Eva Diah Setijowati

AUTOSOMAL DOMINANT INHERITANCE

Parents

Gametes

AUTOSOMAL DOMINANT INHERITANCE

Parents

Gametes

At
conception

AUTOSOMAL DOMINANT INHERITANCE

Parents

Gametes

At
conception

AUTOSOMAL DOMINANT INHERITANCE

Parents

Gametes

At
conception

AUTOSOMAL DOMINANT INHERITANCE

Parents

Gametes

At
conception

AUTOSOMAL DOMINANT INHERITANCE

Parents

Gametes

At
conception

Affected

Affected

Unaffected

 One

Trait, 2 alleles
A = dominant abnormal allele
a = recessive normal allele

Homozygous dominant = affected, often lethal (AA)

Heterozygous dominant = affected (Aa)

Homozygous recessive = normal (aa)

 One parent affected (usually

heterozygous)
Second parent normal
50% chance for affected offspring
50% chance for normal offspring
Males and females equally
affected
Penetrance
Variable expression

 Vertical
Equal numbers of males and

females affected

One parent genotypically &

phenotypically normal

Other parent heterozygous

affected

50% recurrence risk

 Marfans Syndrome

Huntingtons Chorea
Neurofibromatosis

Achondroplasia

Myotonic dystrophy

Clinical hallmarks:
Facial weakness, distal extremity weakness, neck muscle
weakness, myotonia (usually not prominent) frontal
baldness, cataracts, gonadal atrophy, cardiomyopathy,
diabetes, percussion myotonia on exam
Prevalence 1/8000 in Caucasian
Inheritance: Autosomal dominant with variable
expression and anticipation

Chromosome: 19q13
Gene affected: Myotonin (a protein kinase)
Mutation: Expanded CTG trinucleotide repeat in
3 UTR of myotonin gene
Two types of Myotonic Dystrophy :
MD1 is known as Type 1
MD2 is know as Type 2 ( also known as PROMM or
"Proximal Myotonic Myopathia" )

Mildest Mildest [CTG]n < 150 repeats

Onset: middle to old age
Mayor findings: cataracts, minimal or no muscle abnormality
Classical Classical [CTG]n 300-1000 repeats
Onset: adolescence and early adult life
Mayor findings: myotonia, muscle weakness (face, forearms,
foot dorsiflexors)
Congenital Congenital [CTG]n > 1500 repeats with some cases
occuring with sizes as small as 800 repeats
Onset: at birth, frequent history of hydramnios and reduced fetal
movements.
Mayor findings: neonatal respiratory distress, hypotonia, bilateral
facial weakness, feeding difficulty, talipes, mental retardation.

Lab: mildly elevated serum creatine kinase

Electromyography to identify subclinical myotonia
Slit-lamp examination to detect characteristic cataracts
Muscle biopsy (diagnostic but not for routine clinical
evaluation)
Atrophic small type I fibers
An increase in central nuclei
Ringed fibers

Radiography
Electrocardiogram abnormalities
DNA testing
CTG repeat size gold standard for the diagnosis of
MD1
PCR test (beware false negatives!) or Southern blot test
(essential if PCR does not show two distinct products)
Prenatal testing available

Neurofibromatosis type I (NF1) is caused by mutation in

the neurofibromin gene

Von Recklinghausen disease , Watson disease

An autosomal dominant neurogenetic disorder

Characterized by the presence of multiple benign

neurofibromas

Affects the bone, the nervous system, soft tissue, and the
skin

Clinical symptoms increase over time (can involve various

body systems over time)

Neurologic problems and malignancy may develop

There are two main types of neurofibromatosis, NF1 and NF2.

NF1 is by far the more common, with an incidence at birth of
approximately 1 in 3000.
Signs can range from benign cutaneous manifestations to
extreme disfigurement
The mortality rate is higher than that of the healthy population
because of the increased potential for malignant transformation
of diseased tissues and the development of neurofibrosarcoma

Patients with NF-1 have about a 3-15% additional risk of

malignant disease in their lifetime

All racial groups are affected equally

Women and men are affected equally

The spontaneous mutation rate is 100 times greater than for
many genes, and approximately 50% of cases of NF1 are due to
new mutations

(The diagnostic criteria are met

if 2 or more of the features
listed are present.)

Six or more caf au lait macules

larger than 5 mm in greatest
diameter in prepubertal
individuals and those larger than
15 mm in greatest diameter in
postpubertal individuals
Two or more neurofibromas of
any type or 1 plexiform
neurofibroma
Freckling in the axillary or inguinal
regions
Optic glioma
Two or more Lisch nodules (iris
hamartomas)
A distinctive osseous lesion, such
as sphenoid dysplasia or thinning
of the long bone cortex, with or
without pseudoarthrosis
A first-degree relative with NF-1
according to the above criteria

Scoliosis
Pseudarthrosis of the tibia
Pheochromocytoma
Meningioma
Glioma
Acoustic neuroma
Optic neuroma
Mental retardation
Hypertension
Hypoglycemia
Fibromas in Iris
Glaucoma - rare

Most common benign tumor of NF-1

These tumors are made of Schwann

cells, fibroblasts, mast cells, and
vascular components
They can form at any place along a
nerve

Three subtypes of neurofibroma

exist: cutaneous, subcutaneous, and
plexiform
Cutaneous lesions and subcutaneous
lesions are circumscribed. These
nodules may be brown, pink, or skin
colored. They may be soft or firm to
the touch
Plexiform neurofibromas are
noncircumscribed, thick, and
irregular, and they can cause
disfigurement by entwining
important supportive structures
Cellular loss of wild type NF1 allele is
associated with neurofibromas

Neurofibromin is a cytoplasmic protein that

is expressed in neurons, Schwann cells,
oligodendrocytes, astrocytes and leukocytes
Neurofibromin acts as a tumor suppressor
It is encoded by the gene NF1
It is located on chromosome 17, at the band
q11.2
In 95% of NF1 individuals, a mutation is
found in the NF1 gene

Surgery
Chemotheraphy (10-20% malignancies )
Death, because of malignancies

Obvious phenotype documented throughout

history
- Ancient Egyptian artwork

- Diego Velazquez series

of dwarf paintings in the 1600s

Disease most
associated with
human
dwarfism
Occurs in 1 /
15,000
17,000 people

Symptoms of Achondroplasia
Abnormal body
proportions
-Short arms and
legs, normal torso
size
-Reduced height
-Upper arms/thighs
more shortened
than
forearms/lower legs
(Rhizomelia)

Facial Features
Large head
Indicates
hydrocephalus

Flat nose at bridge

Other Features
Shortened, stubby
fingers
Trident Hand
Separation between
middle and ring
fingers

Childhood Problems
Hump on back
Usually disappears
after child begins
walking

Delayed Walking
and Bowed Legs
Markedly Curved
Spine
After walking

Achondroplasia (ACH) is caused by a missense

mutation in FGFR3 (fibroblast growth factor
receptor 3) on chromosome 4p in humans

This nucleotide, # 1138 in exon 10 on

chromosome 4, has the highest mutation rate
known
In 97% of patients, an adenine replaces the
normal guanine at this position (observed in
cDNA)

 Achondroplasia
literally
means
without
Cartilage
and
Bones
cartilage
However, because FGFR3 limits bone
development, when there is a mutation on
the gene, it causes malfunctions in bone
growth
Cartilage is not properly converted to bone,
so there is a shortage of bone

Studies show correlation with paternal age

Appears that the vast majority of FGFR3 mutations
arise as new mutations during spermatogenesis
before Meiosis I
All mutations studied so far occur on the paternal
chromosome

Achondroplasia

aa = unaffected

Aa = dwarf
AA = embryonic lethal

a
a

80-90% of cases from a spontaneous de novo

mutation (in spermatogenesis of father)
20% inherited from one or two affected parents

Aa

aa

Aa

aa

Affected parent and nonaffected parent

50% chance of having
affected child

A
AA

a
Aa

Aa

aa

Both parents affected

75% chance of having affected child

Diagnosa Prenatal
Dengan analisa DNA untuk mengetahui mutasi
FGFR 3 dan USG untuk melihat adanya kelainan
skeletal serta panjang, bentuk dan kalsifikasi
tulang
Diagnosa setelah bayi lahir/masa neonatus
Dengan ukuran panjang yg kurang ( lahir rata-2
panjang
46.90 cm); terutama tungkai pendek sekali dan
dilakukan X-ray untuk kepastian diagnosa. Pada
MRI didapatkan spinal stenosis pada
lumbal/foramen magnum

Dystrophia dysplasia; kelainan pada lengan tungkai,

telinga yang tak ada pada achondroplasia
Defisiensi kel. thyroid
Ibu dan ayah memang pendek
Defisiensi kel. pituitari
Hypochondroplasia; beberapa dengan retardasi
mental; Tb >achondroplasia
Sindroma Turner

Inherited disorder of the connective tissue that

causes abnormalities of the patients eyes,
cardiovascular system, and musculoskeletal
system
Inheritance: Autosomal dominant
French pediatrician, Antoine Marfan (18581942), who first described it in 1896
It is estimated that one person in every 3,0005,000 has Marfan syndrome

Single gene disorder

15-25% caused by spontaneous mutation
FBN1 gene on 15q21, a large gene with 65
exons spanning 200kb and containing five
distinct regions, or domains
Most are missense
Mutation causes defect in Fibrillin protein
production

a protein that is an important part of

connective tissue
the primary component of the microfibrils
that allow tissues to stretch repeatedly
without weakening

connective tissues are looser than usual,

which weakens or damages the support
structures of the entire body

Three major organ systems of the body: the

heart and circulatory system, the bones and
muscles, and the eyes

Cardiovascular system disorders

Skeletal disorders
Eye disorders
Family history

Aortic enlargement
Aortic regurgitation
Mitral valve prolapse

Scoliosis
Kyphosis
Spondylolisthesis
Dural ectasia

Pectus excavatum
Pectus carinatum
Foot disorders: Flat feet, Chronic pain
Protrusio acetabulae

Myopia
Ectopia lentis
Cataracts
Retinal detachment

Depend on the specific symptoms of each

patient.
Cardiovascular : should be monitored with an
echocardiogram every 6 months (until it is
clear that the aorta is not growing larger)
(After that) echocardiogram 1x / year
MEDICATIONS : beta-blockers ( blood
pressure & forcefulness of the heartbeat
the rate of aortic enlargement )
prophylactic antibiotic, ex. Penicillin and
amoxicillin (before having dental work or
minor surgery) risk of endocarditis

SURGICAL : if the width of the patients aorta

increases rapidly or reaches a critical size
(about 2 in, 5 cm)
Scoliosis between 20 and 40 in children is
usually treated with a back brace.
Dislocation of lens : combination of special
glasses & daily use of 1% atropine sulfate
ophthalmic drops, OR surgery

Life expectancy (1995) : up to 72 years

(increase from 48 years in 1972).

Huntington Disease (HD) is a genetically

inherited disorder which involves gradual loss
of nerve cells in the brain.
It is sometimes referred to as Huntington's
chorea due to abnormal movements of the
arms and legs (chorea).
HD is named after Dr George Huntington who
recognised that it was was an inherited
condition in 1872.

Huntington disease affects about 1 in 10 000

people.
It affects men and women equally and and occurs
in people of all ethnic origins.
4p16.3
Trinucleotida repeat : CAG in 5' translated region
Normal 26
Mutable 27-35
Reduced penetrance 36-39
Fully penetrant 40
Early onset form : Juvenile, usually paternally
transmitted

MOTOR

KOGNITIF

EMOSIONAL

Clinical Classification
Movement/Cognitive/Psychiatric disorder
Mean onset age 35-55 years.

Genetic Testing
Diagnostic
Presymptomatic counselling protocol.

Physical features:
- involuntary movements
- weight loss
- abnormal gait
- speech & swallowing difficulties.

Psychiatric Manifestations:
- personality changes
- depression
- aggression
- early onset dementia.

Gangguan
keseimbangan

Chorea:gerak
tanpa sadar
Sulit tidur,
gelisah
Gerak mata
pelan

Normal

HD lanjut

Kesulitan
menelan
Gerak
perlahan

The age at which symptoms first appear varies but it has

been found that the longer the triplet repeat, the earlier in
life the symptoms start.
Generally the first symptoms become apparent between the ages 35
and 50, appear slowly and are often not noticed by the person

It has been shown that the triplet repeat

tends to expand (become longer) from one
generation to the next.
This is referred to as anticipation and means
that symptoms may start earlier in life and be
more severe when the altered gene is passed
on to the next generation.

GENE

Protein

Normal :
Gray area
Huntington disease:

<36 CAG
36-38 CAG
> 38 CAG

Not at present.
There is also no treatment to slow the
progression of the disease.
Treatment is aimed at supporting the patient
and his/her family.
Prescription drugs can help control some of
the symptoms, especially the involuntary
movements and psychiatric conditions such
as depression.

The person with HD eventually succumbs to

pneumonia or complications of falls or
choking.
Life expectancy is usually about 15-20 years
after the disease starts.