Transcript Sex Chromosome Abnormalities

Introduction: Genetic and Rare diseases
Dr Ravinder Makkar
Medical Director -Genzyme
Dione Pompe disease Brazil
www.genzyme.com
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Some very fundamental questions
• Why do we resemble
our parents?
• How does a single cell
grow into a whole
human?
• Why are
some diseases more
common in some
races than in others?.
Genetics
aims to find
the answers
Genetics?
 Genetics -science of inheritance/ study of heredity
On December 10, 1962, the
Nobel Prize in Physiology or
Medicine was awarded to
Francis Crick, James Watson,
and Maurice Wilkins for their
roles in discovering the double
helix structure of DNA.
 transmission of physical, biochemical, and physiologic traits from
biological parents to their children
 mechanism by which blueprints for life passed through
generations
 Genetic information is carried in genes
strung together on strands of DNA to
form chromosomes
 Disorders can be transmitted by gene
mutations that can result in disability or
death
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Why study genetic /rare disease?
Rare disease problem worldwide: stats
Definition of rare:
 Approximately 7,000 different types of rare diseases

USA = 30 million people living with rare diseases (1 in
10 or 10% of the U.S. population!!)

Europe =30 million people living with rare diseases.

Worldwide = 350 million people worldwide suffer from
rare diseases
USA: < 200,000 persons
combined in a particular rare
disease.
UK: <5/1000 persons per
disease
 80% of rare diseases are genetic in origin
 Approximately 50% of the people affected by rare diseases are children
 30% of children with rare disease will not live to see their 5th birthday
 Rare diseases are responsible for 35% of deaths in the first year of life
 80% of all rare disease patients are affected by approximately 350 rare diseases
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Scope of Clinical Genetics is vast and
expanding
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Congenital anomalies / birth defects
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Neurogenetics
Dysmorphology
Fetal medicine & prenatal diagnosis
OBG: consanguinity, infertility, recurrent miscarriages, teratogens,
pre-implantation genetic diagnosis (PGD)
Cancer genetics
Hearing loss syndromes
Ocular genetics
Inborn errors of metabolism
Skeletal dysplasias
Terminology
• hereditary disease= derived from parents ;
resulting from a chromosome abnormality or a
defective gene
• familial disease = transmitted in the gametes
through generations
• congenital disease = present at birth
• Not all congenital disease are genetic in origin (e.g. congenital syphilis,
toxoplasmosis)
• Not all genetic diseases are congenital - e.g. Huntington disease - 3rd
to 4th decade of life
Basics of Genetics
• Chromosomes: composed of double coils
of DNA
• Genes: segments of DNA chains
• Genome: sum total of all genes contained
in a cell’s chromosomes; the same in all cells
•
In human beings, normal chromosome
component:
− 22 pairs of autosomes
− 1 pair of sex chromosomes (XX in females and
XY in males)
• Genetic code: precise sequence of AT and
CG pairs on the DNA molecule
• Karyotype: a representation of a person’s
set of chromosomes
Etiology of diseases
Environmental factors
may affect how genes
are expressed
Mendelian
inheritance
require interaction
of ≥ 1 genes
For any condition the overall balance of genetic and
environmental determinants can be represented by a
point somewhere within the triangle.
Contributions of genetic & environmental factors to
human diseases
Haemophilia
Osteogenesis imperfecta
Club foot
Pyloric stenosis
Dislocation of hip
Duchenne
muscular dystrophy
GENETIC
Phenylketonuria
Galactosaemia
Rare
Genetics simple
Unifactorial
High recurrence rate
Peptic ulcer
Diabetes
Tuberculosis
ENVIRONMENTAL
Spina bifida
Ischaemic heart disease
Ankylosing spondylitis
Common
Genetics complex
Multifactorial
Low recurrence rate
Scurvy
Concept of penetrance
Continuum of penetrance
There is a continuum of penetrance from fully penetrant conditions, where other genes and
environmental factors have no effect, through to low-penetrance genes that simply play a small
part, along with other genetic and environmental factors, in determining a person’s susceptibility
to a disease.
Classification
3 groups of genetic diseases
• Polygenic
− Disorders with multifactorial inheritance
(polygenic)
+ environment
• Monogenic
− Monogenic (mendelian) disorders
− Dominant/recessive pedigree patterns
• Chromosomal
− Chromosomal aberrations
− Thousands of genes may be involved
Male
“Environmental”
influences act on a
genetic predisposition to
produce a susceptibility
to a disease.
- Can affect structural
proteins, enzymes,
receptors,
transcription factors.
e.g. trisomies,
deletions,
duplications
translocations
1. Polygenic Disorders (multifactorial inheritance)
• Influence of multiple genes + environmental factors
• Relatively frequent
− Diabetes mellitus
− Hypertension
− Gout
− Schizophrenia
− Congenital heart disease
− Some types of cancer (ovarian, breast, colon)
• Often familial occurrence - probability of disease in 1st
degree relatives about 5-10%; 2nd degree relatives –
0.5-1%
2. Monogenic (mendelian) disorders
• mutation of 1 gene
• mendelian type of inheritance
• today about 5000 diseases
− Dominant/recessive pedigree
I:1
I:1
AA
I:2
I:3
I:1
I:2
AB
II:1
II:1
II:1
AA
II:2
AB
II:3
BB
II:2
II:3
II:4
II:5
II:6
II:7
II:8
II:9
II:10 II:11
II:12 II:13
II:2
I:2
II:3
II:5
III:1
III:1
III:2 III:3
III:4
III:5 III:6
III:7
III:2
III:8 III:9 III:10 III:11 III:12 III:13 III:14III:15 III:16III:17
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III:1
BB
Tom
IV:1
IV:2
IV:3
IV:4
IV:5 IV:6 IV:7
IV:8 IV:9 IV:10
IV:11
II:6
II:14 II:15
IV:12 IV:13
IV:1
II:8
Modes of Transmission (pedigree)
• Autosomal dominant (e.g. Huntington's disease, achondroplasia, neurofibromatosis)
• Autosomal recessive (e.g. cystic fibrosis, phenylketonuria, tay sachs, Gaucher)
• Co-dominant (e.g. sickle cell trait)
• X-linked (e.g hemophilia)
• Most genetic/hereditary diseases are transmitted on
autosomes
• Few are carried on sex chromosomes
Dominant vs recessive inheritance
Autosomal Dominant
Heterozygotes with one copy of the altered gene are
affected
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both males and females are affected
transmission from one generation to the other
50% of children are affected
E.g., FH, Marfan’s, Ehler danlos, Huntingtons
Autosomal Recessive
Homozygotes with two copies of the altered gene are
affected (heterozygotes (parents) are only carriers)
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majority of mendelian disorders
25% of descendants are affected
frequently enzymatic defect- LSDs (gaucher, fabry, pompe)
X-linked recessive
Male
Males with one copy of the altered gene on the
X-chromosome are affected
Hereditary Diseases Caused by
Dominant Genes
• Only one copy of the gene (from either parent) is needed
for a person to have the disease
• A person with a dominant hereditary disease usually has
at least one affected parent
• Parents have a 50% chance of passing these types of
diseases to children
Ex. Huntington’s Disease
• Caused by the inheritance of a dominant gene; autosomal dominant
mutation in either of an individual's two copies of a gene called
Huntingtin
• neurodegenerative genetic disorder that affects muscle coordination
and leads to mental decline and behavioral symptoms
• Produces incorrect protein that eventually leads to destruction of
brain cells
• Symptom’s include abnormal body movements, lack of coordination,
impaired mental abilities and altered personality
• Patients generally live 15 to 20 years after the appearance of the first
symptoms
• Currently no cure
Hereditary Diseases Caused by
Recessive Genes
• majority of mendelian disorders
• Two copies of the defective gene must be inherited (one from each
parent) -only homozygotes are affected
• Affected persons usually have 2 non-affected parents (carriers)
• carrier parents have a 25% chance of having a child with the disease
(25% of descendants are affected)
• onset of symptoms often in childhood
• frequently enzymatic defect
Cystic fibrosis
• 1:2000 live births - most common lethal genetic disease in white
population
• defect in the transport of chloride ions across epithelia - increased
absorption of Na+ and water to the blood
• mutations in gene for the cystic fibrosis transmembrane
conductance regulator (CFTR) protein
• widespread defect in the exocrine glands - abnormally viscid mucous
secretions
• blockage of pulmonary airways, pancreatic ducts, biliary ducts,
genital tracts
• death usually in 3 decade due to respiratory failure
Phenylketonuria (PKU)
• Commonest acute onset inborn metabolic disorder (IMD)worldwide
• 1 in 5,000 - 15,000 live births
• absence of enzyme phenylalanine-hydroxylase (PAH) causes
increase of plasmatic Phe since birth - rising levels
• Untreated causes impairs brain development- severe mental
retardation , severe cognitive, behavioral problems, movement
disorders and epilepsy
• If treatment is begun in the first month of life, near normal intelligence
and quality of life
• EARLY SCREENING TEST!!!
• DIET!!!
Galactosemia
• defect of galactose metabolism
• lactose -> Gal+Glc
• Gal -> Glc - defect - accumulation of Gal in blood
• liver, eyes, brain are affected
• hepatomegaly (fatty change - fibrosis - cirrhosis)
• lens - opacification - cataracts
• brain - loss of neurons, gliosis, edema
• Symptomatology - from birth
• vomiting, diarrhea, jaundice, hepatomegaly
• later - cataracts, mental retardation
• DIET!
Glycogen storage diseases (glycogenoses)
• deficiency of any one of the enzymes
involved in degradation or synthesis
• depending on the type of defect - tissue
distribution, type of accumulated product
• 12 forms - most important:
• type I - von Gierke disease - hepatorenal
type
• type II - Pompe disease - generalized
type (liver, heart, skeletal muscle)
• type V - McArdle syndrome - skeletal
muscle only
Lysosomal storage diseases
• defect of lysosomal enzymes
• hydrolyzing various substances (sphingolipids,
mucopolysacharides) - storage of insoluble metabolites in
lysosomes
• extremely rare
− Gaucher
− Fabry
− MPS
− Some are Treatable
Gaucher disease
• defect of
glucocerebrosidase - 3
types (type 1 - survival,
type 2 - lethal, type 3 intermediate)
• accumulation of
glucocerebroside (Glcceramide) -
• Gaucher cells - spleen
(red pulp), liver
(sinuses), bone marrow
Pompe disease
• The affected gene was identified
in 1965 by Henri G. Hers
• Deficiency of alpha glucosidase
• AR inheritance
• Buildup of glycogen in cells.
Mucopolysacharidoses
• MP synthesized in the connective tissue by fibroblasts - part of the ground
substance
• several clinical variants (I-VII)
• involvement of liver, spleen, heart (valves, coronary arteries), blood
vessels
• Symptoms: coarse facial features (gargoylism), clouding of the cornea,
joint stiffness, mental retardation
• usually death in childhood (cardiac complications)
• most frequent Hurler syndrome and Hunter syndrome (X-linked!)
Ex. Sickle-Cell Anemia
• Caused by the inheritance of two recessive
genes
• Causes red blood cells to be abnormally shaped
• Cells may stick to each other or become stuck in
blood vessels preventing oxygen flow which may
lead to organ damage or stroke
• Individuals are often well, but experience painful,
possibly fatal attacks from time to time
Hereditary Disease Caused by
Sex-Linked Recessive Genes
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Caused by defective genes carried on the X chromosome
Males affected more than women
Males inherit one defective gene on X from mother to have disorder
Females only affected if they inherit 2 defective genes (one from
each parent)
Hemophilia
Caused by the inheritance of one
recessive gene on the X (males) or
two recessive genes on both X’s
(females)
Affects blood – blood does not clot
Leads to severely increased risk of
bleeding from common injuries
Potentially fatal
Congenital Malformations
• Congenital malformation:
any abnormality present at
birth
• Four factors in congenital
malformations
− 1. Chromosomal abnormalities
− 2. Abnormalities of individual
genes
− 3. Intrauterine injury to embryo
or fetus
− 4. Environmental factors
Causes
• 2-3% of all newborn
infants have congenital
defects
• Additional 2-3% defects:
-NOT recognized at birth;
-developmental defects demonstrated
later as infants grow older
• 25% to 50%
spontaneously aborted
embryos, fetuses, and
stillborn infants have
major malformations
Chromosomal Abnormalities
• Non-disjunction:
− failure of homologous chromosomes in germ cells to separate in
first or second meiotic division
− May involve either sex chromosomes or autosomes
− Causes abnormalities in distribution of chromosomes
between germ cells
− One of two germ cells has an extra chromosome while
the other lacks a chromosome
Numerical Chromosomal abnormalities
• Euploidy - normal 46 (2n)
• Polyploidy (3n or 4n) - spontaneous abortion
• Aneuploidy
• Trisomy (2n+1)
- 47 - compatible with life
• Monosomy (2n-1) - autosomal - incompatible with life
- sex chromosomal - compatible with life
Structural Chromosomal Abnormalities
• Deletions: chromosome breaks during meiosis
and broken piece is lost
• Translocations: misplaced chromosome or part
of it attaches to another chromosome
Sex Chromosome Abnormalities
(1 of 3)
• Variations in normal number of sex chromosomes are often
associated with some reduction of intelligence
− Y chromosome: directs masculine sexual differentiation, associated
with male body configuration regardless of number of X chromosomes
present
− Extra Y: no significant effect as it mainly carries genes concerned with
male sexual differentiation
− Absent Y: body configuration is female
− Extra X in female: has little effect (one X chromosome is inactivated)
− Extra X in male: has adverse effects on male development
Diseases with Sex Chromosome Abnormalities
(2 of 3)
• Two most common ones in the female
− 1. Turner’s Syndrome: absence of one X chromosome(X0)
− 2. Triple X Syndrome: extra X chromosome (XXX)
• Two most common ones in the male
− 1. Klinefelter’s Syndrome: extra X chromosome (XXY)
− 2. XYY Syndrome: extra Y chromosome(XYY)
Sex Chromosome Abnormalities
(3 of 3)
• Fragile X Syndrome (x-linked
mental deficiency)
− Not related to either excess or deficiency
of sex chromosomes
− Associated with a characteristic
abnormality of the X chromosome
− Mutations in the FMR1 gene
− 1 in 1000 males; Normal looking males; X
linked inheritance
− Gene test available; Triplet repeat
disorder
− Second to Down syndrome as a major
cause of mental deficiency
Autosomal Abnormalities (1 of 2)
• Down syndrome:
− most common chromosomal abnormality, an
autosomal trisomy
• With trisomy of small chromosome 21
• Many fetuses are aborted early in
pregnancy (70%)
− Those who live have Down syndrome
− Nondisjunction during oogenesis occurs in
95% of cases
• Increased frequency with advancing
maternal age: 1 in 50 if mother is > 40
years old
• Extra chromosome 21 acquired as part
of the translocation chromosome
Autosomal Abnormalities (2 of 2)
• Trisomy 13: (Patau syndrome)
1:15000
− Cleft lip and palate; abnormal development of
skull, brain, and eyes; congenital heart defect;
polydactyly
− Death within the first year
− Low recurrence risks; Prenatal diagnosis can
be offered
• Trisomy 18:(Edwards syndrome)
1:8000
• Both 13 and 18 trisomies are usually
fatal in the neonatal period or in
early infancy
Van der Woude Syndrome
VDWS: a genetic disorder characterized by
the combination of lower lip pits, cleft lip
with or without cleft palate,
Velo-cardio-facial syndrome
Chromosome 22q-
• Micro-deletion
syndrome
• Characteristic face
• Cleft palate
• Heart defect
• Learning difficulty
• Immune problems
• Psychiatric problems
Prenatal Diagnosis of Congenital Abnormalities
• Ultrasound examination:
− Major structural abnormalities of nervous system (anencephaly; spina
bifida)
− Hydrocephalus
− Obstruction of urinary tract
− Failure of kidneys to develop
− Failure of limbs to form normally
• Fetal DNA analysis: determination of biochemical
abnormalities by analysis of DNA of fetal cells
− Amniocentesis
− Chorionic villus sampling
Establishing a diagnosis
• Is it genetic?
• Single defect or part of a larger picture-E.g.
syndrome, association, teratogen
• Inheritance pattern
• Confirmatory tests
Investigations
Routine:
• Chromosomes
• FISH for micro-deletions
• DNA tests for single gene
disorders
Newer diagnostic aids
• Telomere studies
• 1-3 megabase interstitial deletion
screening
• Micro-array studies (silicon chip
based)
Prenatal diagnosis
Ultrasound examination:
Major structural abnormalities of
nervous system (anencephaly;
spina bifida)
 Hydrocephalus
 Obstruction of urinary tract
 Failure of kidneys to develop
 Failure of limbs to form
normally
Fetal DNA analysis:
determination of biochemical
abnormalities by analysis of DNA of
fetal cells
• Amniocentesis
• Chorionic villus sampling
Amniocentesis and CVS
•
Alpha fetoprotein: high
concentration in amniotic fluid is
suggestive of a neural tube defect
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Amniotic fluid for study:
transabdominal amniocentesis
− Usually performed between the 14th
and 18th week of pregnancy
− Primary use: prenatal detection of
chromosomal abnormality in women
over age 35 due to higher incidence of
Down syndrome in infants born to
older women
Chorionic villi: frond-like structures
that form part of placenta and attach to
lining of uterus
• Fetal cells are obtained for
evaluation using chorionic villi
sample
• Amniotic fluid not used for
analysis
• Small catheter inserted through
cervix to the site where villi are
attached on the uterus
• Small area is suctioned
Newborn screening
• One of the most successful public health
initiatives world wide!
• Available in all developed countries for PKU
• First started New Zealand 1965, 1970 in UK
and USA
• Done on Day 3 of life in all newborns
• 3-4 drops of blood on a filter paper
• Enzyme based assay/ TMS (upto 56 disorders
can be tested in one run)
• Confirmation by gene test
Genetic Counselling:
• About the condition
• Inheritance pattern
• Prognosis for affected individual
• Recurrence risks & future reproductive options
• Information about support groups
• Continued support
Our strength: our patients
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Thank you!