Biochemistry Flashcards
(186 cards)
1
Q
Drugs that inhibit dihydrofolate reductase
A
Methotrexate
Trimethoprim
Pyrimethamine
2
Q
Which drug inhibit thymidine synthase
A
5-fluorouracil (5-FU)
3
Q
Drug that inhibit dihydroorotate dehydrogenase
A
Leflunomide
4
Q
Which drug inhibits ribonucleotide reductase
A
Hydroxyurea
5
Q
Which drug inhibits de novo purine synthesis
A
6-mercaptopurine (6-MP) and azathioprine (prodrug)
6
Q
Which drugs inhibit inosine monophosphate dehydrogenase
A
Mycophenolate and ribavirin
7
Q
Pathology of adenosine deaminase deficiency
A
ADA degrades adenosine and deoxyadenosine
Deficiency —> increased dATP —> toxicity to lymphocytes
Major cause of AR SCID (severe combined immunodeficiency)
8
Q
Pathology of Lesch-Nyhan syndrome
A
Deficiency of HGPRT - hypoxanthine guanine phosphoribosyl transferase —> excess purine production and uric acid
X-linked recessive
9
Q
Signs and symptoms of Lesch-Nyhan syndrome
A
HGPRT
- Hyperuricemia
- Gout
- Pissed off (aggression, self-mutilation)
- Retardation
- DysTonia
10
Q
Treatment of Lesch-Nyhan syndrome
A
Allopurinol
Febuxostat (2nd line)
11
Q
Drugs that inhibit xanthine oxidase
A
Allopurinol
Febuxostat
12
Q
Drug that increase uric acid excretion
A
Probenecid
13
Q
Features of the genetic code
A
- Unambiguous
- Redundant/degenerate (except for methionine - AUG - and tryptophan - UGG)
- Commaless/non-overlapping
- Universal
14
Q
Function of DNA topoisomerases
A
Create single/double-stranded break in helix to add or remove supercoils
15
Q
Drugs that inhibit topoisomerases
A
Eukaryotic: Topoisomerase 1 - Irinotecan/topotecan Topoisomerase 2 - Etoposide/Teniposide Prokaryotic: Topoisomerase 2 (DNA gyrase) and IV - fluoroquinolone
16
Q
Function of the DNA polymerases
A
DNA polymerase III - adds DNA bases to leading and lagging strands
DNA polymerase I - Degrades RNA primer and replaces it with DNA
Both are prokaryotic
17
Q
Types of mutations in DNA and eg of diseases
A
Silent - codes same DNA
Missense - nucleotide substitution (sickle cell disease)
Nonsense - codes stop codon
Frameshift - deletion/insertion of nucleotide not divisible by 3 (Duchenne muscular dystrophy, Tay-Sachs Disease)
Splice site - eg retained intron
18
Q
3 types of single-stranded DNA repair (and associated diseases)
A
1- nucleotide excision repair:
endonuclease release oligonucleotides with damaged bases. DNA polymerase and ligase fill and seal gap. G1 cycle. Xeroderma pigmentosa
2- Base excision repair:
GEL PLease - glycosylase, endonuclease, lyase, polymerase B, ligase
Throughout cell cycle. Spontaneous/toxic deamination
3- Mismatch repair:
Newly synthesized strands. G2 phase. Lynch syndrome (HNPCC)
19
Q
Double-stranded DNA repair and associated pathologies
A
Non-homologous end joining
Ataxia telangiectasia, breast/ovarian CA (BRCA1), Fanconi anaemia
20
Q
Start and stop codons (mRNA)
A
Start: AUG or rarely GUG (AUG inAUGurates protein synth) Stop: UGA (U Go Away) UAA (U Are Away) UAG (U Are Gone)
21
Q
Types of eukaryotic RNAs
- which polymerase makes what
- what substance inhibits it
A
rRNA - RNA polymerase I mRNA - RNA polymerase II - alpha-amanitin (from death cap mushrooms), cx severe hepatotoxicity tRNA - RNA polymerase III - Actinomycin D (pro and eukaryotes)
22
Q
Drug that inhibit prokaryotic RNA
A
Rifampicin
23
Q
Antibodies (and diseases) associated with snRNPs
A
snRNP = small nuclear ribonucleoprotein
- Anti-Smith to spliceosomal snRNP: SLE
- Anti-U1 RNP: MCTD (mixed connective tissue disease)
24
Q
3 types of cells (based on cell cycle) with eg
A
Permanent - neurons, skeletal and cardiac muscles, RBCs
Stable (quiescent) - hepatocytes and lymphocytes
Labile - bone marrow, hair follicles, gut epithelium, skin, germ cells
25
I-cell disease: pathophysiology
Inclusion cell disease/mucolipidosis type II
Inherited lysosomal storage ds - defect in N-acetylglucosaminyl-1-phosphotransferase —> failure of golgi to phosphorylate mannose residues on glycoproteins —> proteins secreted rather than delivered to lysosomes
26
I-cell disease: signs and symptoms
Coarse facial features
Clouded corneas
Restricted joint movements
High plasma level of lysosomal enzymes
27
Vesicular trafficking proteins
COPI - retrograde, golgi-golgi, cis-golgi to ER
COPII - anterograde, ER to cis-Golgi
Clathrin: trans-golgi to lysosomes, plasma membrane to endosomes
28
Function of peroxisomes
Catabolism of fatty acids (B-oxidation), amino acids, ethanol
29
Pathophysiology of peroxisomal disorders
Deficit in synthesis of plasmalogens (NB phospholipid in myelin)
Cx neurological diseases: Zellweger syndrome and Refsum disease
30
Features of peroxisomal diseases
Zellweger syndrome:
- hypotonia, seizures, hepatomegaly, early death
Refsum disease:
- scaly skin, cataracts/night blindness, ataxia, shortening of 4th toe, epiphyseal dysplasia
31
Types of intermediate filaments
```
Vimentin
Desmin
Cytokeratin
GFAP
Neurofilament
```
32
What does vimentin stain and identify?
Mesenchymal tissue
- Mesenchymal tumours (eg sarcomas)
- Endometrial CA
- RCC
33
What does desmin stain and identifies?
Muscles - muscle tumours eg rhabdomyosarcoma
34
What does cytokeratin stain and identifies?
Epithelial cells
| Epithelial tumours eg squamous cell CA
35
What does GFAP stain and identifies?
Glial fibrillary acid proteins - neuroglia (eg astrocytes, Schwann cells, oligodendrocytes)
Astrocytoma, glioblastoma
36
Describe Kartagener syndrome
```
Primary ciliary dyskinesia - due to defect of dynein arm
Cx:
-male and female infertility
-increased risk of ectopics
-bronchiectasis
-recurrent sinusitis and chronic ear infections
-conductive hearing loss
-situs inversus
```
37
MOA of cardiac glycosides
Eg digoxin and digitoxin (also ouabain - arrow poison)
Inhibits Na/K ATPase - indirect inhibition of Na/Ca exchanger —> increased intracell [Ca] —> increased cardiac contractility
38
Types of collagens (and assoc diseases)
Be (So Totally) Cool, Read Books
Type I - Bone, Skin, Tendons, late wound repair.. Osteogenesis Imperfecta Type 1
Type II - Cartilage
Type III - Reticular.. vascular type of Ehlers-Danlos (ThreE D)
Type IV - Basement membrane.. Alport and Goodpasture syndrome
39
Steps of collagen synthesis
1- synthesis: translation of preprocollagen (Gly-X-Y)
2- hydroxylation: of specific proline and lysine residues, requires Vit C
3- glycosylation: forms procollagen triple helix by hydrogen and disulfide bonds
4- exocytosis
5- Proteolytic processing: cleaves disulfide rich terminal regions —> tropocollagen
6- Cross-linking: covalent lysine-hydroxylysine cross-linking by lysyl oxidase
40
Which step of collagen synthesis does scurvy affect?
2- hydroxylation
| Due to Vit C deficiency
41
Which step of collagen synthesis does osteogenesis imperfecta affect?
3- glycosylation
| Can’t form triple helix
42
Which step of collagen synthesis does Ehlers-Danlos affect
5- Proteolytic processing
| 6- Cross-linking
43
Which step of collagen synthesis does Menkes disease affect?
| Describe Menkes
6- Cross-linking
X-linked recessive ds
Mutation in ATP7A gene —> decreased Cu absorption and transport protein —> lack of Cu for lysyl oxidase
44
Signs and symptoms of Menkes disease
Brittle, kinky hair
Growth retardation
Hypotonia
FTT
45
Genetics and manifestations of osteogenesis imperfecta
```
Variety of gene defects, commonly COL1A1 and COL1A2
Most common = autosomal dominant
Patients can’t “BITE”
Bones - multiple #
I (eyes) - blue sclera
Teeth - dentinogenesis imperfecta
Ear - hearing loss (abn ossicles)
```
46
Features of Ehlers-Danlos syndrome
```
Hyperextensible skin
Hyper mobile joints and dislocations
Bleeding tendencies
Berry and aortic aneurysms
Organ rupture
```
47
3 types of Ehlers Danlos syndrome
Hypermobility type - joint instability, most common type
Classical type - Type V collagen (COL5A1/2), joint and skin sx
Vascular type - Type III collagen, vascular and organ rupture
48
Genetics of Marfan’s syndrome
AD connective tissue ds —> affects skeleton, heart and eyes
| FBN1 gene mutation on chromo 15 —> decreased fibrillin (glycoprotein that forms sheath around elastin)
49
Features of Marfan’s
Skeleton:
- Tall with long extremities, pectus carinatum/excavatum, hypermobile joints, long tapering fingers and toes (arachnodactyly)
Heart:
- cystic medial necrosis of aorta, aortic incompetence, dissecting aortic aneurysms, floppy mitral valve
Eyes:
- Subluxation of lenses
50
Function of FISH
```
Fluorescent in situ hybridization
Localization of genes and direct visualization of chromosomal anomalies
- Microdeletion
- Translocation
- Duplication
```
51
Define mosaicism and outline the 2 types
Presence of 2 distinct cell lines in same individual
Somatic - mutation after fertilization
Gonadal - mutation in egg or sperm cells
52
Describe Mccune-Albright syndrome
- genetics
- s&s
Somatic mosaicism - spontaneous mutation of GNAS (G-protein signalling).
Dx need 2 of:
- unilateral cafe au lait spots with ragged edges
- polyostotic fibrous dysplasia
- endocrinopathy: precocious puberty, testicular abn, hyperthyroid, GH excess, Cushing’s
53
Locus heterogeneity and eg of disease
Mutation at different loci can produce similar phenotype
| Eg albinism
54
Loss of heterozygosity and eg of diseases
mutation in a tumour suppressor gene, complementary allele must be developed before CA develops.
Eg retinoblastoma, HNPCC, Li-Fraumeni
55
Define allelic heterogeneity and eg of disease
Different mutations at same locus produce same phenotype
| Eg B-thalassemia
56
Define heteroplasmy
Presence of both mutated and normal mitochondrial DNA regulating in variable expression of mt-inherited disease
57
Define uniparental disomy
Offspring inherits 2 pairs of chromosomes from 1 parent and none from other
Heteroisomy - meiosis I error
IsoIsomy - meiosis II error
58
Define genetic imprinting and eg 2 diseases
At same loci, only 1 allele is active (other is imprinted/inactivated by methylation)
- Prader-Willi
- Angelman syndrome
59
Describe Prader-Willi syndrome
Chromo 15
P = paternal. Maternal imprinting with paternal gene deleted/mutated.
Hyperphagia, obesity, ID, hypogonadism, hypotonia
25% due to maternal uniparental disomy (2 pairs of imprinted maternal genes received)
60
Describe Angelman syndrome
Chromo 15
AngelMan = maternal. Paternal imprinting, maternal gene deleted/mutated
Severe ID, seizures, ataxia, inappropriate laughter “happy puppet”
5% due to paternal uniparental disomy
61
Examples of X-linked dominant diseases
Hypophosphataemic rickets
Fragile X syndrome
Alport syndrome
62
Genetics of cystic fibrosis
AR
| Defect in CFTR gene on Chromo 7 - deletion of Phe508
63
Pathophysiology of cystic fibrosis
Defect in the chloride channel that secretes Cl in lungs and GI and reabsorb Cl in sweat glands
Mutation —> misfolded protein —> retained in RER
Decreased Cl (and H2O) secretion + compensatory Na resorption
Contraction alkalosis and hypoK
Abn thick mucus
64
Diagnosis of cystic fibrosis
Sweat test: [Cl] in sweat > 60mEq/L
| Increased immunoreactive trypsinogen (newborn screening)
65
Manifestations of cystic fibrosis
Resp:
- recurrent pulm infections (S aureus in infancy, Pseudomonas in adolescence), chronic bronchitis and bronchiectasis (reticulonodular on CXR), opacification of sinuses
GIT:
- pancreatic insuff, malabsorption with steatorrhoea, ADEK deficiency, biliary cirrhosis, liver ds, meconium ileus in newborns
Other: infertility in men, subfertility in women. Nasal polyps, clubbing
66
Treatment of cystic fibrosis
Chest physio, B-agonists, aerosolized dornase alpha (DNAse), hypertonic saline
Azithromycin (anti-inflamm)
Ibuprofen (slows ds progression)
Pancreatic enzymes
67
Examples of AD diseases
Achondroplasia, AD polycystic kidney disease, FAP, familial hypercholesterolemia, hereditary spherocytosis, hereditary haemorrhagic telangiectasia, Huntington disease, Li-Fraumeni, Marfan, MEN, neurofibromatosis I & II, tuberous sclerosis, von Hippel-Lindau
68
Eg of AR diseases
Albinism, ARPKD, cystic fibrosis, glycogen storage ds, haemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except Hunter), phenyketonuria, sickle cell, sphingolipidoses (except Fabry), thalassemias, Wilson disease
69
List the X-linked recessive disorders
Oblivious Females Will Often Give Her Boys Her x-Linked Disorders:
- Ornithine transcarbamylase deficiency
- Fabry disease
- Wiskott-Aldrich syndrome
- Ocular albinism
- G6PD deficiency
- Hemophilia A & B
- Bruton agammaglobulinemia
- Hunter syndrome
- Lesch-Nyhan
- Duchenne (and Becker) dystrophy
70
Define lyonization
In X-linked recessive ds:
| Female carriers invariably affected depending on pattern of inactivation of X-chromosome carrying mutant vs normal gene
71
Duchenne muscular dystrophy
- genetics
- lab findings and dx
- features and major cx of death
-X-linked recessive, frameshift or nonsense
Deleted dystrophin (DMD) gene - largest protein-coding gene. Anchors crib to transmembrane alpha/beta-dystroglycan.
- increased CK and aldolase. Dx = genetic testing
- Gower sign, calf pseudohypertrophy , waddling. Weakness begins in pelvic girdle and progress superiority.
Dilated cardiomyopathy cx death
72
Becker muscular dystrophy
| - genetics
X-linked, non-frameshift deletions in DMD —> functional gene therefore less severe than Duchenne
73
Myotonic type 1 muscular dystrophy
- genetics
- features
AD
CTG trinucleotide repeats in DMPK gene —> abn expression of myotonin protein kinase
CTG - Cataracts, Toupee, Gonadal atrophy + myotonia, arrhythmia
74
Fragile X sydrome - genetics
```
X-linked dominant
Trinucleotide repeats (CGG) in FMR1 gene —> hypermethylation —> decreased expression
Most common cx of inherited ID and autism. 2nd most common genetic cx of ID (after Down’s)
```
75
Fragile X syndrome - features
Trinucleotide repeats CGG: Chin (protrude), Giant Gonads
- Long face with large jaw
- Large exerted ears
- Mitral valve prolapse
- Post-pubertal macro-orchidism
- Autism
76
List the trinucleotide repeat diseases
```
“Try Hunting for My Fragile Free-range eggs”
Huntington (CAG) - Caudate has low ACh and GABA
Myotonic dystrophy (CTG) - cataracts, toupee, gonadal atrophy
Fragile X (CGG) - chin, Giant Gonads
Friedreich Ataxia (GAA) - ataxic GAAit
```
77
Genetics of Down syndrome T21
Incidence = 1:700
95% due to meiotic non-disjunction (1:1500 in <20yo women, 1:25 if >45yo)
4% due to unbalanced Robertsonian translocation (typically between 14 and 21)
1% due to mosaicism (post-fertilization mitotic error)
78
Pre-natal findings for T21
- 1st Trimester
- 2nd Trim
1st Trimester:
- US: nuchal lucency, hypoplastic nasal bone
- Serum: decreased PAPP-A, increased free B-hCG
2nd Trimester quad screen:
- low a-fetoprotein, high B-HCG, low estriol, high inhibit A
79
Clinical features of T21 - dysmorphic features
```
Upslanting palpebral fissures
Epicanthic folds
Brushfield spots
Bradycephaly, flat facial profile/nasal bridge
Low-set/dysplastic ears
Small chin, protruding tongue
Short neck
Single palmar crease, sandal gap
```
80
Systemic clinical features of T21
- Brain: ID, psych (Autism, disruptive behavioural ds), Alzheimers
- Heart: AVSD, ASD/PDA, VSD, TOF
- GIT: duodenal atresia, annular pancreas, Hirschsprung
- Growth: short stature, obesity
- Eyes: refractive errors, strabismus, nystagmus
- Hearing: loss, otitis media
- Endocrine: Thyroid ds, DM
- Haem: Leukemias
- Pulm: OSA and asthma
- Skin: palmoplanar hyperkeratosis, seborrhoeic dermatitis
81
Serum features of the T21, T18 and neural tube defect
a-FP B-hCG estriol inhibin A
T21 low high low high
T18 low low low low
NTD high -- -- --
82
Features of Edwards syndrome
```
Trisomy 18
1:8000
PRINCE Edward:
- Prominent occiput, Rocker-bottom feet, ID, Non-disjunction, Clenched-fist (with overlapping fingers), low-set Ears, micrognathia, CHD
Death by 1yo
```
83
Features of Patau syndrome
```
Trisomy 13
1:15000
1st Trim: low free B-hCG and low PAPP-A
Severe ID, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydachtyly, cutis aplasia, CHD.
Death by 1yo
```
84
Describe Robertsonian translocations
- definition
- common chromosomes involved
Long arms of 2 acrocentric chromosomes fuse at centromere and the 2 short arms are lost
13, 14, 15, 21, 22
Balanced - usually no abn phenotype
Unbalanced - miscarriage, stillbirth or chromo imbalance
85
Genetics of Cri-du-chat syndrome
Congenital microdeletion of short arm of chromo 5 (46, XX or XY, 5p-)
86
Clinical features of Cri-du-chat
Microcephaly, epicanthic folds, moderate-severe ID, high-pitched crying/meowing, CHDs (VSD)
87
Williams syndrome - genetics and features
Congenital microdeletion of long arm of chromo 7 (region includes elastin gene)
Elfin facies, ID, well-developed verbal skills, extreme friendliness to strangers, hypercalcemia (increased sensitivity to Vit D), CVS prob (aortic stenosis)
88
Describe 22q11 deletion syndromes
Microdeletion at 22q11 --> aberrant development of 3rd and 4th branchial pouches. AD
CATCH-22
- Cleft palate
- Abn facies
- Thymic aplasia --> T-cell deficiency
- Cardiac defects
- Hypocalcemia (secondary to parathyroid aplasia)
89
2 types of 22q11 deletion syndromes
DiGeorge - thymic, parathyroid and cardiac defects
| Velocardiofacial - palate, facial and cardiac defects
90
Common cardiac defects in 22q11 deletion
Interrupted aortic arch, truncus arteriosus, TOF
91
Functions of vitamin A
```
Antioxidant
Constituent of retinal pigments
Normal differentiation of epithelial into specialised tissues (eg pancreatic, goblet cells)
Prevents squamous metaplasia
Treats:
- measles
- acute promyelocytic leukemia (all-trans retinoic acid)
- cystic acne (oral isotretinoin)
```
92
Signs and sx of Vit A deficiency
```
Night blindness (nyctalopia)
Xerosis cutis
Keratomalacia
Bitot spots
Immunosuppression
```
93
Signs of acute Vit A toxicity
Nausea and vomiting
Vertigo
Blurred vision
94
Signs of chronic Vit A toxicity
```
Alopecia
Dry skin (scaliness)
Hepatic toxicity and enlargment
Arthralgias
Pseudotumour cerebri
Teratogenic
```
95
Thiamine NB for which enzymatic reactions
Forms thiamine pyrophosphate (TPP), cofactor in:
Think ATP:
- alpha-ketoglutarate dehydrogenase
- Transketolase
- Pyruvate dehydrogenase
also: Branched chain ketoacid dehydrogenase
96
Diseases of thiamine deficiency
Wernicke-Korsakoff
| Beri-beri
97
Describe Wernicke-Korsakoff syndrome
- signs and sx
- pathology
- Prevention
- Dx
- confusion, ophthalmoplegia, ataxia (classic triad), confabulation, personality changes, retrograde and anterograde amnesia
- damage to medial dorsal nucleus of thalamus
- prevent by giving thiamine before dextrose in alcoholic/malnourished px
- increased RBC transketolase activity after giving B1
98
Features of beri-beri
Dry beri-beri: polyneuritis, symmetrical muscle wasting
| Wet beri-beri: high-output cardiac failure (dilated CMO), edema
99
Functions of Vit B2
Riboflavin
Component of FAD and FMN (redox reactions)
B2 = 2ATP.
100
Signs of Vit B2 deficiency
"2 C's of B2"
Cheilosis
Corneal vascularization
101
Functions of Vit B3
Niacin - from tryptophan
Constituent of NAD+ and NADP+ (B3 = 3ATP)
Treats dyslipidaemia - lowers VLDL and increases HDL
102
Signs and sx of Vit B3 deficiency
```
Glossitis
Pellagra (3D's)
- Diarrhoea
- Dementia (also hallucinations)
- Dermatitis (C3/4 dermatome - broad collar rash/casal necklace", hyperpigmentation of sun-exposed limbs
```
103
Causes of pellagra
Hartnup disease
Malignant carcinoid syndrome (increased tryptophan metabolism)
Isoniazid (decreased B6)
104
Pathophysiology of Hartnup disease
AR
Deficiency of neutral amino acid (eg tryptophan) transporters in proximal tubule cells and enterocytes --> neutral aminoaciduria and decreased absorption from gut --> decreased tryptophan for conversion to niacin
105
Treatment of Hartnup disease
High protein diet and nicotinic acid
106
Signs of niacin excess
- Facial flushing (cx by prostaglandins, avoided by taking aspirin with niacin)
- Hyperglycemia
- Hyperuricemia
107
Function of Vit B5
Pantothenic acid
B5 = "pento"thenic
Component of CoA and fatty acid synthase
108
Features of Vit B5 deficiency
Dermatitis, enteritis, alopecia, adrenal insufficiency
109
Function of Vit B6
Pyridoxine
Converted to pyridoxal phosphate (PLP), cofactor in:
- transamination (eg AST/ALT)
- decarboxylation
- glycogen phosphorylase
Synthesis of:
- cystathionine, heme, niacin, histamine, neurotransmitters
110
Signs and sx of pyridoxine deficiency
Convulsions, hyperirritability, peripheral neuropathy, sideroblastic anaemias
111
Function of Vit B7
Biotin: Co-factor for carboxylation enzymes
- Pyruvate carboxylase (pyruvate --> oxaloacetate)
- Acetyl-CoA carboxylase (acetyl-CoA --> malonyl CoA)
- Propionyl-CoA carboxylase (propionyl-CoA --> methylmalonyl-CoA)
112
Signs of Vit B7 deficiency and causes
Dermatitis, alopecia, enteritis
Cx by Ab use or excessive egg white ingestion
"Avidin in egg whites avidly binds biotin"
113
Functions of Vit B9
Folate: converted to THF NB for 1-C transfer/methylation
| NB for synthesis of nitrogenous bases
114
Folate deficiency results in:
Megaloblastic anaemia
Hypersegmented PMN cells
Glossitis
Neural tube defects
115
Drugs that cx folate deficiency
Phenytoin, sulfonamides, methotrexate
116
Functions of B12
Co-factor for methionine synthase and methymalonyl-CoA mutase
117
Causes of B12 deficiency
- Insufficient intake
- Malabsorption
- Lack of intrinsic factor
- Absence of terminal ileum
118
Functions of Vit C
- Antioxidant
- Hydroxylation of proline and lysine to preprocollagen
- Facilitates Fe absorption (by converting to Fe2+)
- Necessary for conversion of dopamine to NE (dopaine B-hydroxylase)
119
Ancillary treatment of methemoglobinemia
Vit C - converts Fe3+ to Fe2+
120
Signs of Vit C deficiency
```
Scurvy (think poor collagen + bleeding):
- swollen gums
- bruising, petechiae
- hemarthrosis, subperiosteal haem
- corkscrew hair
Also: weakened immune response
```
121
Sx and signs of Vit C excess
N&V, diarrhoea, fatigue
Calcium oxalate nephrolithiasis
Increased risk of iron toxicity in the predisposed
122
Pathologies in Vit D deficiency
Rickets, osteomalacia, hypocalcaemic tetany
123
Signs of Vit D excess
Hypercalcemia
Hypercalciuria
Loss of appetite
Stupor
124
Vit E deficiency can cx:
```
Haemolytic anaemia
Acanthocytosis
Neuro signs similar to B12 deficit:
- muscle weakness
- posterior column and spinocerebellar tract demyelination
```
125
Name of Vit E
tocopherol/tocotrienol
126
Functions of Vit K
Activated by epoxide reductase to reduced form, co-factor for y-carboxylation of glutamic acid residues on clotting factors: II, VII, IX, X
127
Difference between folate and B12 deficiency in lab findings
Both increased homocysteine
Normal methylmalonic acid in folate deficit
Increased for B12 deficit
128
Clotting times seen in Vit K deficiency
Eg neonatal haemorrhage
- Increased PT and aPTT
- Normal bleeding time
129
Sx and Sn of Zinc deficiency
```
Delayed wound healing
Hypogonadism
Decreased adult hair
Dysgeusia
Anosmia
Acrodermatitis enteropathica
```
130
Antidote for methanol/ethylene glycol
Fomepizole - inhibits alcohol dehydrogenase
131
5 co-factors that make up pyruvate dehydrogenase complex
"The Lovely Co-enzymes For Nerds"
- Thiamine pyrophosphate (B1)
- Lipoic acid
- CoA (B5)
- FAD (B2)
- NAD+ (B3)
132
Factors that activate pyruvate dehydrogenase
Increased:
- NAD+/NADH ratio
- ADP
- Ca2+
133
Which component of pyruvate dehydrogenase does arsenic inhibit? Clinical findings of arsenic poisoning:
Inhibits lipoic acid
| - Vomiting, rice-water stools, garlic breath, QT prolongation
134
Pyruvate dehydrogenase deficiency:
- Findings
- Treatment
Think: pyruvate has to go somewhere =
- lactic acid(osis)
- alanine (increased in serum starting in infancy)
- neurologic defects (low energy)
Rx: Increased ketogenic nutrients (high fat or lysine and leucine) "the onLy pureLy ketogenic aa's"
135
Electron transport inhibitors in OP:
Causes decreased H+ gradient and blocks ATP synthesis:
Complex I: RotenONE
Complex III: An-3-mycin (antimycin) A
Complex IV: CO and cyanide
136
What inhibits ATP synthase?
Oligomycin
| Cx increased H+ gradient and no ATP synthesis
137
Name 2 uncoupling agents in OP
2,4-dinitrophenol (DNP) - illicit weight loss drug
| aspirin overdose
138
4 key (irreversible) enzymes in gluconeogenesis
"Pathway Produces Fresh Glucose"
- Pyruvate carboxylase
- Phosphoenolpyruvate carboxylase
- Fructose-6-phosphatase
- Glucose-6-phosphatase
139
Pathophysiology of G6PD deficiency
Glucose-6-phosphate provides source of NADPH - reduces glutathione (antioxidant) --> detoxifies radicals and peroxides
Deficiency --> decreased NADPH in RBCs --> haemolytic anaemia (precipitated by infection)
X-linked recessive, most common human enzyme deficiency. Increased malarial resistance
140
What's seen on blood smear in G6PD deficiency
- Heinz bodies - denatured Hemoglobin precipitates in RBCs
- Bite cells - phagocytic removal of Heinz bodies
"Bite into some Heinz ketchup"
141
Outline Essential Fructosuria
AR
Defect in fructokinase
Benign, asymptomatic. not trapped in cells. Increased fructose in blood/urine
142
Pathophysiology of Fructose Intolerance
AR
Defect in aldolase B
Fructose-1-phosphate accumulates in cells --> reduced phosphate --> inhibits gluconeogen and glycogenolysis
143
Fructose intolerance:
- sx and sn
- Dx
- Rx
```
Sx present after consuming fructose (honey, juice, fruit):
- hypoglycemia
- jaundice
- cirrhosis
- vomiting
Dx: reducing sugars in urine
Rx: avoid fructose and sucrose
```
144
Outline galactokinase deficiency
AR
Galactosemia and galactosuria
Infantile cataracts
145
Classic galactosemia
- enzyme deficient
- genetics
- signs and sx
- galactose-1-phosphate uridyltransferase
- AR
- galactitol accumulates in cells (eg lens of eyes):
- FTT, jaundice, hepatomegaly, infantile cataracts, ID, predispose to E.coli sepsis
146
Mnemonic for enzymes in fructose and galactose intolerance
FAB GUT
| Fructose is to Aldolase B as Galactose is to UridylTransferase
147
Cells/tissues that only has aldose reductase (and not sorbitol dehydrogenase)
```
NB because sorbitol dehyd converts sorbitol to fructose (used as energy) but sorbitol trapped in cells cx osmotic damage (seen in DM):
- Lens (primarily aldose reductase)
- Retina
- Kidneys
- Schwann cells
"LuRKS"
```
148
Tests for lactose intolerance
```
Stool = decreased pH
Breath = increased hydrogen content (lactose hydrogen breath test)
```
149
Essential amino acids
```
Glucogenic:
"I MEt HIS VALentine, she is so sweet"
- Methionine
- Histidine
- Valine
Glucogenic/ketogenic:
- Isoleucine
- phenyalanine
- threonine
- tryptophan
Ketogenic
- leucine
- lysine
```
150
Acidic amino acids
Aspartic acid
| Glutamic acid
151
Basic amino acids
"HIS Lys (lies) ARe basic"
- Histidine
- Lysine
- Arginine
152
Treatment given for hypoammonemia
- lactulose: acidifies GIT and traps NH4+ for excretion
- antibiotics (eg rifaximin): decrease colonic ammoniagenic bacteria
- benzoate, phenyacetate and phenylbutyrate - reacts with glycine/glutamine --> renal excretion
153
What does a picture of decreased BUN, increased orotic acid (blood and urine) and hypoammonemia suggest? Describe the condition
Ornithine transcarbamylase deficiency
- X-linked recessive
- Excessive carbamoyl phosphate converted to orotic acid
154
Describe phenylketonuria
- genetics
- pathophysiology
AR, 1:10000
Defect in phenylalanine hydroxylase or tetrahydrobiopterin (BH4) cofactor --> increased phenylalanine --> increased phenyl ketones in urine
155
What are the phenyl ketones
phenylacetate
phenyllactate
phenylbutyrate
156
Signs and sx of phenyketonuria
```
ID (think dopamine comes from phenylalanine)
Growth retardation
Seizures
Fair skin
Eczema
musty skin odor
```
157
Pathophysiology of Maple syrup urine disease
AR
Decreased branched-chain alpha-ketoacid dehydrogenase --> blocked degradation of branched chain aa's (isoleucine, leucine, valine) --> severe ID, CNS defects, death
"I Love Vermont maple syrup from maple trees (B1ranches)"
158
Presentation and Rx of maple syrup urine ds
Vomiting, poor feeding, urine smells like maple syrup
| Rx: restrict branched chain aa's and thiamine supplementation
159
What to think about when px has blue sclera
Osteogenesis imperfecta
| alkaptonuria
160
Describe alkaptonuria
- enzyme deficit
- genetics
- findings
- homogentisate oxidase (degrades tyrosine to fumarate)
- -> pigment forming homogentisic acid accumulates in tissue
- AR
- bluish-black CT, ear cartilage and sclera (ochronosis); urine turns black in prolonged exposure to air, debilitating arthralgias
161
3 types of homocysteinuria and their Rx
- cystathionine synthase deficiency: decrease methionine, increase cysteine, B6, B12 and folate in diet
- decreased affinity of cystathionine synthase for pyridoxal phosphate: high B6 intake, increase cysteine
- methionine synthase deficiency: increase methionine in diet
162
Findings in homocysteinuria
HOMOCYstinuria:
- Homocysteinura
- Osteoporosis
- Marfanoid features
- Ocular changes (lens displace inward and downward)
- CVS: MI and strokes
- kYphosis
- ID
163
A positive urinary cyanide-nitroprusside test indicates:
Cystinuria
164
Describe cystinuria
-AR (1:7000)
- Inability of PCT to reabsorb COLA: cystine, ornithine, lysine, and arginine
- precipitation of hexagonal cystine stones
Rx by urinary alkalinization (K citrate), chelating agents (penicillamine), good hydration
165
4 NB types of glycogen storage diseases and their deficit enzymes
"Very Poor Carbohydrate Metabolism"
- Von-Gierke disease (type I) - glucose-6-phosphatase
- Pompe disease (typeII) - lysosomal acid a-1,4-glucosidase
- Cori disease (type III) - a-1,6-glucosidase
- McArdle (type V) - myophosphorylase
166
Which glycogen storage disease affects mainly the heart
"PomPe trashes the PumP (1,4)"
| - cardiomegaly, HCOM, hypotonia, exercise intolerance
167
Difference between Von Gierke and Cori disease
Different enzymes
| Gluconeogenesis intact in Cori
168
Which glycogen storage disease mainly affects muscles
McArdle = muscle
| muscle cramps, myoglobinuria, arrhythmias
169
Difference between Tay-Sachs and Niemann-Pick disease
- HeXosaminidase A (TAy-SaX) vs sphingomyelinase "No man picks his nose with his sphinger"
- No hepatosplenomeg in Tay-Sachs; foam cells in NP
- Both have progressive neurodegen, cherry-red spot in macula
170
Triad of Fabry disease
- Episodic peripheral neuropathy, angiokeratomas, hypohidrosis
- Late: progressive renal failure, CVS disease
171
Which lysosomal storage disease affects oligodendrocytes
Krabbe disease
Cx periph neuropathy, developmental delay, optic atrophy
Globoid cells
172
List of sphingolipidoses
- Tay-Sachs
- Fabry
- Metachromatic leukodystrophy
- Krabbe disease
- Gaucher
- Niemann-Pick
173
Findings of hepatosplenomeg, pancytopenia, osteoporosis, avascular necrosis of femur, developmental delay, optic atrophy suggests:
Gaucher disease
| Deficient glucocerebrosidase
174
2 types of mucopolysaccharidoses
Hurler syndrome - a-L-iduronidase
| Hunter syndrome - iduronate sulfatase
175
Findings in Hurler syndrome
Previously called gargoylism, developmental delay, airway obstruct, hepatosplenomeg, corneal clouding
176
Findings in Hunter syndrome
"Hunter sees clearly (no corneal clouding) and aggressively aim (aggressive behaviour) for the X (X-linked recessive)."
177
Increased incidence of what lysosomal storage diseases in Ashkenazi Jews?
- Tay-Sachs, Niemann-Pick, some Gaucher
178
Hypoketotic hypoglycemia can be caused by:
- Systemic primary carnitine deficiency
| - Medium-chain acyl-CoA dehydrogenase deficiency
179
Pathophysiology of abetalipoproteinemia
- AR
| - Deficient ApoB48 and ApoB100 - no chylomicrons, LDL or VLDL
180
Findings in and Rx of abetalipoproteinemia
Early: severe fat malabsorption, steatorrhoea, FTT
Later: retinitis pigmentosa, spinocerebellar degen (Vit E deficiency), progressive ataxia, acanthocytosis
Rx: restrict intake of long-chain FAs, high dose oral Vit E
181
4 types of familial dyslipidaemias
- Type I - familial hyperchylomicronemia: AR, deficit LPL or apoCII --> high chylomicrons --> pancreatitis, HSM, eruptive xanthomas
- Type II - familial hypercholesterolemia: AD, deficit LDL receptors --> increased LDL and cholesterol --> accelerated atherosclerosis, tendon xanthomas, corneal arcus
- Type III - dysbetalipoproteinemia: AR, deficit ApoE --> increased chylomicrons and VLDL --> premature atherosclerosis, xanthomas
- Type IV - hypertriglyceridemia: AD, hepatic overproduction of VLDL --> increased VLDL and TG --> acute pancreatitis
182
NB amino acids needed for synth of:
- nitric oxide
- urea
- heme
- creatinine
- arginine
- arginine and aspartate
- glycine and succinyl-CoA
- glycine + arginine + SAM
183
Glutamate is NB for synthesis of:
GABA and glutathione
184
NB amino acids for synth of:
- purines
- pyrimidines
- histamine
- glutamine, aspartate, glycine
- glutamnine, aspartate
- histidine
185
Tyrosine is precursor of:
```
Dopamine
Norepinephrine
Epinephrine
Thyroxine
Melanin
```
186
Tryptophan is precursor of:
Serotonin
Melatonin
Niacin
