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Inherited Diseases > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

Clinical manifestations of Mitochondrial Disease

A
  • Stroke
  • Basal ganglia lesions
  • Encephalopathy - hepatopathy
  • Epilepsy
  • Cognitive decline
  • Ataxia
  • Ocular signs (ptosis, optic nerve atrophy, retinopathy)
  • Sensorineural hearing loss
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2
Q

Genetic of mitochondrial disease

A

37 genes encode 13 proteins and 24 RNAS

More than 200 nDNA-encoded mito genes - encode over 1500 proteins

Circular mitome

100 known mito disease genes

Defects affect the ETC (electron transport chain/respiratory chain)

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3
Q

mtDNA syndromes

A

MELAS - Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

MERRF - Myoclonic epilepsy with ragged red fibers

NARP - neuropathy, ataxia, retinitis pigmentosa

MILS - maternally inherited Leighs syndrome

LHON - Leber’s hereditary optic neuropathy

KSS/Pearson - sideroblastic anemia, pancreatitis (caused by mtDNA deletions)

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4
Q

Heteroplasmy

A

Percentage of affected mitochondria determines severity of phenotype

High percentage - more severe phenotype

Low percentage - may not exhibit any phenotype

ex. T8993G mutation-carrying individuals appear normal from 0-60% affected DNA, have retinitis pigmentosa from 60-75%, have NARP from 75-90%, and have Leighs syndrome if 90% or more of the mitochondria is affected

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5
Q

Fission and Fusion (mitochondria dynamics)

A

Mitochondria replicate by fission, require fusion to operate
Several genes regulate this and gene defects lead to mitochondrial disease

  • OPA1 - AD Optic Atrophy
  • MFN2 - AD axonal variant Charcot-Marie-Tooth
  • KIF5A - AD HSP
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6
Q

Coenzyme Q10 Deficiency

A

6 Major clinical phenotypes

  • Encephalomyopathic form with seizuers and ataxia
  • Multisystem infantile form with encephalopathy, cardiomyopathy, and renal failure
  • Predominantly cerebellar form with ataxia and cerebellar atrophy
  • Leigh syndrome with growth retardation
  • Isolated myopathy
  • Steroid resistant nephrotic syndrome

May respond dramatically to Coenzyme Q10 treatment

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7
Q

mtDNA depletion syndrome symptoms

A
  • Lactic acidosis in neonatal/childhood period
  • Failure to thrive
  • Hyoptonia
  • Muscle weakness in childhood and adulthood
  • Ataxia in adulthood
  • Polyneuropathy in adulthood
  • Liver impairment in childhood
  • Epilepsy
  • Migrane-like headaches in juvenile period
  • Developmental delay/cognitive impairment
  • Psychiatric symptoms in teens and adulthood
  • GI symptoms in adulthood
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8
Q

Defects of intergenomic communication

A

Mitochondrial neuro gastrointestinal encephalomyopathy

  • pstosis and opthalmoplegia
  • GI dysmotility
  • cachexia
  • peripheral neuropathy
  • leukoencephalopathy
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9
Q

Mitochondrial Disease Therapeutics

A
  • Therapy based on specific pathway of respiratory chain affected
  • Three parent children - Mitochondrial genome transfer to avoid mitochondrial diseases
  • Gene therapy to reduce mutant mtDNA
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10
Q

Ammonia excretion - non-hepatic tissues

A
  • Glutamate dehydrogenase and glutamine synthetase remove 2 ammonia molecules from tissues to rid them of nitrogen waste
  • Glutamine deposits ammonia in kidney for excretion
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11
Q

Urea excretion - hepatic tissues

A

Requires water
Nitrogen waste ends up in urea
Goes into urea cycle
Amino acids derived either from breakdown of protein in tissues or from what is synthesized in those tissues

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12
Q

Hyperammonemias

A

Acquired - liver disease leads to portal systemic shunting

Inherited - Urea cycle enzyme defects of CPS1 (carbonyl phosphate synthetase 1) or ornithine transcarbamylase lead to severe hypoammonemia

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13
Q

Metabolic functions of the liver

A
  • Production and storage of glycogen
  • Catabolism of glycogen to glucose
  • Conversion of excess glucose to fat
  • Transport of lipids/glucose to other tissues
  • Conversion of ammonia to urea
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14
Q

Deammination as a source of ammonia production

A

Removal of an amino group from amino acids results in the production of an ammonia molecule

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15
Q

Non-IEM causes of Hyperammonemias

A
  • Drug-related (valproate)
  • Acute liver failure
  • Reye syndrome
  • Massive tissue necrosis
  • Chronic UTIs with urine retention
  • Overgrowth of bowel flora
  • Portocaval shunts
  • Transient hyperammonemia in newborns
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16
Q

Urea cycle functions

A
  • Prevents the accumulation of toxic nitrogenous compounds by removing nitrogen through urea
  • Contains several biochemical reactions for the de novo synthesis of arginine
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17
Q

Urea Cycle Disorders

A
  • Carbamyl phosphate synthetase deficiency
  • Ornithine transcarbamylase deficiency (most common)
  • Argininosuccinic acid synthetase deficiency
  • Argininosuccinic acid lyase deficiency
  • Arginase deficiency (lease common)

Characterized by hyperammonemia, encephalopathy (due to accumulation of glutamine in the astrocyte), respiratory alkalosis

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18
Q

N-Acetylglutamate Synthase deficiency (NAGS)

A
  • Autosomal recessive
  • Lethargy, persistent vomiting, poor feeding, hyperventilation, enlarged liver, seizures
  • Total deficiency - symptoms appear immediately following birth
  • Partial deficiency - may occur later in life following a stressful event such as infection
  • Low cirtulline levels, normal orotic acid levels
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19
Q

Carbamyl phosphate synthetase deficiency (CPS)

A
  • Autosomal recessive
  • Lethargy, coma, seizures, vomiting, poor feeding, hyperventilation, heptaomegaly
  • Total deficiency - symptoms appear immediately following birth
  • Partial deficiency - symptoms appear in childhood
  • Low citrulline levels, normal orotic acid levels
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20
Q

Ornithine transcarbamylase deficiency

A
  • X-linked
  • Most common
  • Lethargy, coma, seizures, vomiting, poor feeding, hyperventilation, hepatomegaly
  • Hemizygote males - onset immediately after birth
  • Hemizygote females - 10% are symptomatic
  • Low citrulline levels, high orotic acid levels
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21
Q

Argininosuccinic acid synthetase deficiency (ASS)

A
  • Autosomal recessive
  • Lethargy, coma, seizures, vomiting, hyperventilation, poor feeding, hepatomegaly
  • Total deficiency - symptoms appear immediately following birth
  • Partial deficiency - symptoms appear in childhood
  • High citrulline levels, high orotic acid levels
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22
Q

Argininiosuccinic acid lyase deficiency (ASL)

A
  • Autosomal recessive
  • Lethargy, coma, seizures, vomiting, hyperventilation, poor feeding, hepatomegaly
  • Total deficiency - symptoms appear immediately following birth
  • Partial deficiency - symptoms appear in childhood
  • High citrulline levels, high orotic acid levels
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23
Q

Arginase Deficiency (ARG)

A
  • Autosomal recessive
  • Delayed development, protein intolerance, spasticity, seizures, irritability, vomiting, poor appetite
  • Slower onset, often present with symptoms of muscle weakness, hyperammonemia is rare
  • High citrulline levels, high orotic acid levels
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24
Q

Treatment of Urea Cycle Defects

A
  • Goal is to maintain plasma glutamine levels at or near normal (Glutamine represents a storage form of nitrogen that can buffer ammonium)
  • Measure of plasma glutamine levels may be single best guide to therapy (levels can predict hyperammonemia)
  • Restricted intake of dietary protein
  • Activation of other waste nitrogen pathways - CPS, OT, ASS - sodium phenylbutyrate activates phenylacetylglutamine - new vehicle for removal of waste nitrogen
  • Arginine supplementation in ASS and ASL
  • Ammonul medication
  • Liver transplant in severe phenotypes
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25
Q

Functions of the lymphatic system

A
  • Anatomic organization
  • Fluid homeostasis
  • Local tissue inflammation and edema
  • Infection management
  • Cancer
  • Nutrition
  • Organ rejection
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26
Q

Lymphatic development

A
  1. Embryonic veins express high levels of VEGFR-3 while a subpopulation of endothelial cells in large central veins express LYVE-1
  2. SOX-18 transcription factor is induced in LYVE-1 positive cells
  3. VEGFR-3 is downregulated in veins but remains high in lymphatic endothelial cell (LEC) precursors
  4. LEC precursors express neutrophilin-2 which makes them more responsive to VEGF-C, required to form lymph sacs
  5. LECs express proteins that lead to platelet aggregation to prevent lymphatico-venous connections
  6. LECs differentiate into lymphatic capillaries and vessels
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27
Q

Clinical manifestations of lymphedema

A
  • Abnormal accumulation of fluid (possibly lymph) in the interstitial spaces (often extremities)
  • Abnormality in the structure or function of the lymph system
  • Swollen extremities
  • Phenotype is imprecise and penetrance is incomplete
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28
Q

Primary Lymphedema (PL)

A
  • AD w/ reduced penetrance (80%)
  • Disabling and disfiguring swelling of the limbs
  • Variable expression
  • Variable age of onset
  • Genetic heterogeneity
  • VEGFR-3 and SOX-18 mutations
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29
Q

VEGFR-3

A

Expressed in vascular endothelium - lymphatic precursor cell line

  • prominent at lymphatic points of origin
  • VEGFR3 KO mice showed enlarged pericardial lymphocytes, enlarged paws
  • Causes is PL
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30
Q

Lymphedema-Distichiasis

A
  • AD
  • Lymphedema, predominantly of lower limbs
  • onset around puberty
  • Distichiasis (double row of eyelashes)
  • Varicose veins
  • Cleft lip/palate (4%)
  • Congenital heart defect (7%)
  • FOXC2 mutations
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31
Q

Hypotrichosis-Lymphedema-Telangiectasia

A
  • SOX18 mutations

- AR or AD

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32
Q

Galctosemias

A
  • GALK - Galactokinase deficiency
  • GALT - Galactose uridyl transferase deficiency
  • GALE - Uridine diphosphotase deficiency
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33
Q

Fructose diseases

A
  • Fructokinase deficiency
  • Hereditary fructose intolerance
  • Fructose 1,6-bisphosphotase deficiency
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34
Q

Glutamate-Glutamine conversion as ammonia buffer

A
  • Glutamine is a storage form of nitrogen that can provide a short-term buffering of ammonia
  • Gluatamate dehydrogenase and gluatmine synthase remove two ammonia molecules from tissues to remove excess nitrogen waste
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35
Q

Population-Specific Galactosemia Mutations

A

S135L - GALT gene mutations - common in African Americans

Q188R - GALT gene mutations - most common mutation in Caucasians

N314D - Duarte allele

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36
Q

Clinical Manifestations of GALK

A
  • High galactose, low galactitol, low Gal1P

- Cataracts only

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37
Q

Clinical Manifestations of GALT

A
  • High galactose, high galactitol, high Gal1P
  • Cataracts, kidney failure, cerebral consequences, ovarian failure irrespective of diet, hepatomegaly, liver failure, sepsis, bulging fontanelle (pseudotumor cerebri), failure to thrive, leukodystrophy, developmental delay (verbal apraxia), motor difficulties

-NEVER DEVELOP AN AVERSION TO GALACTOSE-CONTAINING FOODS

38
Q

Clinical Manifestations of GALE

A
  • High galactose, high galactitol, high Gal1P
  • Normal galactose uridyl transferase activity
  • Cataracts, kidney failure, cerebral consequences, ovarian failure, psychomotor retardation
39
Q

Nutritional treatments for galactosemias

A
  • Lactose (glucose + galactose) restriction for life
  • Supplement with soy protein
  • Calcium supplements
  • Monitory Gal1P and urinary galactitol levels
40
Q

Polyols and cataract formation

A
  • Galactose accumulates in the lens
  • Converts to galactitol which cannot be degraded by the enzyme polyol dehydrogenase
  • Galactitol remains in the lens, favoring osmotic movement of water into the lens
  • Water retainment in the lens leads to formation of cataracts
41
Q

Golgi apparatus and sorting of lysosomal enzymes

A
  • Golgi apparatus processes and sorts proteins
  • Primary lysosomes bud from trans face of golgi complex - go on to undergo exocytosis and fuse with vesicles to digest contents
  • Lysosomal hydrolases covalently modified by mannose-6-phosphate groups on cis face of golgi complex
  • Mannose-binding transport vesicles segregate these modified compounds
  • Vesicles fuse with late endosomes
42
Q

Gaucher disease and glucocerebrosidase function

A

Gaucher - most common LSD, AR, chromosome 1

Glucocerebrosidase - normally converts glucocerebroside into its core components glucose and ceramide
-deficiency leads to buildup of glucocerebroside

Gaucher patients exhibit increased glucocerebroside and decreased cholesterol

43
Q

Type 1 Gaucher

A

Non-neuronopathic

  • panethnic, but common in AJ pop
  • Onset at any age
  • 10-30% of normal enzyme activity
  • Hepatosplenomegaly, bone disease, thrombocytopenia, anemia, growth retardation, bone pain/bone crisis, fatigue, abdominal pain
44
Q

Type 2 Gaucher

A

Acute Neuronopathic - most severe

  • panethnic
  • onset in infancy
  • lifespan 2-3 years
  • strabismus, retroflexion of neck, cortical thumbs, visceromegaly, failure to thrive, cachexia (wasting syndrome), early death
45
Q

Type 3 Gaucher

A

Chronic Neuronopathic

  • panethnic
  • onset in infancy/childhood
  • Less than 10% normal enzyme activity
  • Severe early onset, progressive developmental delay, oculomotor apraxia, anemia, thrombocytopenia, visceromegaly, bone disease, bone pain/bone crisis
46
Q

Non-specific Gaucher treatments

A
  • Iron and vitamin supplementation
  • Blood transufsions
  • Partial or total splenectomy
  • Pain management
  • Calcium supplementation
47
Q

Specific Gaucher treatments

A
  • ERT for type 1 - Cerezyme

- Bone marrow transplantation (risky, ethically debated)

48
Q

ERT for Gaucher

A
  • Targeted lysosomal enzyme delivery to site where enzyme is needed
  • 50% increase in platelets in patients with thrombocytopenia
  • 45% decrease in splenic volume in patients with intact spleens after 9 months
  • 15% of patients develop IgG antibodies against enzyme
  • only 1 patient reported that developed IgE against enzyme
49
Q

Fabry Genetics

A
  • X-linked LSD
  • Deficiency of alpha-galactosidase
  • Leads to accumulation of glycosphingolipids in body tissues
50
Q

Clinical Manifestations of Fabry

A
  • Renal failure, cardiomyopathy, GI problems, cerebrovascular problems, chronic pain (usually in extremities), Fabry crises (episodes of extreme pain), angiokeratomas (non-blanching lesions), hypohidrosis, heat or cold intolerance, exercise intolerance, corneal whorl, neurological complications (vertigo, tinnitus)
  • Presents in childhood but may be unrecognized into adulthood
  • Females can exhibit signs and symptoms to varying degrees
  • Males usually have <1% enzyme levels, females may exhibit anywhere from 0-100% enzyme levels
51
Q

ERT for Fabry

A
  • Fabrazyme
  • Provides exogenous source of alpha galactosidase
  • Significant reduction of GL-3 in kidney, heart, and skin (major glycosphingolipid that builds up due to Fabry)
  • GL-3 still present in vascular smooth cell muscles
  • Creatinine levels remained normal up to 30 months after starting treatment
  • Kidney function remained normal
52
Q

Function of Glycogen in Energy Storage

A
  • glucose is stored as glycogen for later use in energy uptake during fasting
  • glyocgen is rapidly depleted during fasting and rapidly replaced upon feeding
  • buffers glucose levels in the blood in liver
  • provides glucose for energy during exercise/survival reactions in muslce
53
Q

Regulation of glycogen synthase in fasting and feeding

A

Active form - dephosphorylated
Inactive form - phosporylated

Fasting - Glucagon or epinephrine increases cAMP production which activates protein kinase A to phosphorylate glycogen synthase - inactivates the enzyme to prevent glycogen from being made

Feeding - Insulin reduces cAMP, induces and activates protein phosphatase-1 which activates glycogen synthase by dephosphorylating it resulting in increased production of glycogen

54
Q

Key steps of glycogen degredation

A

Glycogen phosphorylase - hydrolyzes glucose unites from glycogen, producing glucose-1-phosphate in the process

Debranching enzyme complex - removes branch points to break down glycogen

55
Q

Regulation of glycogen phosphorylase during fasting and feeding

A

Fasting - glucagon or epinephrine increases cAMP which activates protein kinase A which phosphorylates and activates glycogen phosphorylase resulting in increased glycogenolysis

Feeding - insulin reduces cAMP and induces activation of protein phosphatase-1 which inactivates glycogen phosphorylase and decreases glycogenolysis

56
Q

Type-1a “von Gierke” Glycogen storage disease

A
  • Glucose-6-phosphatase deficiency (first step in glycogen breakdown)
  • Glycogen accumulates in cytoplasm
  • Glycogen and fat accumulate in liver and kidneys
  • Hepatomegaly, hypoglycemia, renomegaly, failure to thrive, growth retardation, lactic acidemia, hyperuricemia (increased production of and decreased renal clearance of uric acid), hyperlipidemia, neutropenia
  • Autosomal Recessive
  • 50% mortality
57
Q

Management and Treatment of Type 1 Glycogen Storage Disease

A
  • Glucose infusion
  • Cornstarch
  • Liver transplant
  • Prevent hypoglycemia - frequent carb-rich meals throughout day
  • Glycosade medical food
58
Q

Fatty acid transport and activation

A
  • Fatty acids are transported bound to albumin and are the primary source of energy during fasting via oxidation in the liver, cardiac muscle, and skeletal muscle
  • A series of acyl co-A synthetases activate fatty acids to form CoA thioesters
  • Carnitine cycle is required to transport long-chain fatty acids into the mitochondria for beta-oxidation
59
Q

Carnitine Cycle

A

-Consists of many carnitine transporter enzymes that convert acyl Co-As to acylcarnitines in order to cross the mitochondrial membrane

60
Q

Beta-Oxidation spiral

A
  • Acyl Co-A esters enter beta-oxidation spiral and with each “turn” of the spiral acyl-CoA ester chain is shortened by two carbons in a saturated fatty acid
  • Two carbon acetyl-CoA compounds are released as a result
61
Q

Carnitine defects

A
  • Coma
  • Seizures
  • Hepatomegaly
  • Hypoglycemia with fasting
62
Q

Key steps of beta-oxidation

A
  • Occurs in mitochondria
  • Each step mediated by enzymes specific to the link of the fatty-acid chain
  • Acyl-CoA dehydrogenase mediates the first step of oxidation
  • Enzymes insert double bonds into carbons, transfer electrons into ETF
  • Acyl-CoA dehydrogenase utilizes electron transfer flavoprotein (ETF) as final protein acceptor
63
Q

ETF dehydrogenase and multiple Acyl-CoA dehydrogenase (ACAD) deficiency

A
  • Deficiencies in ETF dehydrogenase result in secondary deficiencies of all primary dehydrogenase enzymes
  • Multiple ACAD deficiency can result in severity ranging from severe lethal neonatal disease to adult onset myopathy
64
Q

Ketone Body Metabolism

A
  • The liver can channel acetyl-CoA into ketone body formation
  • Ketogenesis is increased during fasting to provide an alternative source of oxidation to glucose and to prevent proteolysis
  • Ketone body metabolism catalyzed by three enzymes:
    • HMG-CoA synthetase
    • HMG-CoA lyase
    • D-3-hydroxybutyrate dehydrogenase
65
Q

Metabolic impairments in ACAD deficiency

A
  • Hypoglycemia
  • Less reducing equivalent to oxidative phosphorylation
  • No ketone bodies to extrahepatic tissues
  • Depletion of the tricarboxcylic acid cycle (Kreb’s cycle)
66
Q

Symptoms of ACAD deficiences

A
  • Hypoketotic hypolgycemia
  • Reye syndrome (rash, vomiting, liver damage)
  • Hypotonia and/or myopathy
  • Liver failure
  • Peripheral neuropathy
  • Failure to thrive
  • Coma
  • Sudden death
67
Q

Treatment of ACAD deficiences

A
  • Avoid fasting
  • Low fat diet (25-35% diet from fat)
  • MCT (medium chain triglycerides) oil for long chain defects
  • High caloric intake when ill or stressed to avoid fasting
  • Nighttime nasogastric feedings
  • Carnitine for transporter defects
68
Q

Triheptanoin as a treatment for long-chain fatty acid disorders

A
  • Triheptanoin is composed of three seven-carbon fatty acids
  • Able to provide a substrate for the TCA cycle
  • Can replace missing substrates in LCAD deficiencies
  • Reduced episodes of hypoglycemia, hospitalizations, and rhabdomyolysis
  • Improved cardiomyopathy
69
Q

Public Health Significance of congenital heart defects (CHD)

A
  • Most common birth defect (1% of all births)
  • Estimated 1 million adults in the US with CHD
  • Leading cause of birth-defect associated infant illness and death
  • 1.4 billion spent in one year on hospitalizations for individuals with CHD
  • Over 40,000 deaths contributed to CHD in 10 years
70
Q

Ventriculoseptal Defects (VSD)

A

-hole between two ventricles affects flow

71
Q

Atrial-septal defects (ASD)

A

-hole between two atria affects flow

72
Q

Patent-ductus arteriosus (PDA)

A

-ductus arteriosis fails to close, leaves an open connection between pulmonary artery and aortic arch

73
Q

Pulmonary-valve stenosis (PVS)

A
  • Narrowing of the pulmonary valve

- Leads to reduction in blood flow to lungs, thickening of ventricular septal walls

74
Q

Aortic stenosis (AS)

A

Narrowing of the aortic valve leading to reduction of blood flow to the body

75
Q

Coarctation

A

Narrowing of the aorta at the ductus arteriosis, left ventricular thickening as it must work harder to pump blood, decreased blood flow to the body

76
Q

Transposition of the great artery (TGA)

A

Arteries are transposed in abnormal arrangement
-two separate pathways result wherein oxygenated blood continuously pumps to the lungs while deoxygenated blood continuously pumps to the body

77
Q

Tetralogy of Fallot (TOF)

A

Involves four anatomical abnormalities of the heart

  • VSD
  • Obstruction to flow through pulmonary valve
  • Oxygen poor blood circulated through body
  • Blue babies
78
Q

Aneuploidy and microdeletion syndromes

A

All viable trisomies (13, 18, 21) have CHD associated
-ASD, VSD, PDA, TOF

Turner, Kleinfelter, DiGeorge and William Syndrome all have CHD

Syndromic CHD found in deletions
Isolated CHD (nonsyndromic) tends to be due to duplications
79
Q

Forward genetic screens to identify CHD genes

A
  • Completely phenotype driven
  • No genotype bias
  • Saturation level can provide a complex genetic landscape
  • Suggests multigenic cause of CHD
  • Interactome of CHD genes
80
Q

Mechanism by which ciliary dysfunction results in CHD

A

-Motile cilia required for flow

  • Primary cilia mediate signal transduction
  • Cilia regulated cell signaling pathways contribute to CHD

-SHARPEI mutants have immotile cilia and result in CHD phenotypes

81
Q

Neonatal hyperbilirubinemia

A

Most common medical condition in newborn period

  • occurs because RBCs have a shorter lifespan in neonates
  • there are more RBCs in neonates than in adults
  • there is diminished capacity to conjugate the bilirubin in neonates
  • there is increased enterohepatic circulation in neonates

Causes jaundice

Breastmilk feeding my enhance risk for neonatal hyperbilirubinemia

82
Q

Bilirubin Metabolism

A
  1. Heme from red blood cells is converted to CO and biliverdin by heme oxygenase
  2. Biliverdin is converted to unconjugated bilirubin by biliverdin reductase
  3. Bilirubin-albumin compound transported to the liver
  4. UGT1A1 conjugates toxic unconjugated bilirubin into non-toxic conjugated bilirubin
  5. Liver excretes conjugated bilirubin
  6. Entero-hepatic circulation
83
Q

Kernicterus

A

Hyperbilirubinemia may develop into kernicterus

  1. Movement disorder of the choreoathetoid cerebral palsy
  2. Central neural hearing loss
  3. Paresis of the vertical gaze
  4. Dental enamel hypoplasia
84
Q

G6PD (glucose-6-phosphate dehydrogenase) deficiency

A

Accounts for 22% of all kernicterus cases
-Regenerates NADPH which in turn reduces oxidized glutathione in RBC antioxidant defense system

X-linked

Four major variants

  • G6PD A and G6PD Mediterranean confer advantage to malaria
  • G6PD Canton and G6PD Kaiping found in Asian populations
85
Q

G6PD deficiency and hyperbilirubinemia

A

Two modes of hyperbilirubinemia:
-Acute, often severe hemolytic episodes triggered by oxidant stress and resultant hyperbilirubinemia

-Low-grade hemolysis coupled with genetic polymorphisms of UGT1A1 that limits hepatic bilirubin conjugation

86
Q

Immune-mediated hemolysis

A
  • Major ABO blood group - mother O, infant A or B
  • Rh blood group - mother Rh negative, infant positive
  • Minor blood groups
87
Q

Red cell membrane defects

A

Hereditary spherocytosis

Eliptocytosis

88
Q

UGT1A1 and Gilbert syndrome

A

Wildtype promoter region contains 6 TA repeats

Gilbert syndrome (G71R variant):

  • Number of repeats exceeds 6
  • Affinity of TATAA binding protein for promoter weakens
  • Decreased UGT1A1 activity
  • Hyperbilirubinemia in absence of liver disease and clinically overt hemolysis

Combination of Gilbert genotype with G6PD deficiency, other hemolytic issues (ABO bloodtype, hereditary spherocytosis) leads to dose-dependent interaction enhancing severity of neonatal hyperbilirubinemia

89
Q

Crigler-Najjar Syndrome Type I

A

Autosomal recessive

Familial non-hemolytic jaundice associated with hyperbilirubinemia and kernicterus

Premature truncation or frameshift of UGT1A1

90
Q

Crigler-Najjar Syndrome Type II

A

Autosomal recessive

Significant hyperbilirubinemia but low risk for kernicterus

UGT1A1 mutation resulting in markedly reduced enzyme activity

Almost all CN-2 patients carry one allele for Gilbert promoter

91
Q

Co-inheritance and compound heterozygotes in hyperbilirubinemia

A

Compound heterozygotes experience more severe phenotypes - 10-15% of enzyme activity (Gilbert and CN-1)

Co-inheritance of polymorphisms increases the severity of hyperbilirubinemia in neonates

Inherited Diseases (2 decks)

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