genetic diseases 3 - pbt.guc.edu.egpbt.guc.edu.eg/download.ashx?id=539&file=lecture 3- genetics...

Genetic Diseases 3

Dr. Nabila Hamdi

MD, PhD

ILOs

• Define and use in proper context the genetic terminology.

• Have an understanding of how genome variation arises and its role in health and disease

• Be able to describe the main modes of Mendelian and non-Mendelian inheritance.

• Given a family history or pedigree, indicate the most likely mode of inheritance:

• Understand the clinical implications of incomplete penetrance and variable expressivity

• Appreciate the risk of individuals suffering simple Mendelian disorders.

• Be able to describe clinical features of common Mendelian diseases.

• Be able to describe clinical features of common chromosomal disorders.

• Understand the principles of cytogenetics and analysis of karyotypes.

• Recall major types of structural chromosome abnormalities and their basic implications.

• Discuss and contrast examples of diseases following an atypical pattern of inheritance.

• Recognize the genetic and environmental contribution to multi-factorial conditions.

• To have a clinical knowledge of several Mendelian and chromosomal conditions.

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Outline

I. NATURE OF GENETIC ABNORMALITIES CONTRIBUTING TO HUMAN DISEASE

II. MENDELIAN DISORDERS: DISEASES CAUSED BY SINGLE-GENE DEFECTS

1. Transmission Patterns

2. Diseases Caused by Mutations in Genes Encoding Structural Proteins

3. Diseases Caused by Mutations in Genes Encoding Receptor Proteins

4. Diseases Caused by Mutations in Genes Encoding Channels

5. Diseases Caused by Mutations in Genes Encoding Enzyme Proteins

III. COMPLEX MULTIGENIC DISORDERS

IV. CYTOGENETIC DISORDERS

1. Chromosomal Abnormalities

2. Cytogenetic Disorders Involving Autosomes

3. Cytogenetic Disorders Involving Sex Chromosomes

IV. SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE

1. Triplet Repeat Mutations

2. Diseases Caused by Mutations in Mitochondrial Genes

3. Diseases Caused by Genomic Imprinting

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Mendelian Disorders

3. Diseases Caused by Mutations in Genes Encoding Enzyme Proteins

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Glycogen Storage Diseases


• Lack of glucose-6-phosphatase

• HMG (storage of glycogen)

• Hypoglycemia (no glucose production)

• Convulsions (profound hypoglycemia)

• Hyperlipidemia, lactic acidosis, ketosis and hyperuricemia

• Renomegaly (storage of glycogen)

• Definitive diagnosis: enzyme activity in the liver

Hepatic Type: Von Gierke disease (type I glycogenosis)

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Histology shows increased amounts of glycogen, as well as fatty infiltration of the liver.


• Deficiency of muscle phosphorylase.

• Exercise intolerance with muscle weakness and cramps

• Post-exercise Myoglobinuria (rhabdomyolysis)

• Second wind phenomena (improvement after 10 min)

• Ischemic-forearm test: Failure of exercise to induce an elevation in blood lactate levels because of a block in glycolysis.

Myopathic form: McArdle disease (type V glycogenosis)

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Case

• A 2-month-old child is evaluated for failure to thrive. During the examination, the child has a seizure. Serum chemistries demonstrate severe hypoglycemia, hyperlipidemia, lactic acidosis, and ketosis. Physical examination is remarkable for hepatomegaly, a finding confirmed by CT scan, which also reveals renomegaly. Which of the following diseases best accounts for this presentation?

(A) Gaucher disease (B) McArdle disease (C) Niemann-Pick disease (D) Pompe disease (E) Von Gierke disease

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Complex Multigenic Disorders

Even monozygous twins reared separately may achieve different heights because of nutritional or other environmental influences

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Complex Multigenic Disorders Multifactorial ( polygenic, multigenic) inheritance is involved in many of the physiologic

characteristics of humans (height, weight, blood pressure, hair color).

Additive effect of two or more genes of small effect, conditioned by environmental influences.

Polygenic disorders occur when many polymorphisms, each with a modest effect and, are co-inherited.

This form of inheritance is believed to underlie common diseases:

• Diabetes mellitus

• Hypertension

• Gout

• Schizophrenia

• Certain forms of congenital heart disease

For example, clinically affected persons with type 2 diabetes often exhibit clinical manifestations after weight gain. Thus, obesity as well as other environmental influences, unmask the diabetic genetic trait.

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Cytogenetic Disorders

• Result from alterations in the number or structure of chromosomes and may affect autosomes or sex chromosomes.

• Approximately 1 in 200 newborn infants has some form of chromosomal abnormality.

• It is estimated that in 50% of first-trimester spontaneous abortions, the fetus has a chromosomal abnormality.

A karyotype is a photographic representation of a stained metaphase spread in which the chromosomes are arranged in

order of decreasing length.

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G-banded (Giemsa stained) karyotype from a normal male (46,XY). Also shown is the banding pattern of the X-chromosome with nomenclature of arms, regions, bands, and sub-bands 11


Numeric Abnormalities • In humans, the normal chromosome count is 46 (i.e., 2n = 46).

• Euploidy: any exact multiple of the haploid number (n)

• Polyploidy: Chromosome numbers such as 3n and 4n, generally results in a spontaneous abortion.

• Aneuploidy: any number that is not an exact multiple of n (2n+1 or 2n-1).

Monosomy involving autosomes is incompatible with life. Monosomy involving sex chromosomes is compatible with life.

Trisomies of certain autosomes are compatible with life.

Mosaicism is a term used to describe the presence of two or more populations of cells with different complements of chromosomes in the same individual.

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The chief cause of aneuploidy is nondisjunction of homologous pair of chromosomes at the first meiotic division or a failure of sister chromatids to separate during the second meiotic division or during mitosis in somatic cells, leading to the production of two aneuploid cells.

http://www.uic.edu/classes/bios/bios100/lectures/mitosis.htm

Numeric Abnormalities

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Structural Abnormalities Usually result from chromosomal breakage followed by loss or

rearrangement of material:

• Translocations

• Isochromosomes

• Deletions

• Inversions

• Ring chromosomes

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•The entire broken fragments are exchanged •Not harmful to the carrier •Example, 46,XX,t(2;5)(q31;p14)

•Breaks occur close to centromere of acrocentric chromosomes •The carrier has 45 chromosomes •Compatible with survival •Example, 45,XX,der(14;21)

• Translocation implies transfer of a part of one chromosome to another chromosome • Difficulties arise during gametogenesis, resulting in the formation of unbalanced gametes that could lead to abnormal offspring. 15


• Centromere divides horizontally rather than vertically. • One of the two arms of the chromosome is lost • The most common isochromosome present in live births is i(Xq)

• A single break may delete a terminal segment • Two interstitial breaks may result in loss of an intermediate segment. • The isolated fragment, which lacks a centromere, almost never survives, and thus many genes are lost.

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Two interstitial breaks in a chromosome, and the segment reunites after a complete turnaround.

• Is a variant of a deletion. • After loss of segments from each end of the chromosome, the arms unite to form a ring

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General Features of Chromosomal Disorders • May be associated with absence (deletion, monosomy), excess (trisomy), or

abnormal rearrangements (translocations) of chromosomes.

• In general, loss of chromosomal material produces more severe defects than does gain of chromosomal material.

• Excess chromosomal material may result from a complete chromosome (as in trisomy) or from part of a chromosome (as in robertsonian translocation).

• Excess or loss of sex chromosomes are tolerated much better than are similar imbalances of autosomes.

• Sex chromosomal disorders often produce subtle abnormalities, sometimes not detected at birth. Infertility, a common manifestation, cannot be diagnosed until adolescence.

• In most cases, chromosomal disorders result from de novo changes.

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Cytogenetic Disorders Involving Autosomes

Trisomy 21 (Down Syndrome) • The most common of the chromosomal disorders.

• About 95% of affected persons have trisomy 21, so their chromosome count is 47.

• The most common cause is meiotic nondisjunction.

• The parents of such children have a normal karyotype and are normal.

Maternal age has a strong influence: • Trisomy 21 occurs in 1 in 25 live births in women older than 45 years

(versus 1 in 1550 in women younger than 20 years).

• in 95% of cases the extra chromosome is of maternal origin (meiotic nondisjunction occurs in the ovum).

• No effect of paternal age has been found in those cases in which the extra chromosome is derived from the father.

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Flat facial profile, oblique palpebral fissures, and epicanthic folds are usually readily evident, even at

birth.

www.thesebrokenvases.com/2010/10/physical-characteristics-of-down.html

Sandal toe deformity

www.pyroenergen.com/articles07/downs-syndrome.htm

Single transverse palmar crease.

http://medgen.genetics.utah.edu/photographs/pages/down_syndrome.htm

20 Clinical Features http://ellietheurer.blogspot.com.eg/2012/08/friends-dont-count-chromosomes.html


80% have an IQ of 25 to 50

40%, AV valve malformations, ventricular/atrial septal defects Cardiac problems are responsible for a majority of death in infancy and early childhood.

10- to 20-fold increased risk of acute leukemia

Neuropathologic changes of Alzheimer disease in all patients older than age 40.

Abnormal immune responses and predisposition to serious Infections

21 Clinical Features


In about 4% of all patients with trisomy 21, the extra chromosomal material is present as a translocation of the long arm of chromosome 21 to chromosome 14.

Such cases frequently are familial, and the translocated chromosome is inherited from one of the parents, who typically is a carrier of a robertsonian translocation.

46XX,der(14;21)(q10;q10), +21 22


46XX,der(14;21)(q10;q10), +21 23


Approximately 1% of patients with trisomy 21 are mosaics, usually having a mixture of 46- and 47-chromosome cells.

These cases result from mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis.

Some have mild phenotypic changes and often even have normal or near-normal IQ.

46XX/47XX,+21

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The molecular basis for this disease remains elusive • Chromosome 21 carries about 500 annotated genes, including

approximately 170 that are conserved protein-coding genes and 5 miRNAs.

• Increased gene dosage of protein coding genes on chromosome 21??

• Effects of deregulated miRNA expression on target genes located on other chromosomes??

• DYRK1A (codes for a serine threonine kinase) and RCAN1 (regulator of calcineurin 1) are the “top culprits” in the pathogenesis of Down syndrome.

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References

ROBBINS Basic Pathology 9th Edition ROBBINS Basic Pathology 8th Edition Source of the cover image: http://www.interactive-biology.com/tag/genetics/

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Thank you…

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