Kelainan Genetik

dr. Zainuri Sabta N

Departemen Anatomi Fakultas Kedokteran UII

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

GENETIC DISORDERS AND HEREDITARY DISORDERS

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 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 Genetik42% unknown8% Taratogen - Obat : Thalidomide , Warfarin , Tetracycline3% 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 X‐linked and Y‐linked) and Non‐Mendelian disorders (i.e, do not follow mendelian orderof inheritance e.g. mitochondrial inheritance)

2. MULTIFACTORIAL INHERITANCE DISORDER/POLYGENIC (COMPLEX) DISORDER

3. Disorders with variable modes of transmission4. Cytogenetic disorder: including autosomal disorders and sex

chromosome disorders.

1.Single Gene Disorders

Disebabkan oleh mutasi dari single gene tertentu. - satu atau kedua chromosome.

Subtipe:Autosomal dominantMisal: Huntington’s disease, Marfan syndrome

Autosomal recessiveMisal: Sickle cell anemia, Cystic fibrosis

AB

C

D

ab

c

d

Homologs

From Dad

From Mom

X-linked dominant traitMisal: Hypophosphatamia,

X-linked recessive traitMisal: Hemophilia A, Duchenne muscular dystrophy, Color blindness, Muscular dystrophy, Androgenetic alopecia and also includes G‐6‐PD deficiency.

Y-linkedMisal: Male infertility

Mitochondrial (also known as maternal inheritance),

Misal: Leber’s 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 it’s not shown here

Autosomal recessive inheritance pattern:

recessive gene is “d” and normal gene is “N”

X‐Linked 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 all‐but in a fraction only of mitochondria transmitted•to the next generation; then according to the number of gene mutations in mitochondria.•variable expressivity.

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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 fibrillin‐1. 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 providedby fibrillin many connective tissues are weakened, which can have severe consequences for support and stability.

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Sickle Cell Disease

PATHOLOGY Normal RBC has a flexible, round shape RBC w/HbS has a normal shape until it’s O2

delivered to tissue, then sickle shape occurs Stiff, non-pliable – can’t 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

Photo Source: Del Mar Image Library; Used with permission

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 life‐shortening, childhood‐onset 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 (X‐linked 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 X‐linked Recessive genetic disorder.icals.

Biology, Sixth Edition

Chapter 10, The Basic Principles of Heredity

Color Blindness

Cri du Chat SyndromeA chromosomal deletion is responsible for cri du chat (cat’scry) syndrome, which has a frequency of one in 50,000 livebirths (Fig. 19.12). An infant with this syndrome has a moonface, a small head, and a cry that sounds like the meow of acat because of a malformed larynx. An older child has aneyelid fold and misshapen ears that are placed low on thehead. Severe mental retardation becomes evident as thechild matures. Akaryotype shows that a portion of one chromosome5 is missing (deleted), while the other chromosome5 is normal, as are all the other chromosomes.

Sex Chromosomal InheritanceToo Many/Too Few Sex Chromosomes

Normal

Individuals sometimes are born with the sexchromosomes 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 Ychromosome develops into a male.

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 Klinefelter’s 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 (thusa 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

HIRSHSPRUNG’S

Aganglionic megacolonNo ganglion cells at affected area usually at rectum/proximal portion of lower intestineAbsence of peristalsis leads to intestinal distension, ischemia & maybe enterocolitis

Treatment Mild-mod: stool softeners & rectal irrigationsMod-severe: single or 2-step surgeryColostomy 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 X‐chromosome.

Other disorders include Down’s Syndrome in which the number of chromosomes is increased by a third“21st chromosome” and hence a total of 47 chromosomes occur.

Fragile X SyndromeMales 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 birthsand 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.

TrisomyFaktor 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, non-disjunction 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-disjunctionDown Syndrome

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.

Nondisjunction of chromosomes during meiosis.

a. Nondisjunction can occur during meiosis I if homologouschromosomes fail to separate and

b. during meiosis II if the sisterchromatids fail to separate completely. In either case, certainabnormal gametes carry an extra chromosome (n 1) or lack achromosome (n 1).

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Down’s 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

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

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Spina Bifida: Occulta and Cystica (meningocele and myelomeningocele)

Etilogy is unknown, but genetic & 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

Photo Source: Del Mar Image Library; Used with permission

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/whataregd/

http://learn.genetics.utah.edu/units/disorders/ http://www.ornl.gov/sci/techresources/

Human_Genome/medicine/assist.shtml http://www.noah-health.org/en/genetic/

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THANK YOU……!!!