Inborn Errors of Metabolism Flashcards
(141 cards)
1
Q
Incidence of inborn errors of metabolism
A
1/2000
2
Q
IEM with alopecia
A
biotinidase deficiency
3
Q
IEM with brittle hair
A
arginosuccinic lyase deficiency
arginosuccinic acid synthetase deficiency
Menkes
4
Q
IEM with cardiomyopathy
A
LCHAD deficiency
glutaric aciduria II
carnitine deficiency
Pompe
mitochodrial
mucoplipodoses (I cell disease)
5
Q
IEM with Cataracts
A
Galactosemia
galacokinase deficiency, mevalonic aciduria
6
Q
high forehead, flat orbital ridges, open AF, epicanthal folds, flat nasal bridge
A
Zellweger
7
Q
large AF, high forehead, hypertelorism, epicathal fold, long philtrum, low set ears
A
mevalonic aciduria
8
Q
coarse facial features
A
mucopoloysacharidoses
9
Q
IEM hydrops
A
G6PD
lysosomal
GSD type IV
10
Q
IEM thromboemboli
A
homosystinuria
11
Q
Sweaty feet
A
isovaleric aciduria
glutaric aciduria II
12
Q
Hyperammonemia
A
think UCD
13
Q
++ NH4, ++ acidosis, ++ ketones
A
propionic/methylmalonic/isovaleric acidurias
lactic acidemia
glutaric aciduria
pyruvate carboxylase deficiency
beta methylcrotonyl glycinuria
14
Q
++ NH4, ++ acidosis, no ketones
A
FAO
15
Q
++ NH4, no acidosis, no ketones, normal citrulline, no arginosuccinic acid, normal arginine
A
transient
lysine protein intolerance
16
Q
++metabolic acidosis, high anion gap, normal lactate , ++ organic acids
A
organic acidemia
17
Q
++metabolic acidosis, high anion gap, ++ lactate , ++ organic acids
A
organic acidemia
FAO defect
18
Q
++metabolic acidosis, high anion gap, ++ lactate , normal organic acids, ++pyruvate (normal lactate:pyruvate)
A
glucose low: glycogen storage or fructose intolerance
glycose normal: pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial
19
Q
++metabolic acidosis, high anion gap, ++ lactate , normal organic acids, normal pyruvate (++ lactate:pyruvate)
A
pyruvate carboxylase deficiency
mitochondrial
20
Q
hypoglycemia, ++ reducing substances
A
galactosemia
tyrosinemia
hereditary fructose intolerance
21
Q
hypoglycemia, NO reducing substances, ++ ketones, ++ lactate
A
GSD
fructose 1,6 bisphosphonate deficiency
phosphoenol pyruvate carboxykinase deficiency
22
Q
hypoglycemia, NO reducing substances, ++ ketones, normal lactate
A
abnormal urine organic acids: organic acidemia, MSUD, propionic or MMA aciduria
normal urine organic acids: GH, corisol deficiency; succinyl coA deficiency, SCHAD
23
Q
hypoglycemia, absent reducing substances, low ketones, low insulin
A
FAO
3 hydroxymethylglutaryl coA lyase deficiency
do of glycosylation
SCHAD
24
Q
hypoglycemia, no acidosis, no beta OHB, ++ FFA
A
FAO
25
hypoglycemia, no acidosis, ++beta OHB, ++ FFA
hyperinsulinism
26
hypoglycemia, ++ acidosis, ++ beta OHB
GH or cortisol deficiency
GSD
27
hypoglycemia, ++ acidosis, ++ lactate
fructose 1,6 bisphosphatase deficiency
phosphoenol-pyruvate carboxykinase deficiency
28
urine male cat odor
3 methylcrotonyl glycinuria
29
musty urine
pku
30
acetonuria
organic acidemias
31
dinitrophenylhydrazine urine test
MSUD, pku, tyrosinemia, histidinemia
32
ferric chlorine urine test
blue-green: PKU, histidinemia
green-gray: MSUD
green: tyrosinemia
33
nitroanilline urine test
methylmalonic aciduria
34
nitroprusside urine test
homcystinuria
35
urine pterins
BH4 if normal DHPR activity or
DHPR deficiency
36
risk of premature ovarian failure
galactosemia even if treated
37
what are the 4 types of GSD?
1. liver with direct effect on blood glucose: 1, 6,8
2. muscle affecting anaerobic work: 5,7
3. liver and muscle: III
4. various tissues without affecting blood glucose or anaerobic work: 2,4
38
type 1 GSD
von Gierke/G6P
hepatic tumor risk, bleeding risk
39
type 2 GSD
Pompe/lysosomal a-glucosidase
40
type 3 GSD
Forbes/debranching enzyme amylo-1,6 glucosidase
41
type 4 GSD
Anderson/branching enzyme
42
type 5 GSD
McArdles/muscle phosphorylase
43
type 6 GSD
Hers/liver phosphorylase
44
type 7 GSD
Tarui/muscle phosphoro fructokinase
45
type 8 GSD
phosphorylase kinase
46
Lactose pathway
Lactose (Lactase) galactose + glucose (galactokinase) galactose1P+UDP glucose (GALT) UDP +G1P
47
Fructose pathway
fructose (fructokinase) F1P (F1P aldolase - liver intestines kidney) glyceraldehyde and dihydroxyacetone
48
UCD
glutamate (n acetyle glutamate synthase - with acteyl CoA + ammonia) N-ag (carbamoyl phosphate synthase) CP (OTC) citrulline (arginosuccinic acid synthase) arginosuccinic acid (AS lyase) arginine (arginase) ornithine + urea
49
CP breakdown
CP > carbamyl aspartate > orotic acid > pyrimidines
50
which UCD product goes out and in of mitochondria
citrulline and ornithine
51
NH4 scavengers
benzoate and phenylacetate
52
if early cycle defects what can you supplement?
citrulline or for N-ag synthetase deficiency can give N-carbamyl L glutamate
53
how does lactulose help UCD?
intestinal bacteria turn lactulose to lactic acid and the low pH inhibits NH4 absorption`
54
MSUD deficiencies:
ketoacid dehydrogenases limiting the breakdown of branched chain AA (leucine, isoleucine and valine)
55
PKU pathway
phenyalanine (phenylalanine hydroxylase) tyrosine
1. dopamine via tyrosine hydroxylase
2. phenylpyruvate + fumarylacetoacetate to fumarate + acetoacetate via fumarylacetoacetate hydrolase
hydroxylases need BH4
56
differentiate types of tyrosinemia
1. hepatorenal (also heart and bones), Faa hyrolase deficiency
2. oculocutaneous + neuro, tyrosine degradation defect
3. neuro, tyrosine degradation defect
transient: late fetal maturation of tyrosine pathway, some neuro impact
57
treatment of tyrosinemia
diet low in phenlyalanine, tyrosine, methionine
nitisinone *** prevents phenylalanine breakdown decreasing toxic compounds
if no response may need liver tx
ascorbic acid helps transient type
58
nititisone decreases risk of____
hepatocellular carcinoma
59
++ methionine, ++ homocysteine
homocysteinuria = cystathionine beta ssynthase deficiency
60
++ methionine, normal homocysteine
MAT, GMT, AH deficiency
61
no methionine, ++ homocysteine, normal MMA
MTHFR or Cobalamin deficiency
62
no methionine, ++ homocysteine, ++ MMA
cobalamin deficiency
63
treatment of homocysteinuria
B6 and B12, decrease methionine, increase cysteine
vit C for endothelial function
64
nonketotic hyperglycinemia pathway
BH4 + glycine --> methylene tetrahydrofolate + NH4 + CO2
65
nonketotic hyperglycinemia symptoms
in utero hiccups and seizures, burst suppression EEG --> then hypsarrhythmia, elevated CSF glycine
66
Treatment in nonketotic hyperglycinemia
benzoate
dextromethorphan - NMDA anatagonist may help neuro
variable response to ketogenic diet
67
histidinemia pathway
- histidase deficiency
- urine histidine and imidazole pyruvic acid
- ferric chloride to urine - turns blue green
68
cystinuria pathway
defect in AA transport --> cysteine deficiency
69
cystinuria diagnosis
nitroprusside test;
70
cystinuria treatment
- alkalinize urine
- restrict methionine
- thiol drugs (d-penicillamine, mercaptopropionylglycine)
71
lysinuric protein intolerance
- abnormal AA transport across cell membrane
- deficiency lysine arginine and ornithine
- hyperammonemia with lysinuria
- low serum lysine
72
lysinuric protein intolerance treatment
citrulline
sodium benzoate or sodium phenylbutyrate
carnitine
cholesterol if hypercholesterolemia
treat crisis like UCD
73
lysinuric protein complications
renal
74
leucine metabolism defects
isovaleric acidemia
3 methylcrotonyl glycinuria
** pathway requires biotin **
75
isovaleric acidemia diagnosis
- c5 acylcarnitine
- urine isovalerylglycine and isovaleric acid
- skin fibroblasts with decreased isovaleryl coa dehydrogenase activity
76
isovaleric acidemia treatment
- l carnitine and glycine
- limit protein
- treat nh4
77
isoleucine metabolism defects
proprionic aciduria
methylmalonic aciduria
78
lysine and tryptophan defects
glutaric aciduria type 1 (riboflavin B2 dependent)
79
diagnosis glutaric aciduria type 1
low enzyme activity in skin fibroblasts
80
neuroimaging in glutaric aciduria
frontotemporal atrophy and demyelination
81
abnormal C4-C5
SCHAD
82
abnormal C6, C8, C10:1
MCHAD
83
abnormal C16:1-OH, C16-OH, C18:1-OH, C18-OH
LCHAD
84
C14:1, C14:2, C16:1, C18:1
VLCHAD
85
dysostosis multiplex
mucopolysaccharidoses
86
types of mucopolysacchridosis
MPS 1 Hurler: a-iduronidase
MPS 2 Hunter iduronidase 2-sulfatase
MPS 3 Sanfilipo degrading heparain sulfates
MPS 4: Morquio galactosamine 6 - sulfate sulfatase
MPS VI Maroteaux Lamy N-acetylgalactosamine-4-sulfatase
MPS VII Sly b-glucuronidase
87
mucopolysacchridosis triad
1. dysostosis multiplex
2. Alder-Reilly bodies in WBCs
3. urine mucopolysaccharides
88
HSM, cherry red spot and CNS in
Gaucher 1, Niemann Pick A, Tay-Sachs
Gaucher:++ HSM, no cherry red spot and no CNS
Niemann: ++ HSM, +++ cherry red spot and ++ CNS
Tay-Sachs no HSM, ++ cherry red spot and ++ CNS
89
Mitochondrial disorders
lactate dehydrogenase
pyruvate carboxylase
pyruvate dehydrogenase
respiratory chain disorders (Avoid valproic acid and barbiturates)
90
Cholesterol synthesis disorders
mevalonic aciduria
smith-lemli-opitz
bile acid disorders
91
increase humidity ___
double walled___
plastic heat shields ___
portholes ___
rubber foam mattress___
plastic film___
evaporative
radiant
radiant
convective
conductive
convective and evaporative
92
wilsons dx and tx
low ceruloplasmin
d penicillamine to chelate copper
93
menkes dx and tx
- low ceruloplasmin
- low copper
- parenteral copper histidine
94
zellweger dx and tx
increased C22, C24 and C26
increased methyl branched FAs (phytanic and pristanic acids)
increased bile acid
decreased plasmalogen
skin fibroblasts
DNA testing
tx: supportive, vit K supplement, bile acid therapy
95
abnormal posturing a/w which IEM
glutaric acidemia type 1
96
major nonenzymatic intracellular antioxidant
glutathione
97
most abundant free radical
superoxide anion
98
Presentation of IEM
1. intoxication
- acute encephalopathy
- chronic encephalopathy
- acid based disturbances
2. energy deficit
- problems making
- problems using
3. complex molecule
99
key strategy in acute encephalopathy IEM
- stop catabolism; provide adequate calories
- dilute toxins and promote excretion with hydration
- hemodialysis if severe
100
common examples leading to chronic encephalopathy
PKU and homocystinuria
101
IEM categories that present as intoxications
- AA disorders
- Urea Cycle defects
- Organic acidurias
- Sugar intolerances
102
AA disorder labs
- plasma amino and urine OA
- metabolic acidosis with urine ketones
- increased AG
103
UCD labs
- +++ NH4 plasma
- minimal metabolic acidosis
- **respiratory alkalosis**
- no liver dysfunction
- no ketoacidosis
104
Organic aciduria labs
- metabolic acidosis w/ urine ketones
- + NH4
- + glycine
- abnormal urine OA
- increased AG
105
sugar intolerance labs
- NBS
- urine OA
- liver enzyme analysis
106
Order of energy use in fasting
1. blood glucose
2. breakdown glycogen
3. FAO
4. breakdown AA
107
Categories of energy deficit disorders
- FAO
- glycogen storage
- mitochondrial
108
Presentation of FAO
- hypoketotic hypoglycemia
- hypotonia
- cardiomyopathy
- SIDS
- Reyes
109
Presentation of glycogen storage
- hepatomegaly
- hypoglycemia
- lactic acidosis
- FTT
110
Presentation of mitochondrial disorder
- lactic acidosis
- seizure
- cardiomyopathy
- hypotonia/myopathy
- +/- hypoglycemia
111
Presentation of complex molecule disorders
1. progressive dysmorphic/coarse facies
2. severe bone dysplasia
3. neurologic
112
Types of complex molecule defects
- lysosomal storage
- peroxisomal diseases
- intracellular trafficking and processing
- IE of cholesterol synthesis
113
what complex molecules do lysosomes deal with
- glycosaminoglycans
- glycoproteins
- gangliosides
- glycolipids
114
what complex molecules do peroxisomes deal with
- bile acid and plasmalogen synthesis
- oxidation of VLCFA
- degradation of phytanic and pipecolic acids
115
genetics of AA metabolis is normally what type?
single gene defects
116
PKU pathophys
- defect in phenylalanine hydroxylase
- AR
- gene 12q24.1
- +++ plasma phenylalanine
- +++ urine phenylpyruvic acid
117
treatment PKU
limit phenylalanine
some forms may benefit from biopterin and 5 hydroxytryptophan and dopa (biogenic amine precursors)
118
tyrosinemia types
- transient
- type 1: succinylacetone buildup, FTT, hepatic adenomas>hepatic blastoma, RTA, rickets, NOT NDI
>>>treatment: NTBC - prevents tyrosine breakdown to succinylacetone (toxic)
- type 2: deficiency of tyrosine aminotransferase, corneal ulcers, keratitis, tyrosine build up only
>>> treat: low tyrosine
- type 3: 4 hydroxyphenypyruvate deioxygenase (RARE)
>>> treat: low tyrosine
119
alkaptonuria
- deficiency homogentistic acid dioxygenase (3rd step tyrosine metabolism)
- tyrosine **NOT** elevated
- dark colored urine
- ochronosis (pigment deposits in ears and sclera), aortic root dilation
- good prognosis
120
MSUD
- AR
- symptoms DOL 3-5
- feeding difficulties, irregular RR, loss of Moro, seizures, neuro
- +++ plasma and urine leucine, lysine, valine
- **alloisoleucine** is diagnostic
>>> tx: diet
121
glutaric aciduria type I
- AR
- lysine, hydroxylysine and tryptophan catabolism
- **chr19**
- **macrocephaly at birth**
- normal development until stress (illness or metabolic stress), sudden hypotonia or dystonia
- frontal or **cortical atrophy**
122
diagnosis of glutaric aciduria type 1
- urine OA: increased glutaric and 3-hydroxyglutaric acids
- low carnitine
123
treatment of glutaric aciduria type 1
- L - carnitine
- riboflavin
- diet
- IVF with glucose when ill
124
homocystinuria pathophy
- AR
- chr 21q
- cystathione beta-sythetase deficiency
- marfanoid
- NDI
- lens dislocation **down**
- atherosclerosis
125
treatment of homocystinuria
pyridoxine
low methionine diet
betaine - helps convert homocysteine back to methionine
126
nonketotic hyperglycinemia
- AR
- intractable seizures
- hiccups in utero
- Dx: increased glycineCSF : glycineplasma
- Tx: sodium benzoate may help decrease CSF glycine
127
determining level of UCD
check plasma levels
1. arginine = low in all, except argininemia
2. citrulline = low then its OTC or CPS
3. urinary orotic acid = elevated in OTC, but normal/low in CPS and NAGS
128
types of organic acidemia
- isovaleric acidemia **sweaty feet**
- 3-methylcrotonyl coA carboxylase
- propionic acidemia - valine, methionine, isoleucine, threonine
- carboxylase - (these ones need biotin)
- methylmalonic acidemias
Dx: check urine
Tx: limit protein, carnitine helps
129
fatty acid pathway
FAO major source of energy in skeletal muscle and heart
1. FA conjugated to carnitine
2. carnitine-FA transported across mitochondrial membrane
3. released as an acyl-Coa
4. catabolized in Beta oxidation
130
Types of FAO
- reducing carnitine uptake
>> primary carnitine deficiency
- inhibit FA from entering mitochondria
>>carnitine palmitoyltransferase I and II and carnitine acylcarnitine translocation defects
- block beta oxidation
>> VLCAD, MCAD, LCHAD
>> glutaric acidemia type 2 - defect in electron transfer flavoprotein and ETF:ubiquinone oxidoreductase
131
GSD types
_hypoglycemia and hepatomegaly_
1. (von Gierke; glucose 6 phosphatase)
3. (cori; debrancher)
4. (Anderson; branching enzyme; amylopectinosis)
6. (Hers)
9. (liver phosphorylase kinase deficiency)
0. (glycogen synthase)
11. (hepatic glycogenesis + Fanconi; Glut2)
_muscle problems_
5. (McArdles, muscle phosphorylase)
7. (Tarui, muscle phoshofructokinase)
2. (Pompe, lysosomal acid glucosidase deficiency, a1,4 glucosidase deficiency, acid maltase deficiency) **accumulates in lysosomes** unlike others in cytoplasm
132
Galactosemia diagnosis
suspect with reducing substance in urine
**definitive diagnosis is deficient GALT**
133
if sugar intake causes hypoglycemia think ___
fructose 1,6 bisphosphate aldolase deficiency
134
mitochondrial disorders
- Kearns Sayre and Chronic Progressive External Ophthalmoplegia: ptosis, ophthalmoplegia, ragged red fiber myopathy
- MERRF: epilepsy, cerebellar ataxia. ragged red fiber myopathy
- MELAS - lactic acidosis, stroke like, cerebellar ataxia before stroke
- Leigh syndrome: cranial nerve findings and respiratory
Dx: southern blot, greatly reduced mitochondrial dna
135
Mucopolysaccharidoses
- defect in catabolism of glycosaminoglycans by lysosomal enzymes
MPS I: Hurler; a-L iduronidase 4p14.3, atlantoaxial subluxation, coarse facies, midface hypoplasia, large tongues, hernias, *corneal clouding*, cardiomyopathy
MPS 2: Hunter: XL, nodular rase on scapulae and extensor surfaces, hernias, coarse facies, HSM
MPS 3: Sanfilippo: chr 17, heparan sulfatase
MPS4: Morquio: galactose 6- sulfatase; defective keratan sulfate degradation; spondyloepiphyseal
136
Mucolipidosis
I. Cherry red spot myoclonus snydrome
2. I cell deficiency
3. Pseudohurler
137
Sphingolipidoses
- build up of ceramide, oligosaccharide (glycosphingolipid) or phosphorylcholine (shingomyelin)
- neonatal: gaucher type 4
- age 1-6 months: gaucher type 2, niemann pick type A
enzyme replacement help skeletal issues not neuro
138
peroxisomal disorders
Zellweger
infantile Refsum
neonatal adrenoleukodystrophy
139
menkes
XL
ATP7a
impaired copper uptake
progressive neuro deterioration
seizures
subdural hemorrhage
retinal hemorrhages
Dx: low serum copper and ceruloplasmin; need to also measure **dopamine beta hydroxylase**
140
smith lemli opitz
AR
7 dehydrocholesterol reductase deficiency
Dx: 7 dehydrocholesterol will be elevated, cholesterol low normal
- 2/3 syndactyly, cleft palate, microcephaly/hypertelorism, abnormal GU
141
porphyrias
enzyme defect in heme synthesis
_hepatic_
- acute intermittent (AIP) AD, HMB synthetase
- porphyria cutanea tarda (MCC), hepatic URO- decarboxylase
_erythropoeitic_
- XL sideroblastic anemia; sideroblasts, urine porphyrin normal Dx: ALA synthase gene mutation
- erythropoietic protoporphyria; ferrochelatase; protophyrin buildup
