Kelainan Genetik

dr. Zainuri Sabta N

Departemen Anatomi Fakultas Kedokteran UII

GENETIC DISORDERS AND HEREDITARY DISORDERS

Currently around 4,000 genetic disorders are known, with more being discovered. Most disorders are quite rare and affect one person in every several thousands or millions. Cystic fibrosis is one of the most common genetic disorders; around 5% of the population of the United States carry at least one copy of the defective gene.

Chromosom
Kromosom manusia dibedakan dalam 2 tipe, yaitu Autosom* dan Kromosom seks**. Dari 46 kromoson didalam inti sel tubuh manusia , maka 44 buah atau 22 pasang merupakan autosom, dan sepasang seks kromoson dibedakan atas 2 macam yaitu Kromosom X dan Kromosom Y.
Perempuan homogametic (XX) Laki-laki heterogametic (XY)
*Kromosom yang tiada hubungan dengan penetuan jenis kelamin **Sepasang kromosom yang menentukan jenis kelamin

What is genetic disorder?

Adalah suatu kondisi penyakit yang

disebabkan oleh adanya abnormalitas satu atau beberapa gen atau chromosom.

Penyebab Kelainan Genetik

42% unknown 8% Taratogen Obat : Thalidomide , Warfarin , Tetracycline 3% Kondisi Maternal Diabetes, Alcoholism, Intrauterine infections

Pengkategorian kelainan genetik:

1. Single gene disorders including Mendelian Disorders (i.e, follow mendelian order of inheritance i.e. Autosomal and Xlinked and Ylinked) and NonMendelian disorders (i.e, do not follow mendelian orderof inheritance e.g. mitochondrial inheritance) MULTIFACTORIAL INHERITANCE DISORDER/POLYGENIC (COMPLEX) DISORDER Disorders with variable modes of transmission Cytogenetic disorder: including autosomal disorders and sex chromosome disorders.

2. 3. 4.

1.Single Gene Disorders

Disebabkan oleh mutasi dari single gene tertentu. - satu atau kedua chromosome. Subtipe: Autosomal dominant Misal: Huntingtons disease, Marfan syndrome
A B a b

Homologs
C
From Dad

Autosomal recessive Misal: Sickle cell anemia, Cystic fibrosis

D
From Mom

X-linked dominant trait Misal: Hypophosphatamia, X-linked recessive trait Misal: Hemophilia A, Duchenne muscular dystrophy, Color blindness,
Muscular dystrophy, Androgenetic alopecia and also includes G6PD deficiency.

Y-linked Misal: Male infertility Mitochondrial (also known as maternal inheritance), Misal: Lebers Hereditary Optic Neuropathy

Autosomal dominant inheritance pattern:

Either parent can be dominant D, and normal gene is n, here just for the example, the father is dominant I.e. affected, It is possible to construct a pattern with the mother to be dominant too but its not shown here

Autosomal recessive inheritance pattern:

recessive gene is d and normal gene is N

XLinked recessive inheritance pattern:

Mitochondrial Inheritance pattern:

Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children
A mitochondrial gene disease is transmitted : solely by women. to all her descents. Often the genetic defect is not present in allbut in a fraction only of mitochondria transmitted to the next generation; then according to the number of gene mutations in mitochondria. variable expressivity.

Marfan syndrome (autosomal dominant)

Marfan syndrome is an autosomal dominant genetic disorder of the connective tissue characterized by disproportionately long limbs, long thin fingers, a relatively tall stature and a predisposition to cardiovascular abnormalities, specifically affecting the heart valves and aorta. The disease may also affect numerous other structures and organs including the lungs, eyes, dural sac surrounding the spinal cord, and hard palate. It is named after Antoine Marfan, the French pediatrician who first described it in 1899. Pathogenesis: Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15,[6] which encodes a glycoprotein called fibrillin1. Fibrillin is essential for the formation of the elastic fibers found in connective tissue, as it provides the scaffolding for tropoelastin.[3] Elastic fibers are found throughout the body but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye, consequently these areas are among the worst affected. Without the structural support provided by fibrillin many connective tissues are weakened, which can have severe consequences for support and stability. 13

Sickle Cell Disease

PATHOLOGY

Photo Source: Del Mar Image Library; Used with permission

Normal RBC has a flexible, round shape RBC w/HbS has a normal shape until its O2 delivered to

tissue, then sickle shape occurs Stiff, non-pliable cant flow freely Trapped in small vessels = causes vaso-occlusions, tissue ischemia and infarctions painful episodes, most common area is joints Hemolysis of RBC- lifespan down to 20 days Compensatory mechanism is increased reticulocytes

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Cystic fibrosis (autosomal recessive)

Cystic fibrosis (CF), also called mucoviscidosis, is a hereditary

disease that affects the entire body, causing progressive disability and early death. Cystic fibrosis is one of the most common lifeshortening, childhoodonset inherited diseases. In the United States, 1 in 3900 children are born with CF Difficulty breathing and insufficient enzyme production in the pancreas are the most common symptoms.

Color blindness (Xlinked recessive)

Color blindness, (also known as Dyschromatopsia) or color

vision deficiency, in humans is the inability to perceive differences between some or all colors that other people can distinguish. It is most often of genetic nature, but may also occur because of eye, nerve, or brain damage, or due to exposure to certain chem Color blindness is usually classed as disability; however, in selected situations color blind people may have advantages over people with normal color vision. It is a Xlinked Recessive genetic disorder.icals.

Color Blindness

Biology, Sixth Edition

Cri du Chat Syndrome

A chromosomal deletion is responsible for cri du chat (cats cry) syndrome, which has a frequency of one in 50,000 live births (Fig. 19.12). An infant with this syndrome has a moon face, a small head, and a cry that sounds like the meow of a cat because of a malformed larynx. An older child has an eyelid fold and misshapen ears that are placed low on the head. Severe mental retardation becomes evident as the child matures. Akaryotype shows that a portion of one chromosome 5 is missing (deleted), while the other chromosome 5 is normal, as are all the other chromosomes.

Sex Chromosomal Inheritance

Too Many/Too Few Sex Chromosomes
Individuals sometimes are born with the sex chromosomes XO (Turner syndrome), XXY (Klinefelter syndrome), XXX (poly-X syndrome), and XYY (Jacob syndrome). No matter how many X chromosomes there are, an individual with a Y chromosome develops into a male.

Normal

Abnormal sex chromosomal inheritance. a. Female with Turner (XO) syndrome, which includes a web neck, short stature, and immature sexual features. b. A male with Klinefelter (XXY) syndrome, which is marked by small testes and breast development in some cases.

Table 3 - Syndromes Associated with Aneuploidy of the Sex Chromosomes

Karyotype Syndrome Frequency Description

45,X (XO)

Turner syndrome

1/5000 female live births

Phenotypic female, gonadal dysgenesis and sexual immaturity after puberty, infertility

XXY

Klinefelters syndrome

1/1000 male live births

Phenotypic male, gonadal dysgenesis and sexual immaturity after puberty, infertility

XYY (XXYY)

XYY syndrome

1/1000 male live births

Phenotypic male, behavioral abnormalities

2.Multifactorial inheritance disorders

Kelainan ini disebabkan oleh kombinasi dari variasi gen-gen kecil, yang terjadi karena pengaruh faktor lingkungan dan lifestyle. Misal: asthma
autisme autoimmune diseases such as multiple sclerosis cancers cleft palate diabetes heart disease hypertension inflammatory bowel disease mental retardation obesity

3. Disorders With Variable Modes of Transmission

Heredity malformations are congenital malformations which may be familial and genetic or may be acquired by exposure to teratogenic agents in the uterus. Heredity malformations are associated with several modes of transmission. Some multifactorial defects are cleft lip, congenital heart defects, pyloric stenosis etc. Certain congenital malformations are either multifactorial or by a single mutant gene (thus a different class of their own).

Cleft Lip/Palate

May present as single defect or combined Non-union of tissue and bone of upper lip and hard/soft palate during fetal development CL-failure of nasal & maxillary processes to fuse at 5-8 weeks gestation CP-failure of palatine planes to fuse 7-12 weeks gestation Cleft interferes with normal anatomic structure of lips, nose, palate, muscles depending on severity and placement Open communication between mouth and nose with cleft palate

CLEFT LIP & CLEFT PALATE: Operative Care

Cleft lip surgery by 4 weeks & again at 4-5 yrs Cleft palate surgery at 6-24 months of age, usually

done by 1 year so speech will not be affected Protect suture lines- priority Monitor for infection

Clean Cleft Lip incision

Pain Management Cleft Palate starts feedings 48-hour post-op: Clear and advance to soft diet No straws, pacifiers, spouted cups Rinse mouth after feeding

HIRSHSPRUNGS
Aganglionic megacolon
No ganglion cells at affected area usually at rectum/proximal portion of lower intestine Absence of peristalsis leads to intestinal distension, ischemia & maybe enterocolitis

Treatment
Mild-mod: stool softeners & rectal irrigations Mod-severe: single or 2-step surgery Colostomy with later pull-through
Photo Source: Del Mar Image Library; Used with permission

4. Cytogenetic Disorders:
These may be from alterations in the number or structure of the chromosomes and may affect autosomes or sex chromosomes. E.g. Fragile X chromosome. It is characterized by mental retardation and an inducible cytogenetic abnormality in the X chromosome. It is one of the most common causes of mental retardation. The cytogenetic alteration is induced by certain culture conditions and is seen as a discontinuity of staining or constriction of in the long arm of the Xchromosome. Other disorders include Downs Syndrome in which the number of chromosomes is increased by a third 21st chromosome and hence a total of 47 chromosomes occur.

Fragile X Syndrome
Males outnumber females by about 25% in institutions for the mentally retarded. In some of these males, the X chromosome is nearly broken, leaving the tip hanging by a flimsy thread. These males are said to have fragile X syndrome Fragile X syndrome occurs in one in 1,000 male births and one in 2,500 female births. As children, fragile X syndrome individuals appear to be normal except they may behyperactive or autistic. Their speech is delayed in development and is often repetitive in nature. As adults, they are short in stature with a long face. The jaw is prominent, and there are big, usually protruding ears Malesalso have large testicles. Stubby hands, lax joints, and a heart defect may also be seen. The symptoms, including mental retardation, are not as severe in females.

Trisomy
Faktor umur ketika melahirkan juga berpengaruh, misalnya pada Kasus Sindroma Down trisomi 21, biasanya lahir sebagai anak terakhir keluarga besar, atau dari usia ibu yang lanjut, nondisjunction terjadi pada meiosis I menghasilkan ovum yang mengandung 2 buah autosom nomor 21 dan bila ovum ini dibuahi oleh sperma normal yang membawa nomor 21 maka terbentuklah zigot trisomi 21

Non-disjunction
Down Syndrome
Nondisjunction of chromosomes during meiosis. a. Nondisjunction can occur during meiosis I if homologous chromosomes fail to separate and b. during meiosis II if the sister chromatids fail to separate completely. In either case, certain abnormal gametes carry an extra chromosome (n 1) or lack a chromosome (n 1).

Down syndrome occurs when the egg has an extra chromosome 21 due to nondisjunction in either meiosis I or meiosis II. Characteristics include a wide, rounded face and narrow, slanting eyelids. Mental retardation to varying degrees is usually present.

Downs Syndrome
Most common cause of cognitive
impairment (moderate to severe) 1 in 600 live births Risk factor- pregnancy in women over 35 yrs old Cause - extra chromosome 21 (faulty cell division) Causes change in normal embryogenesis process resulting in:
Cardiac defects, GI conditions, Endocrine disorders, Hematologic abnormalities, Dermatologic changes

Physical features: small head, flat facial

profile, broad flat nose, small mouth, protruding tongue, low set ears, transverse palmar creases, hypotonia

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Talipes (Clubfoot)
Most common type is when foot is pointed

downward and inward Often associated with other disorders May be due to decreased movement in utero Treatment requires surgical intervention Serial casting is begun shortly after birth and usually lasts for 8-12 weeks Priority nursing interventions are skin care and facilitating normal growth and development

Osteogenesis Imperfecta (OI)

Inherited disorder of connective tissue and excessive

fragility of bones Pathologic fractures occur easily Incidence of fractures decrease at puberty related to increased hormones making bones stronger Treatment is supportive: careful handling of extremities, braces, physical therapy, weight control diet, stress on home safety Surgical techniques for correcting deformities and for intermedullary rodding

Spina Bifida:
Occulta and Cystica
(meningocele and myelomeningocele)
Etilogy is unknown, but genetic &

Photo Source: Del Mar Image Library; Used with permission

environmental factors considered. Maternal intake of folic acid Exposure of fetus to teratogenic drugs The severity of clinical manifestations depend on the location of the lesion. T12 - flaccid lower extremities, sensation, lack of bowel control and dribbling urine S 3 and lower - no motor impairment Other complications may occur. Hydrocephalus (80-90%) Orthopedic issues such as scoliosis, kyphosis, club foot Urinary retention Skin breakdown/Trauma

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CONCLUSION
A genetic disorder is a disease caused in whole or in part by variation or mutation of a gene.
May or may not be heridetary. Currently about 4,000 genetic disorders are known, with more being discovered.

Reff
http://learn.genetics.utah.edu/units/disorders/whatare

gd/ http://learn.genetics.utah.edu/units/disorders/ http://www.ornl.gov/sci/techresources/Human_Geno me/medicine/assist.shtml http://www.noah-health.org/en/genetic/

THANK YOU!!!