GENETIC DISORDERS

By Dr.Bizunesh
Nov.20,2014
Basic terminologies in medical
genetics
 Gene
 Locus
 Allele
 Genotype
 Phenotype
 Homozygote
 Heterozygote
 Dominant
 recessive
Classification
1) Genome mutation – loss or gain of whole
chromosome (monosomy , trisomy)
2) Chromosome mutation – rearrangement of
genetic material & give rise to visible
structural changes in chromosome
3) Gene mutation – majority of mutation with
hereditary disease
◦ Results in partial or complete deletion of gene,
more often affect single gene

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MUTATIONS
 Missense
 Nonsense
 deletions
 Insertions
 frameshift
 Gain of function
 Loss of function
STANDARD PEDIGREE SYMBOLS
 Four categories of genetic disorders
1. Those related to mutant genes of large effect
(mendelian disorders)
2. Diseases with multifactorial (polygenic)
inheritance
3. Those arising from chromosomal aberrations
(cytogenetic disorders)
4. Single gene disorders with non classic
inheritance

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(1) Single Gene disorders with Mendelian inheritance

 are the result of expressed mutations in

single gene of large effect
 They typically follow one of the three patterns

of inheritance
◦ Autosomal dominant – expressed in the
hetrozygous state
◦ Autosomal recessive – expressed in the
homozygous state
◦ X-inked – males are affected, female usually
carriers
Autosomal Dominant
 Disease is produced in the heterozygous
 Male and female affected equally
 In many cases age of onset is delayed
 Structural and regulatory proteins
 Autosomal Dominant Disorders
System Disorder
Nervous Huntington disease
Myotonic dystrophy
Neurofibromatosis
Tuberous sclerosis
Urinary Polycystic kidney disease
Gastrointestinal Familial polyposis coli
Hematopoietic Hereditary spherocytosis
von Willebrand disease
Skeletal Marfan syndrome
Ehlers-Danlos syndrome (some variants)
Osteogenesis imperfecta
Achondroplasia
Marfan’s Syndrome
 Transmitted by autosomal dominant
inheritance
 A disorder of the connective tissues of the

body manifested by changes in

◦ Skeletal
◦ Eye
◦ Cardiovascular
Marfan’s syndrome
 Pathogenesis
◦ Mutation of the FBN1 gene on chromosome 15q21
underlie Marfan syndrome
◦ Marfan syndrome results from an inherited defect
in an extracellular glycoprotein called fibrillin-1
◦ Fibrillin-1 is a major component of the microfibrils
that are found in the extracellular matrix of
connective tissue and participate in the formation
of elastic fibers
◦ They are particularly abundant in the aorta,
ligaments, and ciliary zonules of the lens
Marfan Syndrome
Marfan’s syndrome
 Clinical manifestations
◦ Skeletal - a long thin body, hyper extensive joints,
arachnodactyly (spider fingers),and scoliosis.
◦ Eye – upward displacement of the lens, retinal
detachment
◦ Cardiovascular – dissecting aortic aneurism, mitral
valve disease
Marfan Syndrome
Autosomal Recessive
 Disease occurs in homozygous state
 Heterozygous are carriers
 Age of onset is usually early in life
 Most of the time enzymatic proteins affected
Autosomal Recessive - continued
 Consequences of enzyme
defects
◦ Accumulation of a substrate
◦ Decreased amount of end product
◦ Failure of inactivation of a harmful
substance
 Autosomal Recessive Disorders
System Disorder
Metabolic Cystic fibrosis
Phenylketonuria
Galactosemia, Homocystinuria
Lysosomal storage diseases
α1-Antitrypsin deficiency
Wilson disease , Hemochromatosis
Glycogen storage diseases
Hematopoietic Sickle cell anemia
Thalassemias
Endocrine Congenital adrenal hyperplasia
Skeletal Ehlers-Danlos syndrome (some variants)
Alkaptonuria
Cystic Fibrosis
 Autosomal recessive transmission, hence
heterozygote carriers are asymptomatic
 Pathogenesis
◦ The primary defect is mutation in cystic fibrosis
transmembrane conductance regulator (CFTR) gene
on chromosome band 7q31.2.
◦ The gene (CFTR) codes for the epithelial chloride
channel
◦ Abnormally viscid mucus secretion
Cystic Fibrosis
widespread disorder in
epithelial transport affecting
fluid secretion in exocrine
glands and the epithelial lining
of the respiratory,
gastrointestinal, and
reproductive tracts
Cystic Fibrosis - Clinical
Manifestations
 Chronic Ling
Disease
 Pancreatic

insufficiency
 Steatorrhea
 Malnutrition
 Hepatic cirrhosis
 Intestinal

obstruction
 Male infertility
Albinism
 The basic biochemical defect is absence or
non functioning of the enzyme thyrosinase
which is necessary for the prod of melanin
which gives skin its color
 Transmitted in an autosomal recessive

pattern
Albinism Continued
 Clinical
manifestations
◦ Pale skin , hair
◦ Skin burn
◦ Increased risk of skin
cancer
◦ Visual problems
X-linked recessive
 Males affected more frequently than females
 There in no male to male transmission
 Skipped generations
 X-Linked Recessive Disorders
System Disorder
Musculoskeletal Duchenne muscular dystrophy
Blood Hemophilia A and B
Chronic granulomatous disease
Glucose-6-phosphate dehydrogenase deficiency
Immune Agammaglobulinemia
Wiskott-Aldrich syndrome
Metabolic Diabetes insipidus
Lesch-Nyhan syndrome
Nervous Fragile-X syndrome
Hemophilia A & B
 X- linked recessive hereditary disease associated
with serious bleeding
 Caused by coagulation factor deficiency
 Hemophilia A – Factor VIII
 Hemophilia B – Factor IX
 Most severe deficiencies result from an unusual
inversion involving the X chromosome that
completely abolishes the synthesis of factor VIII.
Less commonly, severe hemophilia A is associated
with point mutations in factor VIII that impair the
function of the protein.
Hemophilia Continued
 Clinical manifestation
◦ A and B are clinically indistinguishable
◦ Bleeding
 Joints (hemarthroses), soft tissue and muscle
 Post surgery – cercumcision
 Retroperitonial, CNS, life treatening
 Treatment - Factor replacement
Hemophilia
Hemophilia
Hemophilia - Hemarthrosis
Hemophilia
Duchenne muscular dystrophy

 Most sever and common form of MD

 incidence of about 1 per 3500 live male

births.
 Pathogenesis
◦ abnormalities in a gene that is located in the Xp21
region and encodes a 427-kDa protein termed
dystrophin
◦ dystrophin and the dystrophin-associated protein
complex form an interface between the intracellular
contractile apparatus and the extracellular
connective tissue matrix
Duchenne MD
DMD

 Histopathology of gastrocnemius muscle from patient who died of

pseudohypertrophic muscular dystrophy, Duchenne type. Cross section
of muscle shows extensive replacement of muscle fibers by adipose cells
Duchenne Muscular dystrophy
 Clinical manifestations
◦ Usually normal at birth but walking may be delayed
◦ Weakness starts in the pelvic girdle mm and
extends to the shoulder, they become wheelchair
dependent by the age 10-12
◦ Heart failure and arrhythmia
◦ Death from resp insufficiency, pulm infection, or
heat failure in their 20’s
DMD
(2) Single Gene Disorders with
Atypical Inheritance
 These are single-gene disorders which do not
follow the classic Mendelian principles.
 They can be classified into four categories
◦ Triple repeat mutations
◦ Disorders due to mitochondrial mutations
◦ Genomic imprinting
◦ Gonadal mosaicism
Triple Repeat Mutations (Fragile-X
syndrome)
 Fragile-X syndrome is the prototype disease
in which triple repeat mutations take place
 Second most common genetic cause of

mental retardation
 X-linked disorder
Fragile-X syndrome
 It affects males like other x linked diseases
 But it has some pattern of transmission not
typically seen in X-linked recessive disorders
◦ Carrier male – 20% with mutation are phenotipically
normal (transmitting male)
◦ Affected female – 50 % of carrier females affected
(MR)
◦ Sharman paradox- positional risk (brothers of
transmitting males 9% risk, but grandsons have 40%)
◦ Anticipation – worse with each successive generation
Fragile-X syndrome
Fragile-X syndrome
 Mutation is located on Xq27.3 which houses the
FMR gene - FMRP
 Normal population – CGG repeat 10-55
 Normal transmitting male and carrier female -

55-100 repeats (premutations)

 Affected individuals – 200-4000 repeats (full

mutation)
 it appears that during the process of oogenesis,

but not spermatogenesis, premutations can be

converted to mutations by triplet-repeat
amplification
Fragile X Syndrome
 Clinical manifestations
◦ Affected males are mentally retarded (IQ – 20-60)
◦ Long face and large mandible
◦ Large everted ear
◦ Large testicles (macro-orchidism)
◦ Hyperextensible joints
◦ Mitral valve prolapse
Fragile-X syndrome
Mitochondrial Gene Mutations
 feature unique to mitochondrial DNA
(mtDNA) is maternal inheritance
 There are 37 mitochondrial genes

◦ 24 needed for translation, 13 encode respiratory

chain enzymes
◦ CNS, skeletal m, cardiac m, liver, kidney
mtDNA mutation
 Leber hereditary optic neuropathy
 Neurodegenerative disease which manifests

with visual impairment and subsequent

blindness
Genomic Imprinting
 Functional difference between paternal and
maternal gene
 Selective inactivation of either the maternal

or paternal allele- imprinting

 Imprinting occurs in the ovum or the sperm

before fertilization
Genomic Imprinting
 Prader-Willi Syndrome and Angelman
Syndrome
 Prader-Willi syndrome – Mental retardation,

short stature, hypotonia, obesity, small hand

and feet and hypogonadism
 Angelman syndrome – mental retardation,

ataxic gait, seizure, inappropriate laughter,

“happy puppets”
 Both caused by deletion of chromosome 15

(q11.2q13)
Genomic Imprinting
Gonadal Mosaicism
 Only the gametes carry the mutation and
somatic cells are normal.
 So an apparently normal parent passes the

disease to his/her off-springs because of the

mutations carried in the spermatozoa/ovum
 It explains why some autosomal dominant

disorder occur without affected parents

(3) Chromosomal Disorders
 may take the form of an abnormal number of
chromosomes or alterations in the structure
of one or more chromosomes
 Number – aneuploidy (47,XXX) ; (45,X) etc

 monosomy or trisomy
 Structure - deletion, inversion, translocation
Chromosomal Disorders
Trisomy 21 (Down Syndrome)
 47,XX,+21 or 47,XY,+21
Trisomy 21 (Down Syndrome)
 Down syndrome is the most common of the
chromosomal disorders.
 47,XX,+21 or 47,XY,+21 ___95%
 Robertsonian translocation___4%
 Mosaic__1%
 Maternal age has a strong influence on the

incidence of trisomy 21. It occurs once in

1550 live births in women under age 20, in
contrast to 1 in 25 live births for mothers
over age 45.
Down Syndrome
 flat facial profile,
oblique palpebral
fissures, and
epicanthic folds
 mental retardation
 congenital heart
disease
 Increased risk for
acute leukemia
 Alzheimer disease
by Age 40
Down Syndrome
Autosomal Trisomies
 Trisomy 18 –
Edwards
syndrome
 47XX,+18
Autosomal Trisomies
 Trisomy 13 :
Patau syndrome
 47XX,+13
Sex Chromosomal Disorders
 More common than autosomal
 they cause subtle, chronic problems relating

to sexual development and fertility.

 often difficult to diagnose at birth, and many

are first recognized at the time of puberty.

 the higher the number of X chromosomes, in

both male and female, the greater the

likelihood of mental retardation.
Turner Syndrome
 It is the most common sex chromosome
abnormality in females, affecting about 1 in
2000 live born females
 Karyotype

◦ 45,X ( 57% )
◦ X chromosome structural abnormality (14%)
◦ Mosaic (29%)
Turner Syndrome
 neck webbing
 Congenital heart

disease
 failure to develop

normal secondary sex

characteristics
 Short stature
 Primary Amenorrhea
 Autoimmune thyroiditis
Turner Syndrome
Klinefelter syndrome
 The classic pattern of Klinefelter syndrome is
associated with a 47,XXY karyotype (82% of
cases).
 15% mosaic patterns 46,XY/47,XXY,

47,XXY/48,XXXY
 Incidence 1:500
Klinefelter Syndrome
Klinefelter syndrome
 Male Hypogonadism
 Tesicular dysgenesis
 Decreased secondary male sex characterstics
 Tallness, gynecomastia, and female

distribution of hair
 Infertility
Klinefelter Syndrome
(4) Diseases with multi-factorial
Inheritance
 Result from combined action of
◦ 1. two or more mutant genes (polygenic
inheritance)
◦ 2. Environmental influences
Multi-factorial Disorders

Cleft lip or cleft palate

Congenital heart disease

Hypertension

Coronary heart disease

Gout

Diabetes mellitus

Pyloric stenosis
Type II Diabetes
 Obesity and other environmental influences
unmask the Diabetic genetic trait.
 Concordance of type 2 DM in identical twins

is between 70 and 90%

 Both parents diabetic – 40%
 The genes that predispose type II DM

incompletely identified