Common genetic disease

related hormonal and

metabolism
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.
Mitochondrial : Leber optic atrophy , Mitochondrial myopathies
,Pearson syndrome

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.

Sindrom Down
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

Trisomy 21
The most frequent viable chromosome disease.
Like other inborn autosomal chromosome
diseases, associates dysmorphia + psychomotor 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 nonlymphoblastic (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.

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:
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 normal

Grafik pertumbuhan linier

Sindrom Turner
Tinggi akhir 130 - 148 cm

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 %; bitrochanteric 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

deficiency
substrate excess

product

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
About 30% of cases represent new mutations.
Absence of dystrophin, a cell membrane protein
(approximately 0.01 % of skeletal muscle protein).

All muscles involved

1. Generalized weakness and muscle wasting
affecting limb and trunk muscles first.
Calves often enlarged. Wheels at 12 y.o.

Life threatening dysrhythmia or heart failure

develops in about 10 %.
Death ay 10th-20th after pulmonary problems (breathing)

Dystrophin
Provide links between
the intracellular cytoskeleton
and the actin filaments
with the extracellular matrix
Whole complex
stabilizes the membrane.

Laminin22:
congenital MD chr 6

Sarcoglicans:
Limb Girdle MDs (4 types)
Duchenne and Becker MDs

 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-onsetobesity, 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 1