Vitamins & Genetics Flashcards
Vitamin A (retinol, retinal, & retinoic acid)
Features
An antioxidant
Retinal pigments (rhodopsin & iodopsin)
Cellular differentiation (pancreatic & mucus cells)
All-trans retinoic acid to treat acute myelocytic leukemia
Retinal-acne
Vitamin Def:
- Nyctalopia (night blindness)
- Xerosis cutis (dry + scaly skin)
- Corneal squamous metaplasia
- Bitot spots (Keratin debris & foamy spots in conjunctiva)
- Keratomalacia (blindness)
- Immunosuppression
Vitamin A deficiency
Vitamin Toxicity:
Nausea
Vomiting
Increased intra corneal pressure (vertigo & blurred vision)
Acute vitamin A toxicity
Vitamin Toxicity:
Alopecia
Cheilosis
Osteoporosis
Hepatic toxicity & enlargement
Dry skin
Arthralgias
Idiopathic intracranial hypertension
Teratogenic effects
Chronic vitamin A toxicity
Vitamin toxicity:
Yellow/orange skin
B-carotene excess
Vitamin D features
- D3 (Cholecalciferol) absorbed through the skin (stratum Basale) via sun
- D2 (Ergocalciferol) plants, fungi, & yeast
Both get converted to 25-OH-D3 (storage form) in liver & 1,25-OH2D3 (active form aka calcitriol)
Vitamin D functions
- Increase intestinal absorption of Ca2+
- Increase bone mineralization (makes Ca2+ binding protein aka osteocalcin on osteoblasts)
- Increase bone reabsorption via RANKL activation to raise osteoblast levels
Vitamin regulation:
High PTH
Low Ca2+
Low PO4^-3
Increased 1,25(OH)2D3 aka active calcitriol its feedback inhibits it’s own production
Vitamin regulation:
High PTH triggers ________ & _____reabsorption in the kidneys
increased Ca2+ & decreased PO4^-3 reabsorption in the distal renal tubules
Vitamin Deficiency:
During first year of life
- Craniotabes
- Frontal bossing
- Square head (excess osteoid)
- Rachitic Rosary (overgrown cartilage & osteoid tissue in costosternal junctions)
Vitamin D deficiency
Vitamin Deficiency:
- Rickettes (Genu varum) in kids
- Osteomalacia, Osteoporosis, & hypocalcemia tetany in adults
Vitamin D deficiency
Vitamins:
- Lack of UVB (sun exposure)
- Mineral oil as a laxative
- Chronic kidney disease
- Advanced liver disease
Causes of vitamin D deficiency
Vitamins:
Hypercalcemia
Hypercalciuria
Low appetite
Stupor
Vitamin D toxicity
Vitamin A
&
B-carotene/retinal absorption
- Vit A & B-Carotene can be turned into one-another & bile helps them be absorbed into the intestine & gets incorporated into chylomicrons to move through lymph
- Apolipoprotein E receptors on liver bring them into hepatocytes to be stored in Ito cells & adipose cells
Vitamin A
&
B-carotene/retinal release
- Stored Vitamin A & B-carotene bind to retinol-binding proteins (RBP) made in the liver before being released into the blood
- Peripheral tissues with RBP-specific receptors binds retinol while the RBP is sent back into the blood
- Within the tissues retinol is oxidized into usable form retinoic acid
Vitamin:
Synthesis of vitamin A
Retinol is oxidized all-trans-retinol which is isomerized into 11-cis-retinol which is covalently associated with 7-transmembrane protein opsin to make rhodopsin
Function of vitamin A:
Cell growth & differentiation
Retinoic acid receptors with retinoic acid forms heterodimers with retinoic x receptors
The RAR/RXR heterodimers bind retinoic acid response elements (RAREs) in regulatory genes for growth factors, tumor suppressors, & secreted proteins
Vitamin deficiency:
Squamous metaplasia (loss of mucus secreting epithelium & pancreatic cells)
Vitamin A deficiency
All-trans retinoic acid has _________ for RAR it induces differentiation of ________ by binding PML-RARa
The highest affinity for RAR & it induces differentiation of promyelocytic leukemia cells by binding PML-RARa
Vitamins:
All-trans Retinoic acid + RXR/RAR + PML means
Activated transcription causing increased differentiation of malignant promyelocytes into short-lived PMN CANCER
Vitamins:
Retinoic acid + RXR/RAR + PML
Block transcription & differentiation of acute promyelocytic leukemia NO CANCER
Vitamin:
Retinoic acid + RXR/RAR
Activates transcription & differentiation into short-lived PMN’s CANCER
Vitamin A:
RXR is activated by _____ which form heterodimers
9-cis-RA
RXR/RAR (Acute promyelocytic leukemia)
RXR/PPARs (High fatty acid oxidation, angiogenesis, & lipolysis)
Vitamin D synthesis
- Absorbed in the gut
- Vitamin D binds alpha globin (Vit D binding protein) & gets moved to the liver
- Vit D is converted to 25-OH-D via 25-Hydroxylases (CYP27AI & other CYPs)
- 25-OH-D is converted into 1,25OH2D3 (aka active form) via 1 alpha hydroxylase in the kidney
Chronic renal disease & vitamin D deficiency is caused by
Secondary hypertension (low GFR)
Causing hyperphosphatemia & low 1,25(OH)2D3 which reduces more PTH secretion causing secondary hyperparathyroidism
Hyperphosphatemia
Hypocalcemia
Hyperparathyroidism
Osteodystrophy
Low vitamin D (1,25(OH)2D3)
Chronic renal disease & vitamin D deficiency
Morphology of vitamin D
- Excess of unmineralized bone matrix
- Overgrown epiphysial cartilage
- Distorted & irregular masses
- Bone deformities
Vitamins:
Tocopherol & Tocotrienol
Vitamin E
Vitamin Deficiency:
- Hemolytic anemia
- Acanthocytosis
- Ophthalmoplegia
- Pigmented retinopathy
- Muscle weakness
- Demyelination of posterior columns & spinocerebellar tracts
(Progressive ataxia, poor proprioception, impaired joint position, & vibration sensation)
Vitamin E deficiency
Vitamin toxicity:
Enterocolitis (Infants)
Increased need for vit K
Patients taking oral anticoagulants have heavy bleeding
Vitamin E toxicity
Used in redox reactions as a cofactor for dehydrogenases (constituent for NAD & NADP) derived from tryptophan
Vitamin B3 Niacin deficiencies, Pellagra
Vitamin Deficiency:
Dementia
Diarrhea
Dermatitis
Insomnia
Fatigue
Nervousness
Irritability
Depression
Vitamin B3 (Niacin) deficiency pellagra
Can be caused by alcoholism or Hartnup disease
Nutrition:
Hypoalbuminemia
Hyperkeratosis
Malnutrition
Edema (Anasarca)
Anemia
Fatty liver
Skin lesion
Kwashiorkor
Genetics:
Tall + long extremities
Anterior meningocele
Arachnodactyly
Pectus carinatum
Hypermobile joints
Aortic root aneurysm/dissection
Mitral valve prolapse
Ectopia lens (up/out lens dislocation)
Marfan’s syndrome
Fibrillin 1 defect (FB1N) on x15 & TGFB receptor 2 defect
Pathophysiology of Marfan’s disease
- Missense mutations of FB1N & TGFB2 genes alter Ca2+ binding domains in the epidermal growth factor-like domains of proteins
- This causes tropo-elastin to be deposited on fibrillin to form elastin fibers (more in the aorta, ligaments, & lungs)
- The mutations lead to more TGFB signaling increasing risk of aneurysms & deleterious effects on vascular smooth muscle development & over activation of metalloproteases which decreased ECM
Describe the symptoms of Marfan’s syndrome
Tall + long extremities
Anterior meningocele
Arachnodactyly
Pectus carinatum
Hypermobile joints
Aortic root aneurysm/dissection
Mitral valve prolapse
Ectopia lens (up/out lens dislocation)
Describe the Ghent diagnostic criteria for Marfan’s syndrome
2 cardinal signs (Aortic root dilation & ectopia lens
OR
1 cardinal sign with a FB1N missense mutation
Genetics:
Onset 25-45yrs
Chorea (sudden jerks)
Athetosis (slow writing fingers)
Aggression
Depression
Dementia
Huntington’s disease
AUTO DOM, CAG trinucleotide repeat in X4p16.3 causing atrophy of the caudate nucleus & putamen
Genetics:
High Dopamine
Low Ach
Low GABA
Huntington’s disease
Describe the pathophysiology of Huntington’s disease
CAG trinucleotide repeats during spermatogenesis leads to anticipation (early onset in the next generation). The caudate and putamen portions of the brain have shrunk, causing the ventricles to expand. Because the death of striatal neurons, which was caused by the binding of a chemical called NMDA-R and the overstimulation of another chemical called glutamate excitotoxin
Genetics:
one gene copy is silenced by methylation, and only the other copy is expressed diseases are dependent on parent-of-origin effects
Genetic imprinting for conditions like Prader-Willis syndrome & Angelman syndrome
Genetics:
Paternal imprinting
paternal gene is silenced
Genetics:
Maternal imprinting
Maternal gene is silenced
Genetics:
Hyperphagia
Obesity
Hypogonadism
Hypotonia
Adult-onset diabetes mellitus
Prader Willis syndrome X15
Due to maternal imprinting (maternal gene is silenced & paternal gene is deleted)
Genetics:
Prader-Willis & Angelman’s syndrome can be caused by _______ & ________
- Maternal imprinting
- Uniparental disomy (person inherits two copies of a chromosome from only one parent (both silenced), instead of one copy from each parent)
Genetics:
Seizures
Ataxia
Intellectual disability
Laughter
Poor language development & motor milestones
Angelman’s syndrome
Due to paternal imprinting (paternal silenced, maternal deleted)
Genetics:
Describe the symptoms of Prader Willis syndrome
Hyperphagia
Obesity
Hypogonadism
Hypotonia
Adult-onset diabetes mellitus
Genetics:
Describe the symptoms of Angelman’s syndrome
Seizures
Ataxia
Intellectual disability
Laughter
Poor language development & motor milestones
Genetics:
Intellectual disability
Flat facies
Single palmar crease
5th finger gap
Hirschsprung’s disease
Atrioventricular canal
Brushfield spots (white spots on iris)
Early (40yrs) onset Alzheimer’s
High risk Acute lymphoblastic leukemia
Downs syndrome (X21)
95% cases due to meiotic nondisjunction during meiosis I (separation during anaphase I or separating pairs during Anaphase II)
4% cases due to unbalanced Robertsonian translocation between X14 & X21
1% cases due to post fertilization mitotic error
Genetics:
What is the test used for Down’s syndrome?
Ultrasound during the first trimester to evaluate nuchal translucency & hypoplastic nasal bone
AND
Labs for:
High B-hCG + Inhibin A
Low Alpha fetoprotein + PAPP-A
Genetics:
Labs for:
High B-hCG + Inhibin A
Low Alpha fetoprotein + PAPP-A
Describe the syndrome & its 5A’s
Down’s Syndrome (X21)
&
1. Advanced maternal age (big risk)
2. Atresia (duodenal)
3. Atrioventricular septal defect
4. Early onset Alzheimer’s (40yrs)
5. Acute lymphoblastic leukemia
Genetics:
- Prominent occiput
- Rocker-bottom feet
- Intellectual disability
- Clenched fists with overlapping fingers
- Low-set ears
- Omphalocele
- Myelomeningocele
- Ventricular septal defect or patent ductus arteriosus
Edward’s syndrome (X18)
A non-disjunction mutation causing death before the age of 1
Genetics:
Labs:
Low B-hCG
Low Alpha-fetoprotein
Low PAPP-A
Nondisjunction mutation
What is the condition & its symptoms?
Edward’s syndrome (X18)
&
Symptoms:
- Prominent occiput
- Rocker-bottom feet
- Intellectual disability
- Clenched fists with overlapping fingers
- Low-set ears
- Omphalocele
- Myelomeningocele
- Ventricular septal defect or patent ductus arteriosus
Genetics:
- Severe intellectual disability
- Rocker-bottom feet
- Microencephaly
- Polydactyly/Syndactyly
- Cleft lip/palate
- Cutis aphasia
- Holoprosencephaly
- Microphthalmia (eye)
- Ventricular septal defect
- Poly cystic kidney disease
Patau’s syndrome (X13)
Midline defects (fusion of perichondral mesoderm) cause major physical symptoms
Genetics:
Labs:
Low B-hCG
Low PAPP-A
Low Alpha-fetoprotein
Midline defects
What’s the condition & some of its symptoms?
Patau’s syndrome (X13)
&
- Severe intellectual disability
- Rocker-bottom feet
- Microencephaly
- Polydactyly/Syndactyly
- Cleft lip/palate
- Cutis aphasia
- Holoprosencephaly
- Microphthalmia (eye)
- Ventricular septal defect
- Poly cystic kidney disease
Genetics:
Testicular atrophy
Tall eunuchoid body
Gynecomastia
Female body hair distribution
Barr body
Hypogonadism
Higher breast cancer risk
Sterility
Small penis
Higher type 2 diabetes, SLE, & MVP risk
Klinefelter syndrome (47XXY)
Nondisjunction during meiosis
Genetics:
Describe the Lyon hypothesis in relation to Klinefelter syndrome (47XXY)
In a normal person, one copy of each chromosome is active (working) and the other copy is inactive. This inactive copy is called a “barr body”. However, in some situations, not all of the genes on the inactive chromosome are turned off. This can lead to hypogonadism, which means that the reproductive glands (ovaries or testes) don’t produce enough hormones. This can happen because the androgen receptors, which normally respond to testosterone, are not working properly due to having longer than usual stretches of certain DNA building blocks called “CAG repeats”.
Genetics:
Labs:
High Estrogen
High FSH
High LH
Low Testosterone
Low Inhibin E
Nondisjunction during meiosis
What’s the condition & some of it’s symptoms
Klinefelter syndrome 47XXY
&
Testicular atrophy
Tall eunuchoid body
Gynecomastia
Female body hair distribution
Barr body
Hypogonadism
Higher breast cancer risk
Sterility
Small penis
Higher type 2 diabetes, SLE, & MVP risk
Genetics:
- Short (SHOX gene)
- Hypogonadism
- Only pubic hair
- Hypothyroidism
- Ovarian dysgenesis (streak ovary)
- Shield chest (wide based nipples)
- Bicuspid aortic valve
- Coarctation of aorta
- Webbed neck (lymphatic defect)
- Cystic hygroma (swollen feet/hands)
- Horseshoe kidney
- Primary amenorrhea
- Shortened 4th metacarpal
- High arched palate
Turner syndrome (45X0)
Nondisjunction during mitosis or meiosis that leads to complete or partial monosomy of the X chromosome
Genetics:
Labs:
Low Estrogen
High LH
High FSH
What’s the condition & some of it’s key symptoms
Turner syndrome (45X0)
&
- Shield chest (widely based nipples)
- Bicuspid aortic valve
- Coarctation of aorta (Higher femoral pulse than radial)
- Cystic hygroma (swollen feet/hands)
- Hypogonadism
- No axillary hair (only pubic)
Genetics:
Turners syndrome can be inherited by _______ & _____
- Mitotic errors (post zygote formation leads to some lost sex chromosome causing a mosaic karyotype 45X/46XX) & higher risk of gonadoblastoma
- Meiotic errors (usually in paternal gametes missing X or Y)
Genetics:
- Developmental delay
- Cherry red spot on macula
- Hyperacusis
- Lysosomes with onion skin
Tay Sachs disease
Deficient Hexosaminidase A leads to a build up of GM2 Gangliosides
common in Ashkenazic jews
Genetics:
Infantile form:
- Fatal neurodegenerative disease
- Macroencephaly
- Lost motor skills
- Macular cherry red spot
Tay Sachs disease
Deficient Hexosaminidase A leads to a build up of GM2 Gangliosides
Genetics:
Adult form:
- Clumsy in childhood
- Progressive motor weakness (teens)
- Spinocerebellar/LMN symptom & Dysarthria (adults)
- Psychosis
- Low intellegence
Tay Sachs disease
Deficient Hexosaminidase A leads to a build up of GM2 Gangliosides
Genetics:
- Extensive neurodegeneration in
-Cherry red spot on macula - Spasticity
- Failure to thrive
- MASSIVE hepatosplenomegaly with marked visceral accumulation of sphingomyelin
Type A Nieman Pick (X11)
AUTO REC, Deficiency of Sphingomyelinase causing build-up of Sphingomyelin leading to death within the first 3yrs of life
Genetics:
-Cherry red spot on macula
- Progressive pulmonary disease with foam cells in the alveoli, lymph vessels, & pulmonary arteries
- Dyspnea
- Hypoxemia
- Reticular infiltrative pattern on Xray
Type B Nieman Pick disease X11
They survive into adulthood
Deficient sphingomyelinase causes a build-up of sphingomyelin
Genetics:
- Hepatosplenomegaly
- Pancytopenia
- Osteoporosis
- Avascular necrosis (femur)
- Bone crisis
- Lipid-laden macrophages (GC)
Gaucher’s Disease X1
AUTO REC, deficiency of Glucocerebrosidase (B-glucosidase leading to a build-up of glucocerebroside & Gaucher cells (aka lipid-laden macrophages)
Genetics: Gaucher’s
- Hepatosplenomegaly
- Bone pain
- Bleeding
- Gaucher cells
Type 1 Gaucher’s (common) a chronic Non-neuropathic accumulation of glucocerebrosides stored in macrophages (Gaucher cells) within tissues EXCEPT the brain
Genetics: Gaucher’s
-Hepatosplenomegaly
- Bone pain
- Bleeding
- Supranuclear gaze palsy
- Strabismus
Type 2 an acute neuropathic infantile syndrome with accumulation of glucocerebrosides in macrophages in all tissues INCLUDING the brain aka it HAS neurological symptoms
Genetics:
- Severe fasting hypoglycemia
- High blood lactate
- High triglycerides (Hyperlipidemia)
- High uric acid (Gout)
- Renomegaly
- Hepatomegaly
- Xanthomas
- Stunted growth
- Failure to thrive
- Platelet dysfunction (prolonged bleeding time)
Von Gierke disease (type 1)
AUTO REC, deficiency of G6P (Glucose-6-phosphatase)
Complications include hepatic adenomas
Genetics:
Describe the symptoms of Von Gierke’s disease
deficiency of G6P (Glucose-6-phosphatase) causes:
- Severe fasting hypoglycemia
- High blood lactate
- High triglycerides (Hyperlipidemia)
- High uric acid (Gout)
- Renomegaly
- Hepatomegaly
- Xanthomas
- Stunted growth
- Failure to thrive
- Platelet dysfunction (prolonged bleeding time)
Genetics:
- Painful muscle cramps
- Myoglobinuria (post exercise)
- Arrythmia
- High CK
- Unaffected lactate
McArdle disease
Deficient muscle phosphorylase causes glycogen accumulation in skeletal muscle which causes severe cramping in short bursts of exercise but is relieved by prolonged exercise
Genetics:
- Cardiomyopathy
- MASSIVE Cardiomegaly
- Hypotonia
- Exercise intolerance
- Early death
- Mild hepatomegaly with ballooning lysosomes
Pompe disease, deficient acid maltase (aka alpha 1,4, glucosidase with alpha 1,6 glucosidase activity)
Causing glycogen stores in the myocardium & MASSIVE CARDIOMEGALY
Describe the features of Pompe disease
deficient acid maltase (aka alpha 1,4, glucosidase with alpha 1,6 glucosidase activity)
causing:
- Cardiomyopathy
- MASSIVE Cardiomegaly
- Hypotonia
- Exercise intolerance
- Early death
- Mild hepatomegaly with ballooning lysosomes
Describe the features of McArdles disease
Deficient muscle phosphorylase causes:
- Painful muscle cramps
- Myoglobinuria (post exercise)
- Arrythmia
- High CK
- Unaffected lactate
Genetics:
- CGG repeats 50-200
- Tremor
- Ataxia
- Primary ovarian insufficiency
- Developmental/behavioral traits
Fragile X syndrome premutation
X-DOM mutated FMR1 gene causing hypermethylated cysteine residues reducing gene expression
Genetics:
- CGG repeats 200+
- Post pubertal macrochidism
- Long face
- Large jaw
- Large & elevated ears
- Autism
- Mitral valve prolapse
- Hypermobile joints
- Self mutilation
- Intellectual disability
Fragile X syndrome Full mutation
X-DOM mutated FMR1 gene causing hypermethylated cysteine residues because of increased translation of bound mRNAs at synaptic junctions leading to reduced gene expression
Fragile X syndrome is susceptible to _________
Affected females make up _______ & are ________
&
Affected males make up __________& are ______
anticipation, meaning premutation can develop to a full mutation i.e it gets worse with every generation
Affected females make up 30-50% inheritance & are mentally retarded
Affected males make up ~20% & unaffected but can pass the gene along to the next generation
