Genetics II - Mendelian Disorders Cytogenetics II (trans 2)

Question 1

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS

Single Gene Disorder affects only genes or small portions of chromosomes such that karyotyping is unable to expose the abnormality. This results in the transcription of certain proteins producing a metabolic abnormality.

Answer 1

Four Types

1. Autosomal Dominant
2. Autosomal Recessive
3. Sex-linked Dominant
4. Sex-linked Recessive

Question 2

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS: AUTOSOMAL DOMINANT

o Autosomal dominant disorders are manifested in the heterozygous state, so at least one parent of an index case is usually affected.
o In addition, autosomal dominant conditions are characterized by the following:

1. No skip generation - In a dominant condition, even if the abnormal gene is located on only one allele, (either from mother or father) you will manifest the condition. If one of your parents has the abnormal gene, that allele is automatically passed on to the next generation and the condition will manifest.
2. No sexual preference - Since it is an autosomal condition, where in it involves any chromosome from 1 to 22 excluding your X and Y chromosome, no sexual preference is exhibited.
3. When affected person marries a normal person, each child with 50% chance of developing the disease

NOTE: BUT, some affected individuals do not have affected parents.

Answer 2

Possible explanations and things to consider:
 Incomplete penetrance – ability of persons carrying the abnormal gene NOT to express the trait
 Variable expressivity – difference in which the trait is expressed or manifested by persons carrying the gene. E.g. Neurofibromatosis gene.
 In new mutations, siblings are not affected

Question 3

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS: AUTOSOMAL DOMINANT

Answer 3

Pedigree Showing Autosomal Dominant Inheritance. There should be at least one individual affected per generation in this pattern given that at least one of the parents is affected.
Legend: SQUARE-male; CIRCLE-female; RED- affected

Question 4

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

AUTOSOMAL DOMINANT - Neurofibromatosis

 Can appear as multiple lesions in the body. But, it can also be limited to certain facial and cranial nerves. It is a multiple fibrous proliferation in neural tissues.
 Doing a pedigree of neurofibromatosis with no prior knowledge of its variable expressivity may lead to mistakenly treating both presentations as different disorders when they actually are the same.

Answer 4

Neurofibromatosis. An autosomal dominant condition that manifests variable expressivity. Left picture shows multiple skin nodules (peripheral nerve abnormality), and right figure shows deformities due to cranial nerve abnormality.

Question 5

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

AUTOSOMAL RECESSIVE

o Autosomal recessive traits make up the largest category of Mendelian disorders. They occur when both alleles at a given locus are mutated.
o These disorders are characterized by the following:
1. Presence of skip generation
2. No sexual predilection
3. Each child will have 1:4 chance of being affected - The chance of a child having it from a carrier parent (not from a parent who has it) is about 25 percent.
4. Consanguinity common among parents of affected children - Both parents should possess the abnormal gene in order for the condition to manifest. This only happens when there is similar bloodline among parents.

Answer 5

Things to consider
o Complete penetrance common - Incomplete penetrance and variable expressivity doesn’t hold true so much
o Onset frequently early in life
o Expression of defect more uniform
o In new mutations, affected individual is Asxtic

Question 6

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

AUTOSOMAL RECESSIVE

A Pedigree Showing Autosomal Recessive Inheritance. There are generations that do not have affected individuals, and also in the fourth generation, consanguinity is represented as a double line between the parents.

Answer 6

A. Autosomal Dominant
 Single dose needed to manifest the condition/ disease
 If one parent allele manifests the condition, 50 percent of the children will manifest
 Dominant - only one allele is needed to manifest the disease regardless if the individual is HOMOZYGOUS (XdXd) or HETEROZYGOUS (XdXr)

B. Autosomal Recessive
 Double dose needed to manifest the condition/ disease
 Two allele in order to manifest, both parents should be carriers
**Carrier - possess only one allele, will not manifest the gene but will transmit to children.

Question 7

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

SEX-LINKED DOMINANT

o Caused by dominant disease-associated alleles on the X chromosome.

Answer 7

Characterized by the following:

1. No skip generation
2. With sex predilection

• Affected males transmit to all daughters and none to sons
• Affected females (heterozygous) transmit to half of her sons and half to her daughters

Question 8

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

SEX-LINKED DOMINANT

Punnett Square: Sex-linked Dominant. In the left grid, father is affected, so only her daughters are affected. In the right grid, the mother is affected, so half of her sons and half of her daughters are affecte (50:50)

Answer 8

Pedigree Showing Sex-linked Dominant Inheritance. Since in the first generation, only fathers are carrying the gene, only daughters manifest.On the second generation, mothers are carrying the gene, so sons and daughters have equal chance of manifesting the gene.

Question 9

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

SEX-LINKED RECESSIVE

o The Y chromosome, for the most part, is not homologous to the X, and so mutant genes on the X do not have corresponding alleles on the Y. Thus the male is said to be hemizygous for X linked mutant genes, so these disorders are expressed in the male.

Answer 9

1. Presence of skip generation
2. Presence of sex predilection
   a. Affected male does not transmit to sons but all daughters are carriers
   b. Carrier females transmit to 50% of sons
   c. Unaffected males never transmit the gene

Question 10

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

SEX-LINKED RECESSIVE

Punnett Square: Sex-linked Recessive. An offspring may be normal, a carrier of the gene (pink) or could manifest the condition (red). Left-father; right-mother

**In the left grid, the affected father transmits none to his sons but all her daughters become carriers. In the right grid, the carrier mother transmits the gene to half of her sons and half of her daughters. However, only the sons manifest the gene and the daughters only become carriers.

Answer 10

Table Analysis:

 Affected father transmits genes to daughters who become carriers
 Carrier mother transmits to carrier daughter and manifesting son
o There is single gene manifestation because there is only one x-chromosome for a male
o Remember, Y chromosome does not carry any genetic material of significance.
o Nothing inhibits manifestation. The gene has no choice but to express mutation because only the X carries the code for it and there is only one X.
o Most patients affected by sex-linked recessive diseases are male.

Question 11

TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:

SEX-LINKED RECESSIVE

Answer 11

Pedigree showing skipping of generations. Note that affected males do not transmit to sons. Also an affected male (III-2) receives the allele from a carrier mother who does not express the trait (II-2).

Question 12

GENETIC MUTATIONS

 A mutation is defined as a permanent change in the DNA. Mutations that affect germ cells are transmitted to the progeny and can give rise to inherited diseases.
 In the case of Mendelian characteristics, the mutations are very small. It can involve just one nucleic acid.
o Thalassemia: Either the beta-hemoglobin or alpha-hemoglobin is shorter than usual. The reason for that is nonsense mutation, producing a stop codon

Answer 12

1. Point Mutations
2. Deletions and Insertions

Question 13

GENETIC MUTATIONS:

POINT MUTATIONS

o A change in which a single base is substituted with a different base. It may alter the code in a triplet of bases and may lead to the replacement of one amino acid by another in the gene product.

Answer 13

1. Missense Mutation
2. Nonsense Mutation

Question 14

GENETIC MUTATIONS:

POINT MUTATIONS - Missense Mutation

 When the mutation alters the meaning of the sequence
 “Conservative” missense mutation - if the substituted amino acid is biochemically similar to the original, typically it causes little change in the function of the protein.
 “Nonconservative” missense mutation - replaces the normal amino acid with a biochemically different one.

Answer 14

Sickle Cell Anemia DNA Sequence.

Sickle cell mutation affecting the beta-globin chain of hemoglobin. The nucleopeptide triplet CTC, which encodes for glutamic acid, is changed to CAC, which encodes valine. This single amino acid substitution alters the physicochemical properties of hemoglobin.

Question 15

GENETIC MUTATIONS:

POINT MUTATIONS - Nonsense Mutation

 A point mutation where in the amino acid codon is changed to a terminator, or stop codon.
 This change leads to premature termination.

Answer 15

Thalassemia DNA Sequence.

Codon for glycine (CAG) undergoes a point mutation turning it into a stop codon (UAG). This prematurely terminates translation thus producing an abnormal short hemoglobin molecule.

**How do you identify a stop codon? Participles of away.
UAG: U Are Gone.
UAA: U Are Away.
UGA: U Go Away

Question 16

GENETIC MUTATIONS:

DELETIONS AND INSERTIONS

Answer 16

1. Frameshift Mutation
2. 2. Three Base Deletion/Insertion

Question 17

GENETIC MUTATIONS:

DELETIONS AND INSERTIONS - Frameshift Mutation

o If the number of affected coding is not a multiple of three, this will result in an alteration of the reading frame of the DNA strand.
o The result is the incorporation of a variable number of incorrect amino acids followed by truncation resulting from a premature stop codon.

Answer 17

Four-base insertion in the hexosaminidase A gene. This mutation is the major cause of Tay-Sachs disease in Ashkenzai Jews

Question 18

GENETIC MUTATIONS:

DELETIONS AND INSERTIONS - Three Base Deletion/Insertion

• If the number of base pairs involved is three or a multiple of three, the reading frame will remain intact, and an abnormal protein lacking or gaining one or more amino acids will be synthesized.

Answer 18

Three-base deletion in the common cystic fibrosis allele results in synthesis of a protein that lacks amino acid phenylalanine.

Question 19

BIOCHEMICAL MECHANISMS:

AUTOSOMAL DOMINANT

Answer 19

1. LOSS of function mutation
2. GAIN of function mutation

Question 20

BIOCHEMICAL MECHANISMS:

AUTOSOMAL DOMINANT - LOSS of function mutation

**results to loss of significant protein

Answer 20

• All Autosomal Dominant Trait Mutations are due to structural proteins
• It is rare that you’ll find a condition that will manifest due to an enzyme protein (Why? Because there’s only a small amount of enzymes in the body that even if one allele is deficient, the other allele is able to produce enough such that the mutation is not manifested)

Question 21

BIOCHEMICAL MECHANISMS:

AUTOSOMAL DOMINANT - LOSS of function mutation

Enzyme Protein Defect

• Heterozygotes are normal
• Reduced enzyme numbers can be compensated for up to enough numbers to restore normal function
• There is no such thing as enzyme protein deficiency in autosomal dominant traits

Remember: To be dominant, you can only have one abnormal allele for it to manifest. In case of heterozygote dominant, only one abnormal allele will produce the enzyme, that patient will not produce the full volume of enzymes that should be produced but rather, a little only.
 Heterozygote=hetero=half=half the amount of enzyme.
 Body = doesn’t need 100% enzyme production, it only need less than 50%, therefore there is no or minimal manifestation on the heterzygote patient

Answer 21

Non-Enzyme Protein Defect

• Regulatory Proteins as in the cases of Familial Hypercholesterolemia
• Structural Proteins
• Ehlers-Danlos syndrome (collagen deficiency)
• Marfan’s syndrome (fibrillin deficiency)
• Spherocytosis (spectrin deficiency)

Question 22

BIOCHEMICAL MECHANISMS:

AUTOSOMAL DOMINANT - GAIN of function mutation

• results to new proteins that are usually toxic
• Protein products of the mutant allele acquire new properties not normally associated with the wild type protein.
• Gain of an abnormal protein that is toxic to the body - Huntington’s Chorea → gain Huntingtin (an abnormal protein that is toxic to neurons)

Answer 22

Common Autosomal Dominant Disorders

1. Huntington’s disease
2. Marfan’s syndrome
3. Ehlers-Danlos syndrome
4. Familial hypercholesterolemia
5. Von Willebrand disease
6. Hereditary spherocytosis

Question 23

BIOCHEMICAL MECHANISMS:

AUTOSOMAL RECESSIVE TRAITS

Answer 23

1. Enzyme Protein Defect (Most common)
2. Non-Enzyme Protein Defect

Question 24

BIOCHEMICAL MECHANISMS:

AUTOSOMAL RECESSIVE TRAITS - Enzyme Protein Defect

Answer 24

Reduced activity or reduced synthesis of a normal enzyme

May lead to:
a. Accumulation of abnormal substance

• ↑ Galactose: Galactosemia
• ↑ Phenylalanine: Phenylketonuria (due to nonfunctional phenylalanine hydroxylase)

b. Decreased amount of important end product
* ↓ Melanin: Albinism (due to absence or defect of tyrosinase)
c. Failure to inactivate a tissue-damaging substrate
* Toxic substance is accumulated because you can’t deactivate/destroy toxic substance due to loss of enzyme - α-antitrypsin deficiency: result to accumulation of neutrophil elastase

Question 25

BIOCHEMICAL MECHANISMS:

AUTOSOMAL RECESSIVE TRAITS - Non-Enzyme Protein Defect

o Transport protein – Hemoglobin in Thalassemia and Sickle Cell disease

o Hemostasis – Factor VIII in hemophilia

o Structural protein – Dystrophin in muscular dystrophy

Answer 25

Common autosomal dominant and autosomal recessive disorders

Remember:
 Autosomal Dominant – No enzyme deficiency (non-enzyme protein).
 Autosomal Recessive – All enzyme deficiency (enzyme protein).

Question 26

AUTOSOMAL DOMINANT DISORDERS:

Answer 26

1. MARFAN’S SYNDROME
2. EHLER’S DANLOS SYNDROME
3. FAMILIAL HYPERCHOLESTEROLEMIA

Question 27

AUTOSOMAL DOMINANT DISORDERS:

MARFAN’S SYNDROME

 Fibrillin protein deficiency or abnormality
 From mutation of fibrillin-1 gene mapping 15q21.1
 Inheritance – Autosomal dominant with variable expressivity

Answer 27

Variable expressivity
o Functions of Fibrillin

1. Normal support or base product or scaffold for elastin in the aorta, ligaments and cilliary zonules (eyes)
2. Inhibits transforming growth factor (TGF) to bones. (Reason why those with Marfan’s syndrome have excessively long bones because there is uninhibited long bone growth and weakness of connective tissue.)

 Requires major manifestations of 2 of the 4 systems (CVS, cutaneous, ocular and skeletal) + Minor manifestation of another for a diagnosis

Question 28

AUTOSOMAL DOMINANT DISORDERS:

MARFAN’S SYNDROME

Skeletal Abnormalities
o Unusually tall (due to lack of inhibitory factor)
o Laxity of bones
o Ratio of upper body segment to lower body segment is low.
o Long and tapering extremities, fingers and toes (arachnodactyly)
o Dolichocephalic (long face/head)
o Bossing of frontal eminences
o Prominent supraorbital ridges
o Spinal deformities, no support for vertebrae
 Kyphosis – Kuba
 Scoliosis – S-shaped
o Chest deformities - Pigeon chest
o Loose jointedness/ laxity of joints - Hyperextension of thumb

Answer 28

Ocular Change
o Ectopia lentis – Bilateral (both eyes) movement of eye away from the usual, commonly upward or downward subluxation or dislocation of the lens/ displacement of the lens
o Severe myopia
o Retinal Detachment

CVS lesions (Most life-threatening)
o Mitral Valve Prolapse - Lack of collagen = Tendinae cannot support mitral valve = Valve rupture = Immediate death
o Cystic Medionecrosis - Leads to Aortic rupture when aortic dissection (medial aspect of the wall of the aorta)
o Aortic Dilation - Aortic insufficiency

There is looseness of skin
o Clinical Diagnosis: MAJOR manifestations in 2 organ systems + MINOR manifestation in 1 organ system

Question 29

AUTOSOMAL DOMINANT DISORDERS:

EHLER’S DANLOS SYNDROME

 Inheritance: Mostly Autosomal Dominant with Varying Expressivity
 Defective collagen synthesis
o Skin has no support
o Easy bruisability

 Shows molecular heterogeneity resulting in clinical variable disorder with several pattern of inheritance (Can be Autosomal Dominant OR Autosomal Recessive).
 Manifests in the joints, skin and blood vessels
o Skin – Hyperextensible, Easily bruised, Fragile
o Joints – Hypermobile
o Visceral complications – Large artery ruptures
 Manifestations can be predominantly joints or predominantly skin.
 If metabolic/significant enzyme is lost, it is autosomal recessive; in contrast, if structural protein is lost, it is autosomal dominant

Answer 29

Types of EDS and their clinical manifestations, mode of inheritance, and gene defects. (Don’t memorize but spot the difference).

**Autosomal Dominant: Collagen:Autosomal Recessive: Enzymes

Question 30

AUTOSOMAL DOMINANT DISORDERS:

FAMILIAL HYPERCHOLESTEROLEMIA
 Increased cholesterol in the blood stream
o Decreased or defective LDL receptors (liver)
 Levels of cholesterol are genetically determined
 Gene that encodes for the LDL receptor is mutated

Normal metabolism of cholesterol: Cholesterol enters the liver => increase in cholesterol level, production is inhibited by the liver; if no cholesterol, the liver will produce a lot for distribution throughout the blood.

Familial Hypercholesterolemia: Receptors (proteins determined by DNA) at the surface of the liver are lost/defective, so liver doesn’t detect the levels of cholesterol so it produces more cholesterol (DOUBLE DOSE). Inhibitory control of the liver is lost; cholesterol accumulation activates phagocytosis depositing it to various parts of the body, some of them very significant such as the heart and the brain.

Answer 30

Manifests as increased cholesterol in the blood stream
o Causes:
 Defective/decreased receptors
- Less LDL uptake in the liver from the blood thus having low metabolism.
- LDL remains in the blood
 Defective inhibitory mechanism
- Free cholesterol is usually released into the cytoplasm when LDL is processed
- When this happens, it suppresses cholesterol synthesis by inhibiting HMG-CoA reductase and LDL receptor synthesis
- No intracellular feedback inhibition occurs increasing the plasma cholesterol
 Scavenger system activation
- LDL uptake by other cells through scavenger receptors for chemically altered LDL

Clinical Manifestation:
o Xanthoma formation
 Intracellular accumulation of cholesterol within macrophages which is a characteristic of acquires and hereditary hyperlipidemic states. Cluster of foamy cells found in the subepithelial connective tissue of the skin.)
o Atherosclerosis

Molecular genetics
o Mutations affecting receptor production and activity (Synthesis, Transport, Binding, Release)
 Missense, insertion or deletion
 Variable mutations affecting different aspects of receptor production and activity. LDL receptors will either:
- not be synthesized
- if synthesized, receptors are not transported properly
- binds abnormally with LDL
- cannot enclose LDL into vesicles
- and/or cannot be recycled or released
 Therefore, there are a lot of mutations that can happen

Question 31

AUTOSOMAL DOMINANT DISORDERS:

FAMILIAL HYPERCHOLESTEROLEMIA

Answer 31

LDL receptor mutations based on abnormal functions of mutant protein (synthesis, transportation, binding, enclosure and recycling or releasing)
*Most common defects location: Receptor
*Every step requires a protein

Question 32

AUTOSOMAL RECESSIVE DISORDERS

Answer 32

1. ALBINISM
2. ALKAPTONURIA

Question 33

AUTOSOMAL RECESSIVE DISORDERS:

ALBINISM

 Inability to synthesize melanin due to the absence of tyrosinase which converts DOPA to melanin
 If no melanin, age early since it is protective to the skin
 Clinical significance:
o High sensitivity to sun exposure due to melanin deficiency

• Melanin protects from sun exposure-related malignancies
• Examples: Squamous cell CA and solar keratosis
• Impaired visual acuity

Answer 33

ALKAPTONURIA
 Lack of homogentisic oxidase, causing an increase/accumulation of hemogentisic acid which binds to CT and stains then blue black (ochronosis)
 Lack of chromosome 3
 Clinical significance:
o Brittle cartilage – due to hemogentisic acid depositing in cartilage (usual complication)
o Degenerative arthropathy (Usually affected is the vertebral column, knee, shoulders and hips)
o Osteoarthritis

Question 34

LYSOSOMAL STORAGE DISEASES

 Group of disorders arising from the lack or abnormality of any protein essential for normal function of the lysosomes.
 Glucose can enter the cell to be stored as glycogen. When glycogen is needed, it can be degraded again to glucose for use.
o However in LSD, the stored complex material cannot be reused because there is no enzyme for degradation. This complex material will eventually gain more substrates (glucose or amino acids) producing a very large molecule that cannot be used. The cell can increase in size especially when lipids are being stored.

Answer 34

1. GLYCOGENOSES
2. MUCOPOLYSACCHARIDOSES (MPS)
3. SPHINGOLIPIDOSIS (Fat Accumulation)

Question 35

LYSOSOMAL STORAGE DISEASES:

GLYCOGENOSES - The glycogen storage diseases that result from a hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen.

Answer 35

o Hepato-renal form: Von Gierke’s disease
 Clinical picture: Hepatomegaly and Renomegally with Severe Hypoglycemia, Hyperlipidemia, Hyperuricemia
 Severe Hypoglycemia => presents with seizures
o Myopathic form: McArdle’s disease
 Clinical picture: Muscle cramps after exercise, muscle cells cannot utilize glycogen
 Skeletal muscles are affected
 Lacks phosphorylase
o Generalized glycogenosis: Pompe’s disease
 Clinical picture: Involves glycogen storage defects in all organs, but cardiomegaly is most prominent.
 Lacks lysosomal acid maltase
 Most severe of all 3 forms

Question 36

LYSOSOMAL STORAGE DISEASES:

MUCOPOLYSACCHARIDOSES (MPS) - A group of closely related syndromes that results from genetically determined deficiencies of enzymes involved in the degradation of mucopolysaccharides (glycoaminoglycans)

Answer 36

o Hurler Syndrome (MPS I-H)
 Results from a deficiency of α-1-iduronidase
 One of the most severe MPS.
 Affected children appear normal at birth, but develops hepatosplenomegaly by age 6-24 mos.
 Retarded growth
 Develop coarse facial features and skeletal deformities.
 Death occurs by 6 to 10 years; often due to CV complications.
o Hunter syndrome (MPS II)
 Differs from Hurler syndrome in mode of inheritance (X-linked)
 Absence of corneal clouding
 Milder clinical course

Question 37

LYSOSOMAL STORAGE DISEASES:

SPHINGOLIPIDOSIS (Fat Accumulation)

Answer 37

1. Tay Sachs/Sandoff Disease (Very severe, Untreatable)
2. SULFATIDOSES (Niemann-Pick Disease, Gaucher’s Disease)

Question 38

LYSOSOMAL STORAGE DISEASES:

SPHINGOLIPIDOSIS (Fat Accumulation) - Tay Sachs/Sandoff Disease

Answer 38

 Gangliosides accumulate in CNS, ANS, retina (cherry red spots) = destructions of neurons
 Mnemonics from Dr. Jacoba: PaTay ang Tay Sachs; GANGsters nagpapatayan (Gangliosides)
 Prominence of macula, big neurons due to the accumulation of lipids in the retina
 Lacks hexoaminidase thus accumulation of gangliosidase
o Histology: Ballooned neurons, Cytoplasmic Vacuoles, Whorled configuration within lysosomes
o Clinical Manifestations: Symptoms begin at 6 months => Severe progressive Motor and Mental Retardations => Vegetative stage in 2 years => Death in 3 years

Question 39

LYSOSOMAL STORAGE DISEASES:

SPHINGOLIPIDOSIS (Fat Accumulation) - SULFATIDOSES (Niemann-Pick Disease)

 Deficiency of sphingomyelinase
 Mnemonics from Dr. Jacoba: No man Picks his nose with his “SPHINGERS.”
 Affect the Reticuloendothelial system
 Accumulate Sphingomyelin (Component of cell membranes) and Cholesterol mainly in CNS and Phagocytic system (SPLENOMEGALY, Liver, Lymph nodes, Bone Marrow, Tonsils, GIT)
 Location: Chromosome 11p15.4
 Histology: Lipid laden phagocytic foam cells and tubular membranous cytoplasmic bodies (liver and pancreas)
 Electron microscopy: concentrated lamellated myelin figures (“zebra bodies”)
 CNS: Vacuolation and ballooning of neurons
 Subtypes: Type A/B (deficiency of sphingomyelinase) and Type C (defect in transport of cholesterol from plasma

Answer 39

Type A
 Progressive Infantile Neurologic involvement & marked Visceral Enlargement
 Death in 2 years
 Present at birth and evident by 6 months of age
 Infants have Protuberant Abdomen because of Hepatosplenomegaly
 Manifestations followed by Progressive Failure to thrive, Vomit, Fever, and Generalized Lymphadenopathy as well as Progressive Deterioration of Psychomotor function

Type B
 Organomegally without CNS involvement
 Live adulthood

Type C
 Heterogenous clinical picture
o Still birth
o Neonatal Hepatitis, or
o Chronic form of neurologic damage
 The most common form present in childhood and marked as Ataxia, Vertical Supranuclear Gaze Palsy, Dystonia, Dysarthria and Psychomotor regression.

Question 40

LYSOSOMAL STORAGE DISEASES:

SPHINGOLIPIDOSIS (Fat Accumulation) - SULFATIDOSES (Gaucher’s Disease)

 MOST COMMON lysosomal storage disorder
 Mutations in the gene encoding glucocerebrosidase (Cleaves the glucose residue from Ceramide).
 As a result, glucocerebroside accumulates principally in phagocytes but in some subtypes also in CNS.
 Not just caused by burden of storage material but also by activation of macrophages and the consequent secretion of cytokines such as IL-1, IL-6, and TNF.
 Skeletal and CNS
 Location: Chromosome 1q21
 Histology: Gaucher cells enlarged, distended phagocytes with accumulation of glucocerebrosides. Have a fibrillary cytoplasm linked to crumpled tissue paper (PAS +)

Answer 40

Type 1

• Chronic Non-Neuropathic (99%)
• Skeletal and Spleen
• Decreased enzyme activity

Type 2

• Infantile Acute Cerebral Pattern
• Complete absence of enzyme

Type 3
- Intermediate

Question 41

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE

• Single gene disorder that does not follow classic Mendelian principles

Answer 41

o Trinucleotide Repeat Mutations
o Mutations in Mitochhondrial Genes
o Genomic Imprinting
o Gonadal Mosaicism

Question 42

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:

TRINUCLEOTIDE REPEAT MUTATIONS

 Expansion of a stretch of nucleotides from numerous repeats, as few as 20 or as numerous as 200
e.g. ACC CGG CGG CGG CAG GAA CTG
 Almost always cytosine (C) and guanine (G)
 More repetitions, more chance of manifestation (pre-mutation if it’s still few and doesn’t manifest yet)
 The longer the repeat, the more fragile the chromosome is, the more serious the problem is
o Huntington’s chorea – CAG repeats
o Freidrich’s ataxia – GAA repeats

Answer 42

 Tendency of expansion depends upon the sex of the transmitting parent
o Fragile X Syndrome – aggravated by repeats in oogenesis
o Huntington chorea – aggravated by repeats in spermatogenesis
 2 groups depending on where the repeat expansions occur:
o In noncoding regions: e.g. Fragile-X Syndrome, myotonic dystrophy
o In coding regions: Huntington disease
 Causes enlargement of DNA
 Trinucleotide repeats can occur anywhere – introns, extrons, promoter genes, or untranslated region

Question 43

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:

TRINUCLEOTIDE REPEAT MUTATIONS

Answer 43

Triple Repeat Mutations in oogenesis

Question 44

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:

TRINUCLEOTIDE REPEAT MUTATIONS - Anticipation

Answer 44

 Clinical features worsen and the disease occurs earlier with each successive generation.
 The risk of manifestation depends on position in the pedigree.
 Example: Fragile X presents with mental retardation.
1. Grandmother finished college but finished a four-year course in six years.
2. Mother was not able to enter high school.
3. Daughter was not able to enter grade school

Question 45

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:

TRINUCLEOTIDE REPEAT MUTATIONS - Maternal Transmission

**(figure): Triple Repeat Mutations in spermatogenesis. The number of repeats transmitted by the male carrier to his offsprings is longer.

• Therefore only males are affected in sex linked recessive diseases and males are more affected than females in trinucleotide repeat mutations.

Answer 45

Similar to Sex-linked recessive except for the following patterns:

1. Has a Male carrier
2. Female carriers:
   - Sex Linked Recessive: sons are affected and daughters are carriers,
   - Trinucleotide Repeat Mutations: both sons and daughters are affected (30%-50% are affected).

Question 46

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:

TRINUCLEOTIDE REPEAT MUTATIONS - Paternal Transmission

Answer 46

 Similar to autosomal dominant
 Huntington’s Chorea
1. Disease amplification will only occur if the male transmits the disease.
2. Repeat occurs during spermatogenesis
3. CAG repeats

Question 47

SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:

FRAGILE X SYNDROME

Answer 47

 During oogenesis, permutations can be converted to mutations by triple repeat amplifications
 Disease amplification will only occur if the female transmits the disease (2017B)
 CGG repeats
 Disease caused by long repeating sequence of three nucleotides
 IR 1:1550 males; 1:8000 females
 Second most common cause of mental retardation (most common cause: Trisomy 21 – Down Syndrome)
 Abnormal gene: FMR1 (familial mental retardation 1)
 Clinical picture
o Mental retardation in affected males
o Autistic-like manifestations
o Long narrow face with large mandible
o Large everted ears
o Macro-orchidism (Large Testicles)

Question 48

MUTATIONS IN MITOCHONDRIAL GENES

 Transmission of DNA material located in mitochondria (gene inside the mitochondria seen in X chromosome only).

 Transmission exclusively via FEMALES since the Y chromosome does not contain the genes for the mitochondria (maternal inheritance)
 Disease associated with mitochondrial inheritance are rare and many of them affect the neuromuscular system
 Affected individuals will have similar levels of expression.
o Because mtDNA encodes enzymes involved in oxidative phosphorylation, mutations affecting these genes exert their deleterious effects primarily on organs most dependent on oxidative phosphorylation.

Answer 48

 If mother is affected, 100% of kids will have it. If father is affected, 0% of kids will have it
o Ova contains numerous mitochondria in cytoplasm whereas spermatozoa contain few.
o mtDNA complement of zygote is derived entirely from ovum.
o This is the reason why mothers transmit mtDNA to all their offsprings but only daughters can transmit the DNA further to their progeny.
 Mostly affects the neuromuscular system
o e.g. Leber Hereditary Optic Neuropathy (progressive bilateral loss of central vision, first noted between ages 15-35, eventually leading to blindness)

Question 49

GENOMIC IMPRINTING

 A genetic phenomenon by which certain genes are expressed according to the parent of origin
 Every autosomal gene, one copy from our mother and one from our father
 Both copies are functional for the majority of these genes
 A small subset copy is turned off in a parent-of-origin dependent manner
 Called ‘imprinted’ because one copy of the gene was epigenetically marked or imprinted in either the egg or the sperm
 Imprinted alleles are silenced such that the genes are either expressed only from the non-imprinted allele inherited from the mother or father

Answer 49

Epigenic mechanism
o Epigenic = outside the gene, above the gene
o It alters gene function other than those that rely on DNA sequence change
o Has nothing to do with genetic material
o Altering the gene without affecting DNA sequence by:
 Histone formation
 Methylation: attaching methyl groups to promoter regions of genes that leads to inactivation

Question 50

GENOMIC IMPRINTING

Answer 50

Figure shows how genomic imprinting leads to deletion of either maternal or paternal chromosome that causes two different manifestations

Question 51

GENOMIC IMPRINTING: PRADER WILI SYNDROME

7 genes on chromosome 15q11-13 are deleted or unexpressed on the paternal chromosome

Answer 51

Characteristics:
 Mental retardation
 Short Stature
 Hypotonia (Low muscle tone)
 Hyperphagia (Increased appetite)
 Obesity
 Small hands and feet
 Hypogonadism
 Infertility (males and females)
 Sparse pubic hair
 Learning disabilities
 Borderline intellectual functioning (but some cases of average intelligence)
 Prone to Diabetes Mellitus

Question 52

GENOMIC IMPRINTING: ANGELMAN SYNDROME

Maternal deletion in chromosome 15q11-13 causing an absence of UBE3A expression

Answer 52

Characteristics:

• Mental retardation
• Ataxic gait
• Impairments in hippocampal memory
• Intellectual and developmental delay
• Sleep disturbance
• Seizures
• Jerky movements (Especially Hand-flapping) and inappropriate laughter (aka Happy Puppet Syndrome)