat kromatin pada binatang (Salamander) dijelaskan secara detail oleh ahli anatomi Walter Flemming (1843-1905), penemu mitosis pada tahun 1882. Nama kromosom kemudian dicetuskan oleh ahli anatomi Belanda Heinrich von Waldeyer.

Morfologi kromosom

Kariotipe

Kromosom, Kromatin, Kromatid

(1) Chromatid. One of the two identical parts of the chromosome after S phase.

(2) Centromere. The point where the two chromatids touch, and where the microtubules attach. (3) Short arm. (4) Long arm.

Morfologi Dua kromatid bersatu pada sentromer Klasifikasi kromosom berdasarkan panjang, letak sentromer dan ada atau tidaknya satelit Letak sentromer : 1. Metasentris 2. Submetasentris 3. Akrosentris

Nomenklatur Cara mengidentifikasi kromosom : 1. ukuran 2. pola setelah pengecatan 3. posisi sentromer

Konstitusi kromosom : 1. nomor kromosom 2. lengan 3. region e.g. 13q12

Jumlah Kromosom Spesies Tikus Putih Merpati Cacing tanah Kucing Tikus Kelinci Gorilla Gajah Keledai Anjing Kupu-kupu

# 16 16 36 38 40 44 48 56 62 78 380

Spesies Manusia Siput Rubah Tibet Babi Celurut Hamster Domba Sapi Kuda Ayam

# 46 24 36 38 42 44 54 60 64 78

Kelainan struktur kromosom #1 Delesi : bagian dari kromosom ada yang hilang atau terhapus e.g. Jacobsen syndrome (11q) Duplikasi : bagian dari kromosom terduplikasi, menghasilkan ekstra material genetik. E.g. Charcot-MarieTooth disease type 1A (17)

Inversi : bagian dari kromosom berpindah tempat ke atas atau bawah sehingga material genetik menjadi inverted

Kelainan struktur kromosom #2 Insersi

Translokasi

Kelainan jumlah kromosom Monosomi

Trisomi

Aberasi Kromosom Beberapa kelainan struktur kromosom tidak mengakibatkan kelainan bawaan, seperti translokasi atau inversi, tapi meningkatkan kemungkinan mempunyai anak dengan kelainan kromosom. Kelainan jumlah kromosom atau kromosom set (aneuploidi) biasanya fatal, atau memberikan penyakit genetik. Cri du chat Wolf-Hirschhorn syndrome Jacobsen syndrome Down syndrome Edward's syndrome Patau syndrome

Klinefelter's syndrome

Turner syndrome XYY syndrome

Triple-X syndrome

Cri du Chat Cri du chat syndrome / deletion 5p syndrome /5p minus Pertama kali dijelaskan oleh Jérôme Lejeune th 1963. 1 : 20,000 - 50,000 kelahiran hidup, lebih sering pada perempuan.

Cri du Chat Karakteristik Tangisan mengeong --> perkembangan abnormal laring Karakter Fisik: Underweight, mikrosefal, hipotonia, round face, lowset ear, strabismus, facial asimetri Malformasi jantung Perkembangan lebih lanjut:

Retardasi mental Autis Hipersensitivitas terhadap suara Bersifat sosial dan periang

Wolf-Hirschhorn syndrome Disebabkan oleh delesi parsial dari lengan pendek kromosom 4 Karakteristiknya retardasi pertumbuhan berat dan mental retardasi.

Jacobsen Syndrome Jacobsen Syndrome / 11q deletion merupakan kelaianan yang merupakan hasil delesi dari daerah terminal

kromosom 11 (11q24.1)

Mengakibatkan mental retardasi ringan, wajah khas dan beberapa problem fisik termasuk kelainan jantung dan perdarahan (Paris-Trousseau syndrome)

Sindroma ini pertama kali dikenali oleh Petra Jacobsen

th 1973, 1 : 100,000 kelahiran

Down Syndrome Sindroma Down / Down's Syndrome / Trisomi 21 Merupakan kondisi yg terjadi akibat adanya ekstra kromosom 21. Pertama kali ditemukan oleh John Langdon Down, tahun 1866.

Down Syndrome Karakteristik Fisik Fissura mata mendatar

Hidung rata, makroglossia, leher pendek hipotoni simian crease Penyakit jantung kongenital

Retardasi mental ringan (IQ 50–70) sampai sedang (IQ 35–50)

Edward's Syndrome Trisomy 18 / Edwards Syndrome Trisomi paling sering setelah Down Syndrome.

Mengakibatkan BBLR, mikrosefal, low-set ears, penyakit jantung dan malformasi organ Survival rate Edwards Syndrome sangat rendah. Setengahnya mati dalam kandungan. Pada kelahiran hidup hanya 50% hidup sampai 2 bulan, 5-10% sukses sampai umur 1 tahun Penyebab utama kematian adalah apneu dan kelainan jantung.

Patau Syndrome Patau syndrome / Trisomi 13 Karakteristik: mental retardasi, mata sipit, bibir/palatum sumbing, hipotonia

1 : 10,000 angka kelahiran hidup Semakin tua, resiko wanita mempunyai bayi dengan Patau syndrome meningkat

Klinefelter's Syndrome Klinefelter's syndrome / XXY syndrome Merupakan kondisi yang disebabkan oleh kegagalan disjungsi kromosom, mengakibatkan laki-laki mempunyai 2 kromosom X Dinamakan oleh Dr. Harry Klinefelter, peneliti di Massachusetts General Hospital, Boston, Massachusetts, 1942

Klinefelter's Syndrome Gejala dan Tanda Pria XXY hampir selalu steril Ginekomasti timbul pada 1/3 penderita.

Meningkatkan resiko kanker payudara, penyakit paru, DM, rheumatoid artritis dan osteoporosis. Kebanyakan orang tidak menunjukkan gejala yang spesifik

Turner Syndrome Turner syndrome merupakan sekumpulan kelainan akibat monosomi X, disebut juga 45,X or 45,X0

1 : 2.500 angka kelahiran bayi perempuan hidup. Pada Turner syndrome, karakteristik seksual perempuan ada namun tidak berkembang.

Gejala: ● ●

Perawakan pendek Dada lebar (shield chest) dan puting susu jauh satu sama lain

●

Steril

●

Amenore

XYY Syndrome XYY syndrome adalah aneuploidi (khususnya trisomi) dari kromosom sex dimana laki-laki menerima kromosom Y ekstra, menjadikan kariotipenya 47,XYY. Beberapa ahli genetik (Allanson & Graham 2002) mempertanyakan penggunaan istilah sindrome yang tidak tepat untuk kondisi penyakit karena fenotipenya normal dan mayoritas (97%) laki-laki di Inggris tidak menyadarinya. Mempunyai resiko kesulitan belajar yang lebih tinggi, rata-rata penderita IQ berbeda 10-15 poin dari normal

Triple-X Syndrome Triple X syndrome / triplo-X / trisomy X / XXX syndrome / 47,XXX aneuploidy Merupakan variasi kromosom yang ditandai dengan adanya ekstra kromosom X pada setiap sel dari perempuan Perempuan dengan kondisi ini tidak mempunyai resiko kesehatan Dapat mengalami ketidakteraturan haid, kadang-kadang juga meningkatkan resiko kesulitan belajar dan keterlambatan bicara dan bahasa

PRENATAL SCREENING #1

Relatively simple, non invasive, examine mother’s blood Test measure level of three markers: Serum alpha fetoprotein (MSAFP) Chorionic gonadotropin (hCG) Unconjugated estriol (uE3) This measurement are not a definitive test.

PRENATAL SCREENING #2 AMNIOCENTESIS The removal and analysis of a small sample of fetal cells from the amniotic fluid Cannot be done until the 14-18th week of pregnancy Lower risk of miscarriage than CVS CHORIONIC VILLUS SAMPLING Extraction of a tiny amount of fetal tissue at 9 to 11 weeks of pregnancy The tissue is tested for the presence of extra material from chromosome 21 Carries a 1-2% risk of miscarriage

PRENATAL SCREENING #3 PERCUTANEOUS UMBILICAL BLOOD SAMPLING (PUBS) Most accurate method used to confirm the result of CVS or amniocentesis The tissue is tested for the presence of extra material from chromosome 21 PUBS cannot be done untill the 18-22nd week Carries the greatest risk of miscarriage CURRENT TECHNIQUES: Cell culture and karyotyping; 99% correct

CYTOGENETIC AND MOLECULAR DIAGNOSIS DNA analysis Detection of inherited mutations that underline the development of genetic disease Direct gene diagnosis  DNA sequencing Cytogenetic analysis: Cell culture and karyotyping; 99% correct

SELAMAT SURFING Selamat Surfing