BVII. Overview of Genetic Disorders Flashcards
1
Q
i. Associated defects of Mendelian Disorders
A
- Marfan Syndrome
- Ehlers-Danlos Syndrome
2
Q
ii. Associated with defects in receptor proteins
A
- Familial Hypercholesterolemia (FH)
3
Q
iii. Associated with defects in enzymes
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- Lysosomal Storage Diseases
- Tay-Sachs Disease
- Niemann-Pick Disease
- Gaucher’s Disease
- Mucopolysaccharidoses
- Glycogen Storage Diseases
- Alkaptonuria
4
Q
iv. Associated with defects in proteins that regulate cell growth
A
- Neurofibromatosis
a) Multifactorial
b) Single Gene Disorders with non-classic inheritance - Triplet Repeat Mutation – Fragile X Syndrome
5
Q
B. CYTOGENETIC DISORDERS
A
a) Involving autosomes
b) Involving sex chromosomes
c) Mutations in Mitochondrial genes
6
Q
a) Involving autosomes
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• Trisomy 21
• Trisomy 18
• Trisomy 13
• Cri-du-Chat
7
Q
b) Involving sex chromosomes
A
• Klinefelter’s Syndrome
• XYY Syndrome
• Turner’s Syndrome
• Hermaphroditism
• Pseudohermaphroditism
7
Q
c) Mutations in Mitochondrial genes
A
Leber’s Hereditary Optic Neuropathy
a) Genomic Imprinting ·
Prader-Willi Syndrome
Angelman’s Syndrome
8
Q
is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence
A
genetic disorder
9
Q
c) Mutations in Mitochondrial genes
A
10
Q
mutation in one gene
A
monogenic disorder
11
Q
mutations in multiple genes or by a combination of gene mutations and environmental factors
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multifactorial inheritance disorder
12
Q
by damage to chromosomes
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changes in the number or structure of entire chromosomes, the structures that carry genes
13
Q
● It is one of the most common inherited disorders of connective tissue.
A
Marfan Syndrome
14
Q
● Autosomal dominant condition
A
Marfan Syndrome
15
Q
● Cause: mutation in the FBN1 gene
A
Marfan Syndrome
16
Q
mutations are associated with a broad continuum of physical features ranging from isolated features to a severe and rapidly progressive form in newborns.
A
○ FBN1
17
Q
: abnormally longer than normal, dolichostenomelia, arachnodactyly, scoliosis, pectus excavatum, pectus carinatum, high palate, malocclusions
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○ Bones
18
Q
: angina pectoris, tachycardia, cystic medial degeneration, aortic dissection, heart murmur
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○ Heart
19
Q
: risk of spontaneous pneumothorax, emphysema, COPD, collapsed lung, sleep apnea
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○ Lungs
20
Q
: myopia or hyperopia, astigmatism, glaucoma, cataract, detachment or tear in the retina
A
○ Eyes
21
Q
● Defect in the synthesis of collagen
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Ehlers-Danlos Syndrome
22
Q
: Hyper-flexible joints, Unstable joints that are prone to sprain, dislocation, subluxation and hyperextension, osteoarthritis, Chronic degenerative joint disease, Swan neck deformity of the fingers, Muscle fatigue that increases with use, hypotonia in infancy, Osteopenia, Stretchy ligaments and tendons, Tearing of tendons or muscles, Deformities of the spine, Myalgia and arthralgia
A
○ Musculoskeletal
23
Q
: Stretchy skin with a velvety texture, Fragile skin, Easy bruising, Abnormal wound healing and scar formation, Redundant skin folds, Molluscoid pseudotumors, Subcutaneous spheroids, Fatty growths on forearms or shins, Angioplasia
A
○ Skin
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: Fragile blood vessels, Life-threatening carotid-cavernous fistula, Unpredictable rupture of medium-sized arteries, Valvular heart disease
○ Cardiovascular
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○ Orthostatic intolerance, Dilation and/or rupture of ascending aorta, Cystic medial necrosis, Varicose veins
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: Raynaud's phenomenon, Livedo reticularis
○ Vascular skin conditions
27
1 and 2
Autosomal dominant
COL5A1
COL5A2
COL1A1
Classical
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3
Dominant/Recessive
Tenascin- X def.
COL3A1
TNX B
Hypermobility
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4
Autosomal dominant
Type 3 collagen
COL3A1
Vascular
30
6
Autosomal recessive
Lysyl hydroxylase def.
PLOD1
Kyphoscoliosis
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7A and 7B
Autosomal recessive
Type 1 collagen
COL1A1
COL1A2
Arthrochalasis
32
C
ADAMTS2
Dermatosparaxis
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• An inherited condition that causes high levels of LDL cholesterol levels beginning at birth, and heart attacks at an early age.
Familial Hypercholesterolemia (FH)
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• It is caused by a defect on chromosome 19
Familial Hypercholesterolemia (FH)
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• The defect makes the body unable to remove low density lipoprotein from the blood.
Familial Hypercholesterolemia (FH)
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• This results in a high level of LDL in the blood.
Familial Hypercholesterolemia (FH)
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Familial Hypercholesterolemia (FH)
• Other names:
o Type II hyperlipoproteinemia;
o Hypercholesterolemic xanthomatosis;
o Low density lipoprotein receptor mutation
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Familial Hypercholesterolemia (FH)
• Symptoms: Fatty skin deposits called (?) over parts of the hands, elbows, knees, ankles and around the cornea of the eye, Cholesterol deposits in the eyelids (?)
xanthomas
(xanthelasmas)
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• A physical exam may show fatty skin growths called xanthomas and cholesterol deposits in the eye (?).
corneal arcus
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• 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
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• Life-threatening disease of the nervous system passed down through families.
Tay-Sachs Disease
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occurs when the body lacks hexosaminidase A
Tay-Sachs Disease
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caused by a defective gene on chromosome 15
Tay-Sachs Disease
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• When both parents carry the defective TaySachs gene, a child has a 25% chance of developing the disease.
Tay-Sachs Disease
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• The child must receive two copies of the defective gene, one from each parent, in order to become sick
Tay-Sachs Disease
46
• The disease is most common among the Ashkenazi
Tay-Sachs Disease
47
• Jewish population.
Tay-Sachs Disease
48
Tay-Sachs Disease
• Other names:
o GM2 gangliosidosis - Tay-Sachs;
o Lysosomal storage disease - TaySachs disease
49
Symptoms: Deafness, decreased eye contact, blindness, Decreased muscle tone (loss of muscle strength), loss of motor skills, paralysis, Slow growth and delayed mental and social skills, Dementia (loss of brain function), Increased startle reaction, Irritability, Seizures
Tay-Sachs Disease
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• A primary deficiency of acid sphingomyelinase and the resultant accumulation of sphingomyelin.
Niemann-Pick Disease
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• Affected cells and organs
Niemann-Pick Disease
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Niemann-Pick Disease: Affected cells and organs
o phagocytic cells of spleen, liver, bone, marrow, lymph nodes, lungs
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▪ stuffed with droplets or particles of the complex lipid, imparting a fine vacuolation or foaminess to the cytoplasm
o phagocytic cells of spleen, liver, bone, marrow, lymph nodes, lungs
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o enlarged and vacuolated as a result of the storage of lipids.
o phagocytic cells of spleen, liver, bone, marrow, lymph nodes, lungs
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- Classic infantile form, manifests itself in infancy with massive visceromegaly and severe neurologic deterioration
Niemann-Pick Disease Type A
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- Visceral juvenile form, no neurologic disorders
Niemann-Pick Disease Type B
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- Subacute/ Juvenile form, most common form of the disease, subtype with brain complications into C1 and C2
Niemann-Pick Disease Type C
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(“Nova Scoatian type”)- 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
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Niemann-Pick Disease Other names:
o lipid histiocytosis o neuronal cholesterol lipidosis
o neuronal lipidosis
o NPD
o sphingomyelin lipidosis
o sphingomyelin/cholesterol lipidosis
o sphingomyelinase deficiency
60
• rare genetic disorder that is one of a group called lysosomal storage disorders.
Gaucher’s Disease
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• 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
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• It is caused by a missing or deficient enzyme called ‘glucocerebrosidase‘.
Gaucher’s Disease
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• In people with Gaucher disease, the gene that would normally tell the body to produce this enzyme is altered
Gaucher’s Disease
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• Signs and Symptoms: enlarged liver and spleen, low platelet and hemoglobin counts, problems with bones and joints
Gaucher’s Disease
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• group of inherited lysosomal storage disorders
Mucopolysaccharidoses
66
Mucopolysaccharidoses
• In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (?) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes [?] to cells, tissues, and various organ systems of the body.
mucopolysaccharides or glycosaminoglycans
progressive damage
67
• Signs and Symptoms: “coarse” facial features, short stature, heart abnormalities, breathing irregularities, liver and spleen enlargement (hepatosplenomegaly), and/or neurological abnormalities
Mucopolysaccharidoses
68
• rare condition that changes the way the body uses and stores glycogen, a form of sugar or glucose.
Glycogen Storage Diseases
69
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
70
• Types of GSD
o Type I or von Gierke disease
o Type III, Cori disease, or Forbes disease
o Type IV or Andersen disease
71
This is the most common form of GSD. People with type I don’t have the enzyme needed to turn glycogen into glucose in the liver. Glycogen builds up in the liver. Symptoms often appear in babies around 3 to 4 months old. They may include low blood sugar (hypoglycemia) and a swollen belly because of an enlarged liver.
o Type I or von Gierke disease
72
People with this type don’t have enough of an enzyme called the debranching enzyme, which helps break down glycogen. The glycogen can’t fully break down. It collects in the liver and in muscle tissues. Symptoms include a swollen belly, delayed growth, and weak muscles.
o Type III, Cori disease, or Forbes disease
73
People with this type form abnormal glycogen. Experts think the abnormal glycogen triggers the body’s infection-fighting system (immune system). This creates scarring (cirrhosis) of the liver and other organs such as muscle and the heart.
o Type IV or Andersen disease
74
• rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body.
Alkaptonuria
75
• Cause: mutation of the homogentisate 1,2dioxygenase (+) gene
Alkaptonuria
76
• Inherited as an autosomal recessive trait
Alkaptonuria
77
• Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid.
Alkaptonuria
78
• Affected individuals may have dark urine or urine that turns black when exposed to air.
Alkaptonuria
79
Symptoms:
o Dark/ Black urine upon long standing exposure to the air
o Ochronosis- connective tissue such as cartilage turns blue, grey or black due to the chronic accumulation of homogentisic acid
o Whites of the eyes (sclera) also become discolored
o Tendonitis
o Arthritis and ochronotic arthropathy
Alkaptonuria
80
• rare genetic disorder that causes typically benign tumors of the nerves and growths in other parts of the body
Neurofibromatosis
81
Neurofibromatosis Two Major Types:
1. Neurofibromatosis type I (NF1)
2. Neurofibromatosis type II (NF2)
3. Schwannomatosis
82
o caused by mutations in the gene that controls production of a protein called neurofibromin (neurofibromin 1)
Neurofibromatosis type I (NF1)
83
o manifests itself at birth or during early childhood
Neurofibromatosis type I (NF1)
84
o characterized by multiple light brown (café-au-lait) spots concentrated in the groin and underarms and benign tumors under the skin
Neurofibromatosis type I (NF1)
85
o results from mutations in a different tumor-suppressing gene (neurofibromin 2, merlin)
Neurofibromatosis type II (NF2)
86
o may appear during childhood, adolescence or early adulthood
Neurofibromatosis type II (NF2)
87
o 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)
88
o more frequently diagnosed in adults aged 30 and older
Schwannomatosis
89
• characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females.
Triplet Repeat Mutation – Fragile X Syndrome
90
• caused by an abnormality (mutation) in the 5 gene. 5 is a gene located on the X chromosome that produces a protein called FMRP needed for proper cell function.
Triplet Repeat Mutation – Fragile X Syndrome
91
• Symptoms:
o large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes
o 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
92
● It is the only human autosomal trisomy in which a significant number of individuals survive longer than a year past birth.
Trisomy 21
93
● Discovered in 1966 by Langdon Down
Trisomy 21
94
● Symptoms: Mental retardation, Multiple physical abnormalities such as heart defects, affected children are small in stature because of delayed maturation of the skeletal system, Poor muscle tone resulting in a characteristic facial appearance, Shortened life span
Trisomy 21
95
● Most cases of Downs syndrome are caused by non-disjunction ○ Failure of homologous chromosomes to separate in meiosis
Trisomy 21
96
● Nondisjunction of chromosome 21 is more likely to happen in oogenesis than in spermatogenesis, and so the abnormal gamete in Down syndrome is usually the egg.
Trisomy 21
97
● Rare conditions associated with major developmental abnormalities
Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome)
98
● Affected infants can survive for only a few days or weeks
Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome)
99
In 1960, Klaus Patau and his associated observed an infant with severe developmental malformations with a karyotype of 47 chromosomes
Trisomy 13
100
○ average survival: Less than six months
Trisomy 13
101
○ Majority are male
Trisomy 13
102
Affected infants are not mentally alert
Trisomy 13
103
Are thought to be deaf
Trisomy 13
104
Characteristically have a harelip, clef palate
Trisomy 13
105
Demonstrate polydactyly
Trisomy 13
106
Autopsy reveals congenital malformation of most organ systems
Trisomy 13
107
Condition indicative of abnormal developmental events occurring as early as 5-6 weeks of gestation.
Trisomy 13
108
In 1960, John H. Edwards and his colleagues reported on an infant trisomic for a chromosome in the E group
Trisomy 18
109
Survival: Less than 4 months
Trisomy 18
110
Symptoms: Congenital heart defects, growth retardation, dysmorphic features, facial clefts, spina bifida, severe developmental delay
Trisomy 18
111
Smaller than the average newborn
Trisomy 18
112
Skulls are elongated in an anterior-posterior direction
Trisomy 18
113
Ears are set low and malformed
Trisomy 18
114
Webbed neck
Trisomy 18
115
Congenital dislocation of hips
Trisomy 18
116
Receding chin
Trisomy 18
117
Due to a missing piece (deletion) of a specific part of chromosome 5 known as the 'p' arm. In general, the severity of the symptoms is determined by the size and location of the deletion on chromosome 5.
Cri-du-Chat
118
This deletion occurs very early in the development of an embryo and is usually not inherited in families.
Cri-du-Chat
119
present from birth and affects growth and development
Cri-du-Chat
120
Infants with this condition often have a high-pitched cat-like cry, small head size, and a characteristic facial appearance.
Cri-du-Chat
121
Symptoms:
Cat-like cry
Small head size (microcephaly)
Characteristic facial features
Hypotonia
Intellectual disability
Global developmental delay
Behavior issues
Growth delay
Cri-du-Chat
122
Diagnosis: based on the clinical examination, symptoms and confirmed by the results of genetic testing.
Cri-du-Chat
123
Treatment is focused on managing the symptoms.
Cri-du-Chat
124
47, XXY
Males
Klinefelter’s Syndrome
125
Tall, do not undergo normal sexual maturation, are sterile, and in some cases have enlargement of the breasts.
Klinefelter’s Syndrome
126
Mild mental impairment is common
Klinefelter’s Syndrome
127
rare chromosomal disorder that affects males. It is caused by the presence of an extra Y chromosome.
XYY Syndrome
128
Affected individuals are usually very tall. Many experience severe acne during adolescence.
XYY Syndrome
129
Additional symptoms may include learning disabilities and behavioral problems such as impulsivity.
XYY Syndrome
130
Intelligence is usually in the normal range, although IQ is on average 10-15 points lower than siblings.
XYY Syndrome
131
Synonyms of XYY Syndrome:
47, XYY syndrome
Jacob's syndrome
XYY karyotype
YY syndrome
XYY Syndrome
132
45, X
Turner’s Syndrome
133
Monosomy of the X chromosome in females
Turner’s Syndrome
134
Phenotypically female but are short in stature and do not exhibit sexual maturation.
Turner’s Syndrome
135
Mental abilities are typically within the normal range.
Turner’s Syndrome
136
the condition of having both male and female reproductive organs
Hermaphroditism
137
Conditions that involve discrepancies between external genitalia and internal reproductive organs are described by the term
intersex
138
Intersex conditions are sometimes referred to as
disorders of sexual development (DSDs)
139
- individual has both ovarian and testicular tissue
True gonadal intersex or True hermaphroditism
140
The ovarian and testicular tissue may be separate, or the two may be combined in what is called an ovotestis
True gonadal intersex or True hermaphroditism
141
Affected individuals have sex chromosomes showing male-female mosaicism (where one individual possesses both the male XY and female XX chromosome pairs).
True gonadal intersex or True hermaphroditism
142
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
143
refers to an individual with ovaries but with secondary sexual characteristics or external genitalia resembling those of a male.
Female Pseudohermaphroditism
144
is a common cause of female pseudohermaphroditism.
Congenital adrenal hyperplasia, also known as adrenogenital syndrome
145
refers to individuals whose gonads are testes but whose secondary sexual characteristics or external genitalia resemble those of a female
Male pseudohermaphroditism
146
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
147
condition characterized by vision loss. Vision loss is typically the only symptom of LHON
Leber’s Hereditary Optic Neuropathy
148
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
149
Blurring and clouding of vision (usually the first symptoms) affecting the central visual field
Leber’s Hereditary Optic Neuropathy
150
Severe loss of visual acuity (sharpness of vision) and color vision over time
Leber’s Hereditary Optic Neuropathy
151
Loss of ability to complete visual tasks such as reading, driving, and recognizing faces
Leber’s Hereditary Optic Neuropathy
152
A growing, dense central scotoma (blind spot) seen during visual field testing
Leber’s Hereditary Optic Neuropathy
153
Development of optic atrophy
Leber’s Hereditary Optic Neuropathy
154
are genetic disorder that results in a number of physical, mental and behavioral problems.
Prader-Willi Syndrome
155
Caused by a defect on chromosome 15 disrupts the normal functions of the hypothalamus
Prader-Willi Syndrome
156
A key feature is a constant sense of hunger that usually begins at about 2 years of age.
Prader-Willi Syndrome
157
Infants: Poor muscle tone, Distinct facial features, Poor sucking reflex, Generally poor responsiveness, Underdeveloped genitals
Prader-Willi Syndrome
158
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
159
rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); 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
160
Ataxia
Angelman’s Syndrome
161
hold their arms up with the wrists and elbows bent and may flap their hands repeatedly when walking or excited
Angelman’s Syndrome
162
hypotonia of the trunk, hypertonia of the arms and legs
Angelman’s Syndrome
163
hyperreflexia
Angelman’s Syndrome
164
unprovoked, prolonged laughter and smiling
Angelman’s Syndrome
165
easily excited, hypermotoric and hyperactive
Angelman’s Syndrome
166
is the process of using recombinant DNA (rDNA) technology to alter the genetic makeup of an organism
Genetic engineering
167
Traditionally, humans have manipulated genomes indirectly by controlling breeding and selecting offspring with desired traits
Genetic engineering
168
involves the direct manipulation of one or more genes. Most often, a gene from another species is added to an organism's genome to give it a desired phenotype
Genetic engineering
169
creates combinations of DNA sequences from different source
Recombinant DNA technology
170
A common application of recombinant DNA technology is to (?) a DNA segment of interest.
clone
171
specific DNA segments are inserted into vectors to create recombinant DNA molecules that are transferred into eukaryotic or prokaryotic host cells, where the recombinant DNA replicates as the host cells divide
cloning
172
are collections of cloned DNA and were historically used to isolate specific genes
DNA libraries
173
DNA segments can be quickly amplified and cloned millions of times using the
polymerase chain reaction (PCR)
174
DNA, RNA, and proteins can be analyzed using a range of
molecular techniques
175
reveals the nucleotide composition of cloned DNA, and major improvements in sequencing technologies have rapidly advanced many areas of modern genetics research, particularly genomics
DNA sequencing
176
have become invaluable for studying gene function in vivo
Gene knockout methods and transgenic animals
177
GOAL- the delivery of therapeutic genes into a genetic disease conditions caused by a faulty gene or genes.
GENE THERAPY
178
The treatment of a human genetic disease by (?) is the ultimate application of genetic technology.
GENE THERAPY
179
Recombinant DNA technology was made possible by the discovery of specific proteins called (?), which cut DNA at specific recognition sequences, producing fragments that can be joined together with other DNA fragments to form recombinant DNA molecules.
restriction enzymes
180
Recombinant DNA molecules can be transferred into any of several types of host cells where cloned copies of the DNA are produced during (?). Many kinds of host cells may be used for replication, including bacteria, yeast, and mammalian cells.
host-cell replication
181
The (?) allows DNA to be amplified without host cells and is a rapid, sensitive method with wide-ranging applications.
polymerase chain reaction (PCR)
182
Historically, (?) have been important for producing collections of cloned genes to identify genes and gene regulatory regions of interest.
DNA libraries
183
Once cloned, (?) are analyzed through a variety of molecular techniques that allow scientists to study gene structure, expression, and function.
DNA sequences
184
By determining the nucleotide sequence of a DNA segment, (?) is the ultimate way to characterize DNA at the molecular level.
DNA sequencing
185
Rapid advances in (?) have led to greatly increased sequencing capacities at reduced costs over historically used sequencing methods, providing scientists with unprecedented access to sequence data.
sequencing technologies
186
(?) are widely used to study gene function in vivo.
Gene knockout methods and transgenic animals
