genetic diseases 4 - the german university in...

Genetic Diseases 4

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.

2

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

3

Cytogenetic Disorders Involving Sex Chromosomes

Abnormal karyotypes involving the sex chromosomes, ranging from 45,X to 49,XXXXY, are compatible with life.

Phenotypically normal males with two and even three Y chromosomes have been identified.

Why?

Lyonization of X chromosomes (X inactivation in females)

Small amount of genetic information carried by the Y chromosome (for male differentiation).

4


Klinefelter Syndrome • Best defined as male hypogonadism that develops when there

are at least two X chromosomes in males.

• Results from nondisjunction of sex chromosomes during meiosis.

• The extra X chromosome may be of either maternal or paternal origin.

• Advanced maternal age and a history of irradiation in either parent may contribute to the meiotic error resulting in this condition.

6


Klinefelter Syndrome

• 47,XXY (most common)

• Mosaic patterns (15%): 46,XY/47,XXY

47,XXY/48,XXXY

• The presence of a 46,XY line in mosaics usually is associated with a milder clinical condition.

7


Klinefelter Syndrome • Distinctive body habitus with an increase in length between the

soles and the pubic bone, which creates the appearance of an elongated body.

• Reduced facial, body, and pubic hair and gynecomastia.

• Testicular atrophy (micro-orchidism) with low serum testosterone levels and elevated urinary gonadotropin levels.

• Klinefelter syndrome may be associated with mental retardation. The reduction in intelligence is correlated with the number of extra X chromosomes.

8


Klinefelter Syndrome • Klinefelter syndrome is the most common cause of

hypogonadism in males.

• Only rarely are patients fertile, and presumably such persons are mosaics with a large proportion of 46,XY cells.

• The sterility is due to impaired spermatogenesis, sometimes to the extent of total azoospermia.

• Klinefelter syndrome is associated with a higher frequency of several disorders, including breast cancer, and autoimmune diseases.

9


Turner Syndrome

• Characterized by primary hypogonadism in phenotypic females.

• Results from partial or complete monosomy of X chromosome.

• In adult patients, a combination of short stature and primary amenorrhea should prompt strong suspicion for Turner syndrome.

• The diagnosis is established by karyotyping.

10


(57%)

Most severely affected, and the diagnosis often can be made at birth or early in childhood.

(43%)

The karyotypic heterogeneity associated with Turner syndrome is responsible for significant variations in the phenotype

In contrast with the patients with monosomy X, those who are mosaics or have deletion variants may have an almost normal appearance and may present only

with primary amenorrhea. 11

Typical clinical features associated with 45,X

Growth retardation

Distended lymphatic channels

Increase in the carrying angle of the arms

High-arched palate

Congenital malformations: • Horseshoe kidney • Bicuspid aortic valve • Coarctation of the aorta

Fibrous stroma devoid of ova and follicles

Estrogen?

12

http://www.webmd.com/heart/bicuspid-aortic-valve


Turner Syndrome • Cardiovascular abnormalities are the most common cause of death

in childhood.

• In adolescence, affected girls fail to develop normal secondary sex characteristics; the genitalia remain infantile, breast development is minimal, and little pubic hair appears.

• The mental status of these patients is usually normal.

• Hypothyroidism caused by autoantibodies occurs, especially in women with isochromosome Xp.

13


The molecular pathogenesis of Turner syndrome is not completely understood

• Both X chromosomes are active during oogenesis and are essential for normal

development of the ovaries.

• During normal fetal development, ovaries contain as many as 7 million oocytes which then gradually disappear.

• In Turner syndrome, the absence of the second X chromosome leads to an accelerated loss of oocytes, which is complete by age 2 years.

“Menopause occurs before menarche” 14

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

15

Single Gene Disorders with Atypical Patterns of Inheritance

Triplet Repeat Mutations: Fragile X Syndrome • Results from a mutation in the FMR1 gene, which maps to Xq27.3

• The syndrome gets its name from the karyotypic appearance of the X chromosome: a discontinuity of staining or constriction in the long arm of the X chromosome.

• Fragile X syndrome is the second most common genetic cause of mental retardation, after Down syndrome.

• Frequency of 1 in 1550 for affected males and 1 in 8000 for affected females.

16

Fragile X Syndrome

(Very large expansions of DNA repeats outside coding sequences)

Fragile X

Highly expressed in brain and testicles

Fragile X Syndrome • Mental retardation • Abnormal phenotype (large everted ears, large Testicles…)

17


Fragile X Syndrome:

• Silencing of the product of the FMR1 gene, familial mental retardation

protein (FMRP).

• The normal FMR1 gene contains CGG repeats in its 5′ UTR.

• When the number of CGG repeats exceeds approximately 230, the DNA of the entire 5′ becomes abnormally methylated.

• Methylation extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FMR1 (“loss of function” of FMRP).

18


FMRP is widely expressed in higher levels in the brain and the testis.

FMRP plays a critical role in regulating the translation of axonal proteins from bound RNAs.

These locally produced proteins play diverse roles in the microenvironment of the synapse. 19

Fragile X Syndrome:

FMRP-mRNA complex


Fragile X Syndrome:

Clinically affected males have moderate to

severe mental retardation.

The characteristic physical phenotype:

• Long face with a large mandible

• Large everted ears

• Large testicles (macroorchidism)

20


Fragile X Syndrome: • As with all X-linked diseases, fragile X syndrome predominantly

affects males.

But

• Carrier males (20%) known to carry a fragile X mutation are clinically and cytogenetically normal. They transmit the trait through all their daughters (phenotypically normal) to affected grandchildren.

• Affected females: From 30% to 50% of carrier females are affected (mentally retarded).

21

Dynamic CGG repeats: amplification of the CGG repeats during oogenesis 22


Fragile X Syndrome • In the normal population, the number of CGG repeats of in the FMR1 gene

is small, averaging around 29.

• Affected persons have 200 to 4000 repeats (full mutation).

• These so-called full mutations are believed to arise through an intermediate stage of premutations characterized by 52 to 200 CGG repeats.

• Carrier males and females have premutations.

• During oogenesis (but not spermatogenesis), premutations can be converted to full mutations by further amplification of the CGG repeats, which can then be transmitted to both the sons and the daughters of the carrier female.

23


Diseases Caused by Mutations in Mitochondrial Genes

Inheritance of mitochondrial DNA differs from that of nuclear DNA in that it is associated with maternal inheritance.

Mitochondria contain several genes that encode enzymes involved in oxidative phosphorylation

24


Diseases Caused by Mutations in Mitochondrial Genes

• The mitochondrial DNA complement of the zygote is therefore derived entirely from the ovum.

• Thus, only mothers transmit mitochondrial genes to all of their offspring, both male and female.

• However, daughters but not sons transmit the DNA further to their progeny.

• Diseases caused by mutations in mitochondrial genes are rare and affect organs most dependent on oxidative phosphorylation (skeletal muscle, heart, brain).

25


Diseases Caused by Mutations in Mitochondrial Genes: Leber hereditary optic neuropathy

• This neurodegenerative disease manifests itself as progressive bilateral loss of central vision that leads in due course to blindness.

http://hihg.med.miami.edu/code/http/modules/education/Design/Print.asp?CourseNum=2&LessonNum=4

26


Diseases Caused by Alterations of Imprinted Regions: Prader-Willi and Angelman Syndromes

It has now been established that functional differences exist between the paternal and the maternal copies of some genes.

These differences arise from an epigenetic process called genomic imprinting, whereby certain genes are differentially “inactivated” during paternal and maternal gametogenesis.

27

15q12 Prader-Willi Syndrome Angelman Syndrome

Diseases Caused by Genomic Imprinting

Prader-Willi Syndrome Results from deletion of paternal chromosomal region 15q12 (imprinting on the

maternal chromosome).

Infants:

• Distinct facial features

• Hypotonia

• Failure to thrive

• Lack of eye coordination

Early childhood to adulthood

• Food craving and weight gain

• Hypogonadism

• Poor growth and physical development

• Short stature with small hands and feet

• Intellectual disability

• Speech problems

• Delayed motor development

People with Prader-Willi Syndrome, exhibiting characteristic facial appearance including

narrow temples, an elongated face, thin upper lip, and a prominent nose.

http://en.wikipedia.org/wiki/Prader%E2%80%93Willi_syndrome

29


Angelman Syndrome • Results from deletion of maternal chromosomal region 15q12

(imprinting on the paternal chromosome).

• Developmental delays and intellectual disability • Inability to walk, move or balance well (ataxia) • Lack of or minimal speech • Seizures • Stiff or jerky movements • Frequent smiling and laughter • Happy, excitable personality • Hypopigmentation • Sleep disorders

“Happy Puppet Syndrome” http://kosmixmedia.com/angelman-syndrome/

30

Case

• A 13 year old male with moderate mental retardation and a dysmorphic face is found to have 226 trinucleotide repeats in a gene located on the X chromosome. Which of the following is the most likely cause of this condition?

• A) Exon deletion

• B) Chromosomal breaks

• C) Gene methylation

• D) Impaired intron splicing

• E) Mismatch repair defect

31

Case

• A couple has a daughter who is ataxic and has a seizure disorder. She also has a strange affect characterized by excessive laughter at inappropriate times. Cytogenetic analysis demonstrates a normal genotype with 46 chromosomes. These symptoms are most likely due to:

• (A) genomic imprinting on a maternal autosome

• (B) expansion of a trinucleotide repeat

• (C) a point mutation in an autosome

• (D) random inactivation of the X chromosome

• (E) deletion on the maternal chromosome 15

32

References

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

33

genetic diseases 4 - the german university in...

Documents