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Inherited diseases exam 2 > test > Flashcards

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1
Q

Clinical presentations of mitochondrial disease

A

skeletal muscles: fatigue, weakness, myopathy, neuropathy
Heart: conduction disorder, Wolff-Parkinson-White, cardiomyopathy
Eye: optic neuropathy, retinopathy, opthalamoplegia
Liver: hepatomegaly
Kidney: Fanconi’s syndrome, Glomerulopathy
Pancreas: diabetes
Blood: Pearson’s syndrome
Inner ear: sensorineural hearing loss
Colon: pseudo obstruction
Brain: seizures, myoclonus, ataxia, stroke, dementia, migraine

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2
Q

Compounds in Metabolic screenings in mito pts

A

Lactate, pyruvate, ammonia, serum amino acids, Urine organic acids, carnitine, acylcarnitine

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3
Q

Neurologic signs of mito

A

Stroke, basal-ganglia lesions, encephalopathy-hepatopathy, epilepsy, cognitive decline, ataxia, ocular signs, sensorineural hearing loss

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4
Q

Tissue biopsies in mito pts

A

Skin, muscle or liver: histopath, EM, mtDNA, RC/PDH, DNA copy number

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5
Q

The mtGenome composition

A

37 mtDNA genes encode 13 proteins (part of RC)
1500 nuclear encoded proteins in the mitoproteome (aka the mitoexome)
Mutations have been found in all 37 of the mtDNA and in >200 of the nDNA genes

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6
Q

RC reaction

A

mtDNA+nDNA= RC subunits-> OXPHOS and ATP

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7
Q

Mitochondrial respiratory chain

A 
5 complexes:
CI- 46 subunits, 7 mt and 39 n
CII- 4 subunits, all n coded
CIII- 11 subunits, 1 mt, 10 n
CIV- 13 subunits, 3 mt, 10 n
CV- 17 subunits, 2 mt, 15 n

produces ATP, roughly 30 molecules for each molecule of glucose

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8
Q

Heteroplasmy and homoplasmy

A

homoplasmy is when all of the mtDNA in an organism is the same, it can be wt or mutant DNA. Heteroplasmy is usually the case when there is a mutation; all mtDNA are NOT identical

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9
Q

coQ10 deficiency

A

6 major phenotypes:
1. encephalomyopathic form with seizures and ataxia
2. multisystem infantile with encephalopathy, cardiomyopathy and renal failure
3. predominantly cerebellar with ataxia and atrophy
4. leigh syndrome with growth retardation
5. isolated myopathy
6. steroid resistant nephrotic syndrome
treated with coQ10, causes dramatic rehabilitation

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10
Q

Fission defect

A

OPA1: AD optic atrophy

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11
Q

Fusion defect

A

MFN2 (mitofusion 2): AD axonal varient Charcot marie tooth type A2

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12
Q

Anabolic Vs Catabolic reactions

A 
Anabolic reactions (use energy) include: glucose + glucose-> glycogen for storage, Glucose + Fatty acid -> triglycerides, Amino acid + amino acid-> protein 
Catabolic reactions (release energy) include: Glycogen-> glucose, triglycerides-> glycerol + fatty acid, protein-> amino acid.
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13
Q

Metabolic functions of the liver

A
  • conversion of ammonia to urea
  • converts sugars for storage or energy (anabolic and catabolic reactions)
  • packages lipids for transport
  • produces bile and ketones
  • produces non-essential amino acids
  • produces plasma proteins
  • detoxification
  • stores vinamins and minerals
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14
Q

deamination

A

keto-acid - amino group (ammonia; toxic)
Synthesis of non-amino acids via transamination- transfer of one amino group from one amino acid to a keto acid, producing a non-essential amino acid and a new keto acid. formation of urea (NH3 + CO2)- soluble and easily excreted

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15
Q

Urea excretion

A

water is required for urea excretion: amino acids in the blood are broken down in the liver with ammonia and CO2 that create urea which is then removed back out to the bloodstream and excreted through the kidneys with water

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16
Q

Ammonia Buffer

A

In non hepatic tissues the linked reactions of glutamate dehydrogenase and glutamine synthetase remove 2 ammonia molecules from the tissue as a way of ridding them of nitrogen waste. the glutamine deposits the ammonia in the kidneys from excretion.

In the liver nitrogen waste from amino acids ends up in urea. AA’s are derived either from the breakdown of protein in various tissues or from what is synthesized in those tissues.

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17
Q

Urea cycle

A

draw this

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18
Q

Clinical presentation of urea cycle disorders

A

In infants: after 24-48 hours of life; progressive lethargy, hypothermia and apnea with very high plasma ammonium levels

Milder forms: can occur any time from infancy to adulthood; commonly occur in carrier females of the OTC mutation (x-linked) present with respiratory alkolosis, and episodic mental status changes which can progress to cerebral edema, brain stem compression or death

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19
Q

Ornithine transcarbamylase deficiency

A 
lethargy
coma
seizures
vomiting
poor feeding
hyperventilation
hepatomegaly

X-linked, can occur any time from infancy to adulthood; commonly occur in carrier females of the OTC mutation present with respiratory alkolosis, and episodic mental status changes which can progress to cerebral edema, brain stem compression or death

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20
Q

encephalopathy in urea cycle disorders

A

acute encephalopathy in late onset OTC is characterized by brain edema and swollen astrocytes the cause of which is attributed to intraglial accumulation of glutamine resulting in osmotic shifts of water into the cell

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21
Q

goal of treatment of urea cycle disorders

A

provide a diet sufficient in protein, arginine and energy to promote growth and development while preventing metabolic perturbations associated with the disease

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22
Q

how to treat urea cycle disorders

A
  1. diet
  2. measurement of plasma glutamine levels to monitor for hyperammonemia
  3. arginine supplementation
  4. sodium phenylbutyrate
  5. liver transplant
  6. Ammonul
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23
Q

Arginine supplemenation

A

for patients with AS and argininosuccincase deficiencies. promotes the synthesis of citrulline in the former and argininosuccinate in the latter (both serve as nitrogen waste products)

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24
Q

Sodium phenylbutyrate

A

actives the synthesis of phenylacetylglutamine in patients with CPS, OTC and AS. Provides a new vehicle for waste nitrogen excretion, suppressing residual urea synthesis in late onset pts. May support nitrogen homeostasis

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25
Q

Ammonul

A

ammonia scavengers: work by removing nitrogen carrier molecules from the blood and trapping nitrogen with their replacement

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26
Q

Liver transplant for urea cycle disorders

A

viable for patients with a severe phenotype, i.e. neonatal patients who are at high risk for brain damage if they have just one episode.

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27
Q

Functions of the lymphatic system

A
  • anatomic organization
  • lymph and cell trafficking in steady and dynamic states (fluid homeostasis)
  • Local tissue inflammation and edema
  • infections (bacterial, viral and parasitic)
  • cancer
  • nutrition
  • organ rejection
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28
Q

Lymphatic development

A

arterial-venous specification expresses high levels of VEGFR3 throughout differentiation which upregulates LYVE-1 to differentiate into lymph. This causes the induction of the transcription factor SOX18 which in turn induces Prox1 and neuropilin-2. These cells are then more sensitive to VEGF-C. The begin to express podoplanin activative the Syk tyrosine kinase in platelets. Platelets then aggregate causeing speration of the blood and lymphatic vascular systems. VEGF-C/VEGR-3 and Ccbe1 drive the growth of the lymphatic vessels and differentiation into cappilaries and vessels with the help of muscle cells to form intralumenal valves and junctions

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29
Q

Clinical manifestations of lymphedema

A

an abnormal accumulation of tissue fluid in the interstitial spaces.
abnormality in the structure or function of the lymphatic system.

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30
Q

Autosomal dominant lymphedema

A
  1. hereditary I
  2. Hereditary II
  3. Adult onset, and yellow nails
  4. Distichiasis (extra row of lashes)
  5. Intestinal (lymphangectasia)
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31
Q

Genes associated with AD lymphedema

A 
FOXC2- eyelashes (Distichiasis)
SOX18- Hypotrichosis-lymphedema-telangiectasia (abn hair)
GATA2
KIF11
FLT4
HGF
MET
GJC2- connexin gene mutation
PTPN14
CCBE1
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32
Q

Key steps of galactose metabolism

A

lactose=> Galactose => Galactitol

Lactose=> Galactose=> Gal-1-P=> UDPGal=>UDPG=> glycogen and glycolipids/glycoproteins

Disorders of glycogenolysis, CHO utilization, gluconeogenesis, ketogenesis

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33
Q

Key steps of galactosemia

A 
Galactokinase deficiency (GALK)- high galactose and galactitol (cataract only)
Galactose uridyl transferase deficiency (GALT)- high galactose, galactitol and GAL1P (cataract, liver and kidney failure cerebral and ovarian interaction)
uridine diphosphate galactose 4'-epimerase deficiency (GALE) Same as GALT, but includes psychomotor retardation
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34
Q

population specific mutations of galactosemia

A

Balkan founder effect in galactokinase: Gk1 P28T found in 1:2500 from the region and berlin
Q188R= caucasian
S135L= African americans
5kb del= AJ

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35
Q

neonatal galactokinase deficiency

A

triggered by lactose/galactose in diet

  • hyperbiliruninemia
  • liver dysfunction
  • cataracts (rare)
  • sepsis (in the first few days of life this is the most obvious symptom)
  • pseudotumor cerebri (bulging fontinel)
  • newborn screen
  • neurologic outcomes
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36
Q

late clinical manifestations of GAL

A
  • infantile liver disease
  • failure to thrive
  • cataracts
  • renal tubular acidosis
  • no aversion to galactose
  • DD
  • POF
  • Leukodystrophy
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37
Q

Nutritional treatments for galactosemias

A 
no milk or dairy
check for these additives in drugs or as fillers 
will never be totally galactose free
- non-dairy protein source
-calcium supplements
-multivitamins
-bone density studies?
-Follow Gal-1-P levels
-powdered soy formula for infants
38
Q

Polyols

A

polyols=>galactitol; polyols are osmotically active and can accumulate. Galactitol forms metabolic cataracts

39
Q

The Golgi apparatus

A

responsible for further processing and final sorting of proteins. Also forms the primary and secondary lysosomes (released from the trans face of the golgi) where they undergo exocytosis and fuse with vesicles to autolyse these marked vesicles

40
Q

Mechanisms of Gaucher Disease

A 
AR located on Chromosome 1 causes progressive, multisystemic, multiorgan dysfunction.
caused by a truncated enzyme that degrades glucocerebrosides (glucocerebrosidase) into glucose and ceramides. 
Labs show:
elevated glucosylceremide
ACE
TRAP
Ferritin
Gammaglobulins
Decreased cholesterol
HDL and LDL
clotting factors
vitamin B12
41
Q

Type 1 Gaucher disease

A

nonneuronopathic, chronic- 1:50000 for gen pop, 1:500 AJ.

  • hepatosplenomegaly
  • bone disease: where the marrow is replaced by lipid laden macrophages thus the blood interaction
  • thrombocytopenia
  • anemia
  • growth retardation
  • bruising/bleeding
  • fatigue
  • bone pain/crisis
  • abdominal pain
42
Q

Type 1 Gaucher disease

A

nonneuronopathic- 1:50000 for gen pop, 1:500 AJ.

  • hepatosplenomegaly
  • bone disease
  • thrombocytopenia
  • anemia
  • growth retardation
  • bruising/bleeding
  • fatigue
  • bone pain/crisis
  • abdominal pain
43
Q

Type 2 gaucher disease

A

Neuronopathic, acute 1:100000 onset in infancy with a life expectancy of 2-3 years

  • strabismus
  • retroflexion of the neck
  • cortical thumbs
  • visceromegaly
  • failure to thrive
  • cachexia
  • discoordination
44
Q

non-specific treatments for gaucher disease- all types

A
  • supplements (iron and b12)
  • transfusions
  • splenectomy
  • pain management for bone crisis
  • joint prosthesis
  • fracture management
  • calcium supplementation
45
Q

Specific treatments for Gaucher Disease type 1

A

ERT, SRT, Bone marrow transplant

46
Q

Specific treatments for Gaucher Disease type 1

A

ERT, SRT, Bone marrow transplant

47
Q

ERT mechanism

A

add enzyme to body to increase the amount of reaction catalyzed, some worry regarding immune reaction if the body does not make any enzyme at all or in ab+. Doesnt cross BBB.

48
Q

ERT outcomes

A

improves anemia and thrombocytopenia, reduces hepatosplenomegaly.

49
Q

SRT mechanism

A

supplements the substrate (glucose and ceremide) to eliminate the need for an enzyme

50
Q

Clinical manifestations of Fabry

A

Late

  • renal failure
  • cardiomyopathy
  • cerebrovascular events
  • neurological complications

Early

  • angiokeratomas (bathing suit area)
  • hypohydrosis or anhydrosis
  • heat or cold and exercise intolerance
  • corneal and lenticular opacities
  • mild proteinuria
  • GI issues
  • Psychological problems
51
Q

Clinical manifestations of Fabry

A

Late

  • renal failure
  • cardiomyopathy
  • cerebrovascular events
  • neurological complications

Early

  • angiokeratomas (bathing suit area)
  • hypohydrosis or anhydrosis
  • heat or cold and exercise intolerance
  • corneal and lenticular opacities
  • mild proteinuria
  • GI issues
  • Psychological problems
52
Q

ERT in Fabry

A

Fabrazyme; reduces GL-3 deposits in endothelial tissues, helps renal cell issues etc.

pts still need pain management, GI symptom management, stroke monitoring and emotional support

53
Q

The function of glycogen in energy storage

A

Glycogen in liver serves to buffer glucose levels in blood (Liver has g-6-p, secretes glucose for other tissues) and glycogen in muscle provides glucose for energy (fight or flight response)

54
Q

Regulation of glycogen synthase in fasting

A

Very little glycogen synthesis during fasting.

Glucagon or epinephrine:

  • Increase cAMP via G-protein linked receptors
  • Protein kinase A which phosphorylates and inactivates glycogen synthase
55
Q

Regulation of glycogen synthase in Feeding

A

Feeding results in glycogen synthesis.

Insulin:

  • reduces cAMP
  • induces and activates protein phosphatase 1
  • inactivates glycogen phosphorylase

(we never actually went over this slide in class…)

56
Q

Key steps of glycogen degredation

A 
Glycogen phosphorylase:
-hydrolyzes glucose from glycogen
-produces glucose 1-p
Removal of branchpoints
-debranching enzyme complex: 
1. Glucan transferase
2. Alpha-1,6-glucosidase
57
Q

Regulation of glycogen phosphorylase in fasting and feeding

A

Active protein kinase A activates glycogen phosphorylase in fasting and the reverse in feeding

58
Q

Von Gierke Disease type 1a: manifestations

A
  • severe autosomal recessive
  • deficient G-6-P activity in liver, kidney and intestines
  • glucose-6-phosphatase deficiency
  • Accumulation of glycogen in cytoplasm
  • affects liver (hepatomegaly)
  • hypoglycemia, renomegaly and failure to thrive
  • ~50% mortality
59
Q

Von Gierke Disease type 1a: Molecular mechanisms

A
  • Hypoglycemia results from inability to transform G6P into glucose
  • hyperlipidemia results from the inability to regenerate Glc…
  • hyperuricemia results from increased production and decreased renal clearance or uric acid as it competes with lactate from excretion
  • lactic acidemia results from inability to regenerate Glc and increased glycolysis
60
Q

Management and treatment of glycogen storage disease type 1

A 
prevent hypoglycemia through glucose in cornstarch and frequenct carb rich meals throughout the day, restrict intake of Fructose and Galactose
glucose infusion
cornstarch
total parenteral nutrition
liver transplant
allopurinol decreases hyperuricemia
61
Q

Public health significance of CHD

A
  • CHD is the leading cause of birth defect associated illness and death
  • btw 1999 and 2006 there were over 41,000 deaths related to CHD in the US
  • $1.4 billion spent on hospitalizations for individuals with CHD
62
Q

Ventricular septal defect/VSD

A

Hole in the wall separating the hearts lower chambers

63
Q

Atrial septal defect/ASD

A

Hole in the wall separating the hearts upper chambers

64
Q

Patent ductus arteriosus/PDA

A

closure not fully formed between aorta and pulmonary artery

65
Q

Pulmonary valve stenosis/PVS

A

Affects structure of valves - increases BP, thickness of the heart wall

66
Q

Aortic stenosis/AS

A

narrowing of aorta- affects blood flow and BP

67
Q

Coarctation

A

restricts blood flow to the rest of the body- life threatening with out surgery

68
Q

Transposition of the great artery

A

multiple structures affected aorta overrides, needs surgery

69
Q

Tetralogy of Fallot

A

Most common CHD 4 key features

  1. pulmonary stenosis
  2. VSD
  3. Right ventricular hypertrophy
  4. over riding aorta
70
Q

Genetic syndromes and CHD

A

trisomy 18, 13 and 21, Turner, Klinefelter, Digeorge (22q11.2) and Williams-Beuren (7q11.23)

71
Q

Forward genetic screen utility

A
  • phenotype driven
  • non-gene biased
  • saturation level screen can provide a comprehensive genetic landscape
  • bottleneck is causative mutation recovery
  • next-gen sequencing revolutionized the mutation recovery process
72
Q

ciliary dysfunction and CHD

A

DYX1C1 mutations affect cilia movement, cilia affect shh, wnt and mechanosensory signaling. CHD genes form a tight interactome network.

73
Q

Carnitine

A

ammonium compound biosynthesized from lysine and methionine

74
Q

Coenzyme A

A

synthesizes and oxidizes fatty acids

75
Q

fatty acid transport

A

plasma membrane transporters guide this action

76
Q

Acyl-coA synthetases

A

Activate fatty acid oxidation

77
Q

Key steps of Beta-oxidation pathway

A
  1. activation and membrane transport of fatty acids by binding to coenzyme A
  2. oxidation of beta carbon on the carbonyl group
  3. cleavage of 2 carbon segments resulting in acetyl-coA
  4. oxidation of acetyl coA to co2 in citric acid cycle
  5. electron transfer from electron carriers to the ETC in ox/phos
78
Q

ETH dehydrogenase deficiency

A

results in secondary deficiencies of all of the primary dehydrogenases

79
Q

ACAD

A

Share electron transfer favopotein as an electron acceptor

80
Q

Ketone body metabolism

A

Where ketone bodies are metabolized in the TCA cycle rather than glucose***

81
Q

Metabolic impairments in ACAD deficiency

A

intoxication (result of buildup) instead of A=>B, A=>C

  • fatty acids
  • acylcarnitines
  • ammonia, lactate, uric acid

Deficiency A does not make B or any other product

  • hypoglycemia
  • less reducing equivalent to oxphos
  • no ketone bodies to extrahepatic tissue
  • TCA cycle depletion
82
Q

symtoms of ACAD

A
  • hypoketotic hypoglycemia
  • Reye syndrome
  • hypotonia of myopathy
  • recurrent /fulminant liver failure
  • peripheral neuropathy
  • coma
  • sudden unexplained death
  • failure to thrive
83
Q

Treatment of ACAD

A
  • avoid fasting
  • Low fat diet (25-35% calories from fat)
  • MCT oil for long chain defects
  • high caloric intake with illness and stress
  • nighttime NG feeding
  • carnitine only for transporter defect
84
Q

Triheptanoin

A

Odd carbon fatty acids, that can produce 5-carbon ketone bodies these can easily cross the BBB

85
Q

bilirubin metabolism

A

RBC-> heme (heme-oxygenase)-> biliverdin and CO (biiverdin ozygenase)-> bilirubin

86
Q

Jaudice

A

Most common clinical condition in newborns, often transient; for a few the bilirubin levels can raise such that it poses a hazard

87
Q

Kernicterus

A

Rare but devastating chronic neurologic condition
tetrad:
1. movement disorder with choreoathoid cerebral palsy
2. CN hearing loss
3. paresis of vertical gaze
4. dental enamal hypoplasia

88
Q

genetic risk factors for neonatal hemolysis

A

Red cell enzyme deficiencies: G6PD, PK
membrane defects: herediatry spherocytosis, eliptocytosis
Immune mediated hemolysis (O mom and A or B fetus, sparks immune rxn)

89
Q

G6PD

A

X-linked, UGT1A1 gene
2 mutations:
Gilbert: TATA repeats 7 times rather than 6 (decreases TATAA binding protein ability)
coding sequence variant G71R (dose sensitive)

90
Q

Criglar-Najjar syndrome

A

2 types:

  1. AR, severe jaundice with hyperbilirubinemia and kernicterus (no activity in UGT1A1)
  2. AR, hyperbilirbinemia, no/low kernicterus (residual UGT1A1)
91
Q

Compound heterozygosity in hyperbilirubinemia

A

One allele: (TA7)- normal code
other allele: (TA6)- missense coding mutation

case study resulted in CN II, but had kernicterus

Overall increases the risk of hyperbilirubinemia in neonates.

Inherited diseases exam 2 (1 decks)

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