CHAPTER VI: A. GENETIC DISORDERS; B. CYTOGENETIC DISORDERS Flashcards
Associated defects of Mendelian Disorders
- Marfan Syndrome
- Ehlers-Danlos Syndrome
Associated with defects in receptor proteins
- Familial Hypercholesterolemia (FH)
Associated with defects in enzymes
- Lysosomal Storage Diseases
- Tay-Sachs Disease
- Niemann-Pick Disease
- Gaucher’s Disease
- Mucopolysaccharidoses
- Glycogen Storage Diseases
- Alkaptonuria
Associated with defects in proteins that regulate cell growth
- Neurofibromatosis
- Triplet Repeat Mutation Fragile X Syndrome
- Neurofibromatosis
a) Multifactorial
b) Single Gene Disorders with non-classic inheritance
CYTOGENETIC DISORDERS
a) Involving autosomes
b) Involving sex chromosomes
c) Mutations in Mitochondrial genes
a) Involving autosomes
Trisomy 21
Trisomy 18
Trisomy 13
Cri-du-Chat
b) Involving sex chromosomes
Klinefelter’s Syndrome
XYY Syndrome
Turner’s Syndrome
Hermaphroditism
Pseudohermaphroditism
c) Mutations in Mitochondrial genes
Leber’s Hereditary Optic Neuropathy
Prader-Willi Syndrome
Angelman’s Syndrome
Genomic Imprinting
Leber’s Hereditary Optic Neuropathy
is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence.
Genetic disorder
mutation in one gene
monogenic disorder
mutations in multiple genes
multifactorial inheritance disorder
disease caused by a combination of gene mutations and [?]
environmental factors
disease caused by damage to chromosomes
changes in the number or structure of entire chromosomes, the structures that carry genes
It is one of the most common inherited disorders of connective tissue.
Marfan Syndrome
Autosomal dominant condition
Marfan Syndrome
Cause: mutation in the FBN1 gene
Marfan Syndrome
are associated with a broad continuum of physical features ranging from isolated features to a severe and rapidly progressive form in newborns.
FBN1 mutations
Marfan Syndrome Symptoms
Bones
Heart
Lungs
Eyes
Ehlers-Danlos Syndrome Signs and Symptoms
Musculoskeletal
Skin
Cardiovascular
Vascular skin conditions
Orthostatic intolerance, Dilation and/or rupture of ascending aorta, Cystic medial necrosis, Varicose veins
Ehlers-Danlos Syndrome Other Signs and Symptoms
Orthostatic intolerance, Dilation and/or rupture of ascending aorta, Cystic medial necrosis, Varicose veins
Hyper-flexible joints
Musculoskeletal
Unstable joints that are prone to sprain, dislocation, subluxation and hyperextension
Musculoskeletal
osteoarthritis
Musculoskeletal
Chronic degenerative joint disease
Musculoskeletal
Swan neck deformity of the fingers
Musculoskeletal
Muscle fatigue that increases with use
Musculoskeletal
hypotonia in infancy
Musculoskeletal
Osteopenia
Musculoskeletal
Stretchy ligaments and tendons
Musculoskeletal
Tearing of tendons or muscles
Musculoskeletal
Deformities of the spine
Musculoskeletal
Myalgia and arthralgia
Musculoskeletal
Stretchy skin with a velvety texture
Skin
Fragile skin
Skin
Easy bruising
Skin
Abnormal wound healing and scar formation
Skin
Redundant skin folds
Skin
Molluscoid pseudotumors
Skin
Subcutaneous spheroids
Skin
Fatty growths on forearms or shins
Skin
Angioplasia
Skin
Fragile blood vessels
Cardiovascular
Life-threatening carotid-cavernous fistula
Cardiovascular
Unpredictable rupture of medium-sized arteries
Cardiovascular
Valvular heart disease
Cardiovascular
Raynaud’s phenomenon
Vascular skin conditions
Livedo reticularis
Vascular skin conditions
Autosomal dominant
Classical 1 and 2
Vascular 4
Dominant/Recessive
Hypermobility 3
Tenascin- X def.
Hypermobility 3
Type 3 collagen
Vascular 4
Autosomal recessive
Kyphoscoliosis 6
Arthrochalasis 7A and 7B
Type 1 collagen
Arthrochalasis 7A and 7B
Lysyl hydroxylase def.
Kyphoscoliosis 6
COL5A1
Classical 1 and 2
COL5A2
Classical 1 and 2
COL1A1
Classical 1 and 2
Arthrochalasis 7A and 7B
COL3A1
Hypermobility 3
Vascular 4
TNX B
Hypermobility 3
PLOD1
Kyphoscoliosis 6
COL1A1
Arthrochalasis 7A and 7B
ADAMTS2
Dermatosparaxis C
abnormally longer than normal
Bones
dolichostenomelia
Bones
arachnodactyly
Bones
scoliosis
Bones
pectus excavatum
Bones
pectus carinatum
Bones
high palate
Bones
malocclusions
Bones
angina pectoris
Heart
tachycardia
Heart
cystic medial degeneration
Heart
aortic dissection
Heart
heart murmur
Heart
risk of spontaneous pneumothorax
Lungs
emphysema
Lungs
COPD
Lungs
collapsed lung
Lungs
sleep apnea
Lungs
myopia or hyperopia
Eyes
astigmatism
Eyes
glaucoma
Eyes
cataract
Eyes
detachment or tear in the retina
Eyes
An inherited condition that causes high levels of LDL cholesterol levels beginning at birth, and heart attacks at an early age.
Familial Hypercholesterolemia (FH)
It is caused by a defect on chromosome 19
Familial Hypercholesterolemia (FH)
The defect makes the body unable to remove low density lipoprotein from the blood.
Familial Hypercholesterolemia (FH)
This results in a high level of LDL in the blood
Familial Hypercholesterolemia (FH)
Familial Hypercholesterolemia (FH) Other names:
o Type II hyperlipoproteinemia;
o Hypercholesterolemic xanthomatosis;
o Low density lipoprotein receptor mutation
Fatty skin deposits over parts of the hands, elbows, knees, ankles and around the cornea of the eye
Familial Hypercholesterolemia (FH)
Fatty skin deposits
xanthomas
Cholesterol deposits in the eyelids
(xanthelasmas)
A physical exam may show fatty skin growths called xanthomas and cholesterol deposits in the eye.
Familial Hypercholesterolemia (FH)
cholesterol deposits in the eye
corneal arcus
A. Lateral borders of thickened [?] are shown with arrows.
Achilles’ tendons
B: can also occur in the extensor tendons of the hands (shown), feet, elbows and knees.
Tendinous xanthomas
C: are cholesterol deposits in the eyelids.
Xanthelasmas
D: results from cholesterol infiltration around the corneal rim.
Arcus cornealis
Lysosomal Storage Diseases
- Tay-Sachs Disease
- Niemann-Pick Disease
- Gaucher’s Disease
- Mucopolysaccharidoses
- Glycogen Storage Diseases
- Alkaptonuria
The disease is named for Warren Tay, a British ophthalmologist who in 1881 described a patient with a cherry-red spot on the retina of the eye.
Tay-Sachs Disease
Life-threatening disease of the nervous system passed down through families.
Tay-Sachs Disease
occurs when the body lacks hexosaminidase A
Tay-Sachs Disease
caused by a defective gene on chromosome 15
Tay-Sachs Disease
When both parents carry the defective gene, a child has a 25% chance of developing the disease.
Tay-Sachs Disease
The child must receive two copies of the defective gene, one from each parent, in order to become sick
Tay-Sachs Disease
The disease is most common among the Ashkenazi
Tay-Sachs Disease
Jewish population.
Tay-Sachs Disease
Tay-Sachs Disease Other names
o GM2 gangliosidosis - Tay-Sachs;
o Lysosomal storage disease - TaySachs disease
Deafness
Tay-Sachs Disease
decreased eye contact
Tay-Sachs Disease
blindness
Tay-Sachs Disease
Decreased muscle tone (loss of muscle strength)
Tay-Sachs Disease
loss of motor skills
Tay-Sachs Disease
paralysis
Tay-Sachs Disease
Slow growth and delayed mental and social skills
Tay-Sachs Disease
Dementia (loss of brain function)
Tay-Sachs Disease
Increased startle reaction
Tay-Sachs Disease
Irritability
Tay-Sachs Disease
Seizures
Tay-Sachs Disease
an autosomal recessive genetic disorder
Tay-Sachs Disease
Autosomal means it affects males and females equally and recessive means both parents must be a carrier for the children to be at risk.
Tay-Sachs Disease
If both parents are carriers, there is a 25% chance with each pregnancy that the child will be affected.
Tay-Sachs Disease
A primary deficiency of acid sphingomyelinase and the resultant accumulation of sphingomyelin.
Niemann-Pick Disease
phagocytic cells of spleen, liver, bone, marrow, lymph nodes, lungs are enlarged and vacuolated as a result of the storage of lipids
Niemann-Pick Disease
stuffed with droplets or particles of the complex lipid, imparting a fine vacuolation or foaminess to the cytoplasm
Niemann-Pick Disease
manifests itself in infancy with massive visceromegaly and severe neurologic deterioration
Niemann-Pick Disease Type A or Classic infantile form
no neurologic disorders
Niemann-Pick Disease Type B Visceral juvenile form
most common form of the disease, subtype with brain complications into C1 and C2
Niemann-Pick Disease Type C Subacute/ Juvenile form
caused by the mutation in the same gene as type C1, was originally separated from type C to delineate a group of patients sharing a common ancestry with otherwise identical disorders, no longer used
Niemann-Pick Disease Type D Nova Scotian Type
o lipid histiocytosis
o neuronal cholesterol lipidosis
o neuronal lipidosis
o sphingomyelin lipidosis
o sphingomyelin/cholesterol lipidosis
o sphingomyelinase deficiency
Niemann-Pick Disease
Nova Scotian type
Niemann-Pick Disease Type D
rare genetic disorder that is one of a group called lysosomal storage disorders.
Gaucher’s Disease
It is an inherited disorder that results in the accumulation of fatty molecules called cerebrosides in the body’s organs and tissues
Gaucher’s Disease
It is caused by a missing or deficient enzyme called ‘glucocerebrosidase’
Gaucher’s Disease
the gene that would normally tell the body to produce this enzyme is altered
Gaucher’s Disease
Signs and Symptoms: enlarged liver and spleen, low platelet and hemoglobin counts, problems with bones and joints
Gaucher’s Disease
Liver and spleen enlargement (hepatosplenomegaly) can occur as the result of an inherited disorder in which the liver cannot process glucocerebroside
Gaucher’s disease
The buildup of this substance in body tissues can cause severe damage to the central nervous system in infants.
Gaucher’s disease
group of inherited lysosomal storage disorders
Mucopolysaccharidoses
abnormal accumulation of certain complex carbohydrates (glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth.
Mucopolysaccharidoses
These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow.
Mucopolysaccharidoses
This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body.
Mucopolysaccharidoses
Signs and symptoms: coarse facial features, short stature, heart abnormalities, breathing irregularities, liver and spleen enlargement (hepatosplenomegaly), and/or neurological abnormalities
Mucopolysaccharidoses
rare condition that changes the way the body uses and stores glycogen, a form of sugar or glucose
Glycogen Storage Diseases
is passed down from parents to children (is hereditary). It is most often seen in babies or young children. But some forms may appear in adults.
Glycogen Storage Diseases
von Gierke disease
Type I
Most common form of GSD
Type I
don’t have the enzyme needed to turn glycogen into glucose in the liver
Type I
Glycogen builds up in the liver.
Type I
Symptoms often appear in babies around 3 to 4 months old.
Type I
They may include low blood sugar (hypoglycemia) and a swollen belly because of an enlarged liver
Type I
rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body.
Alkaptonuria
Cause: mutation of the homogentisate 1,2dioxygenase (HGD) gene
Alkaptonuria
Inherited as an autosomal recessive trait
Alkaptonuria
Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid
Alkaptonuria
Affected individuals may have dark urine or urine that turns black when exposed to air.
Alkaptonuria
Dark/ Black urine upon long standing exposure to the air
Alkaptonuria
- connective tissue such as cartilage turns blue, grey or black due to the chronic accumulation of homogentisic acid
Alkaptonuria-Ochronosis
Whites of the eyes (sclera) also become discolored
Alkaptonuria
Tendonitis
Alkaptonuria
Arthritis and ochronotic arthropathy
Alkaptonuria
rare genetic disorder that causes typically benign tumors of the nerves and growths in other parts of the body
Neurofibromatosis
caused by mutations in the gene that controls production of a protein called neurofibromin
Neurofibromatosis type I (NF1)
manifests itself at birth or during early childhood
Neurofibromatosis type I (NF1)
manifests itself at birth or during early childhood
Neurofibromatosis type I (NF1)
results from mutations in a different tumor-suppressing gene (neurofibromin 2, merlin)
Neurofibromatosis type II (NF2)
may appear during childhood, adolescence or early adulthood
Neurofibromatosis type II (NF2)
characterized by benign tumors of the nerves that transmit sound impulses and balance signals from the inner ears to the brain
Neurofibromatosis type II (NF2)
more frequently diagnosed in adults aged 30 and older
Schwannomatosis
characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females
Triplet Repeat Mutation – Fragile X Syndrome
caused by an abnormality (mutation) in the FMR1 gene
Triplet Repeat Mutation – Fragile X Syndrome
is a gene located on the X chromosome that produces a protein called FMRP needed for proper cell function
FMR1
large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes
Triplet Repeat Mutation – Fragile X Syndrome
flat feet, frequent ear infections, low muscle tone, a long narrow face, high arched palate, dental problems, crossed eyes (strabismus) and heart problems including mitral valve prolapse
Triplet Repeat Mutation – Fragile X Syndrome
Discovered in 1966 by Langdon Down
Trisomy 21
It is the only human autosomal trisomy in which a significant number of individuals survive longer than a year past birth.
Trisomy 21
Mental retardation
Trisomy 21
Multiple physical abnormalities such as heart defects
Trisomy 21
affected children are small in stature because of delayed maturation of the skeletal system
Trisomy 21
Poor muscle tone resulting in a characteristic facial appearance
Trisomy 21
Shortened life span
Trisomy 21
Most cases are caused by non-disjunction
Downs syndrome
Failure of homologous chromosomes to separate in meiosis
non-disjunction
Nondisjunction of [?] is more likely to happen in oogenesis than in spermatogenesis, and so the abnormal gamete in Down syndrome is usually the egg
chromosome 21
Edwards Syndrome
Trisomy 18
Patau Syndrome
Trisomy 13
Rare conditions associated with major developmental abnormalities
Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome)
Affected infants can survive for only a few days or weeks.
Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome)
In 1960, Klaus Patau and his associated observed an infant with severe developmental malformations with a karyotype of 47 chromosomes
Trisomy 13
average survival: Less than six months
Trisomy 13
Majority are male
Trisomy 13
Affected infants are not mentally alert
Trisomy 13
Are thought to be deaf
Trisomy 13
Characteristically have a harelip, clef palate
Trisomy 13
Demonstrate polydactyly
Trisomy 13
Autopsy reveals congenital malformation of most organ systems
Trisomy 13
Condition indicative of abnormal developmental events occurring as early as 5-6 weeks of gestation.
Trisomy 13
In 1960, John H. Edwards and his colleagues reported on an infant trisomic for a chromosome in the E group
Trisomy 18
Survival: Less than 4 months
Trisomy 18
Symptoms: Congenital heart defects, growth retardation, dysmorphic features, facial clefts, spina bifida, severe developmental delay
Trisomy 18
Smaller than the average newborn
Trisomy 18
Skulls are elongated in an anterior-posterior direction
Trisomy 18
Ears are set low and malformed
Trisomy 18
Webbed neck
Trisomy 18
Congenital dislocation of hips
Trisomy 18
Receding chin
Trisomy 18
Due to a missing piece (deletion) of a specific part of chromosome 5 known as the ‘p’ arm.
Cri-du-Chat
In general, the severity of the symptoms is determined by the size and location of the deletion on chromosome 5.
Cri-du-Chat
This deletion occurs very early in the development of an embryo and cri du chat syndrome is usually not inherited in families.
Cri-du-Chat
present from birth and affects growth and development
Cri-du-Chat
Infants with this condition often have a high-pitched cat-like cry, small head size, and a characteristic facial appearance.
Cri-du-Chat
Cat-like cry
Cri-du-Chat
Small head size (microcephaly)
Cri-du-Chat
Characteristic facial features
Cri-du-Chat
Hypotonia
Cri-du-Chat
Intellectual disability
Cri-du-Chat
Global developmental delay
Cri-du-Chat
Behavior issues
Cri-du-Chat
Growth delay
Cri-du-Chat
Diagnosis: based on the clinical examination, symptoms and confirmed by the results of genetic testing.
Cri-du-Chat
Treatment is focused on managing the symptoms.
Cri-du-Chat
47, XXY
Klinefelter’s Syndrome
Males
Klinefelter’s Syndrome
Tall, do not undergo normal sexual maturation, are sterile, and in some cases have enlargement of the breasts.
Klinefelter’s Syndrome
Mild mental impairment is common
Klinefelter’s Syndrome
rare chromosomal disorder that affects males. It is caused by the presence of an extra Y chromosome.
XYY Syndrome
Affected individuals are usually very tall.
XYY Syndrome
Many experience severe acne during adolescence.
XYY Syndrome
Additional symptoms may include learning disabilities and behavioral problems such as impulsivity.
XYY Syndrome
Intelligence is usually in the normal range, although IQ is on average 10-15 points lower than siblings.
XYY Syndrome
Synonyms of XYY
XYY Syndrome
47, XYY
XYY Syndrome
Jacob’s syndrome
XYY Syndrome
XYY karyotype
XYY Syndrome
YY syndrome
XYY Syndrome
45, X
Turner’s Syndrome
Monosomy of the X chromosome in females
Turner’s Syndrome
Phenotypically female but are short in stature and do not exhibit sexual maturation.
Turner’s Syndrome
Mental abilities are typically within the normal range.
Turner’s Syndrome
the condition of having both male and female reproductive organs
Hermaphroditism
Conditions that involve discrepancies between external genitalia and internal reproductive organs are described by the term intersex.
Hermaphroditism
Intersex conditions are sometimes referred to as disorders of sexual development (DSDs).
Hermaphroditism
True gonadal intersex or True hermaphroditism- individual has both ovarian and testicular tissue.
Hermaphroditism
The ovarian and testicular tissue may be separate, or the two may be combined in what is called an
ovotestis
Affected individuals have sex chromosomes showing male-female [?] (where one individual possesses both the male XY and female XX chromosome pairs).
mosaicism
a condition in which the individual has a single chromosomal and gonadal sex but combines features of both sexes in the external genitalia, causing doubt as to the true sex.
Pseudohermaphroditism
refers to an individual with ovaries but with secondary sexual characteristics or external genitalia resembling those of a male
Female pseudohermaphroditism
also known as adrenogenital syndrome, is a common cause of female pseudohermaphroditism.
Congenital adrenal hyperplasia
refers to individuals whose gonads are testes but whose secondary sexual characteristics or external genitalia resemble those of a female.
Male pseudohermaphroditism
is rare and almost always results from autosomal recessive genetic defects (defects that must be inherited from both parents in order to be expressed).
Male pseudohermaphroditism
condition characterized by vision loss. Vision loss is typically the only symptom of LHON
Leber’s Hereditary Optic Neuropathy
characterized by bilateral, painless, and almost sudden vision failure that develops in young adulthood (around 20 to 30 years of age).
Leber’s Hereditary Optic Neuropathy
Blurring and clouding of vision (usually the first symptoms) affecting the central visual field
Leber’s Hereditary Optic Neuropathy
Severe loss of visual acuity (sharpness of vision) and color vision over time
Leber’s Hereditary Optic Neuropathy
Loss of ability to complete visual tasks such as reading, driving, and recognizing faces
Leber’s Hereditary Optic Neuropathy
A growing, dense central scotoma (blind spot) seen during visual field testing
Leber’s Hereditary Optic Neuropathy
Development of optic atrophy
Leber’s Hereditary Optic Neuropathy
are genetic disorder that results in a number of physical, mental and behavioral problems.
Prader-Willi Syndrome
Caused by a defect on chromosome 15 disrupts the normal functions of the hypothalamus
Prader-Willi Syndrome
A key feature of Prader-Willi syndrome is a constant sense of hunger that usually begins at about 2 years of age.
Prader-Willi Syndrome
Infants: Poor muscle tone, Distinct facial features, Poor sucking reflex, Generally poor responsiveness, Underdeveloped genitals
Prader-Willi Syndrome
Early childhood to adulthood: Food craving and weight gain, Underdeveloped sex organs, Poor growth and physical development, Cognitive impairment, Delayed motor development, Speech problems, Behavioral problems, Sleep disorders.
Prader-Willi Syndrome
rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities
Angelman’s Syndrome
absence or near absence of speech
Angelman’s Syndrome
inability to coordinate voluntary movements (ataxia)
Angelman’s Syndrome
tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling
Angelman’s Syndrome
Ataxia
Angelman’s Syndrome
hold their arms up with the wrists and elbows bent and may flap their hands repeatedly when walking or excited
Angelman’s Syndrome
hypotonia of the trunk
Angelman’s Syndrome
hypertonia of the arms and legs
Angelman’s Syndrome
hyperreflexia
Angelman’s Syndrome
unprovoked, prolonged laughter and smiling
Angelman’s Syndrome
easily excited, hypermotoric and hyperactive
Angelman’s Syndrome
