BI 211 Genetics for Healthcare: Ch. 7 Sex Chromosome and Mitochondrial Inheritance/Disorders

5 Sex Chromosome Disorders

Extra X chromosomes

Extra Y chromosomes

Monosomy

Fragile X

Sex reversals

Extra X Chromosomes

relatively common occurence

Extra Y Chromosomes

most are NOT diagnosed

Monosomy

the only survivable monosomy is Turner Syndrome

Fragile X

exhibits both expansion and anticipation

How does Fragile X appear on a karyotype?

constricted or "fragile" site near the end of the long arm of the X chromosome that looks like it could break off

Trisomy X

47, XXX (1:300-400 females), most are undiagnosed

Clinical Presentation of Trisomy X

typically taller than average, slight delay in language and social development

Is the lifespan and reproduction normal with Trisomy X?

yes, because each cell has 2 Barr bodies

Tetrasomy X

48, XXXX

4 copies of X chromosome

Clinical Presentation of Tetrasomy X

Tall

Decreased cognition

Small head

Sunken nasal bridge

Skeletal abnormalities

Pentasomy X

49, XXXXX

5 X chromosomes

Clinical Presentation of Pentasomy X

VERY rare

Severe cognitive impairements, heart defects, and skeletal abnormalities

Klinefelter Syndrome

males have an extra X chromosome, making them XXY instead of XY

How does Klinefelter Syndrome occur?

nondisjunction from either parental gamete and is associated with maternal and paternal aging

Clinical presentation of Klinefelter Syndrome

Relatively normal childhood

Taller than average

Slight speech and reading delays

Increase in ADHD and Autism

Normal puberty

Klinefelter Syndrome in Late Teens

Testosterone production decreases

LH and FSH abnormally increase

Acne increases

Breast development

Issues with sperm production

Smaller than average genitalia

Adult Onset Symptoms of Klinefelter Syndrome

Osteoporosis

Low muscle mass

Thyroid disease (fatigue)

Breast cancer

Loss of body hair

Why is early diagnosis of Klinefelter Syndrome desirable?

Testosterone replacement therapy

Extra Y Chromosome Disorder

47, XYY

What is the cause of extra Y chromosomes?

Paternal nondisjunction

Clinical Presentation of Extra Y Chromosomes

Majority undiagnosed but teenage acne

and typically taller

Monosomy X (Turner Syndrome)

45, X

Only survivable monosomy, 99% do not survive to full term

What is very common with Turner syndrome?

Mosaicism

Mosaicism

a condition in which cells within the same person have a different genetic makeup

There is LOTS of ______ in severity with Turner Syndrome.

variation

Classic Phenotype of Turner Syndrome

Fetal nuchal hygroma

Neck webbing

Pedal edema

Smaller than expected at full term

Malformed ears, hearing loss

Poor dentition

Lifespan of Turner Syndrome

Shorter than average with high likelihood of hypertension, CAD, hyperlipidemia, and diabetes

Reproduction in Turner's Syndrome

Absent (majority) or delayed puberty leads to infertility

Fragile X Syndrome (FXS)

46, XX or 46, XY on Xg27

Most common known genetic cause of autism

What gene is located at Xq27 and why is it important?

FMR1 gene that is important for brain development and maintenance of neural synapse

How is FXS caused?

excessive CGG trinucleotide repeats in FMR1 gene

What is the normal amount of repeats in FMR1 gene?

< 45 repeats

What do more repeats cause?

Gene supression via methylation

More repeats = ....

more severe phenotype

Expansion

abnormal increase in repeats, such as CGG repeats, leading to more methylation that progressively turns off the gene

How does expansion occur?

Misalignment during crossing over because of repeats or duplications during DNA replication

Anticipation

phenotype is expressed with greater severity and at earlier ages with successive generations

Clinical Presentation of FXS

Cognitive delays

Autism

Seizures

Poor verbal skills

Delay in motor skills

Women with premutation

Sex Reversal

Genotype-phenotype gender mismatch which is very rare

Phenotypic women with sex reversal would have what chromosomes?

XY

Phenotypic men with sex reversal would have what chromosomes?

XX

Normal Sex Development in Females

Absence of SRY and AMF

Many autosomal gene products required, such as hCG and estrogen from maternal

Normal Sex Development in Males

Testes determining factor (SRY) gene on Y chromosome and AMF

Active weeks 5-6 in fetal development

Fetal gonads become testes and secrete testosterone

Anti-Mullerian Factor (AMF)

Located on Y chromosome and is active wks 8 and on, suppresses the paramesonephric ducts

Reproductive Development at 6 weeks

precursor gonads and ducts have develop and can develop into either male or female internal and external genitalia

If testosterone is produced around week 10, what occurs?

pushes development to male genitalia and reproductive organs

No testosterone produced results in?

development to female genitalia and reproductive organs

Paramesonephric ducts

develop into female reproductive tract

XY Females

Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome

no androgen receptors on cells and cells cannot respond to testosterone, SRY and AMF produced

XY females are recognizably what gender at birth?

Female

Clinical Presentation of XY Females

Normal growth during puberty

NO menstruation

Why does no menstruation occur?

the vagina ends in a blind pouch, there is no cervix, uterus, or uterine tubes

Therefore, XY females cannot..

reproduce

XX Males

translocation of the SRY gene onto the X

46, XX + SRY

XX males share many characteristics with whom?

Klinefelter males without the reading delay, normal penile length, and undescended testes

Can XX Males reproduce?

no

Mitochondria

produce vast majority of ATP and contain their own DNA

How many genes does mitochondrial DNA have?

37

What does mitochondrial DNA lack?

robust DNA repair mechanisms

Mitochondrial Inheritance

all mitochondria are maternally inherited due to sperm physiology

Why does sperm physiology matter?

The head has DNA that fuses with ovum and the tail contains cytoplasm and mitochondria that break off at the neck upon fusion

Ovum is _______ larger than sperm.

1000x

What does ovum contribute to?

all cytoplasm and organelles to the zygote

Mitochondrial Disorders are typically present where?

skeletal, muscular, or neurological system as they are all very energy-intensive

Most common symptoms of mitochondrial disorders

Fatigue

Progressive cell failure due to accumulated damage from insufficient energy production