CU Biochem Course and NAMA Flashcards
(318 cards)
1
Q
What is the difference between classic PKU, mild PKU< and hyperpheylalaninemia?
A
Untreated Phe levels:
>1200umol/L - classic PKU
600-1200umol/L - mild PKU
<600umol/L - hyperphe
2
Q
Mousy odored urine, light hair, eczema, developmental delay, white matter hyperintensities
A
Untreated PKU
- treatment needs to start within 1 month of life
- “pseudoleukodystrophy”
3
Q
What is pegvaliase
A
Enzyme substitution for PAH deficiency (PKU)
- plant enzyme (phe ammonia lyase)
- Goal to enhance Phe tolerance and normalize diet
- still need tyrosine
- Approved for 16+
4
Q
Elements of PKU diet
A
Low Phe
Supplement tyrosine and tryptophan (share same large neural AA transporter as Phe)
5
Q
What is a goal of sapropterin trial in PKU?
A
20mg/kg/day
Infant: 24 hour trial -> >30% reduction in Phe = positive (no dietary changes)
Adult: 48hr to 30 day trial
6
Q
Mutatons in which subunit of BCKDH can be thiamine (B1) responsive?
A
E2 subunit
7
Q
What is the role of IV destroxe (glucose) in metabolic decompensation?
A
- Prevent gluconeogenesis that drives protein breakdown
- Provide calories
- Drives insulin production (anabolic)
8
Q
Tyrosine aminotransferase deficiency
A
Tyrosinemia type 2
PAA: high Tyr, Phe
UOA: 4-OH phenylpyruvate/lactate/acetate
- corneal lesions, hyperkeratosis
9
Q
UOA: 4-OH phenylpyruvate, 4OH phentyllactate, 4OHphentylacetate
A
Tyrosinemia type II
Tyrosine aminotransfearse deficiency
TAT gene
PAA: high Tyr, Phe
10
Q
4-hydroxyphentylpyruvic dioxygenase deficiency
A
Tyrosinemia type III
HPD gene
- PAA: high Tyr, Phe
- Uncertain clinical significance, may have keratitis
11
Q
Renal fanconi, liver/renal disease, porphyric crisis, hepatocellular carcinoma
A
Tyrosinemia type I
Fumarylacetoacetate hydrolase deficiency
FAH
- High AFP, SUAC, Met (liver disease)
12
Q
high AFP, methionine, aaminolaevulinic acid (ALA)
A
Tyrosinemia type I
FAH
13
Q
What are the 3 presentations for tyrosinemia type I?
A
- Hepato: early severe liver disease
- Renal: rickets (renal fanconi)
- Acute intermittent: porphyria like attacks
14
Q
What are the toxic compounds in tyrosinemia type I?
A
FAH deficiency
- Fumarylacetoacetate, Maleylacetoacetate, Succinylacetone
15
Q
Which steps in porphyrin synthesis does SUAC inhibit?
A
ALAD and HMBS
16
Q
What is 2-nitro-4-trifluoromethylbenzoyl - 1,3- cyclohexane-dione used to treat?
A
Tyrosinemia type I
2-nitro-4-trifluoromethylbenzoyl - 1,3- cyclohexane-dione
NTBC = nitsinone
- inhibits 4-OHphentylpyrvic acid dioxygenase
- Goal: blood level >40 (enzyme inhibition 99%); SUAC suppression
- restrict Phe/Tyr to goal <600 umol/L in blood
17
Q
corneal crystals, plantarpalmar hyperkeratosis with pits
A
Type II or III tyrosinemia
TAT (tyrosine aminotransferase), HPD (hydroxyphenylpyruvate dioxygenase)
- May also have ID/seizures if untreated
18
Q
If NBS shows high Tyr and normal SUAC, what should you do next?
A
Repeat at 6 weeks -> if normal this is transient tyrosinemia of newborn
-> if abnormal work up tyrosinemia type II and III
19
Q
What vitamin will 50% of Cystathione beta syntase deficiency respond to?
A
B6 - pyridoxine
20
Q
What is treatment of homocystinuria is B6 unreponsive?
A
Folate (B9)
B12 if deficient
Low protein (met)
Betaine (alternate remethylation pathway)
21
Q
Which UCD has fair fragility (Trichorrhexis nodosa) + rash?
A
ASL deficiency
- also increased liver disease
22
Q
Which UCD enzymes are in the mitochondria?
A
N-acetylglutamate synthetase
Carbamoyl phsophate synthetase
Carbonic anhydrase 5A (CAVA) - Makes bicarb necessary for carboxylases (including CPS)
Ornithine transcarbamylase
23
Q
Why does citrulline bruild up in citrin deficiency?
A
Aspartate is stuck and mitochondria and unable to conjugate with citrulline in cytoplasm (ASS) to form arginosuccinate.
24
Q
Why is Lys high in OTC deficiency?
A
Shortage of 2-oxoglutarate
25
Gold standard testing for OTC in females
Liver enzyme funciton testing
- Molecular testing cannot find mutation in 10%
- Orotic acid/glutamine may be normal
26
Why does Carbonic anhydrase 5-A deficiency cause hyperammonemia?
CAVA synthesizes bicarb in mitochondria used by CPSI -\> Proximal UCD
27
What is phenylbutyrate?
Prodrug to phentylacetate -\> conjugates to glutamine
28
Which UCD presents with spastic diplegia and intellectual disability?
Arginase deficiency
+ growth arrest
- check PAA when working up DD!
29
What are the cofactors for glycine cleavage system?
Lipoate and pyridoxal-Phosphate
- Deficiency can cause variant NKH
30
high CSF/serum glycine, high homocysteine, high MMA
HCFC1 - Cobalamin X
- XL
- Transcription factor for glycine cleavage system and Cbl pathway
31
What drugs should be avoided in NKH?
Valproic acid and vigabatrin -\> inhibit residual enzyme activity
(both can cause iatrogenic glycine elevation)
32
98% of NKH are caused by variants in what 2 genes?
GLDC and AMT
P and T protein
33
What is treatment for NKH?
**Benzoate** (conjugates with glycine to form hippurate) -\> goal plasma glycine 120-300uM
**Glycine restriction**
**Ketogenic diet** (glycine is gluconeogenic substrate)
NMDA blockade: **Dextromethorphan, ketamine**
34
What is serine synthesized from?
3-phosphoglycerate (glycolysis intermediate)
3PG Dehydrogenase -\> Phosphserine aminotransferase -\> phosphosering phosphatase
35
CSF: low glycine, low serine
Serine synthesis defect
PGDH, PSAT, PSPH
- Severe hypomyelination and epilepsy
36
What is the treatment for neu laxova syndrome?
Serine supplementation + glycine supplementation
37
What is the vulnerable window in GA1
**3 months - 2 years**
- Up to 6yo can be affected
38
High Glutaric acid, 3-OH glutaric acid
GA1
GCDH deficiency
39
What is C5DC?
Glutaryl carnitine
- look for **GA1**
40
What is treatment for GA1?
1) avoid catabolism
2) **low lysine**/trytophan
3) Carnitine
41
What does 2-aminoadipic semialdehyde dehydrogenase deficiency cause?
Pyridoxine dependent epilepsy
ALD7A1 - antiquitin
42
High aminoadipid acid semialdehyde, pipecolic acid, 6-oxo-pipecolate
pyridoxine dependent epilepsy
ALD7A1
43
What is the second most common B6 responsive epilepsy? (after ALDH7A1)
Pyridoxine 5 phosphate oxidase deficiency
PNPO
- Converts pyridoxine to active form
- Normal cognitive development (not true in ALDH7A1)
44
What is the treatment for alpha-aminoadipic semialdehyde DH deficiency or pyridoxamine-5-phosphate oxidase deficiency?
Pyrixodine depedent epilepies (ALDH7A1 and PNPO)
- Will **always respond to pyridoxal phosphate (active form)**
- **might repsond to pyridoxine**
45
Which pathways are mostly affected in riboflavin deficiency?
ETFDH (GA2)
FAOD
BCAA metabolism
Complex I
46
Axonal neuropathy, **hearing loss, bulbar weakness,** myopathy
Riboflavin transporter defects
RFVT2 and RFVT3
Brown-Vialetto- Van Laere
- Tx: Riboflavin
47
Low 5-methyltetrahydrofolate in CSF
Folate transporter deficiency (FOLR1) or Kearns-Sayre
- Ataxia, epilepsy, demyelination
48
megaloblastic anemia, diabetes, SNHL in infancy
Thiamin-responsive megaloblastic anemia
SLC19A2
49
3 thiamine reponsive encephalopathies
TPK1
SLC19A3
SLC25A19 (also severe congenital microcephaly)
50
What does G6Pase translocase deficiency cause?
GSD1b
- GSD1 + neurtropenia
GSD1a is caused by G6Pase (most common GSD)
51
Are glucagon levels low or high in GSD1?
Elevated
Glucagon drives gluconeogenesis and glycogenolysis, both are defective in G6Pase deficiency
- Insulin is low until fed
52
Doll like face, buttock fat pad accumulation, hepatomegaly, nephromegaly, hypotonia, bleeding tendency
GSD1
- No nephro/hepatomegaly in CDG-PMM2
53
Compare Von Gierke and Cori disease
GSD1 (G6Pase) vs GSD3 (amylo-1,6-glucosidase)
- GSD3 has milder hypoglycemia (gluconeogenesis intact), but more early liver dysfunction
- Give high protein diet for GSD3 (glucogeogenesis)
54
What is the mechanism of injury in Anderson disease?
GSD4 - a-1,4-glucan-6-glucosyltransferase deficiency (branching)
- Unbanched glycogen (**polyglucosan**) build -\> toxic -\> hepatosplenomegaly
- other GSDs have branched glycogen buildly
55
Liver pathology findings for Andersen's disease
GSD4 - branching enzyme
- Unbranched glycogen (**polyglusocan**) accumulation
- path: **PAS stain positive**, diastase-resistant with amylopectin-like inclusions
56
Which GSDs have postprandial **hyper**glycemia?
GSD0 - unable to store BG as glycogen
57
What can patients with fanconi Bickel syndrome get that GSD1 patients canno?
Fructose
- Fanconi bickel = glucose/galactose transporter defect
- in GSD1 fructose cannot be used because it is convered into G6P
58
Treatment for tauri disease?
**Avoid sugars/glucose - no NOT give D10 when sick**
- Glucose is high but not sensed by mitochondrial/cannot be used for glycolysis.
- FAO inhibited by high glucose levels
59
In which GSDs should you avoid giving excess glucose?
GSD4 (Andersen) and GSD9 (Tauri)
- Andersen -\> more glucose -\> more polyglucosan; give proteins to promote gluconeogensis instead
- Tauri -\> Glycolysis is blocks, reduce glucose to release inhibition on FAO
60
microcephaly, thin upper lip, long philtrum, wide nasal bridge, DD, leigh syndrome
Pyruvate dehydrogenase deficiency
Most common **X linked**
- Fetal alcohol syndrome-like face + leigh syndrome
- high pyruvate -\> high lactate + alanine
- Lacate/pyruvate ratio low
61
Treatment for PDH deficiency
Ketogenic diet, thiamine, carnitine, lipoic acid
62
Name the 3 glyconeogenic enzymes
Pyruvate Carboxylase, Fructose 1,6 bis phosphatase, Glucose-6-phosphatase
63
Cystic brain lesions, FTT, metabolic acidosis
PAA: High **Cit, Ala, Lys, Pro**
UOA: 2-oxoglutaric acid (aKG)
High lacate/pyruvate with **increased ratio \>20**
**high acetoacetate/betahydroxy-butyrate ratio**
High ammonia
Pyruvate Carboxylase deficiency
- Biotin Dependent
- TCA cycle and gluconeogenesis affected
High lacate -\> high ala, proline (proline oxidase suppressed)
Low OAA (precursor) -\> low aspartate and glutamate
Low aspartate -\> high citrulline and ammonia
64
Compare F1,6BP deficiency with HFI
- F1,6BP can tolerate more fructose
- F1,6BP presents more like GSD1 - F1,6BP buildup inhibits G6Pase
- FBP: **Pseudohypertriglyceridemia, high glycerol, glycerol 3 phosphate**
65
What is the pathophys of HFI?
Aldolase B deficiency
Toxic accumulation of F1P -\> impaired gluconeogensis and glycogenolysis -\> lactic acidosis, hypolgycemia, liver failure
66
Promoter deletion + N314D/Q188R
Biochemical (Duarte) Galactosemia
GALT (~25% activity)
67
UOA: high glycerol-3-phosphate, glycerol
high TG
high alanine, ketones
Fructose 1,6 BP
Glycerol-3-phosphate is not seen in glycerolkinase
68
Contrast HFI and FBPase deficiency
HFI: childrne have no cavities (Aversion to sweets), FTT with fructose ingestion, RTA
FBPase: can tolerate fructose, no renal involvement, UOA with glycerol/**glycerol-3-phosphate**
69
Q188R
K285N
L195P
classic galactosemia
GALT (\<1% activity)
- early e.coli sepsis, FTT, liver disease
+ Premature ovarian insufficiency and DD
70
S125L
Variant galactosemia
GALT (1-10% activity)
Same early presentation (e-coli sepsis, FTT, liver disease etc)
- **Normal development/reproduction**
71
Urine polyol analysis: high ribitol, D-arabitol, erythritol, sedoheptulose
Transaldolase
TALDO
Liver, HSM, anemia, thrombocytopenia, congenial anomalies
72
Urine polyol: high ribitol, D-arabitol
Ribose-5-P Isomerase
RPIA
- Leuckoencephalopathy, ataxia, neuropathy
73
What are the steps of ß-Oxidation?
1) Dehydrogenase (create 2,3 double bond)
2) hydratase (add 3-OH)
3) dehydroganse (create 3 double bonded O)
4) thiolase (remove ketone)
74
Treatment for FAODs
- low fat diet
- avoid catabolism
- triheptanoin (Long chain and above) - can freely diffuse into mitochondrial and bypass carnitine shuttle/long chain breakdown
- Carnitine (allows urine clearance of FA)
75
What is OCTN2 deficiency?
Primary carnitine deficiency (Carnitine transporter)
(SLC22A5)
- carnitine cannot be reabsorbed in kidney -\> unavailable in liver/muscle/heart
- **Presents with hepatic encephalopathy, cardiac, hypoglycemia, rhabdo**
76
What should be done if a baby is NBS positiove for low carnitine but has normal plasma F/T carnitine testing?
Screen for mother with primary carnitine deficiency
- Carnitine comes from breastmilk for young infants
- Mothers w/ carnitine deficiency will have NBS positive child and are **at risk for sudden death**
77
UOA: Hexanoylglycine
MCAD
ACADM
ACP: high C6, C8, C10:1
78
Why are dicarboxylic acids elevated in urine in FAOD?
Long chain FAs build up in cytoplasm go into microsomes -\> gets converted into dicarboxylic acids
79
What is the next step if NBS is positive with elevated C14:1 but plasc ACP is normal?
VLCAD gene sequencing (ACP may be normal between episodes)
80
FAOD + neuropathy, RP, and maternal preeclampia/HELLP/fatty liver
LCHAD/TFP
- hydroxylated FAs can flow into mom and accumulate
- TFP also modified cardiolipin (may explain extra symptoms)
81
if NBS is high for C16OH and ACP/UOA are normal, what is the next step?
Sequencing for LCHAD/TFP - cannot rule out wth ACP alone
82
UOA: High ethylmalonic acid, n-butrylglycine, and methylsuccinic acid
- SCAD
- Isobutyryl glycinuria (+ high isobutyrylgylcine)
- **Ethylmaloni encephalopathy (+ persistent lactic acidosis) - ETHE**
83
What is the final electron acceptor of dehydrogenases?
ETFDH
- Causes GA2 -\> mulitiple DH issues -\> multiple chain length elevations of ACP
- Riboflavin is cofactor
84
What are the main ketogenic AAs?
Leucine, isoleucine, lysine
85
Hypoketotic hypoglycemia, dicarboxylic aciduria, **4-hydroxy-6-methyl-2-pyrone**
- **normal ACP**
3-Hydroxy-3-emethly-glutaryl-CoA synthase deficiency (HMG-coa Synthase)
86
UOA: 3-hydroxy-3-methylglutaric acid, 3-methylglutaric acid
- hyperammonia, hypoketotic hypoglycemia
2-Hydroxy-3-methlyglutayl-CoA Lyase deficiency (HMG-coa Lyase)
- **high HMG and MG** (3-hydroxy-3-methylglutaric acid, 3-methylglutaric acid)
- C6DC (3 methylglutaryl-carnitine), **C5OH** (3-OH-isovaleryl carnitine)
87
high D-3-hyroxybutyrate, tiglylglycine, 2-methyl-3-hydroxybutryrate, 2-methylacetoacetate
beta-ketothiolase (T2)
- ACAT1
- High ketones during illness **+ isoleucine intermediates**
88
High ketones with normal dicarboxylic acids
Disorders of ketolysis
- physiological ketosis comes from FAO -\> thus dicarboxylic acids (adipid, suberic, and sebacic) also build up
- HIgh ketones with normal dicarboxylic acids -\> usually SCOT deficiency
89
High ketones during fed and fasting state
Succinyl-Coa - oxoacid-Coa transferase (SCOT)
SCOT/OXCT1 gene
- Do not see elevated dicarboxylic acids (adipic, suberic, sebacic) which are seen in physiological ketosis
DDx: Monocaroboxylic transporter 1 (MCT1) deficinecy -\> ketone transporter
90
What is Monocarboxylic Transporter 1 (MCT1) deficiency?
Ketone transporder defect
SLC16A1
- looks similar to SCOT -\> episodic ketoacidosis
- Increased acetoacetate + 3 OH butyric acid, normal dicarboxylic acids
91
Renal fanconi, renal failure, cornea crystals, hypothyroidism, hypogonadism, myopathy
Cystinosis
Lysosomal Cystine transporter
- Tx Cysteamine eyedrops + Tablets
- Cysteine (Cystine + Cysteamine) has own transporter; another cysteine can be added and use Lysine transporder
92
GLA N215S
Cardiac Variant Fabry
93
GLA A143T
VUS Fabry
- Most common on NBS
94
Alkylglycerone 3-phosphate acyltransfearse deficiency
GNPAT - RCDP
95
Alkylglycerone 3-phosphate synthase deficiency
AGPS
- RCDP
96
Most common cause of RCDP
PEX7
- Low plasmalogen, also high phytanic acid
97
Fatty Alcholol Reductase deficiency
RCDP without RCDP
98
PEX5L deficiency
RCDP
- mutation in specific long isoform of PEX5 - mutations in exon 9
- Results in abnormal PEX7 activity
99
**Metaphyseal flaring,** epiphyseal stippling, **coronal vertebral clefts, mineralization of intervertebral disks**
RCDP
- ARSE - XL -Male
- Sterol-8-isomerase - XL - Females (male lethal)
- Wafarin/VitK, EtOH, Phenytoin
100
high oxalate, glyoxalate
Primary hyperoxaluria type I
AGT
Alanine-glyoxylate aminotransferase - peroxisomal enzymes
- Renal stones + nephrocalcinosis
- Tx: Pyrixosone, Hydration, Liver/Kidney transplant
101
Neuropathy, loss of night vision, deafness, conduction defects, short metacarpals/metatarsals
Adult refsum disease
- Phytanol-CoA hydroxylase deficiency
- High phytanic (found in animal fats and plants), low pristanic acid
102
Which amino acides do glycosylation occur on?
N-linked - Asparagine
O-linked - Serine or threonine
103
Which organelles does glycosylation occur in?
Early - cytosol and ER (Type I isoelectric focusing pattern)
Late - Golgi (Type II pattern)
104
What methods to defect CDG is more sensitive and specific than isoelectric focusing?
Mass Spec
- Can see both N and O linked CDGs
- Can use flow-intection electrospray ionization to digest N-glycan off protein and get more specific results
105
What does phosphomannomutase do?
PMM2 -\> converst mannose 6P to mannose 1P
Causes CDG
106
Which CDG causes protein losing enteropathy and hyperinsulinism with no neurological diasease
MPI - CDG1b
- treat w/ mannose
107
Which CDG is associated with elevated alk phos?
GPI anchor disorders
PIGA, PIGN, PIGO
- Seizures and DD
108
m.8993 T\>G
Leigh syndrome - ATP6
109
m.3243 A\>G
MELAS
rRNA leu
- Diabetes + hearing loss most common
- Complex I, III, IV deficiency
- Treat w/ Arg/Cit/Tauring
110
m.8344A\>G
MERRF
tRNA Lys
+ lipomas
111
m.1555G\>A
Hearing loss when exposed to aminoglycosides
(Mitocondria are derived from bacteria symbiotes!)
112
Homoplasmic m.11778 G\>A (MT-ND4)
LHON
- Males \> females
- incomplete penetrance
113
names 2 mtDNA deletion syndromes
Kearns-Sayre = CPEO + conduction block, RP, diabetes, renal, ID, hearing loss
Pearson Syndrome = KSS + sideroblastic anemia and exocrine pancreas dysfunction
114
SDH deficiency
AD paraganglioma + pheo
AR Leigh syndrome
115
Leigh syndrome + hypertrichosis/hirsutism
SURF1
- nuclear gene involved in complex IV assembly
- most common leigh gene
116
X-linked leigh syndrome
Pyruvate dehydrogenase deficiency
Tx - thiamine and ketogenic diet
- Males = mild mutations (severe mutations lethal)-\> leigh syndrome, normal brain structure
- Females = het for severe mutations -\> structural abnormalities, normal lactate (X inactivation)
117
POLG related disease
Alpers syndrome
- Multisystemic with many neurologicalm manifestations
- Polymerase Gamma
- VPA use can precipitate liver failure
- mtDNA depletion + Complesed I/III/IV deficiency
118
Steroid resistant nephrotic syndrome
CoQ10 synthesis defect
- ADCK4, PDSS2, COQ2, COQ6
119
Non-compaction cardiomyopathy, neutropenia, myopathy + high 3-methylglutaconic acid
Barth syndrome
TAZ (X Linked)
120
What does CblJ and CblF deficiency cause?
Combined HCy and MMA
- Cbl transport out of lysosome into cytosol where CblC is
- **Serum B12 levels low - but NOT B12 deficiency**
121
What does Methylmalonyl CoA Epimerase deficiency cause?
MMA and PA
- Slight elevation in MMA (only D-Methylmalonyl=CoA high) and proximal buildup of PA + 2-methylcitrate (secondary PA metabolite)
122
What should be ruled out if baby presents with NBS high MMA but no mutation is found?
Maternal B12 deficiency
123
What are the first steps after diagnosing sick child w/ MMA/PA?
- Determine B12 resonsiveness with hydroxocolbalamin
- Can try biotin if PA suspected (PA Carboxylase)
124
Bulls eye maculopathy
CblC (rarely CblD)
Bulls eye maculopathy can progress to RP and optic nerve atrophy despite treatment
125
Macocytic anemia, pancytopenia, high MMA, high HCy
Transcobalamin 2 deficiency
TCN2
- Treat with OH-Colbalamin injections
- Looks like neonatal leukemia/SCID
- TC2 colbalmin receptor deficiency tends to be milder/transient
126
What Cbl defects can have low B12 levels?
Cbl J and Cbl F
- abnormal lysosomal efflux
127
What is CblX?
HCFC1 and epi-cblC mutations
**HCFC1 is X-linked**
- Promoters/regulators of CblC expression
128
What is the first clinical sign of MSUD?
Maple syrup odor in ceruloplasmin
129
most common creatine disorder
Creatine transporder deficiency
XL - transports GAA (produced in liver) into brain/muscle
- autisim
- 1-2% of ID in males
- variable sieizures
- usually achieve motor sckills, **may have decreased muscle bulk**
130
Arginine Glycine Amidinotransferase Deficiency
Rarest Creatine synthesis disorder
- Arginine + glycine -\> Ornithine (negative feedback) + GAA
- Static encephalopathy
- Seizures rare, no regression
131
AGAT vs GAMT vs CT
AGAT tends to be static with **no regression**, also less seizures; may have FTT
GAMT tends to have progression, intractable **epilepsy**, and movement d/o, no FTT
Creatine transporter (**XL**) usually **delay + autism** (may have FTT)
132
Low GAA, Low/nl Creatine
Arginine Glycine Amidinotransferase deficiency
- static encephalopathy, no regression, rare seizures
133
high GAA, low/nl creatine
Guanidinoacetate methyltransferase deficiency
- Epilepsy, regression, movement disorder
134
Normal GAA and Creatine.
Urine Creatine/Creatinine ratio \> 1600
XL Creatine Transporder Deficiency
ID/Autism
- Creatine cannot get into musclae cells were it gets converted into createnine
135
Treatment for creatine synthesis defects
AGAT/GAMT -\> Creatine monophosphate supplement
GAMT -\> Arginine restriction, ornithine supplement to decrease production of GAA (Ornithine is inhibitor of AGAT)
Creatine Transport - no therapy
136
High Hypoxanthine, Xanthine, **and Uric Acid**
Lesch Nyhan (HGPRT)
Hypoxanthine Guanine Phosphoribosyltransferase deficiency
- Hypoxanthine and Guanine recycline defect
- Neuro + Gout + nephrolithiasis
137
High succinyladenosine (S-Adenosine) and SAICA Riboside
Adenylosuccinase/Adenylosuccinate lyase deficiency
ADSL
Seizure/ID
138
What are the main phenotypes of purine metabolism disorders?
Neurological
Immunological
Gout/Renal Failure
139
High inosine and guanosine, low uric acid
Purine Nucleoside Phosphorylase Deficiency
PNP
Neuro + immunodeficiency
140
High adenosine + adenine
Immunodeficiency
Adenosine Deaminase Deficiency
ADA
- NBS TRECs
- SCID
- Enzyme replacment (PEG-ADA)
141
Name 3 purine disorders that cause primarily nephrolithiasis
PRPPS - Phosphoribosyl-pyrophosphate synthetase **superactivity** (high urine acid)
XO - Xanthine Oxidase (high xanthing, hypoxanthine, **low uric acid (high in HGPRT)**)
APRT - Adenine phosphoribosyltransferase deficiency (high adenine)
142
What is cyclic pyranopterin monophosphate used to treat?
Molybdenum cofactor deficiency (cPMP)
143
Which purine disorders present with SCID?
ADA - high adenosine, adenine
PNP (PNP = neuro + scid) - high inosine, guanosine
144
High xanthine, hypoxanthine
Low uric acid
- Xanthine Oxidase deficiency - renal stones
- Molybdenum Cofactor deficiency - neuro, lens dyslocation
(Xanthine/Hypoxanthine high in HGPRT, but urine acid also high)
145
High succinyladenosine
ADSL deficiency
- neuro
146
High adenine, normal adenosine
APRT deficiency
- nephrolithiasis
(if adenosine also high then ADA)
147
High uric acid and hypoxanthine
PRP Superactivity
- gout + stones
148
Main neurological Purine disorders?
Molybdenum cofactor (High xanthine, hypoxanthine, low uric acid)
ADSL (Succinyladenosine)
HGPRT (high xanthine, hypoxanthine, uric acid)
149
anemia + orotic aciduria
Hereditary orotic aciduria
UMPS
Uridine monophosphate synthease deficiency
- Anemia unresponsive to B12, folate, iron
150
High uracil and thymine
Dihydropyrimidine Dehydrogenase Deficiency
Neuro, FTT, epilepsy
- may be asymptomatic, 5FU toxicity
151
high dihydrouricil, dihydrothymine, uracil, thymine
Dihydrophrimidinase deficiency
Asymptomatic, may be neuro, epilepsy
152
mitochondrial disease with high thymidine levels
MNGIE
Thymidine phosphorylase deficiency
153
High dihydrouracil, dihydrothymine, urediopropionic and urediosiobutyric acid
Ureidopropionase Deficiency
UPB1
- asympatomatic vs neuro + seizure + dystonia
154
Low dopamine and VMA, high 3-o-methyldopa
AADC deficiency
155
Low Homovanillic acid/5-HIAA ratio
Tyrosine hydroxylase deficiency
| (Tryptophan hydroxylase is normal)
156
X Linked monoaminemetabolism defect
MAOD
- usually mild ID with aggressive behavior
157
high CSF and plasma GABA
hypomyelination, movement disorder, EIEE
GABA transaminase deficiency
ABAT gene
- 2-pyrrolidinone biomarker
158
High 4-hydroxyisobutyric acid, high GABA
Succinic Semialdehyde Dehydrogenase Deficiency
Neurodevelopmental, EIEE
159
Why do SLOS patients have dysmorphology?
Cholestrol and 7DHC are activators of SHH
SLOS -\> low cholesterol, high 7DHC
160
RCDP + ichthyosis, coarse hair
XL CDP -\> male lethal
Sterol 7.8 isomerase
161
High Lathosterol
Lathosterolosis
SLOS like
Sterol 5 desaturase
162
high desmosterol
Desmosterolosis
SLOS like
DHCR24
163
SLOS like cholesterol disorders
SLOS - DHCR7
Lathosterolosis - SC5DL (5 desaturase)
Desmosterolosis - DHCR 24
- squaline synthase deficiency also looks similar (rare) - FDFT1
164
High mevalonic acid
Mevalonic Kinase (MVK) deficiency
- High IgD w/ recurrent fevers
- Dysmorphic, RP, Ataxia + immune
165
High lanosterol and dihydrolanosterol
Antley Bixler
POR/CYP450
166
high sitosterol, campesterol
Sitosterolemia- Sterol transporter defect
ACBG5, ACBG8 (AR)
Increased plant sterol absorption
- Xanthomas (including buttock), artherosclerosis, splenomegaly, arthralgies
167
Cholesterol disorders with primary severe skin manifestations
SC4MOL - sterol C4 methyoxidase (MSMO1)
CHILD syndrome - 4-demethylase (NSDHL)
- **high 4 methylsterols**
168
Where are NPC1 and NPC2 located?
NPC is disorder of cellular cholestrol trafficking -\> accumulation of cholesterol esters in lysosomes
NPC1 - late endosomal membrane protein
NPC2 - lysosomal cholesterol binding protein
169
3 presentations of NPC
1) Hydrops
2) neonatal liver disease
3) late onset neurological + hepatomegaly
170
"sea blue histiocytes"
Positive Filipin Stain
NPC
171
**diarrhea, cataracts**, DD, hepatitis, xanthomas, neurodegeneration
High **Cholestanol**
CTX
Sterol-27 hydroxylase (CYP27A1)
- Bile acid metabolism block -\> buildup of cholestanol in CNS
- Treat with chenodeoxycholenic acid
172
Low LDL cholesterol and neurological deterioation
Abetalipoproteinemia
MTTP (microsomal triglyceride transfer protein)
173
Sebelipase Alfa
ERT for Lysosomal Acid Lipase Deficiency
Wollman or Cholesterol Ester Storage disease
- LSD with adrenal calcifications, microvesicular steatosis
174
Orange Tonsils
Tangier Disease
ABCA1
low HDL
175
acrodermatitis, diarrhea, alopecia, FTT
Acrodermatitis enteropathica
Zinc deficiency, Transporter defect (ZIP4 or ZnT2)
ZIP4- Symptom onset **when weened from breastmilk**
ZnT2 - Symptom onset when baby is **on breastmilk**
176
ATP7A deficiency
Menkes
**X-linked**
Enterocyte Cu transporter -\> deficiency
177
ATP7B deficiency
Wilson's
Liver/CNS Cu secretory protein
- Liver overloaded with Cu, serum Cu low, urine Cu high
178
Polycythemia, Parkinsonsim, Dystonia
Manganese toxity (and transporter defects)
SLC30A10 - + liver disease (cannot leave liver)
SLC39A14 - no liver disease (not absorped by liver)
179
What metabolites tell you about cytoplasmic NADH/NAD ratio?
Lactate/pyruvate
180
What does 3-hydroxybutyrate/acetoacetate ratio tell you?
Intramitochondrial NADH/NAD+ ratio
181
high deoxyuridine, deoxythymidine levels
MNGIE
Thymidine Phosphorylase deficiency
182
high thiosulfate, hydrogen sulfide, ethylmalonic acid, C4/C5 acyl-carnitines
Ethylmalonic encephalopathy
ETHE1 persulfide dioxygenase
183
Normal complex 1-4 activity, low combined complex 2-3 and 1-3 activity
CoQ10 deficiency
184
What are FGF21 and GDF15 used for?
Markers of mitochondrial dysfunction
- useful for mtDNA maintenance/depletion/translation disorders
- Not useful for complex subunit disorders
185
SURF1 mutation cause what disease? What mito complex finding?
Leigh syndrome
isolated complex IV decrease (Complex IV assembly factor)
186
What mito complex pattern do you see in POLG?
Decreased 1, 3, and 4
| (complex 2 is nuclear encoded)
187
Treatment for MELAS
Arginine, Citrulline, Taurine (Natural Taurio-methyl uridine modification is impaired by 3243 mutation)
188
How do you treat NKH?
Sodium Benzoate (conjugates with glycine to form hippurate)
NMDA blockade
189
What is the end product of AA transamination?
Ammonia (NH3) and a-ketoacid (R-CO-COOH)
190
Why is lysine high when ammonia is high?
2KG used to synthesize glutamate instead of saccharopine
191
What is rate limiting step of urea cycle?
NAGS -\> senses glutamate levels (protein breakdown product)
192
Carbohydrate induced hyperammonemia
Citrin deficiency
- High protein, low carb diet
193
hyperammonemia, diarrhea, PTT, pneumonitis
PAA: Low arginine, ornithine, lysine
UAA: high arginine, ornithine, lysine
- high LDH/ferritin
LPI
SLC7A7 - dibasic AA transporter
+ macrophage activation syndrome
194
What is the name for organic acids with the following C chain lengths:
2, 3, 4, 5, 6
2 - acetic
3 - propionic
4 - butyric
5 - valeric
6 - caproic
195
What is the name for **dicarboxylic** organic acids with the following C chain lengths:
2, 3, 4, 5, 6
2 - oxalic
3 - malonic
4- succinic
5- glutaric
6 - adipic
196
what is the cofactor used by enzyme that causes PA?
Biotin
PA = propionyl-CoA **carboxylase** deficiency
197
C5DC
Glutarylcarnitine
- GA1
198
C5
Isovalerocarnitine
IVA
199
Boiled cabbage odor
Tyrosinemia type I
FAH deficiency
200
Treatment for ALD7A1 (antiquitin) deficiency
Pyrodoxine 5 Phosphate
B6 dependent epilepsy
201
methylcitric acid
MMA or PA
202
methylcrotonylglycine
3MCC
Also seen in multiple carboxylase deficiency
203
Tiglylglycine
PA, HSD10, 3-ketothiolase
204
Most common cause of adipic acid elevation
Jello
205
Alanine/lysine \> 3.0
mitochondrial dysfunction
206
3-hydroxy-3-methylglutaric acid
HMG-CoA Lyase deficiency
207
2-keto-isovaleric and 2 hydroxy-isovaleric acid
MSUD
- 2-keto acids = MSUD
208
3-methylglutaconic acid
HMG-CoA lyase deficiency
Barth syndrome + other mito membranse disorders
209
methylsuccinic acid
Ethylmalonic encephalopathy
210
very high ethylmalonic and adipic acid in urine
Ethylmalonic aciduria
211
5-oxoproline
Glutathione synthetase deficiency
212
4-OH-butyric acid
Succinic semialdehyde dehydrogenase deficiency (SSADH)
213
4-hydroxycyclohexylacetic acid
Hawkinsonuria - 4OHphenylpyruvate dioxygenase deficiency
- metabolic acidosis + tyrosinemia
- Resolve in first year of life
214
What is C5OH?
Hydroxyisovaleryl-CoA
- B-ketothiolase
- HMC-CoA Lyase
- 3MCC
- Multiple carboxylase deficiency
215
C4DC
C4DC = succinyl-CoA
- SUCLA2 (Succinyl-CoA synthetase) deficiency
216
Postprandial hypoglycemia
Hyperinsulinism or HFI
217
Hypoglycemia after 3-12hr fast
Glycogen or gluconeogenesis defect
218
Hypoglycemia after 12 hour fast
FAO defect (low ketones) or ketotic hypoglycemia
219
GSDs that predominant present as liver disease (without hypoglycemia)
Type IV (Branching enzyme)
Type VI (liver phsophorylase/phosphorylase kinase)
220
GALT Q188R
Classical galactosemia, caucasians
221
GALT S135L
Classic galactosemia, African Americans
222
GALT N314D
Duarte variant
223
GALT K285N
Variant galactosemia
224
Adolase B deficiency
HFI
225
How to tell apart SBCAD from Ethylmalonic encephalopathy?
SBCAD: EMA, methylsuccinic acid, C4
ETHE: EMA, adipic acid, C4
226
What does ACAD9 cause?
mito complex I deficiency
- Cardiomyopathy, neuro, muscle
- May have signs of FAOD and liver failure
227
Bulbar palsy, optic atrophy, SNHL, neuropathy, respiratory failure
Brown-Vialetto-Van Laere syndrome
Most common Riboflavin transporter defect
SLC42A3
228
Name 4 glucose transporters
SGLT1 - **Glu+Galactose** malabsorption -\> profuse diarrhea
SGLT2 - renal glucosuria
GLUT1 - epilepsy
GLUT2 - fanconi bickel (GSD like)
229
Hyperammonemia, hypoglycemia requiring high GIR
Glutamate Dehydrogenase (GDH)
- Hyperinsulinism + hyperammonemia
230
FAOD with hyperinsulinism
SCHAD
231
What biochemical marker distinguished GSD1 from GSD3?
Lactate. GSD1 is also gluconeogenesis defect so lactate elevated when fasting; this is not true in GSD3
232
What metabolites tell you NAPH/NAD+ in mitochondria?
3OH-butyrate/Acetoacetate
Lactate/pyruvate = cytoplasmic
233
High lactate/pyruvate
Low 3OH Butryate/acetoacetate
Pyruvate carboxylase deficiency
Disconnect between mito and cytoplasmic NADH/NAD+ (redox) state
234
Lactic acidosis with low lactate/pyruvate ratio (\<12)
Secondary lactic acidemia
Pyruvate dehydrogenase (Pyruvate high)
Pyruvate transporter
Thiamine deficiency (PDH affected)
235
Lactic acidosis during fasting
Gluconeogenesis (FBPase or G6Pase - GSD1)
FAOD (secondary gluconeogenesis impariment)
236
Postprantial lactic acidosis
Inability to store glucose -\> GSD0, GSDIII, GSD VI
Glucose metabolism -\> PDH, Pyruvate transporter (normal L/P ratio)
-\> PC, ETC disease (high L/P)
237
Postprantial lactic acidosis and ketosis
high L/P ratio
Hyperammonemia with low glutamine
High citrulline, proline, lysine
Pyruvate Carboxylase
Postprandial ketosis since TCA cycle slowed and acetoacetate is used to synthesize ketones instead
- Low spartate production -\> Urea cycle block
238
Fasting ketotic hypoglycemia + high postprandial lactate
GSD0 or GSD3
239
LSD due to protein associated with autophagolysoomal fusion/pH control
Neuronal Ceroid Lipofuscinoses
240
LSD due to cholesterol binding protein
NPC2
241
sebelipase alfa
ERT for Wolman/cholesterol ester storage disease
sebe**lipase**
242
Alglucosidase alfa
ERT for pompe
al**gluco**sidase
243
Imiglucerase, Velaglucerase, Taliglucerase
ERT for Gaucher (glucocerebrosidase)
- **glucer**ase
244
agalsidase
ERT for fabry (alpha galactosidase)
**agal**sidase
245
PEX7
RCDP type 1 (low plasmalogen)
- Type 1 also high phytanic acid
246
NBS for C5OH
BCAA pathway intermeidates (Leu and Ile)
+ holocarboxylase and HMG-Coa Lyase
247
alpha aminoadipic aciduria
COOH-CH(NH2)3-COOH
Lysine/tryptophan breakdown intermediate; metabolized to acetoacetylcoa via glutaryl coa
- DD/ acidosis vs non-disease
248
treatment for OAT
Pyridoxine, arginine restriction
249
low homocysteine, high methionine
MAT - benign vs CNS
GNMT (methyltransferase) - hepatomegaly, high LFTs
SAHH, AHCY (Adenosylhomocysteinase) - MR, FTT
250
4-OH Phentyllactic, 4OH-phentylpyruvic, and 4OH phenylacetic acid
Tyrosinemia - 4OH phenyl-acids elevated in all three types
TAT, 4HPPD, FAH
251
4OH phenyl acids + 2-L-cystein-S-yl-1,4-dihydroxycyclhex-5-en-1-yl acetic acid
2-L-cystein-S-yl-1,4-dihydroxycyclhex-5-en-1-yl acetic acid = Hawkinsin
4-hydroxyphenylpyruvate dioxygenase deficiency
Normal -\> metabolic acidosis + FTT
252
BH4 defects with high Phe
PTPS, PCD, DHPR
253
BH4 defect wiht high primapterin
PCD
254
BH4 defect with high biopterin
DHPR
255
high 3OMD
AADC
256
High HVA
Dopamine B Hydroxylase Def
257
PAA profile for SUOX
High taurine, low cystine
258
Precursor to sulfur AAs
Methionine
259
High a-aminoadipic semialdehyde and pipecolic acid
antiquitin
A-aminoadipic semialddehyde dehydrogenase deficinecy
Pyridoxine dependent epilepsy
260
High L-Dopa, 3 methoxytyrosine, Thr, Glycine
Low HVA, 5-hydroxyindoleacetic acid
UOA: vanillactate acid
PNPO
Pyridoxal-5-phosphate oxidase deficiency
Pyridocal-phosphate dependent epilepsy + cerebral atrophy
biochem looks like AADC + theronine dehydratase + glycine cleavage sysem)
261
Butyrylcarnitine
Ethylmalonic acid
SCAD
ACADS gene
Butyrylcarnitine = C4 (ddx isobutyrylcarnitine in IBDH deficiency)
EMA ddx MADD, EE, mito, litchee, jamaican vomiting sickness
262
Which AAs are NORMAL in urine of Hartnup disease?
SLC6A19 - neutral AA transporter
Glycine, Proline, Hydroxyproline are normal
263
Urine AA: Cystine, Lysine, ortnithine, argnine
Cystinuria
SLC3A1
-
264
PAA: Low Lys, Arg, Orn
UAA: High Lys, Arg, Orn
LPI
- cationic transporter SLC7A7
Lys, Arg, Orn
265
UOA: Thymine and uracil
Dihydropyrimidine dehytogenase deficiency
- 5FU toxicity, MR, microcephaly, FTT
266
4 OH Butyric acid
Succinic Semialdehyde Dehydrogenase deficiency
ALDH5A1
Succinic semialdehyde cannot be tunred into succinic acid, so becomes 4OHB instead
267
high erythritol, arabitol, ribitol
Transaldolase
TALDO1
Hydrops vs severe liver disease
268
XL Sideroblastic anemia
ALA synthase deficiency
ALAS superactivity = prophyria
269
Stool isocoproporphyrin
UROD
Porphyria cutaneous tarda or heptoerythropoetic porphyria
270
Low serum Cu and Ceruloplasmin, abnormal plasma catecholamines
Menkes (ATP7A)
271
Low serum Cu and ceruloplasmin, high urinary copper
Wilsons (ATP7B)
272
Low serum Cu and absent ceruloplasmin, lower iron, high ferritin
Aceruloplasminemia (CP gene)
Brain iron accumulation
273
petechiae, acrocyanosis, diarrhea, epilepsy, movement d/o
Ethylmalonic encephalopathy
ETHE1
High EMA and Methylsuccinic acid
High C4 and C5
274
4 enzymes that require biotin
Pyruvate carboxylase (Mito)
Propionayl-CoA carboxylase (PA)
B-methylcortonyl CoA Carboxylase (3MCC)
Acetyl-CoA Carboxylase
275
High C5OH, high 3-OH IVA, 3 methylcrotonylglycine, low carnitine
3MCC
- leucine metabolism
276
4 disorders of Leu breakdown
MSUD
IVA - 3IVA, C5
3MCC - 3MCG, 3IVA, C5OH
3MGC - 3MCG, 3MGA, 3IVA, C5OH, C6DC
277
C3 + C4DC
Think MMA/ SUCLA
278
Lamellar lipoproteins
LCAT
low HDL
279
Frederickson Lipid Classification
CLIVE
I - Chylo
II - LDL
III - IDL (VLDL remnant/ B- VLDL)
IV - VLDL
V - Everything else
280
How do you tell apart abetalipoproteinemia from familial hypobetalipoproteinemia
Carriers for a-beta (MTTP - microsomal TG transfer protein) do NOT have hypobetalipidemia;
hypobetalipoproteinemia (APOB) do have hypobetalipidemia.
281
acanthocytosis + steatorrhea; low LDL and TG; carriers have low betalipoproteins
Familial hypobetaliporptoteinemia
APOB gene
- Mostly truncating variants
- Unable to form chylomicrons from dietary fats, Vit E absorption
282
acanthocytosis + steatorrhea; Low LDL and TG; carriers have normal betalipoproteins
Abetalipoproteinemia
MTTP
- Microsomaltransfer protein
- Carriers have no phenotype
Unablte to form chylomicrons from dietary fat - vitE def
283
Low LDL and TG, Apo A1 and ApoB
## Footnote
**Lipid laden enterocytes**
Chylomicron retention disease
SAR1B -\> abnormal trafficking of chylomicrons within enterocytes
Fat malabsorption, FTT, Vit deficiency
284
high Chylomicrons, Cholesterol, **TG very high**
Lipoprotein lipase (LPL) deficiency vs ApoC2
AR, carriers have familial combined hyperlipidemia
- Abd pain/pancreatitis; need low fat diet
- not associated with CAD (**hepatic lipase has arteriopathy**)
285
high ACE, tartrate-resistant acid phosphatase (TRAP), and chitotriosidase
Gaucher
Glucocerebrosidase def
N370S, L444P
286
high cit, argninine, theronine
High ammonia, galactose, AFP
Citrin deficiency
- supplement argnine/aspartate, high protein diet
287
how do you distinguish hypoglycemia caused by hyperinsulinism from FAOD?
Both are non-ketotic
- Free FA high in FAOD
- Free FA (lipolysis) low in hyperinsulin
288
Mousy odor
PKU
289
High ammonia, normal citrulline, high lactate
Pyruvate carboxylase
290
Ways to distinguish GSDI from other GSDs
High uric acid and lactic acid in GSD1
Moderate ketosis in GSDI - higher ketones in GSD0, III, IV, and IX
Nephromegaly most prominent in GSD1
Transient LFTs in GSD1 - Cirrhosis in GSD IV
291
GSDs with postprandial hyperglycemia
GSD0
Fanconi-Bickel
292
GSDs with normal lactate
GSD III
Only elevated postprandially in GSD VI and GSD IX
293
Jaundice, hepatosplenomegaly, lymphadenopathy, anemia
Mevalonic Aciduria
MVK deficiency (Pre-squalene)
- alleleic with hyper IgD
+ DD
294
Male cat urine smell
3-OH IVA
3MCC, multiple carboxylase deficiency
295
Rancid butter smell
Tyrosinemia type 1
- Also cabbage
296
Sulfur smell in urine
Cystinuria and Tyr type 1 (methionine)
297
high alk phos -\> IEMs
bile acid synthesis disorders, GPI anchor disorders
298
IEMs with hypothyroidism
Mito, CDG, TFP
299
MMA vs PA
PA has more cardiomyopathy
MMA has more renal
300
NBS: high C5
IVA vs enthylmalonic encephalopathy vs SBCAD (non disease)
301
etheylmalonic acid + butyrylcarnitine, butyrylglycine
SCAD
302
methylacritic acid
hydratase or 2-hydroxyisubtyryl-Coa Hydrolase deficiency
Val/Ile metabolism
Neuro + cardiomyopathy + hepatomegaly
Hydratase (ECHS1) - 2-methyl-2,3-dihydroxybutryate, C4
HIBCH - C4OH (hydrolase deficiency)
303
MMA + 3OH-isobutyric acid
MMA semialdehyde dehydrogenase
ALDH6A1
- Val metabolism
- non-disease (found on NBS)
304
Hydroxyphntylpyruvate dioxygenase
HPD -\> Tyr type 3 or Hawkinsonuria (c.722A\>G)
- benign
305
Isolated hypermethionine
Mudd's disease
MAT
- Cabbage odor
306
which methionine -\> hcy disorder does not have ID
MAT and GNMT
SAMH and ADK have ID
307
urine uroporphyrin, tool isocoproporphyrin
Porphyria Cutanea Tarda
308
disorders treatable with uridine supplement
Proximal pyrimidine synthesis
UMPS, DHODH, CAD
309
HEXA R247W (739 C\>T), R249W (745 C\>T)
Tay Sachs peudodeficiency alleles
310
SUMF1
Multiple sulfatase defiency
MLD + MPS + ichthyosis
311
C5OH + C6DC
HMG-CoA Lyase
312
C5OH and C5:1
Beta Keto Thiolase
313
Hydrops with MPS
MPS 7 -\> sly
314
What metabolite do you need HPLC to see
Homocitrulline
315
LSD with interstitial lung disease
NP - B (acid sphingomyelinase)
316
HSM + HLH
LPI
High Orn, Arg, Lys
317
HSM + hemolytic anemia
Transaldolase
318
HSM + recurrent inflammation
MVK
