Genetics II - Mendelian Disorders Cytogenetics II (trans 2) Flashcards
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.
Four Types
- Autosomal Dominant
- Autosomal Recessive
- Sex-linked Dominant
- Sex-linked Recessive
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:
- 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.
- 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.
- 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.
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
TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS: AUTOSOMAL DOMINANT
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
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.
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.
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.
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
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.
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.
TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:
SEX-LINKED DOMINANT
o Caused by dominant disease-associated alleles on the X chromosome.
Characterized by the following:
- No skip generation
- 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
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)
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.
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.
- Presence of skip generation
- 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
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.
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.
TRANSCRIPTION PATTERNS OF SINGLE GENE DISORDERS:
SEX-LINKED RECESSIVE
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).
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
- Point Mutations
- Deletions and Insertions
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.
- Missense Mutation
- Nonsense Mutation
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.
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.
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.
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
GENETIC MUTATIONS:
DELETIONS AND INSERTIONS
- Frameshift Mutation
- Three Base Deletion/Insertion
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.
Four-base insertion in the hexosaminidase A gene. This mutation is the major cause of Tay-Sachs disease in Ashkenzai Jews
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.
Three-base deletion in the common cystic fibrosis allele results in synthesis of a protein that lacks amino acid phenylalanine.
BIOCHEMICAL MECHANISMS:
AUTOSOMAL DOMINANT
- LOSS of function mutation
- GAIN of function mutation
BIOCHEMICAL MECHANISMS:
AUTOSOMAL DOMINANT - LOSS of function mutation
**results to loss of significant protein
- 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)
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
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)
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)
Common Autosomal Dominant Disorders
- Huntington’s disease
- Marfan’s syndrome
- Ehlers-Danlos syndrome
- Familial hypercholesterolemia
- Von Willebrand disease
- Hereditary spherocytosis
BIOCHEMICAL MECHANISMS:
AUTOSOMAL RECESSIVE TRAITS
- Enzyme Protein Defect (Most common)
- Non-Enzyme Protein Defect
BIOCHEMICAL MECHANISMS:
AUTOSOMAL RECESSIVE TRAITS - Enzyme Protein Defect
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
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
Common autosomal dominant and autosomal recessive disorders
Remember:
Autosomal Dominant – No enzyme deficiency (non-enzyme protein).
Autosomal Recessive – All enzyme deficiency (enzyme protein).
AUTOSOMAL DOMINANT DISORDERS:
- MARFAN’S SYNDROME
- EHLER’S DANLOS SYNDROME
- FAMILIAL HYPERCHOLESTEROLEMIA
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
Variable expressivity
o Functions of Fibrillin
- Normal support or base product or scaffold for elastin in the aorta, ligaments and cilliary zonules (eyes)
- 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
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
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
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
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
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.
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
AUTOSOMAL DOMINANT DISORDERS:
FAMILIAL HYPERCHOLESTEROLEMIA
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
AUTOSOMAL RECESSIVE DISORDERS
- ALBINISM
- ALKAPTONURIA
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
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
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.
- GLYCOGENOSES
- MUCOPOLYSACCHARIDOSES (MPS)
- SPHINGOLIPIDOSIS (Fat Accumulation)
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.
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
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)
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
LYSOSOMAL STORAGE DISEASES:
SPHINGOLIPIDOSIS (Fat Accumulation)
- Tay Sachs/Sandoff Disease (Very severe, Untreatable)
- SULFATIDOSES (Niemann-Pick Disease, Gaucher’s Disease)
LYSOSOMAL STORAGE DISEASES:
SPHINGOLIPIDOSIS (Fat Accumulation) - Tay Sachs/Sandoff Disease
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
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
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.
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 +)
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
SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE
- Single gene disorder that does not follow classic Mendelian principles
o Trinucleotide Repeat Mutations
o Mutations in Mitochhondrial Genes
o Genomic Imprinting
o Gonadal Mosaicism
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
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
SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:
TRINUCLEOTIDE REPEAT MUTATIONS
Triple Repeat Mutations in oogenesis
SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:
TRINUCLEOTIDE REPEAT MUTATIONS - Anticipation
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
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.
Similar to Sex-linked recessive except for the following patterns:
- Has a Male carrier
- 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).
SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:
TRINUCLEOTIDE REPEAT MUTATIONS - Paternal Transmission
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
SINGLE GENE DISORDERS WITH NON-CLASSICAL INHERITANCE:
FRAGILE X SYNDROME
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)
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.
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)
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
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
GENOMIC IMPRINTING
Figure shows how genomic imprinting leads to deletion of either maternal or paternal chromosome that causes two different manifestations
GENOMIC IMPRINTING: PRADER WILI SYNDROME
7 genes on chromosome 15q11-13 are deleted or unexpressed on the paternal chromosome
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
GENOMIC IMPRINTING: ANGELMAN SYNDROME
Maternal deletion in chromosome 15q11-13 causing an absence of UBE3A expression
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)
