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Step 7 LBM 2 Modul Git
Step 7 LBM 2 Modul Git
• Heritable conditions
Due to a mutation in a single gene
• Chromosomal conditions
Packaging errors caused by structural changes in the
chromosomes or the gain or loss of whole chromosomes, (or
parts of chromosomes) during either the formation of the egg or
sperm or at conception
• Multifactorial conditions
Due to the interaction of the genetic information and
environmental factors such as diet, chemical exposure and
lifestyle
WHAT CAN BE DONE ABOUT GENETIC
CONDITIONS?
• (a) Prevention
to prevent about 70% of the cases of spina bifida in babies if women take
the vitamin folic acid before, and continue it during early pregnancy
Chromosomal :
Abnormalities in chromosome structure as missing
extra copies
gross breaks
rejoinings (translocations), can result in disease. Down syndrome
or trisomy 21 is a common disorder
Chromosomal disorders
• The two most common :
– aneuploidies, trisomies and extra sex chromosomes, can be due
to maternal or paternal factors, including advanced age.
– A number of aneuploidies can be attributed to dispermy—where
two sperm fertilized one egg. The resulting genetic disorders can
occur due to a spontaneous mutation, and a familial tendency
towards these disorders cannot always be found.
– Aneuploidy of the sex chromosomes can cause abnormal
genital development, sterility, and other growth problems. The
most common such aberration are multiple X syndromes. ;
• Triple X females can bear normal children.
• Males with an XXY aneuploidy are afflicted with Klinefelter's
syndrome, have small testes and cannot produce sperm.
• Men with XYY aneuploidy are born more frequently (about 1 in
every 200-1,000 males) than most aneuploidies, and controversy
exists as to whether these individuals have a higher criminal
tendency than the rest of the male population.
Trisomi
– Trisomies make up to 52% of chromosomal abnormalities, with
trisomies 14, 15, 16, 18, 21, and 22 being the most frequent.
– Live-born children with autosomal aneuploidies have trisomy
13, 18, or 21, and all have some mental retardation.
– Trisomy 13 (Patau's syndrome) is characterized by retarded
growth, cleft lip, small head and chin, and often polydactyly.
– Trisomy 18 (Edward's syndrome) is marked by severe, variable
abnormalities of the head, thumbs, ears, mouth, and feet.
– Trisomy 21 (Down syndrome) occurs equally in all ethnic
groups, and is closely related to increased maternal age.
Children with Down syndrome can have poor muscle tone, a
flattened face, extra folds of skin at the eyes, low-set ears, visible
(Brushfield) spots on the iris of their eyes, and a single crease
along the palm of their hands.
Sindrom Down
•Kelainan autosomal
•Gambaran dismorfik jelas
•Mengikuti pola pertumbuhan khas
•TB dewasa L = 155 cm P = 145 cm
•Penyebab perawakan pendek tak jelas
• IV. Karyotype:
– most often free and homogenous trisomy.
– sometimes translocation t(13q 14q).
– sometimes mosaic trisomy.
- TRISOMY 18
• Epidemiology:
– 0.2 / 1 000 births.
– increased parental age.
– pregnancy duration is often prolonged.
– life expectancy: frequently found in miscarriages; stillbirths are
common, and babies often die in the neonatal period; very few
reach adulthood.
• II. Clinics:
– hydramnios; single umbilical artery frequently.
– low birth weight: 2,3 kg.
– constant sign: hypoplasia of the first branchial arch, which
implicates:
• --> low set ears
- TRISOMY 18
– short thorax and sternum, making the
abdomen looking long.
– hernias: diaphragmatic, umbilical, inguinal.
– cryptorchidism (30 %).
• clubfoot; irreducible flexion of forearms;
dysplastic nails, absence of distal flexion
crease of fingers; clenched fingers with
overlap of the 2nd and 5th onto the 3rd
and 4th; dermatoglyphics: frequency of
arches
- TRISOMY 18
• Malformations: constant, heavy, leading to early death in
most of the cases.
– Cardiac: constant.
• ventricular septal defect.
• patent foramen ovale.
• persistence of ductus arteriosus
• valves anomaly, in particular mitral valve
– Renal (1/3): mostly horseshoe kidney, hydronephrosis,
polykystic kidneys, hyploplastic kidneys.
– Digestive: frequent; Meckel, anal atresia; pancreas anomalies.
– Brain
– Bones: spina bifida, hemivertebrae , absence of clavicle.
• IV. Karyotype:
– most often free and homogenous trisomy.
– frequency of doubles aneuploidies and mosaics.
Aneuploidy
Sindrom Turner
•Kromosom 45 X atau mosaik
•Patogenesis tak jelas
•Mungkin kelainan fungsional
poros hipotalamus hipofisis
•Respon terhadap GHRH akut rendah
Tx/
•Hormon pertumbuhan
•steroid anabolik
•Estrogen dosis rendah
diagnosis
• The diagnosis can be evoked either:
– in the newborn (from dysmorphia and/or malformations), or:
– in the girl (from growth retardation, impuberism).
• neo-natal form:
– prenatal (and postnatal) growth retardation
– single umbilical artery frequently.
– Bonnevie-Ullrich (BU) status associating:
• lymphoedema of hands and feet (tough, non inflammatory,
regressive at age 2 yrs).
• excess of skin and webbed skin on the nucha (pterygium colli).
• 1/3 of BU are found in Turner syndrome, and 75 % of Turner have a
BU In the presence of this symptomatology, a karyotype will be
undertaken and (cardiac, renal) malformations will be searched for.
Malformations:
– cardiovascular (20-30%): aortic coarctation (10-15 %) which may
lead to death by dissection or rupture of the aorta; bicuspid aortic
valve; left superior vena cava, and other malformations; in the
presence of aortic coarctation in a girl, a Turner syndrome must
be evoked.
– renal (40-50 %): horseshoe kidney, hydronephrosis...
– congenitally dislocated hip, scoliosis
– sense-organs: deafness (impaired hearing in up to 40%),
myopia, cataract, strabismus.
– X linked recessive inherited traits have the same frequency in
Turner syndrome and in the male, since they both have only 1 X;
this frequency is that of the allele (e.g. daltonism, hemophilia,
Duchenne de Boulogne myopathy...).
karyotype:
• Garrod’s hypothesis
A B C product
deficiency
substrate excess D
toxic metabolite
Inborn errors of metabolism
Definition:
Inborn errors of metabolism occur from a group of
rare genetic disorders in which the body cannot metabolize
food components normally. These disorders are usually
caused by defects in the enzymes involved in the
biochemical pathways that break down food components.
Alternative Names:
Galactosemia - nutritional considerations; Fructose
intolerance - nutritional considerations; Maple sugar urine
disease (MSUD) - nutritional considerations;
Phenylketonuria (PKU) - nutritional considerations;
Branched chain ketoaciduria - nutritional considerations
Background:
Inborn errors of metabolism (IEMs) individually are
rare but collectively are common. Presentation can occur at
any time, even in adulthood.
Diagnosis does not require extensive knowledge of
biochemical pathways or individual metabolic diseases.
An understanding of the broad clinical manifestations
of IEMs provides the basis for knowing when to consider
the diagnosis.
Most important in making the diagnosis is a high
index of suspicion.
Successful emergency treatment depends on prompt
institution of therapy aimed at metabolic stabilization.
A genetically determined
biochemical disorder in which a
specific enzyme defect produces a
metabolic block that may have
pathologic consequences at birth
(e.g., phenylketonuria) or in later life
(e.g., diabetes mellitus); called also
enzymopathy and genetotrophic
disease.
Classification
Inborn Errors of Small molecule Metabolism
Example: Galactosemia
Lysosomal storage diseases
Example: Gaucher's Disease
Disorders of Energy Metabolism
Example Glycogen Storage Disease
Other more rare classes of metabolism error
Paroxysmal disorders
Transport disorders
Defects in purine and pyrimidine metabolism
Receptor Defects
PKU
Pathophysiology:
Single gene defects result in abnormalities in the
synthesis or catabolism of proteins, carbohydrates, or fats.
Most are due to a defect in an enzyme or transport
protein, which results in a block in a metabolic pathway.
Effects are due to toxic accumulations of substrates
before the block, intermediates from alternative metabolic
pathways, and/or defects in energy production and utilization
caused by a deficiency of products beyond the block.
Nearly every metabolic disease has several forms that
vary in age of onset, clinical severity and, often, mode of
inheritance.
Metabolic disease (AR)
• Galactosemia :
- cannot metabolize galactose, the sugar found in milk
- mental retardation may result if normal milk is not avoided by
people with this rare disease
• PKU :
– cannot convert phenylalanine to tyrosine.
– The build-up of phenylalanine leads to severe mental retard.
– 1 in 50 Caucasians.
– can be controlled by diet/ A phenylalanine-free diet containing
sufficient amino acids is available for people diagnosed with
PKU.
– Since 1961, a test has been available to readily screen
newborns for PKU from a blood test, and most states perform
this test routinely.
Syndrom related hormonal
disorders
Sindrom Johanson-Blizzard
•retardasi mental derajad bervariasi
•alae nasi hipoplastik atau aplstik
•gigi susu hipoplastik, gigi permanen (-)
•kriptorkidisme
•mikropenis
•vagina rangkap atau septum
•hidronefrosis
•hipotiroidisme primer
•insufisiensi pankreas
Marfan's syndrome
(arachnodactyly)
• long, thin arms, legs, and fingers.
• stoop-shouldered and have blue sclera of the
eyes.
• a high incidence of eye and aortic heart
problems.
• Statistics show some correlation between older
fathers and offspring with Marfan's.
• Not all people with Marfan's inherit it from a
parent
• about 15% of Marfan's cases are caused by a
fresh mutation in the same locus.
Pathogenesis
• The fibrillin-1 (FBN1)
gene encodes the
glycoprotein fibrillin, a
major building block of
microfibrils
• The microfibrils constitute
the structural components
of the suspensory
ligaments of the lens, and
serve as a substrates for
elastin in the aorta and
the other connective
tissues
Cystic Fibrosis
• CF is one of the most common autosomal
recessive diseases in Caucasian children
• in the U.S. About 4-5% of Caucasians carry this
recessive gene on chromosome 7,
• causes exocrine mucus-producing glands to
secrete an unusually thick mucus that clogs
ducts and collects in lungs and other body
areas.
• CF patients usually die before the age of 20,
while some individuals live to the age of 30.
Duchenne muscular dystrophy
(DMD)
X-linked recessive disorder; 1/3500 boys worldwide
Whole complex
stabilizes the membrane.
Laminin2α2:
congenital MD chr 6
Sarcoglicans:
Limb Girdle MDs (4 types)