Dr Erna Mirani, M.Si.Med Tujuan Pembelajaran Mengetahui kelainan kromosomal yang menyebabkan kelainan kongenital Mengetahui kelainan metabolisme dan hormonal yang berasal dari kelainan genetik
WHAT CAUSES GENETIC CONDITIONS?
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
(b) Early Diagnosis and Treatment screened for phenylketonuria (PKU). Diagnosis and treatment within the first month of life are crucial to avoid intellectual disability.
(c) Genetic Counselling to families and individuals that have concerns about a condition in their family which may have a genetic basis. to provide information and supportive counselling so that families may be better able to understand, and adjust to, the diagnosis of a genetic condition Genetic testing, can also be organised on the basis of informed consent These tests can be used prior to conception, to determine a couple's risk of having an affected child; during pregnancy, to identify possible genetic disorders; and at birth or later in life, to assess an individual's probability of developing a disorder.
(d) Support Groups
Single-gene (also called Mendelian or monogenic) inherited in recognizable patterns: autosomal dominant, autosomal recessive, and X-linked.
Multifactorial (also called complex or polygenic is caused by a combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22.
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 dispermywhere 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.
Kelainan autosomal Gambaran dismorfik jelas Mengikuti pola pertumbuhan khas TB dewasa L = 155 cm P = 145 cm Penyebab perawakan pendek tak jelas
Tx/ dipertimbangkan hormon pertumbuhan Sindrom Down
Trisomy 21 The most frequent viable chromosome disease. Like other inborn autosomal chromosome diseases, associates dysmorphia + psycho-motor delay, and possible visceral malformations (found in more than 1/3 of cases) a medico-pedagogic care and follow up must be undertaken.
Trisomy 21 1,5 /1 000 births. Sex ratio: 3 males/2 females. Increased median maternal age (34 years). Maximal trisomy 21 births from mothers aged: The risk increases with maternal age: <0.1% below 30 yrs; between 0.1% and 1% at ages 30-40 0.2% at 34 yrs, 0.5% at 38 yrs, 0.7% at 39 yrs); >1% above 40 yrs 5% at 46 yrs, 15% at 50 yrs.
CLINICAL EXAMINATION 1 - Dysmorphic syndrome frequent microcephaly, short neck, flat occiput and brachycephaly; moon-shaped face; flat nasal bridge; "socket" nostrils; hypertelorism (or pseudo-hypertelorism); epicanthus (regresse with age); upward slanting palpebral fissures; Brushfield spots in the iris (pathognomonic, detectable in blue eyes). macroglossia; glossitis exfoliativa (geographic tongue); scrotal tongue at late childhood and in adulthood; mouth frequently open; frequently open mouth; narrow/ high arched palate; high arched narrow palate; late appearing/malformed teeth (numerical anomalies, agenesis of lateral incisors...); hands and feet: short and broad; brachymesophalangia of the 2nd and 5th fingers; clinodactyly of the 5th finger; flat feet; first toe set apart from the others by a gap, with a crease. dry skin, mottled skin (livedo), with frequent infections around orifices. hyperlaxity of ligaments. frequent umbilical hernia.
2 - Psycho-motor delay (constant): hypotonia +++ at birth (hold his head at 6 mths, sits at age 1 yr, walks at age 2 yrs). the mental retardation, not obvious in the infant, will soon become manifest. children's behaviour: affectionate, gentle, cheerful; language difficulties; like to play, to mime, to tidy up meticulously; normal memory. seizures (in 3% to 9%, as compared to 1% in the general population).
- Malformations (45% of cases): Heart (40%): atrioventricular septal defect (10 %); ventricular septal defect (10 %); patent foramen ovale (5 %); persistence of ductus arteriosus (5 %)... Digestive (10 %): duodenal stenosis (1/3 of duodenal stenosis are found in trisomy 21patients); imperforate anus... Ocular: cataract (congenital or acquired); astigmatism; myopia; strabismus; congenital glaucoma; nystagmus.
- Malformations (45% of cases): Hematologic: transient leukemoid reaction may occur sometimes with a relapse as acute leukemia (lymphoblastic (ALL) or more frequently non- lymphoblastic (ANLL) leukemias; M7-ANLL (megakaryocytic) is particularly frequent. Watch the hypersensitivity to methotrexate. Immunological: tuberculine hyporeactivity; immune deficiency. Metabolic: hyperuricemia; abnormal glycemia; increased TSH (frequent); hypo or hyper thyroidy.
Free and homogeneous trisomy 21 (92,5 % of cases): sporadic (de novo) cases. role of maternal age (see above in epidemiology). recurrence risk: 1 to 2 %. karyotype: 47,XY,+21 ou 47,XX,+21. due to meiotic non-disjunction: of maternal origin: - lst division: 70 % - 2nd division: 20 % of paternal origin: - lst division: 5 % - 2nd division: 5 %
Free trisomy 21 in mosaic (2,5 % of cases): sporadic cases. karyotype: 46, XY / 47, XY,+21 or 46, XX / 47, XX,+21. post zygotic event (mitotic). most often, the phenotype is typical, at times attenuated.
Trisomy 21 due to translocation de novo or transmitted from a parental translocation (being a balanced translocation in the parent); genetic coonseling is especially needed in the latter case.
karyotype with 46 chromosomes; the extra chromosome 21 is most often translocated with another acrocentric (groupe D: 14, 13 or 15 or groupe G: 21 or 22) chromosome; example: 46, XY, t(14;21).
genetic counseling and recurrence risk: t(Dq;21q) et t(21q;22q) of maternal origin: risk = 15 % of paternal origin: risk = 5% t(21q;21q): risk = 100 %:
either --> trisomy 21 or --> spontaneous miscarriage (monosomy 21). Other: partial trisomy 21 (rare). -->(the segment responsible for most of the syndrome/phenotype is band 21q22.3. associated with other chromosome anomalies (rare).
EVOLUTION statural delay (adult = 1,50 m); weight excess (--> diet). voice becomes hoarse. puberty is delayed but normal; poor libido; fecondity in the female ( --> contraception). hypothyroidy, Basedow (--> T3, T4, TSH, reverse T3 regular determination). mental development: (IQ) = 50 (mean (and median)); between 30 and 80; vary according to age); social insertion: partly according to the familial environment, the guidance and reassurance that the family receives, and according to the medical, paramedical, and pedagogic cares psychomotor therapy from the age of 6 mths, early aging: behaviour may suddenly switch from that of a happy and sociable child to a sad, inactive and inexpressive adult; risk of senile dementia (Alzheimer disease).
PROGNOSIS life expectancy, formerly poor, has greatly increased, due to antibiotherapy and surgery. prognosis can be impaired by: 1 - the extreme susceptibility to infections. 2 - malformations, cardiac malformations in particular. 3 - acute leukemia (in 1 % of trisomy 21 infants/children, i.e. 20 times more frequently than in the general population). TRISOMY 13 (Patau syndrome) I. Epidemiology: 0.1 / 1 000 births. increased parental age. normal pregnancy duration. life expectancy: frequently found in early miscarriages, and in late miscarriages; stillbirths are common, and babies often die in the neonatal period; very few reach adulthood. II. Clinics: microcephaly, receding forehead. microphtalmia/anophtalmia, colobomata of the iris, cataract. arrhinencephaly, probocis. hypotelorism. scalp defect (in relation with neural tube fusion defects). hare-lip / cleft palate. umbilical hernia: 1/3 of cases. genitalia: cryptorchidy in the male, uterus bicornis (constant) and vagina duplex (often) in the female. fingers in flexion position; postaxial polydactyly 80 % (hands and feet); club foot; dermatoglyphics: axial triradius in t"; thenar pattern. III. Malformations: constant, heavy, leading to early death in most of the cases. Central nervous system : arhinencephaly (50 %),hypoplasia of the corpus callosum (20 %).hypoplasia of the frontal lobe.spina bifida. Ocular: micro/anophtalmia (90 %). coloboma. retinal dysplasia. luxation or absence of lens. Cardiac (constant): ventricular septal defect. patent foramen ovale. persistence of ductus arteriosus tetralogy of Fallot. Renal (50 %): hydronephrosis. polykystic kidneys ... Digestive (50 %): malrotation of the intestine. malformation of the pancreas. gallbladder agenesis. Bones: spina bifida. rib malformations.
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.
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 Aneuploidy 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:
45, X homogeneous: 55 % of cases. isochromosomes: i(Xp), i(Xq); deleted chromosomes: del (Xp), del (Xq); rings: r(x); mosaicisms... --> phenotypes are more or less evocative of Turner syndrome some patients having been fertile. most of the phenotypic traits are due to Xp deletion, and only ovarian failure is consistently associated with Xq deletions.
Assessments:
ovarian failure (sex steroid deficiency and amenorrhea). streak gonads (germinal cells regress at the 3rd month in utero; biopsy is not needed). impaired glucose tolerance; hypertension (20-30%). autoimmune thyroid disease (T4, TSH, thyroid-antibody titer determinations). X-rays (skeleton, urinary system, heart). Differential diagnosis: other disorders with Bonnevie-Ullrich status. gonadic dysgenesia. other disorders with primary amenorrhea; e. g.: XY females (sex reversal).
Grafik pertumbuhan linier Sindrom Turner
Tinggi akhir 130 - 148 cm Grafik pertumbuhan normal Sindrom Klinefelter (47 XXY ) Hanya pada anak laki-laki. Retardasi mental (tidak semua) Tinggi dengan proporsi eunuchoid Ginekomastia Testes kecil dan keras volumenya tidak lebih dari 6 ml. Klinefelter syndrome is a syndrome of a normal or gynecoid male with normal intelligence or mild retardation, infertility, and possible behaviour or psychiatric problems, due to a chromosome imbalance: 47, XXY and variants.
Epidemiology: 1.5 /1 000 male births. ,increased maternal age. ,the extra X comes more often from the mother. Clinical ascertainment/examination: wide variability in clinical expression, rarely diagnosed in childhood (from mental retardation or non specific anomalies of genitalia), more often at puberty (from gynecomastia, small testes), or when consulting for infertility. physical aspect is often normal, they may present with tallness and macroskelia, or with gynecoidy (gynecoid obesity: 25 %; gynecomastia: 15-25 %; bi- trochanteric diameter > bi-acromial diameter). normal penis. small, indolent testes. normal or rare, feminine shaped pubic pilosity. libido diminished; impotence at age 30 yrs is frequent. sterility. normal or moderately delayed intellectual development. dyslexia/dysphasia and frontal-executive dysfunction. psychiatric behaviour is not rare. 50-fold increased risk of developing breast cancer as compared to normal males (and 8 times less than in females, as the womens risk is 400 times that of men) (nearly 10% of breast cancers in males are found in Klinelter patients).
Diagnosis: the karyotype: 47 XXY homogeneous: 80 % of cases. XXXY, XXXXY, XXYY: 10 %. in mosaic: 5-10 % (may (rarely) be fertile). Assessments: high gonadotropins and low testosterone plasma levels. azoospermia in most non-mosaic cases; however, intratesticular residual foci of spermatogenesis may occasionally be found, and mature spermatozoa may permit paternity using intracytoplasmic sperm injection. biopsy (not needed): seminiferous tubes atrophia, Leydig hyperplasia . Treatment: testosterone replacement therapy to correct the androgen deficiency and to provide virilization; can also has positive effects on mood and self-esteem. Metabolic disease What is a metabolic disease? Garrods hypothesis
product deficiency substrate excess toxic metabolite A D B C 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) 1. Generalized weakness and muscle wasting affecting limb and trunk muscles first. Calves often enlarged. Wheels at 12 y.o. X-linked recessive disorder; 1/3500 boys worldwide About 30% of cases represent new mutations. Life threatening dysrhythmia or heart failure develops in about 10 %. Absence of dystrophin, a cell membrane protein (approximately 0.01 % of skeletal muscle protein). All muscles involved Death ay 10 th -20 th after pulmonary problems (breathing) Dystrophin Provide links between the intracellular cytoskeleton and the actin filaments with the extracellular matrix Duchenne and Becker MDs Sarcoglicans: Limb Girdle MDs (4 types) Laminin22: congenital MD chr 6 Whole complex stabilizes the membrane. Clinical Examination on identification of areas of muscle strength and weakness and the progression of weakness Family History/Genetic Testing Nerve Conduction and Electromyogram Serum Enzyme Tests muscle mass may be so reduced that serum protein levels may even appear normal. Tests routinely used for diagnosis include creatine kinase, aldolase, lactic dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) levels, pyruvate kinase (PK) Muscle Biopsy - FRAGILE X SYNDROMES (Fragile Xq or fra(X)(q28)) . Epidemiology: FRAXA: 0.2 / 1 000 male births and 0.1 / 1 000 female births. FRAXE: 0.02/ 1 000 male births. II. Clinics: the face reminds of the one found in trisomy 8. macrocephaly. high forehead. midface hypoplasia. large nasal root. prognathism. thick lips. high palate. large, unfolded ears. macroorchidy. fertility is often normal.
Mental development and psychiatric behaviour In the male: Mental retardation is mild to severe (mean IQ = 50): from a delay in school training to the impossibility to acquire writing and reading skills. The Fragile Xq young child is often hypotonic; in the more severe forms, a psychomotor delay is already present (delay in walking...). Speech difficulties: delay language appearance, dysarthria, omissions, mumblings, echolalias (tendency to repeat the same sentences and to ask the same questions). Behaviour problems: anguish, attention deficit, hyperactivity, impulsiveness, escape of glance, resistance to change, aggressiveness, self-mutilation, stereotypies (wings beating, "flapping") and oddities. Sometimes all these symptoms are present, and constitute an autistic syndrome. The various studies carried out among the autists show that 5 to 7 % autists are Fragile Xq. In the female: - The mental retardation is mild or absent. - They can present with: school difficulties (less than in the boy), memory disorders, changing mood, timidity, relational difficulties, and depressive tendency. These symptoms are often misinterpreted for social causes. IV. Diagnosis: the karyotype can show recurrent gaps in Xq27-q28; however, the diagnosis now rely on the molecular study of the genes.
THE PRADER-WILLI SYNDROME is a complex multisystem disorder characterised by a variety of clinical features characterised by hyperphagia, childhood-onset- obesity, severe muscle hypotonia, a typical facies, hypogonadism with absence of a pubertal growth spurt, short stature, small hands and feet and delayed developmental milestones. The typical facial features include a small forehead, almond shaped eyes, micrognathia, a thin upper lip and down-turned corners of the mouth a multistage disorder characterised by three different phases . 1. the hypotonic phase,; varying degrees of hypotonia during the neonatal period and early infancy, a weak cry, hypothermia, hypogenitalism and a poor suck reflex usually necessitating gavage feeding ]. During the first year, PWS children are defined as friendly, easy going and affectionate argumentativeness, anxiety and obsessive compulsive symptoms . 2. the hyperphagic phase, which usually starts between the ages of one and two ; - a voracious appetite, hyperphagia, foraging for food, early onset of childhood obesity, physical inactivity, decreased pain sensitivity, disturbed thermoregulation, psychomotor retardation, speech articulation difficulties and cognitive dysfunction. Simultaneously, with the change in eating pattern, PWS individuals show significant maladaptive behavioural and emotional characteristics including temper tantrums, inappropriate social behaviour, automutilation (skin picking), stubbornness, mood lability, impulsivity, argumentativeness, anxiety and obsessive compulsive symptoms. The third phase adolescence and adulthood -dominated by health problems secondary to obesity - These include scoliosis, dental problems, diabetes mellitus, hypertension, hypercholesterolemia, osteoporosis - About 10% of the adolescents and adults develop major psychiatric problems ranging from severe and agitated depression to psychotic episodes -The psychotic episodes in PWS patients have many features in common including an acute onset, a polymorphous and fluctuating symptomatology with anxieties, agitation, abnormal beliefs and auditory hallucinations. These episodes are classified as acute cycloid psychosis Dysfunction of the hypothalamus may be the basis of a number of symptoms in the Prader-Willi syndrome. The fetal hypothalamus plays a major role in labour and hypothalamic dysfunction may explain the high proportion of children born prematurely or postmaturely. Abnormal LSH-releasing hormones are thought to be responsible for the decreased levels of sex hormones resulting in non-descended testes, undersized sex organs, amenorrhoea and insufficient growth during puberty. Growth hormone deficiency due to hypothalamic dysregulation contributes to the abnormal growth pattern, excess of body fat and deficit of lean body mass with consequent reduced energy expenditure. Hypothalamic disturbances cause aberrant control of body temperature and daytime hypersomnolence. The insatiable hunger and hyperphagia is probably a consequence of the decreased number of oxytocine neurones- the putative satiety neurones in the hypothalamic paraventricular nucleus Molecular genetics of the Angelman and the Prader- Willi syndrome result from loss of paternal or maternal expression, respectively, of genes located on the human chromosome 15q11-13 region Different molecular mechanisms leading to this loss of expression have been identified, including intragenic mutations, uniparental disomy and imprinting defects: 1. Microdeletions 75% of the PWS patients and 70% of the AS patients have large chromosomal deletions of +/- 4 Mb of the same chromosomal 15q11-13 region,). In PWS there is a deletion on the paternally inherited chromosome, while in Angelman there is a deletion on the maternally inherited chromosome. 2. Single gene mutations in PWS and AS There are no known PWS patients with a single gene mutation, suggesting that PWS is a continuous gene syndrome. In 4 % of the cases, Angelman is caused by mutations in the Ubiquitin ligase gene, UBE3AC 3. Imprinting defects in PWS and AS IC defects are found in 2 % of the AS cases and in less than 1 % of the PWS cases. 4. Uniparental disomy in PWS and AS Uniparental disomy occurs in 24% of the PWS patients (maternal disomy) and in 3- 5% of AS patients (paternal disomy). The most likely explanation is trisomy 15 rescue, suggested by the observation of trisomy 15 mosaicism in patients with unusual PWS manifestations
Penugasan Setiap SGD membuat materi tentang penyakit dibawah ini : 1. Down sindrome 2. Patau Syndrome 3. Fragile X sindrome 4. Marfan sindrome 5. Deuschene muscular distrophy (DMD) 6. Prader wili syndrome 7. Turner syndrome 8. Klinefelter syndrome 9. Galactosemia 10. Phenyl ketonuria 11. Glycogen storage disease 12. Congenital adrenal hiperplasia 13. CAIS (complete adrenal onsufisiensi syndrome)/PAIS
Penugasan materi di buat perorangan dan diberi nama di jilid menjadi satu untuk 1 SGD. tugas diketik dengan spasi 1,5 Bila ada yang ketahuan copy paste/ mencuplik dari pekerjaan temannya maka baik yang mencopy atau yang di copy nilai dibatalkan Pekerjaan paling lambat di kumpul sebelum SGD 2 LBM 3