Patho A 1. 4 Genetic Disorders (Gacasan, 2015).pdf

7/24/2019 Patho A 1. 4 Genetic Disorders (Gacasan, 2015).pdf

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Far Eastern University Nicanor Reyes Medical Foundation

Pathology AGenetic Disorders

Jocelyn Q. Gacasan M.D.

Genetics

Study of a single or a few genes and their phenotypic effects.

Genomics

Study of all the genes in the genome and their interactions.

Proteomics

Measurement of all the proteins expressed in a cell or tissue.

GENETIC DISORDERS

More common than appreciated, there are many existing cases

of genetic disorders that are not being observed.

Lifetime frequency of 670 per 1,000

This includes classic genetic disorders, cancer, and cardiovascular

diseases.

Definition of terms

HEREDITARY

Derived from parents and transmitted through the germ line.

Genetically acquired and inherited from the parents.

FAMILIAL

It runs in the family.

CONGENITAL

Present at the time of birth.

It does not necessarily mean it is hereditary.

Congenital Syphilis

Hereditary diseases on the other hand, do not also mean it is

congenital, because there are hereditary diseases that manifest

when an affected individual reaches adulthood.

Huntingtons diseaseusually manifests at 20 y/o.

MUTATIONS

A permanent change in the DNA make up of an individual.

Germ Cellsmay give rise to the inherited diseases.

Somatic Cells do not give rise or do not cause hereditary

diseases but they are important in the genesis of cancers and

some congenital malformations.

TYPES OF MUTATIONS

1.) Point mutations with coding sequences

A single nucleotide base is substituted by a different base.

Missense Mutationalters the genetic code and protein output

Conservative Missense replaced AA is biochemically the

same as the previous amino acid.

Non-conservative Missene replaced with biochemically

different AA.

Nonsense Mutationproduces a stop codon and terminates the

sequence (UAG, UGA, UAA).

In sickle cell anemia, thymine is replaced with adenosine. The previous

triplet: CTT, which codes for glycine, is replaced with CAT which now

codes for valine. The RBC phenotypically manifests a sickle shape rathe

than biconcave disc shape.

2.) Mutations within non-coding sequences

Does not involve mutations of the exons.

Mutations here involve regulatory sequences that may interfere

with binding of transcription factors.

Involvespromotersand enhancers.

Defective splicing, no mature mRNA, and translation does notoccur.

Example is Thalassemia.

3.) Frameshift Mutation

Involves deletionor insertionof one or two amino acids.

Insertion or deletion in the DNA sequence may disrupt the

reading frame, it may displace it forward (insertion) or displace i

back (deletion).

However, if 3 base pairs are inserted, there will be no frameshift

but the amino acid that is translated is different.

Example is the deletion of a base pair in ABO alleles.

4.) Trinucleotide Repeats

Amplification of sequences in 3 nucleotides.

Commonly affects cytosine and guanine.

Dynamic, it continues to amplify through generations.

In fragile X syndrome, FMNR1 gene have 250-4,000 CGG repeats

In a normal population, the amount of repeats is only small

averaging to about 29 repeats.


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TYPES OF GENETIC DISORDERS

1.) Single Gene Mutation Disorders(Mendelian Disorders)

With large effects.

Highly Penetrant

Follows the Mendelian pattern of inheritance.

2.) Chromosomal Disorders

Arise from structural or numerical alteration in the autosomes or

sex chromosomes.

Uncommon and highly penetrant.

Ex: Monogenic disorders

Visible with karyotyping.

3.) Complex Multigenic Disorders

Most common form

Polymorphisms

Multifactorial: interaction of genes and environmental factors.

4.) Single Gene Disorders with Non-classic inheritance

VARIABLE EXPRESSIVITY

A trait seen in all carriers of the disease, but expresses the

mutation differently.

Same genotype, different degrees of phenotype.

Ex: Neurofibromatosis

Some manifests macule type of lesions (brown spots)

Some manifests with tumors.

PENETRANCE

Expressed mathematically in terms of percent.

50% penetrance means 50% of those who carry the gene express

the trait or the phenotype.

AUTOSOMAL AND SEX-LINKED

Autosomal: Located in the autosomes (22 autosomes)

Sex-linked: Located in the X and Y chromosomes

RECESSIVE

Expressed only when the individual is homozygous.

The individual must have the 2 recessive genes on both

chromosomes to be affected with the disease.

DOMINANT

Expressed in homozygous or heterozygous forms.

The individual only needs 1 dominant gene to manifest the

disease. The dominant gene in heterozygous form masks theexpression of the recessive gene.

Alleles Present Allele Expressed

Homozygous Dominant Dominant,

Dominant

Dominant

Heterozygous Dominant Dominant,

Recessive

Dominant

Homozygous Recessive Recessive,

Recessive

Recessive

CO-DOMINANCE

Both of the alleles of the gene pair, dominant and recessive,

contribute to the phenotype.

Ex: Blood group antigens

PLEIOTROPISM

A single mutant gene leads to multiple end effects

GENETIC HETEROGENEITY

Mutations at the several loci may produce the same trait

A.)MENDELIAN PATTERN OF DISORDERS

Result of expressed mutation of single genes of large effect.

More than 4,500 mendelian disorders

Each person is a carrier of at least 5-8 recessive mutant genes.

80-85%are familial, 15-20%are new mutations (de novo).

Transmission patterns

1.

Autosomal Dominant

2.

Autosomal Recessive

3. X-linked

1.) Autosomal Dominant

Manifested both in homozygous and heterozygous states

Some without affected parents, results from de novomutation.

Both male and female can transmit the disease.

An affected one marrying a normal one, 1 out of 2 children may

manifest the disorder (50%)

De novo or new mutations may arise in germ cells of older fathe

Reduced Penetrance and Variable Expressivity.

Onset may be delayed.

The biochemical mechanism of autosomal disorders depend

upon the nature of the mutation and the type of protein affected

Many autosomal dominant disorders arise from deleterious

mutations and result to mutations of:

Those involved in regulation of complex metabolic

pathways that are subject to negative feedback inhibition

- Ex: Familial Hypercholesterolemia

Key Structural Proteins

- The product of the mutant allele can interfere with the

assembly of normal and functional multimeric proteins.

- Ex: Osteogenesis imperfecta


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Autosomal dominant mutations usually affect:

Non enzyme Proteins

Regulatory Proteins

Complex Structural Proteins

Loss-of-function mutations

More common

Dominant negativeimpairs the function of normal alleles

Gain-of-function mutations

Results in an increase in a protein[s normal function.

Imparts a wholly new activity completely unrelated to the

affecter proteins normal function.

Ex: Huntingtons disease results from generation of the

huntingtinprotein which is toxic to the neurons.

2.) Autosomal Recessive

Single largest category of the mendelian disorders.

Both alleles at a given gene locus are mutant.

More uniform clinical expression of the defect.

Complete Penetranceis common.

Early onset, rarely de novo, rarely detected.

Enzyme products are affected.

Parents do not manifest the disorder but they are carrier of the

recessive gene.

1 in 4 chances a child can manifest the disease (25%)

If the gene occurs at low frequency, it is likely a product of a

consanguineous marriage.

3.) Sex-linked Disorders

Affected Male:

zDo not transmit the disease to the sons

But all daughters are carriers.

Heterozygous Females are carriers.

Sons have 1:2 chances of being affected (50%)

Females have 1:2 chances of being a carrier

There is no Y-linked disorder, although it is possible, because

males with mutations affecting the Y-linked genes are usually

infertile.

X-linked recessive is the most common cause of sex-linked

disorders, the Y chromosome is not homologous to X, and so

mutant genes on X have no corresponding gene to the Y

chromosome, hence males are said to be Hemizygous for X

linked disorders.

Females do not manifest the disease because there is an extra

normal X chromosome. However, there are chances that the

normal X chromosome get silenced and the abnormal X

chromosome be fully expressed.

There are few X-linked dominant disorder like Vitamin-D

resistant rickets.


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BIOCHEMICAL AND MOLECULAR BASIS OF MENDELIAN DISORDERS

1. Enzyme defects

2. Defects in membrane receptors and transports

3.

Structural and Functional protein defects

4.

Unusual reaction to drugs

A.) Enzyme defects

Synthesis of an enzyme with reduced activity or reduced amount

of the normal enzyme.

Results to:

Accumulation of substrates

-

Can be accompanied by accumulation of one or more

intermediate substrates which are toxicto the tissues.

- Ex: Lysosomal storage diseases

Metabolic block with decreased end product

- May cause loss of function

- Ex: Albinism (Tyrosinase enzyme defect)

- If the end product involves a negative feedback process,

the deficiency of the end product may permit

overproduction of the intermediates which are toxic to

the tissues.

- Ex: Lesch Nyhan disease

Failure to inactivate tissue damaging substrate.

-

Absence of a regulatory component.

-

Ex: 1-antitrypsin deficiency.

- Patients with this deficiency dont have 1-antitrypsin

which inactivates neutrophil elastase in the lungs.

Without the antitrypsin, elastic structures of the lungs

are destroyed leading to emphysema.

B.) Defects in membrane receptors and transport system

Defective transport may result to accumulation inside the cell

Ex: Familial Hypercholesterolemia

Decreased synthesis of LDL-Receptors may lead to defective

transport of LDL to the liver cells.

Ex: Cystic Fibrosis

Defective transport system of Cl-ions in exocrine glands

C.) Alteration in structure, function, or quantity of non-enzyme proteins

Often have widespread effects

Defects in the structural proteins.

Ex: Sickle Cell Anemia

Defects in the structure of globin molecules

Ex: Osteogenesis imperfecta

D.) Adverse reaction to drugs

The manifestation of the disease unmasks only after exposure to

a certain drug.

Drug-induced injury to genetically susceptible individual.

Ex: G6PD Deficiency (Glucose-6 phosphate dehydrogenase)

Primaquine, an anti-malarial drug, causes hemolytic anemia

MARFAN SYNDROME

Structural protein defect

A disorder of connective tissues manifested principally by

changes in the skeleton, eyes, and cardiovascular system.

Approximately 70-85% of the cases are familialand autosoma

dominant, remainder of it is sporadic.

Inherited defect in the extracellular glycoprotein Fibrillin.

Fibrillin 1 (FBN1)15q21 for Marfan Syndrome

Fibrillin 2 (FBN2) 5q23 for Congenital Contractua

Arachnodactyly

The fibrils provide a scaffold on which tropoelastin is deposited

to form elastic fibers.

Most of these are missense mutations that give rise to abnorma

fibrilin-1 fibers, there can inhibit polymerization of fibrillin fibers

(dominant negative effect).

The reduction of the fibrillin content results to weakening of the

connective tissue (haploinsufficiency).

Loss of microfibrils results to activation of TGF-.

Excessive TGF- activates metalloproteases causing degradation

of extracellular matrix.

In other Marfan syndrome individuals, there is no mutation of

FBN1 but there is a mutation of the gene that encodes for TGF-

receptors.

Morphological Changes in Marfan Syndrome

Skeletal and Eyes

Unusually tall with exceptionally long extremities and long

tapering fingers and toes.

Double jointed, can extend the thumb to the back of the wrist.

Frontal Bossing, Kyphoscholiosis, Pectum Excavatum.

Bilateral Ectopia Lentis

Cardiovascular Lesion

Two most common lesions:

1. Mitral prolapse

2.

Dilation of the ascending aorta due to cystic medionecrosis.

Loss of medial support results in the progressive dilation of theaortic valve ring and the root of aorta resulting to aortic

incompetence.

Weakening of the tunica media can predispose to tunica intima

tear, which may initiate intramural hematoma and cleave the

layers of the media producing aortic dissection.


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EHLER-DANLOS SYNDROME

EDS comprise a clinically and genetically heterogeneous group of

disorders that result from some defect in the synthesis or

structure of collagen fibers.

The mode of inheritance encompasses all the 3 mechanisms of

mendelian pattern.

The tissues rich in collagen have a lack in tensile strength.

The skinis extraordinarily hyperextensible

Thejointsare hypermobile.

The internal structures that contain collagen (e.g. arteries, eyes,

colon) can rupture, detach, or herniate.

6 variants of EDS:

EDS Type Findings Inheritance

Classic

(I, II)

Skin and Joint hypermobility,

atrophic scars, easy bruising

Autosomal

Dominant

Hypermobility

(III)

Joint hypermobility, pain,

dislocations

Autosomal

Dominant

Vascular (IV) Thin skin, arterial or uterine

rupture, bruising, small joint

hyperextensibility

Autosomal

Dominant

Kyphoscoliosis

(VI)

Hypotonia, joint laxity, congenital

scoliosis, ocular fragility

Autosomal

Recessive

Arthrochalasia

(VIIa, b)

Severe joint hypermobility, skin

changes, scoliosis, bruising

Autosomal

Dominant

Dermatosparaxis

(VII c)

Severe skin fragility, cutis laxa,

bruising

Autosomal

Recessive

FAMILIAL HYPERCHOLESTEROLEMIA

Receptor Disease

A mutation in the gene encoding the receptor for LDL

Chromosome 19 encodes for the LDL Receptors

Most frequent mendelian disorder, autosomal dominant.

Heterozygous have 50% normal LDL receptors.

Presence of XanthomasElevated levels of cholesterol can induce premature

atherosclerosis.

5 Classes:

LYSOSOMAL STORAGE DISEASES

Lysosomes are key component of the intracellular digestive tract

they contain hydrolytic enzymes that have two special properties

First, they function in the acidic milieu of the lysosomes.

These enzymes constitute a special category of secretory

proteins that are destined not for the ECF but for the

intracellular organelles.

Lysosomes catalyze complex macromolecules via autophagy o

heterophagy.

Causes of lysosomal storage diseases:

Missing enzyme

-

Called primary accumulation

Lack of Enzyme Activator or protein protector

Lack of Substrate Activator protein

Lack of transport protein

The lysosomal defects can lead to two pathologic consequences:

This leads to an incomplete digestion of the macromolecule

stuck inside the lysosome, also called primary

accumulation.

Impaired autophagy can give rise to secondary

accumulation of autophagic substrates such as

polyubiquinated proteins and old mitochondria.

LYSOSOMAL STORAGE DISEASES

1.) Tay-Sachs Disease

Accumulation of GM2 Ganglioside.

Hexosaminosidase Adeficiency ( -subunit, chromosome 15)

Prominent CNS component

S/Sx appear at 6 months:

Motor and mental retardation, Blindness

Vegetative at 1-2 y/o, Death at 2-3 y/o

Cherry red spoton fundoscopy

Neurons present with cytoplasmic lipid vacuole, and appear as

whorled configurations on electron microscopy.


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2.) Niemann-Pick Disease (Types A and B)

Lysosomal accumulation of sphingomyelin.

Spingomyelinase deficiency, typically autosomal recessive.

Evident at 6 months.

Type A secere infantile form with extensive neurologic

involvement.

Type B Have organomegaly but generally no central nervous

system involvement, usually survives into adulthood.

Cherry red spot is seen in 1/3 of cases.

Fine vacuolization of phagocytic cells.

Zebra bodiesin electron microscopy.

3.) Gauchers Disease

A cluster of autosomal recessive disorder resulting from the

mutation of the glucocerebrosidasegene.

Accumulation of glucocerebroside in phagocytes.

Changes in Gaucher disease are also caused by activation of

macrophages and the consequent secretion of cytokines.

Three clinical subtypes:

Type I

- Chronic non-neuropathic form

- Most common, 99% of cases.

- Splenic and skeletal involvements dominate this type.

-

Glucocerebrosides are limited to mononuclear phagocytes

-

Has a predilection for Jewish of European stock.

Type II

- Acute neuropathic form

-

Infantile cerebral pattern

-

Hepatosplenomegaly, convulsions, mental retardation

- Progressive CNS Involvement

- Early death

Type III

- Intermediate between types I and II

The phagocytic cells have a crumpled-paper appearance.

4.) Mucopolysaccharidoses (MPS)

Typically autosomal recessive,except Hunter syndrome

Due to deficiency of enzyme that degrades GAGs.

Present with severe somatic and neurologic changes

(retardation).

Some types of MPS:

MPS I(Hurler Syndrome)

- Most severe form

-

L-iduronidase deficiency

-

Normal at birth

MPS II(Hunter Syndrome)

-

X-linked

-

L-iduronosulfate sulfatasedeficiency

Coarse facial features

Clouding of the cornea, joint stiffness

Organomegaly, subendothelial deposits

Zebra bodies and Balloon cells

GLYCOGEN STORAGE DISEASES

Defects in the synthesis or catabolism of glycogen

Autosomal recessive

Can be divided into 3 major sub groups:

Hepatic Formvon Gierkes disease

- Glucose 6 Phosphatase deficiency

-

Hepatomegaly and Hypoglycemia

Myopathic FormMcArdles disease

- Muscle phosphorylase deficiency

-

Myopathy, muscle cramps after exercise

-

Failure of lactate to rise after exercises

- Muscle weakness

Miscellaneous FormPompes disease

-

Acid Maltase (-glucosidase) deficiency.

- Storage in heart

- Prominent cardiomegaly


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ALKAPTONURIA (Ochronosis)

Autosomal recessive

Deficiency of homogentisic acid oxidase.

Black color of urine (alkaptonuria)

Blue-black discoloration of collage (ochronosis)

Arthropathy due to deposition in joints.

B.)COMPLEX MULTIGENIC DISORDERS

Environmental influences and the mutant gene have additive

effects.

Dosage effectthe greater the number of inherited deleterious

genes, the more severe the expression of the disease.

Multifactorial disorders:

Cleft lip or Cleft palate (or both)

Congenital Heart Disease

Coronary Heart Disease

Hypertension

Gout

Diabetes mellitus

Pyloric stenosis

C.)CHROMOSOMAL DISORDERS

Humans have either 46XY or 46XX.

Chromosomal result from either alteration in number or in

structure.

Karyotyping

Study of chromosomes.

Also called metaphase spread.

Chromosome pairs are arranged in order of decreasing length.

Total number of chromosomes + sex chromosome + description

of the abnormality:

Ex: 47, XY, +21 (Trisomy 21 male)

Nice to know but not included in the exam:

Each chromosome has 2 arms:

p= short arm, q= long arm.

Each arm is divided into region, bands, and sub-bands.

Disorders or mutations in a specific site of a chromosome is

named as:

[Chromosome number][arm][region][band].[sub-band]

Ex: Xp21.2, meaning there is a mutation in the short arm of the X

chromosome at region 1, band 1, sub-band 2.

Chromosomal Disorders

Chromosomal Number:

Euploidyexact multiple of the haploid

Aneuploidynot an exact multiple of 23

Monosomy (2n-1)

Trisomy (2n+1)

Causes of Aneuploidy

Non-disjunction

When this occurs during gametogenesis, the gametes

formed have either an extra chromosome (n+1) or one less

chromosome (n-1)

Anaphase lag

One homologous chromosome in meiosis or one chromatid

in mitosis lags behind and is left out of the cell nucleus.

One cell is normal, and one is monosomy.

Monosomies involving an autosome generally cause loss of too

much genetic information to permit live birth or even

embryogenesis, but several autosomal trisomies do permit survival.

Structural aberrations

Inversion

Two breaks and inverted reincorporation

Paracentricinvolves only one arm of the chromosome.

Pericentricbreaks are on the opposite sides of the centromere

Isochromosome Formation

Loss of one arms followed by the duplication of the two

remaining arms.

The chromosome either only contains 2 short arms or 2 long

arms.

Translocation

A segment of one chromosome is transferred to another.

Balance reciprocal translocation single breaks in each of two

chromosome with exchange of material.

Centric fusion or Robertsonian fusion long arms of one is

transferred to the short arm resulting to one very long and one

very short arm.


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Deletion

Loss of a portion of the chromosome.

Most deletions are interstitial but rarely terminal deletions may

occur.

Interstitial deletions occur when there are two breaks within a

chromosome arm, followed by loss of the chromosomal material

between the breaks and fusion of the broken ends.

Ring Chromosomes

Deletion of both the ends of the chromosome and fusion of the

damaged ends.

Cytogenetic Disorders involving Autosomes

1.

Trisomy 21Down Syndrome

2. Trisomy 18Edwards Syndrome

3. Trisomy 13Patau Syndrome

4. Chromosome 22q11.2 deletion syndrome

TRISOMY 21 (Down Syndrome)

Most common chromosomal disorder

Major cause of mental retardation (80% have 25-50 IQ).

Due to meiotic non-disjunction.

Maternal age has a strong influence on the incidence.

Increased risks:

Coronary Heart Disease (40%)

Acute Leukemia

Alzheimers Disease

Abnormal Immunity

TRISOMY 18 (Edward Syndrome)

Most severe malformation

Meiotic non-disjunction

Rarely revives beyond one year

TRISOMY 13 (Patau Syndrome)

Also due to meiotic non-disjunction

CHROMOSOME 22q11.2 DELETION SYNDROME

Spectrum of disorders

Result from a small deletion of band q11.2 in the long arm of

chromosome 22.

A fairly common syndrome occurring in 1 in 4,000 births.

Clinical features and manifestations:

Congenital Heart Defects

Facial Dysmorphism

Developmental delay

Variable T-cell deficiency with hypocalcemia


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Fluorescence in Situ Hybridization

Left: Trisomy, Right: Deletion

Cytogenetic Disorders Involving Sex Chromosomes.

More common than autosomal abnormalities.

Better tolerated.

Not usually recognized until puberty

Increase in number of X chromosome is associated with mental

retardation.

Lyon Hypothesis:

Only one X is functionalin females affected.

The other X is seen as a Barr body

The inactivation of X is due to inactivation of XIST molecule

Regardless the number of X chromosome, the presence of Y

chromosome sets the sex to male.

KLINEFELTERS SYNDROME

47 XXY

Most common sex chromosomal disorder and cause of

hypogonadism in males.

Low IQ, Infertile, Gynecomatia

Increased FSH and Estradiol and decreased testosterone.

Due to maternal meiotic non-disjunction

TURNER SYNDROME

45 X

Most common sex chromosomal disorder in females

Edema, congenital heart disease, absence of secondary female

characteristics, normal IQ, and ammenorhea.

Auto antibory to thyroid (50%), glucose intolerant, obesity.

Webbing of the neck, cubitus valgus

HERMAPHRODITISM

Presence of both testis and ovariesExtremely rare

50% is 46XX.

PSEUDOHERMAPHRODITISM

Disagreement of gonadal and phenotypic sex

Maledue to mutations in the gene for androgen receptor

Normal testes and ducts but ambiguous external genitalia

Female due to excessive exposure to androgens during

pregnancy

Normal internal genetalia, virilized external genetalia

Large clitoris.

D.) SINGLE GENE DISORDER WITH NON-CLASSIC INHERITANCE

Four categories:

1. Trinucleotide Repeats

2. Mutation in mitochondrial genes

3. Genomic imprinting

4.

Gonadal Mosaicism

Trinucleotide Repeat Mutation

Long repeating sequences of 3 nucleotides involving G and C.

DNA becomes unstable

Particularly neurodegenerative disorders.

The proclivity to expand depends strongly on the sex of the

transmitting parent.

Fragile Xexpansion occurs during oogenesis

Huntingtonexpansion occurs during spermatogenesis

FRAGILE X SYNDROME

Seen as discontinuity of staining or as a constriction in the long

arm of the X-chromosome, and is liable to chromatid breaks.

One of the most common causes of familial mental retardation

in males.

Reduction in FMR protein due to mutation of the FMR1 gene

Long face, large mandible, large everted ears, macro-orchidism.

Atypical pattern of transmission:

Carrier males transmit to daughters, grandchildren are

affected

Affected females30-50% are affected

Phenotypic effects:

- 9% brothers with Mental Retardation

- 40% grandsons have Mental Retardation

Worsens each generation

Mutations in the mitochondrial genes (mtDNA)

Maternal inheritance, because the mitochondria we inherit is the

one in the egg cells cytoplasm.

Mothers transmit their mtDNA to all their offspring but onlydaughters can pass the mtDNA.


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LEBER HEREDITARY OPTIC NEUROPATHY

mtDNA encodes for enzymes involved in oxidative

phosphorylation, thus mutations affect primarily the CNS,

skeletal, and cardiac muscles, liver, and kidneys.

Progressive bilateral loss of central vision.

First noted between 15 and 35 years and leads to blindness;

cardiac conduction defects and minor neurologic manifestations

may be seen.

Genomic Imprinting

Imprinting selectively inactivates either the maternal or the

paternal allele.

Occurs in the ovum or sperm before fertilization.

Maternal imprinting silences maternal alleles

Paternal imprinting silences paternal alleles.

PRADER-WILLI SYNDROME

Deletion primarily affects the paternally derived chromosome 15

Retardation, short stature, hypotonia, small hands and feet

Hypogonadism

ANGELMAN SYNDROME

Deletion primarily affects the maternally derived chromosome

15

Mentally retarded, ataxic gait, seizures.

Inappropriate smile or laughter (happy puppets)

Gonadal Mosaicism

Mutation occurs postzygotically during early embryonic

development.

Parents are phenotypically normal but diseases are seen in

multiple children.

Germ line mutationthe gametes carry the mutation.

MOLECULAR DIAGNOSIS

PCR and Detection of DNA alterations

Sanger sequencing

Pyrosequencing

Single base primer extension

Restriction Fragment length analysis

Amplicon length analysis

Real-time PCR

Molecular Analysis of Genomic Alterations

Fluorescence in situ hybridization (FISH)

Multiplex Ligation-dependent probe amplification (MLPA)

Southern Blot

Cytogenomic Array Technology

Array based comparative genomic hybridization

SNP Genotyping Array

Polymorphic Markers and Molecular Diagnosis

Epigenetic Alterations

RNA Analysis

Next Generation Sequencing

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Patho A 1. 4 Genetic Disorders (Gacasan, 2015).pdf