Genetic Disorders

Ma. Minda Luz M. Manuguid, M.D.

 Review of Normal Genetics
 Karyotype – the number & type of
chromosomes in an individual’s cells
normal human karyotype: 46 chromosomes= 22
pairs Autosomes (44) + 1 pair Sex
chromosomes (2)--- male XY; female XX
 Diploid no. – 2n=46 – in somatic cells
 Haploid no. – n =23 – in germ cells
 Euploid no. – exact multiple of the haploid no.
 Petit arm – p – short arm of the chromosome
 Long arm – q – long arm of the chromosome
 Other Terms
 Genotype – the chromosome complement (genetic
composition of the chromosomes) of an individual
 Phenotype – morphologic expression of the
genotype; the appearance of a trait
 Allele – an alternative form of a gene (one member
of a pair) located on a specific position on a specific
chromosome; there are two for each trait, each may
be dominant/recessive
 Homozygous – has two identical alleles for a trait
 Heterozygous – has two different alleles for a trait
 Deoxyribonucleic Acid
DNA -blueprint of life (has the
instructions for making an
organism): codes for genes
- double helix of repeating
subunits (nucleotides) as
established by James
Watson and Francis Crick
Gene - a segment of DNA that
codes for a protein, which in
turn codes for a trait (skin
tone, eye color, etc)
Nucleotide - consists of a
sugar (deoxyribose),
phosphate and a base
 DNA structure
• Nucleotides (also called Bases) Adenine, Thymine,
Guanine, and Cytosine pair in a specific way:
the “Base-Pair Rule”:
Adenine always pairs with Thymine;
Guanine always pairs with Cytosine

* The rungs of the DNA “ladder” can occur in any

order as long as the base-pair rule is followed
 DNA Replication
Replication is the process where
DNA makes a copy of itself. Cells
divide for an organism to grow or
reproduce, and every new cell needs
a copy of the DNA or instructions to
know how to be a cell. DNA
replicates right before a cell divides.
DNA replication is semi-conservative.
That means that when it makes a
copy, one half of the old strand is
always kept in the new strand. This
helps reduce the number of copy
errors.
 Ribonucleic Acid
RNA brings the genetic code
from the DNA in the nucleus
to the ribosomes (where
protein synthesis occurs) in
the cytoplasm;
- compared to DNA, RNA:
 has one strand rather than
two
 has ribose sugar rather than
deoxyribose
 has Uracil instead of
Thymine
 The Genetic Code
• How the code works: For instance, a stretch of DNA
that reads AATGACCAT would code for a different
gene than a stretch that reads GGGCCATAG.
• * The 4 bases have endless combinations just like the
letters of the alphabet can combine to make
different words.
• Each triplet / codon represents an amino acid.
• “nonsense” codons terminate AA sequences when the
correct protein has been formed.
 Protein Synthesis

* Transcription - mRNA is
made from DNA
* mRNA takes the message
from the DNA to the
ribosomes
* Translation - proteins are
made from AAs carried by
tRNA to rRNA from the
message on the mRNA
 Genetic Disorders:
Modes of Inheritance
• CYTOGENETIC - defect in the number or structure
of chromosomes
• MENDELIAN - defect is carried by two alleles, one
of which may be dominant over the other
• MULTIFACTORIAL - environmental factors enable
a genetic tendency to be expressed
• NONCLASSIC – all other disorders not included in
the previous categories
 Cytogenetic Disorders
 Aneuploidy – number of chromosomes is not an exact
multiple of 23; caused by nondisjunction or by
anaphase lag
 Monosomy – there is an unpaired chromosome
 Trisomy – there is a chromosome triplet instead of a pair
*Mosaicism – there are two or more populations of
cells with different numbers of
chromosomes
 Mutation – change in chromosome structure
Cytogenetic Disorders: Mutation
 Deletion – loss of a portion of a chromosome
 Inversion – rearrangement from 2 breaks within a single
chromosome & reincorporation of the inverted segment
– may be paracentric or pericentric
 Translocation – a segment of a chromosome is
transferred to another: balanced reciprocal or
Robertsonian (centric fusion)
 Isochromosome formation – one arm is lost, the
remaining arm is duplicated
Cytogenetic Disorders in
Autosomes
Cri du chat Syndrome
Wolff-Hirschhorn Syndrome
Down Sydrome (Trisomy 21)
Edwards Syndrome (Trisomy 18)
Patau Syndrome (Trisomy 13)
 Cri du chat syndrome
 deletion of the short arm of
chromosome 5, usually (in 80%)
the paternal chromosome (5p-)
 characteristic mewling cry like that
of a cat: due to an abnormal
laryngeal development- becomes
normal within a few weeks to a year
 1 in 50,000 live births
 round facies; low birth weight;
respiratory problems; microcephaly;
mental retardation
 most have normal life expectancy;
some have a shortened life span
Cri du chat syndrome
Wolf-Hirschhorn
syndrome
 4p- (paternal chromosome)
 severe growth retardation &
mental defects
 microcephaly
 cleft lip/palate
 coloboma of the eye
 “Greek helmet” facies –
prominent forehead; wideset
eyes; broad, beaked nose
 cardiac septal defects
 Trisomy 21: Down Syndrome
 most common chromosomal disorder :
extra (3rd) copy of chromosome 21
 Aneuploidy (47 XX/XY +21) or
Mosaicism(46XX/47XX +21)
 average: 1 in 800 live births
 maternal age is significant:
≤ 20 yrs : 1 in 1550 live births
≥ 45 yrs : 1 in 25 live births
 varying degrees of physical disabilities & learning
difficulties
 Down Syndrome
 “mongoloid facies” :
eyes slanted upward +
epicanthic folds ( small
folds of skin at the inner
corners of the eyes); flat
nasal bridge & facial
profile; broad face;
small, low-set ears

 gentle, shy manner

 Down Syndrome
 small mouth, poor muscle tone- tongue appears
large & protruding; “simian”/transverse palmar crease
 short stature; small hands & feet
 40% with CHD: ASD, VSD, AV mal, Ostium primum
 accelerated Alzheimer’s
 10-20fold risk of Acute Leukemia
 mental retardation
 predisposition to infections
 prone to thyroid autoimmunity
 Trisomy 18: Edwards Syndrome

 1 in 8000 live births

 Aneuploidy: 47XX/XY+18 or
Mosaicism: 46XX / 47XX +18
 mental retardation
 micrognathia; short neck;
overlapping fingers; prominent
occiput; low-set ears; “rocker-
bottom” feet
 CHD; renal malformations
 Trisomy 13:
Patau Syndrome
 1 in 6000 live births
 Aneuploidy: 47XX/XY +13 or
Mosaicism: 46XX/47XX/XY +13
 microphthalmia, microcephaly,
cleft lip &/or palate, polydactyly,
rocker-bottom feet
 cardiac defects, renal defects,
umbilical hernia, abnormal
genitalia
 mental retardation
 short life span (<20% survive
infancy)
 Review of Normal Genetics:
The Sex Chromosomes
Lyon ( X- inactivation ) Hypothesis:
 Only one X chromosome is genetically active (euchromatin)
 Any X chromosome in excess of one normally undergoes
heteropyknosis (“lyonization”) & becomes inactive
(heterochromatin)
 Inactivation of maternal/paternal X occurs at random among
all the cells of the blastocyst on or about the 16th day of
embryonic life
 Inactivation of the same X persists in all cells derived from
each precursor cell
 X inactivation occurs so that the female, with 2 X
chromosomes, would not have twice as many gene products as
the male, who has only one X chromosome.
Review of Normal Genetics:
The Sex Chromosomes
The Y chromo-
some is very
small com-
pared to the X
chromosome.
The pseudo-
autosomal regions at the tips
contain the genetic material
on the Y that shows
similarity to the X
chromosome. The SRY
gene is located on the p arm
of the Y.
 Normal Genetics:
The Sex Chromosomes
 Barr body – X chromatin – a
dark-staining mass in contact
with the nuclear membrane;
represents the inactivated X
chromosome;
 Y chromosome – genetic
determinant of male gender;
contains the SrY(sex-
determinating region Y
gene), which dictates
testicular development, on
its distal short arm
 Gender Determination
 Genetic – presence / absence of the Y
chromosome = male / female
 Gonadal – histology of gonad :
Ovary=female; Testis=male
 Ductal – derivatives of the primordial tubes:
Mullerian= female; Wolffian= male
 Genital – phenotypic – morphology of external
genitalia: Penis & scrotum = male;
Clitoris & Labiae = female
 Cytogenetic disorders
in Sex Chromosomes

• True Hermaphroditism
• Klinefelter syndrome
• XYY syndrome
• Turner syndrome
• Multi-X syndrome; triple X syndrome
 Hermaphroditism
True hermaphroditism
Presence of Ovotestis or both Ovary & Testis
Usually caused by translocation of Y to the X
chromosome or to an autosome
65% are genetic females (46XX)
35% are mosaics (46XX/47XXY)
Pseudohermaphroditism:
Female- 46XX; ovaries; external genitalia virilized or ambiguous due
to exposure to androgenic steroids e.g. CAH
Male- 46XY; testes; internal genitalia are incompletely differentiated;
external genitalia are ambiguous or feminized due to either a defect
in androgen synthesis or a defect in the androgen receptors
 Klinefelter Syndrome
 Male hypogonadism: 1° cause of
male infertility
 classic : (82%) 47XXY; 15%-
mosaics
 1 in 850 male live births
 eunuchoid body habitus;
abnormally long legs
 small atrophic testes; small penis
 lack of secondary male
characteristics
 ↓testosterone levels; ↑FSH;
↑Estradiol
 atrophy/aplasia of seminiferous
tubules - azoospermia
 other lesions: cryptorchidism;
hypospadias
 Turner Syndrome
 female hypogonadism
 monosomy of sex
chromosomes: 45 X
 short stature, webbed neck,
broad chest
 peripheral lymphedema,
pigmented nevi
 coarctation of the Aorta
 streak ovaries –
amenorrhea, infertility
 Aneuploidy involving Sex
Chromosomes
XYY syndrome Triple X syndrome
• Supernumerary Y : • Multi- X syndrome :
47XYY 47XXX; 48XXXX;
 1 in 1000 l male births 49XXXXX
 excessively tall; prone  1 in 1200 live born
to severe acne females
 1-2% exhibit deviant  menstrual irregularities
behavior – antisocial,  mental retardation if
delinquent, acting out, more than three Xs
impulsive
 Mendelian Disorders

• Autosomal Dominant
• Autosomal Recessive
• X-linked
Autosomal dominant disorders
 manifested even in the heterozygous
state
 onset of Sx usually in adulthood
 manifestations are less uniform,
modified by
Penetrance – percentage of
individuals with the dominant allele
who manifest the characteristic
Variable expressivity – differences
in the expression of a trait seen in all
individuals with the dominant gene
 Autosomal dominant Disorders
• Neurofibromatosis • Huntington’s disease
• Tuberous sclerosis • Myotonic dystrophy
• Hereditary • Polycystic kidney
spherocytosis • Familial Polyposis coli
• Marfan syndrome • Von Willebrand disease
• Ehlers Danlos syndrome • Familial
• Osteogenesis imperfecta hypercholesterolemia
• Achondroplasia • Acute intermittent
Porphyria
Neurofibromatosis Tuberous
Sclerosis
Hereditary Spherocytosis
 Marfan
Syndrome
Ehlers Danlos
Syndrome
Osteogenesis Imperfecta
 Osteogenesis Imperfecta
 Osteogenesis imperfecta type 1 (
OI type 1)is a dominantly inherited,
generalized connective tissue
disorder characterized mainly by
bone fragility and blue sclerae.
 Osteogenesis imperfecta type 2
 Osteogenesis imperfecta type 3
 Osteogenesis imperfecta type 4
 Osteogenesis imperfecta with
opalescent teeth
Achondroplasia
Achondroplasia
Autosomal Recessive Disorders
 manifested only in the
homozygous state
 onset of symptoms in infancy
 complete / 100% penetrance
is common
 more uniform manifestations
 usually enzyme defects
(inborn errors of metabolism)
 siblings have 1 chance in 4 to
be affected
Autosomal Recessive disorders
• Sickle cell anemia • Lysosomal storage
• Phenylketonuria diseases
• Cystic fibrosis • Alpha-1 Antitrypsin
• Galactosemia deficiency
• • Hemochromatosis
Homocystinuria
• • Glycogen storage diseases
Wilson disease
• Thalassemias
• Alkaptonuria
• • Neurogenic muscular
Friedrich’s Ataxia
atrophies
• Spinal muscular atrophy
Sickle Cell
Disease
Sickle Cell
Anemia
Wilson Disease
Hemochromatosis Thalassemia
 X-linked Recessive Disorders
 Practically only males are
affected: rarely, a female will
manifest the disease due to
atypical lyonization, X-autosome
translocation, or a new mutation
 Heterozygous females are
clinically unaffected but carry the
gene
 There is no variation of
expression; the disease always
follows a typical course
Autosomal Recessive Inheritance
 X-linked disorders
• Color-blindness (red & green most common)
• Hemophilia A & B
• Agammaglobulinemia
• Diabetes insipidus
• Lesch-Nyhan syndrome
• Duchenne muscular dystrophy
• Chronic granulomatous disease
• Wiskott-Aldrich syndrome
• Glucose-6-phosphate dehydrogenase deficiency
• Fragile X syndrome
Color blindness
Color blindness
 Fragile X Syndrome
***Fragile X
syndrome is the
leading inherited
cause of
developmental
disabilities and
mental impairment
worldwide. It affects
children of all ethnic
and racial
backgrounds.
Fragile X Syndrome
 Multifactorial Disorders
• Cleft Lip &/or Palate
• Diabetes mellitus type II
• Pyloric stenosis
• Coronary Heart disease
• Gout
• Hypertension
• Congenital Heart disease
 heritable genetic
tendency is expressed
only when certain
environmental factors
are present
 concordance rate in
identical twins is 40%
 rate of recurrence in
subsequent siblings is
2-7%
Cleft Lip & Palate
Pyloric
Stenosis
 Single Gene disorders
of Nonclassic Inheritance
• Triple repeat Mutations –
Fragile X syndrome
• Mitochondrial gene Mutations –
Leber Hereditary Optic Neuropathy (LHON)
• Genomic Imprinting –
Prader Willi syndrome
Angelman syndrome
 Angelman Syndrome
 loss of the normal maternal contribution to a region of
chromosome 15, most commonly by deletion of a segment of
that chromosome.
 A healthy person receives two copies of chromosome 15, one
from the mother, the other from the father. However, in the
region of the chromosome that is critical for Angelman
syndrome, the maternal and paternal contribution express
certain genes very differently. This is due to sex-related
epigenetic imprinting; the biochemical mechanism is DNA
methylation.
 if the maternal contribution is lost or mutated, the result is
Angelman syndrome. (When the paternal contribution is lost,
by similar mechanisms, the result is Prader-Willi syndrome.)
 Angelman syndrome

• “happy puppet” syndrome

• Docile, obedient
• Inappropriate laughter
 Prader-Willi Syndrome
 seven genes (or some subset thereof) on
chromosome 15 are missing or unexpressed
(chromosome 15q partial deletion) on the paternal
chromosome
 The distinction of chromosome by parental origin is
due to imprinting (maternal – Angelman syndrome)
 incidence is 1 in 12,000-15,000 live births
 characterized by hyperphagia, food preoccupations,
hypotonia, small stature & mental retardation
Thank
You