11- Genetic Disorders

What are chromosomal disorders?

A type of genetic disorder occurring when there is an incorrect or abnormal number of chromosomes.

When do chromosomal disorders develop?

They develop during meiosis (egg or sperm) or early in fetal development.

When are chromosomal disorders typically identified?

They are identified in early childhood (congenital).

What are numerical abnormalities in chromosomal disorders?

When a normal pair of chromosomes has missing or extra chromosomes.

What are structural abnormalities in chromosomal disorders?

When part of a chromosome is missing, extra, switched, or reversed.

Can chromosomal disorders be passed down in families?

Yes, they can be passed down in families or develop without a known family history.

What is the prevalence of chromosomal disorders at birth?

1 in 150 babies are born with a chromosomal disorder.

What are some symptoms of chromosomal disorders?

Symptoms can include behavioral changes, cognitive deficits, developmental delays, and breathing problems.

What is nondisjunction?

Members of a chromosome pair fail to separate at anaphase, producing gametes with abnormal numbers of chromosomes.

When can nondisjunction occur?

During meiosis I or II.

What can result from a nondisjunction gamete uniting with a normal gamete during fertilization?

Abnormal zygotes.

What is the chromosome number of a zygote formed from a nondisjunction gamete?

2n ± n chromosomes.

What happens to chromosomes during mitosis if there is a nondisjunction?

Mitosis will duplicate the chromosomes as they are, passing the abnormality to all embryonic cells.

What will happen if an organism with nondisjunction survives?

It will have an abnormal number of chromosomes.

Trisomy 21 (Down Syndrome)

-Three number 21 chromosomes (Making 47 in total)

-Affects about 1 out of every 700 children

-Is the most common chromosome number abnormality

-Is the most common serious birth defect in the U.S.

Down syndrome characteristics

-Specific facial features

-Exhibit varying degrees of developmental delays

-Variable life span (historically, short)

-Risk for syndrome increases with the age of the mother at conception

--Pregnant women aged 35 and older are candidates for chromosomal prenatal screenings

Klinefelter Syndrome

XXY

Origin of Nondisjunction (Meiosis in egg or sperm formation); Frequency in Population = 1 in every 2,000 births.

-Sterile; underdeveloped testes; secondary female characteristics

XYY

Normal Male: Origin of Nondisjunction (Meiosis in sperm formation); Frequency in Population = 1 in every 2,000 births.

-Slightly taller than average

XXX

Normal Female: Origin of Nondisjunction (Meiosis in egg or sperm formation); Frequency in Population = 1 in every 1,000 births.

-Slightly taller than average; slight risk of learning disabilities

Turner Syndrome

Origin of Nondisjunction (Meiosis in egg or sperm formation); Frequency in Population = 1 in every 5,000 births.

-Sterile; immature sex organs

Five other types of chromosomal aberration mechanisms

-Deletion, duplication, inversion, substitution, translocation

-Occur due to errors in meiosis when chromosomes align

-Often severe because they may involve more than one gene

Deletion

When a chromosome breaks and some genetic material is lost

-Deletions, within part of the short arm of chromosome 1 (1p36) are associated with the development of neuroblastoma.

Duplication

When part of a chromosome is abnormally copied

Inversion

When a chromosome breaks in two places and the resulting piece of DNA is reversed and re-inserted into the chromosome

Translocation

When a piece of one chromosome breaks off and attaches to another chromosome

What are monogenic disorders?

Disorders inherited as dominant or recessive traits controlled by a single gene.

Where are the genes for monogenic disorders located?

On autosomes, which are chromosomes other than the sex chromosomes X and Y.

How well understood are the genetic bases of many human characters?

They are complex and poorly understood.

What type of genetic disorders are most human genetic disorders?

Recessive

What is required for a person to develop an autosomal recessive disorder?

They must be homozygous recessive.

What do we call individuals who carry a recessive allele but appear normal?

Carriers

Name a few examples of autosomal recessive disorders.

Albinism, cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Phenylketonuria

How do the severity of genetic conditions caused by recessive alleles vary?

They range from harmless to life-threatening.

Leber congenital amaurosis

-Symptoms = Rare; severe visual impairment from birth; affects the retina and causes nystagmus and photophobia

-Mechanism = Mutations in various genes (CEP290, GUCY2D) affecting photoreceptor function

Usher syndrome

-Symptoms = Rare; retinitis pigmentosa (night blindness, peripheral vision loss); hearing loss; one of the most common causes of deafness and blindness

-Mechanism = Mutations in multiple genes (MYO7A, USH2A) involved in photoreceptor cells and hair cells of the inner ear

Stargardt disease

(Stargardt macular dystrophy or juvenile macular degeneration)

-Symptoms = Progressive central vision loss in childhood or adolescence (1st/2nd decade of life); macular degeneration; difficulty seeing in low light

-Mechanism = Mutation in the ABCA4 gene affecting photoreceptor cells

What are autosomal dominant disorders?

Genetic conditions caused by dominant alleles.

-much less common

What is the range of severity for genetic conditions caused by dominant alleles?

They range from harmless to life-threatening.

Name a few examples of autosomal dominant disorders.

Achondroplasia, Marfan Syndrome, Huntington's Disease, Retinoblastoma.

What genotype causes death of the embryo in autosomal dominant disorders?

Homozygous dominant genotype (AA)

Who has the disorder in autosomal dominant disorders?

Only heterozygotes (Aa) with a single copy of the allele

What is the chance that a person with an autosomal dominant disorder will pass the condition to their children?

50%

Marfan syndrome

-Symptoms = Rare; affects the body’s connective tissue; ectopia lentis (displacement of the lens); myopia; increased risk of retinal detachment

-Mechanism = Mutations in the FBN1 gene affecting connective tissue

Retinoblastoma

-Symptoms = Rare; potentially life-threatening condition; leukocoria (white pupillary reflex); affects retina; strabismus; vision loss

-Mechanism = Mutations in RB1 gene leading to tumor development in the retina

Best disease

(Vitelliform macular dystrophy)

-Symptoms = Rare; yellowish egg yolk-like lesion in the macula; progressive vision loss

-Mechanism = Mutation in the BEST1 gene affecting retinal pigment epithelium

What is a gene located on a sex chromosome called?

A sex-linked gene.

Where are most sex-linked genes found?

On the X chromosome.

What is an example of a condition caused by a sex-linked gene?

-Red-green color deficiency

-Hemophilia

What is a type of muscular dystrophy that is sex-linked?

Duchenne muscular dystrophy.

Red-green colorblindness

a common sex-linked disorder caused by a malfunction of light-sensitive cells in the eyes.

-Mostly, males are affected, but heterozygous females have some defects, too.

-Generally have difficulty distinguishing between reds, greens, browns, and oranges. Often, they confuse different types of blue or purple hues.

-Because they are located on the sex chromosomes, sex-linked genes exhibit unusual inheritance patterns.

What is a multifactorial disorder?

A disorder caused by the interplay between multiple genetic and environmental factors.

What does polygenic mean in the context of multifactorial disorders?

It refers to the cumulative effects of several genes interacting with environmental influences.

Why are multifactorial disorders difficult to study or treat?

Because the specific factors contributing to the disorder are often not fully understood.

Do multifactorial disorders have a clear-cut inheritance pattern?

No, they do not have a clear-cut inheritance pattern.

How do multifactorial disorders behave in families?

They often cluster in families but do not follow an observable pattern of inheritance like single-gene disorders.

What makes predicting the risk of inheriting multifactorial disorders challenging?

The complexity of the disorder makes it challenging to predict an individual's risk of inheriting or passing on the disorder.

Multifactorial Birth Defects

Neural tube defects (spina bifida) & other birth defects are often multifactorial

Multifactorial Chronic Diseases

Heart disease, Type II Diabetes, and obesity are multifactorial, based on genetic predisposition, lifestyle, and environment

Multifactorial Psychiatric Disorders

Schizophrenia and bipolar disorder are considered multifactorial

Multifactorial Cancer

Several types of cancer are multifactorial, with genetic predisposition interacting with environmental exposures

What are mitochondrial disorders?

A diverse group of conditions resulting from problems with the mitochondria.

What type of disorders are mitochondrial disorders?

Multisystem disorders that affect multiple organs and systems.

What can mitochondrial disorders lead to?

Developmental delays, neurological problems, and organ dysfunction.

What causes mitochondrial disorders?

Mutations in the mitochondrial DNA (mtDNA).

-Mutations in the nuclear DNA for proteins essential for mitochondrial function.

-Other genetic or environmental factors.

How can mutations causing mitochondrial disorders be classified?

They can be inherited or acquired.

What are some symptoms of mitochondrial disorders?

Muscle weakness/fatigue.

-Gastrointestinal issues.

-Heart, liver, and kidney disease.

What metabolic condition can be a symptom of mitochondrial disorders?

Diabetes.

What sensory problems can occur due to mitochondrial disorders?

Visual and hearing problems.

What neurological problems can be symptoms of mitochondrial disorders?

Seizures and developmental delays.

What is are examples of mitochondrial disorders?

-MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)

-Kearns-Sayre syndrome

-Leigh syndrome

-ADOA (Autosomal dominant optic atrophy)

-LHON (Leber's hereditary optic neuropathy)

What causes progressive vision loss in Autosomal Dominant Optic Atrophy?

Optic nerve degeneration

What is the appearance of the optic disc in Autosomal Dominant Optic Atrophy?

Pale or atrophic optic disc appearance

At what age does Autosomal Dominant Optic Atrophy typically onset?

4 - 6 years old

Which gene is mutated in Autosomal Dominant Optic Atrophy?

OPA1 gene

On which chromosome is the OPA1 gene located?

Chromosome 3

What type of protein does the OPA1 gene produce?

A protein involved in the structure and function of mitochondria

How does Autosomal Dominant Optic Atrophy affect retinal ganglion cells?

It affects their health in the optic nerve

Is there a cure for Autosomal Dominant Optic Atrophy?

No cure or treatment; therapies are being developed to slow vision loss

What is Leber's Hereditary Optic Neuropathy?

A genetic condition causing optic nerve degeneration and progressive vision loss.

What are the symptoms of Leber's Hereditary Optic Neuropathy?

Progressive vision loss affecting visual acuity and central vision.

What is the appearance of the optic disc in Leber's Hereditary Optic Neuropathy?

Pale or atrophic optic disc appearance.

How does Leber's Hereditary Optic Neuropathy typically begin?

It begins unilaterally, with the other eye progressing later.

What is the typical age of onset for Leber's Hereditary Optic Neuropathy?

Young adulthood, typically between 10 and 30 years old.

What type of genetic mutation is associated with Leber's Hereditary Optic Neuropathy?

Mitochondrial DNA mutation.

What is the defect in Leber's Hereditary Optic Neuropathy related to?

Defect in genes that code for NAD+-producing enzymes.

How does Leber's Hereditary Optic Neuropathy affect retinal ganglion cells?

It affects the health of retinal ganglion cells in the optic nerve.

What are the treatment options for Leber's Hereditary Optic Neuropathy?

Treatment options are limited; gene therapy and antioxidants theoretically help.