General Definitions

- allele alternative variant of genetic information at a locus

- wild type normal allele
- mutant different allele
- polymorphism common alleles in a population
- genotype genetic constitution
- phenotype observable expression of a genotype
- incomplete dominance when heterozygote phenotype is different from both homozygote
- codominant both alleles contribute to the phenotype of the heterozygote
o ex. Sickle cell trait
- haploinsufficiency loss of half of protein activity
- Genetic Heterogeneity.
o May be either in locus or the allele. This situation descripbes different utations at different chromosomal
locations or within the same gene that result in the same clinical condition.
Locus heterogeneity retinitis pigmentosa, ehlers danlos
Allelic heterogeneity cystic fibrosis
- Penetrance
o Probability that the gene will have to express the phenotype
o Reduced penetrance refers to NO expression
o It is an all-or-non concept
- Variable expression
o Severity of the expression of a phenotype. The expression varies amongs individuals.
- Pleiotropy possibility that a gene or gene pairs produce diverse phenotypic effects
- Imprinting refers to when there is one allele active and another is inactivated if there is an deletion of the
active cell, this results in disease.
- Mosaicism presence of genetically distinct cell lines in the same individual

Autosomal Recessive Inheritance

- These genes are located on the autosomes

- Heterozygotes (Aa) are unaffected
- Homozygotes (aa) are affected
- Characteristics of a autosomal recessive pedigree
o Both males and females are affected
o The disorder normally occurs in one generation, with several skipped generation
o Consanguinity between parents

Autosomal Dominant Inheritance

- The impart of these types of mutations depends upon the reserve of that protein present in the cell
- Most people with these conditions are heterozygotes. Homozygotes are usually lethal
- Phenotype usually appears in every generation, each affected person having an affected parent
- Any child of an affected parent has a 50% risk of inheriting the rate
- Phenotypical normal family members do NOT transmit the phenotype to their children

Robertsonian Translocation

- one of the most common translocations.

- Occurs when the long arms of an acrocentric chromosome (with centromere near the end) fuse at the
centromere and the 2 short arms are lost.
- Unbalanced translocations result in miscarriage, stillbirth and chromosomal imbalance (trisomies)

X-linked inheritance

- Lyon Hypothesis
o Only one transcriptionally active X-chromosome
o Inactivation occurs early in embryonic life
o Inactivation is random and permanent in all descendant cells
- An X-linked recessive pedigree has boys that are affected and girls that are carriers
o The mothers are the ones that will be the carriers NOT MEN
 o Incidence of the trait is much higher in males
o No male-to-male transmission
o Isolated cases indicate di novo mutations
- An X-linked dominant trait will affect male and females
o Affected males with normal mates have no affected sons and carrier daughters
o Both male and female offspring can be affected
o Pedigree pattern is the same as that seen with autosomal dominant inheritance

Mitochondrial Maternal Inheritance

- during fertilization, the egg supplies essentially all of the mtDNA

- Mothers transmit mutations in the mtDNA to both sons and daughter but only daughters will pass on the
mutations
- Homoplasmy all mtDna in a cell are identical
- Heteroplasmy both normal and mutatnt DNA co-exist within a tissue
- Mutation accumulation because mitochondria do not have a well-developed repair mechanism and they do not
recombine, there is an accumulation of mutations as mtDNA is passed through maternal inheritance and also over
an individuals life-time
- Threshold effect refers to the critical number of mutated mtDNA that must be present before a phenotype
becomes apparent.

Pathology:

- Phenylketonuria (autonomic recessive disease)

o Children are severely mentally retarded if not identified in time
o There is a defect in phenylalanine metabolism: a decrease in phenylalanine hydroxylase which increases
the amount of phenylalanine and decreases tyrosine.
o TX: low phenylalanine diet and high tyrosine diet
Avoid artificial sweetener aspartame: contains phenylalanine

- Sickle Cell (autonomic recessive disorder)

o mostly affect people with ancestors from the tropic or the Mediterranean
o The B-chain of the human hemoglobin was shown to have a single amino acid substituition (a glutamate
for a valine)

- Cystic Fibrosis (autonomic recessive disorder)

o Most frequent autosomal recessive disease
o Chromosome 7 affects a protein in the CFTR protein which funnels chloride out of the cell, making the
surrounding saltier. Because this protein is defective Cl- stays inside the cell and water goes inside the
cell too, this makes the mucous in the respiratory tracts much more viscous.

- Bardet-Biedl Syndrome (autonomic recessive disorder)

o Characteristics: obesity, polydactyly, pigmentary retinopathy, cognitive impairment, genital anomalies
Anosmia, hypertension (especially in BBS4 and BBS6)
Male infertility
o Common in Bedouin populations in Israel where consanguinity is up to 67%
o In Puerto Rico the locus heterogeneity for this disease is commonly: BBS1 (11q13) and BBS7 (4q27)
o These patients express a low resistance to leptin which makes them prone to overeating and obesity
Leptin sends a signal to the hypothalamus and creates the sense of fullness
o These patients also have problems in their ciliary function

- Retinitis Pigmentosa
o Group of disorders that are inherited, progressive and leads to the eventual atrophy of retinal tissue
o This disease can be passed down through different mechanisms of inheritance
o It is a complication of Bardet-Biedl syndrome
o Retinitis pigmentosa is an inherited condition resulting from mutations that affect rods and cones
o Typically, both rods and cones are lost to apoptosis

- Neurofibromatosis 1 (NF1) (autosomal dominant)

o Most common autosomal dominant disorder.
 o Good example of variable expression in a genetic disease
o Caf-au-lait spots >5mm or >15mm
o Neurofibromas >2
o Lisch nodules >2

- Prader-Willi (microdeletion of 15q11-q13)

o Example of maternal imprinting
Gene from mom is normally silent and the paternal gene is deleted/mutated.
o Results in hypogonadism, obesity, short stature
These patients are not born obese

- Angelman Syndrome (microdeletion of 15q11-q13)

o Example of paternal imprinting:
Gene from dad is normally silent and maternal gene is deleted/mutated
o Results in inappropriate laughter, seizures, ataxia, and severe mental retardation

- Down syndrome (trisomy 21)

o Most common viable chromosomal disorder and most common cause of genetic intellectual disability
(followed by fragile-X)
o Flat facies, prominent epicantal folds, single palmar crease, congenital heart disease, big tongue
o Alzheimer >35years = Downs syndrome
o 95% trisomy 21 ; 4% translocation ; 1% mosaicism

- Cri-du-chat syndrome
o Microdeletion of short arm of chromosome 5 (5p-)
o Microcephaly, mental retardation, cry of cat, small jaw

- Patau Syndrome: (trisomy 13)

o adecuate size/weight for gestation age
o major cardiac malformations
o rocker-bottom feet
o cleft lip/palate
o holosencephaly
o polydactyly

- Edwards Syndrome (trisomy 18)

o Small for gestational age
o Clenched hands
o Death within 1 year of birth

- DiGeorges (22q11)
o CATCH-22: cleft palate, abnormal facies, thymic aplasia (t-cell deficiency), cardiac defects, hypocalcemia
o Aberrant development of 3rd and 4th pharyngeal pouch

- Williams Syndrome
o Congenital microdeletion of long arm of chromosome 7 (elastin gene)
o elfinfacies, intellectual disability, hypercalcemia, stellate iris, extreme friendliness

- Turner Syndrome (45X)

o Amenorrhea and premature loss of ovarian follicles
Most common cause of primary amenorrhea
o Webbed neck, edema of hands and feet, coarctation of aorta
o Fail to develop secondary sex characteristics
o DX: karyotyping (no Barr body), high FSH:LH due to decreased estrogen.

- Klinefelter Syndrome (47,XXY)

o Extra X chromosome. Due to maternal nondisjunction.
o Increased estradiol and decreased testosterone, increased LH
o Hypogonadism, infertility due to azoospermia
 o Long extremities
o Female secondary sex characteristics, female hair distribution
o Each additional X chromosome correlates with an increased abnormal phenotype and with more severe
mental retardation

- Fragile-X syndrome
o X-linked defect affecting the methylation and expression of the FMR1 gene
o 2nd most common cause of genetic intellectual disability
o macroorchidism (enlarged testes), long face, large jaw, everted ears, autism,
o CGG repeats in X chromosome
>200 repetitions
<200 pre-mutations
o Good example of a disease that expressed anticipation because of the accumulation of CGG repeats

- Classification of Oxidative Phosphorylation Disorders OXPHOS (mitochondrial disease)

o Class I disorders of nuclear oxidative phosphorylation genes
Benign infantile mitochondrial myopathy
Weakness, hypotonia, respiratory difficulties, lactic acidosis
Transmitted either dominantly or recessive
Lethal infantile mitochondrial disease
Kearns-Sayre syndrome KSS
Inherited exertional myoglobinuria
Leigh disease
Very lethal
X-linked disease
NARP
Palidez del nervio optico
Cara miopatica without expression

o Class II mtDNA point mutations

Classic examples of mitochondrial disease
Lebers hereditary optic neuropathy (LHON)
Painless loss of central vision
Swelling of the nerve fibers around the optic nerve
LHON + infantile bilateral stratal necrosis
Dementia
Myoclonic epilepsy and ragged red fibers disease (MERRF)
Myoclonic epilepsy
Progressive dementia
Usually first diagnosed at epilepsy but there are complications which lead to the
appropriate Dx.
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)
Neurodegenerative myopathy
o Muscle biopsy reveals degeneration of muscular cells
Lactic acidosis
Stroke-like episodes -> characteristic of mitochondrial problems
Diagnosis can be made between 5-15 years of age
Presentation of disease can be sudden.
These children usually appear tired and hunched
Tx: mitochondrial vitamin cocktail to improve symptoms
o Class III mtDNA deletions and duplications
o Class IV disorders of unknown inheritance

- Inborn Errors of Metabolism

o Newborns present symptoms >12hours after birth because prenatally they are protected by the placenta
o Carbohydrate Metabolism
Essential Fructosuria
Benign
Asymptomatic metabolic disorder
There is an absence or deficiency in fructokinase

Hereditary Fructose intolerance (autosomal recessive)

Deficiency of fructose 1-phosphate aldolase of liver, kidneys and intestines
Severe hyperglycemia
o 10% dextrose IV cannot be administered to these patients
not a very good outlook
Tx: eliminate fructose from diet

Hereditary fructose 1,6 biphosphate deficiency

Episodic spells of hyperventilation
Hypoglycemia must be avoided so that brain is not affected
Lactic acidosis
May be lethal in newborn period but once patients pass early childhood, they develop
normally.
Fasting must be avoided

Glycogen Storage Disorders

liver and muscles have an abundant quantity of glycogen
they mainly affect the liver and these patients present with hepatomegaly and
hypoglycemia as the usual presenting features
muscle cramps, exercise intolerance, weakness
Types I- IV: hepatic

o Amino Acid Metabolism

Phenylketonuria (see above)

o Organic Acidemias
Propionic Acidemia (autosomal recessive)
Propionyl CoA Carboxylase deficiency

Methylmalonic Acidemia (autosomal recessive)

Methylmalonyl CoA mutase deficiency
B-12 deficiency
These newborns are usually treated by removing formula diet and IV 10% dextrose

o Disorders of Urea Cycle Metabolism

Orithine Transcarbamylase deficiency (x-linked)
Only x-liked disease of urea metabolism
Most frequently seen
Proteins must be restricted because they could overwhelm the urea cycle and lead to
accumulation of ammonia
Dx: made because there is an elevation of blood ammonia
Tx: minimize protein intake. Reverse or minimize catabolism (will raise insulin levels)
Ammonia cannot be lowered at extremely fast rates or it can cause edema in the brain

o Disorders of fatty acid oxidation

MCAD deficiency most common
Accumulation of fatty acids intermediates in urine