Inborn Errors of Metabolism Flashcards
Incidence of inborn errors of metabolism
1/2000
IEM with alopecia
biotinidase deficiency
IEM with brittle hair
arginosuccinic lyase deficiency
arginosuccinic acid synthetase deficiency
Menkes
IEM with cardiomyopathy
LCHAD deficiency
glutaric aciduria II
carnitine deficiency
Pompe
mitochodrial
mucoplipodoses (I cell disease)
IEM with Cataracts
Galactosemia
galacokinase deficiency, mevalonic aciduria
high forehead, flat orbital ridges, open AF, epicanthal folds, flat nasal bridge
Zellweger
large AF, high forehead, hypertelorism, epicathal fold, long philtrum, low set ears
mevalonic aciduria
coarse facial features
mucopoloysacharidoses
IEM hydrops
G6PD
lysosomal
GSD type IV
IEM thromboemboli
homosystinuria
Sweaty feet
isovaleric aciduria
glutaric aciduria II
Hyperammonemia
think UCD
++ NH4, ++ acidosis, ++ ketones
propionic/methylmalonic/isovaleric acidurias
lactic acidemia
glutaric aciduria
pyruvate carboxylase deficiency
beta methylcrotonyl glycinuria
++ NH4, ++ acidosis, no ketones
FAO
++ NH4, no acidosis, no ketones, normal citrulline, no arginosuccinic acid, normal arginine
transient
lysine protein intolerance
++metabolic acidosis, high anion gap, normal lactate , ++ organic acids
organic acidemia
++metabolic acidosis, high anion gap, ++ lactate , ++ organic acids
organic acidemia
FAO defect
++metabolic acidosis, high anion gap, ++ lactate , normal organic acids, ++pyruvate (normal lactate:pyruvate)
glucose low: glycogen storage or fructose intolerance
glycose normal: pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial
++metabolic acidosis, high anion gap, ++ lactate , normal organic acids, normal pyruvate (++ lactate:pyruvate)
pyruvate carboxylase deficiency
mitochondrial
hypoglycemia, ++ reducing substances
galactosemia
tyrosinemia
hereditary fructose intolerance
hypoglycemia, NO reducing substances, ++ ketones, ++ lactate
GSD
fructose 1,6 bisphosphonate deficiency
phosphoenol pyruvate carboxykinase deficiency
hypoglycemia, NO reducing substances, ++ ketones, normal lactate
abnormal urine organic acids: organic acidemia, MSUD, propionic or MMA aciduria
normal urine organic acids: GH, corisol deficiency; succinyl coA deficiency, SCHAD
hypoglycemia, absent reducing substances, low ketones, low insulin
FAO
3 hydroxymethylglutaryl coA lyase deficiency
do of glycosylation
SCHAD
hypoglycemia, no acidosis, no beta OHB, ++ FFA
FAO
hypoglycemia, no acidosis, ++beta OHB, ++ FFA
hyperinsulinism
hypoglycemia, ++ acidosis, ++ beta OHB
GH or cortisol deficiency
GSD
hypoglycemia, ++ acidosis, ++ lactate
fructose 1,6 bisphosphatase deficiency
phosphoenol-pyruvate carboxykinase deficiency
urine male cat odor
3 methylcrotonyl glycinuria
musty urine
pku
acetonuria
organic acidemias
dinitrophenylhydrazine urine test
MSUD, pku, tyrosinemia, histidinemia
ferric chlorine urine test
blue-green: PKU, histidinemia
green-gray: MSUD
green: tyrosinemia
nitroanilline urine test
methylmalonic aciduria
nitroprusside urine test
homcystinuria
urine pterins
BH4 if normal DHPR activity or
DHPR deficiency
risk of premature ovarian failure
galactosemia even if treated
what are the 4 types of GSD?
- liver with direct effect on blood glucose: 1, 6,8
- muscle affecting anaerobic work: 5,7
- liver and muscle: III
- various tissues without affecting blood glucose or anaerobic work: 2,4
type 1 GSD
von Gierke/G6P
hepatic tumor risk, bleeding risk
type 2 GSD
Pompe/lysosomal a-glucosidase
type 3 GSD
Forbes/debranching enzyme amylo-1,6 glucosidase
type 4 GSD
Anderson/branching enzyme
type 5 GSD
McArdles/muscle phosphorylase
type 6 GSD
Hers/liver phosphorylase
type 7 GSD
Tarui/muscle phosphoro fructokinase
type 8 GSD
phosphorylase kinase
Lactose pathway
Lactose (Lactase) galactose + glucose (galactokinase) galactose1P+UDP glucose (GALT) UDP +G1P
Fructose pathway
fructose (fructokinase) F1P (F1P aldolase - liver intestines kidney) glyceraldehyde and dihydroxyacetone
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
CP breakdown
CP > carbamyl aspartate > orotic acid > pyrimidines
which UCD product goes out and in of mitochondria
citrulline and ornithine
NH4 scavengers
benzoate and phenylacetate
if early cycle defects what can you supplement?
citrulline or for N-ag synthetase deficiency can give N-carbamyl L glutamate
how does lactulose help UCD?
intestinal bacteria turn lactulose to lactic acid and the low pH inhibits NH4 absorption`
MSUD deficiencies:
ketoacid dehydrogenases limiting the breakdown of branched chain AA (leucine, isoleucine and valine)
PKU pathway
phenyalanine (phenylalanine hydroxylase) tyrosine
- dopamine via tyrosine hydroxylase
- phenylpyruvate + fumarylacetoacetate to fumarate + acetoacetate via fumarylacetoacetate hydrolase
hydroxylases need BH4
differentiate types of tyrosinemia
- hepatorenal (also heart and bones), Faa hyrolase deficiency
- oculocutaneous + neuro, tyrosine degradation defect
- neuro, tyrosine degradation defect
transient: late fetal maturation of tyrosine pathway, some neuro impact
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
nititisone decreases risk of____
hepatocellular carcinoma
++ methionine, ++ homocysteine
homocysteinuria = cystathionine beta ssynthase deficiency
++ methionine, normal homocysteine
MAT, GMT, AH deficiency
no methionine, ++ homocysteine, normal MMA
MTHFR or Cobalamin deficiency
no methionine, ++ homocysteine, ++ MMA
cobalamin deficiency
treatment of homocysteinuria
B6 and B12, decrease methionine, increase cysteine
vit C for endothelial function
nonketotic hyperglycinemia pathway
BH4 + glycine –> methylene tetrahydrofolate + NH4 + CO2
nonketotic hyperglycinemia symptoms
in utero hiccups and seizures, burst suppression EEG –> then hypsarrhythmia, elevated CSF glycine
Treatment in nonketotic hyperglycinemia
benzoate
dextromethorphan - NMDA anatagonist may help neuro
variable response to ketogenic diet
histidinemia pathway
- histidase deficiency
- urine histidine and imidazole pyruvic acid
- ferric chloride to urine - turns blue green
cystinuria pathway
defect in AA transport –> cysteine deficiency
cystinuria diagnosis
nitroprusside test;
cystinuria treatment
- alkalinize urine
- restrict methionine
- thiol drugs (d-penicillamine, mercaptopropionylglycine)
lysinuric protein intolerance
- abnormal AA transport across cell membrane
- deficiency lysine arginine and ornithine
- hyperammonemia with lysinuria
- low serum lysine
lysinuric protein intolerance treatment
citrulline
sodium benzoate or sodium phenylbutyrate
carnitine
cholesterol if hypercholesterolemia
treat crisis like UCD
lysinuric protein complications
renal
leucine metabolism defects
isovaleric acidemia
3 methylcrotonyl glycinuria
** pathway requires biotin **
isovaleric acidemia diagnosis
- c5 acylcarnitine
- urine isovalerylglycine and isovaleric acid
- skin fibroblasts with decreased isovaleryl coa dehydrogenase activity
isovaleric acidemia treatment
- l carnitine and glycine
- limit protein
- treat nh4
isoleucine metabolism defects
proprionic aciduria
methylmalonic aciduria
lysine and tryptophan defects
glutaric aciduria type 1 (riboflavin B2 dependent)
diagnosis glutaric aciduria type 1
low enzyme activity in skin fibroblasts
neuroimaging in glutaric aciduria
frontotemporal atrophy and demyelination
abnormal C4-C5
SCHAD
abnormal C6, C8, C10:1
MCHAD
abnormal C16:1-OH, C16-OH, C18:1-OH, C18-OH
LCHAD
C14:1, C14:2, C16:1, C18:1
VLCHAD
dysostosis multiplex
mucopolysaccharidoses
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
mucopolysacchridosis triad
- dysostosis multiplex
- Alder-Reilly bodies in WBCs
- urine mucopolysaccharides
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
Mitochondrial disorders
lactate dehydrogenase
pyruvate carboxylase
pyruvate dehydrogenase
respiratory chain disorders (Avoid valproic acid and barbiturates)
Cholesterol synthesis disorders
mevalonic aciduria
smith-lemli-opitz
bile acid disorders
increase humidity ___
double walled___
plastic heat shields ___
portholes ___
rubber foam mattress___
plastic film___
evaporative
radiant
radiant
convective
conductive
convective and evaporative
wilsons dx and tx
low ceruloplasmin
d penicillamine to chelate copper
menkes dx and tx
- low ceruloplasmin
- low copper
- parenteral copper histidine
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
abnormal posturing a/w which IEM
glutaric acidemia type 1
major nonenzymatic intracellular antioxidant
glutathione
most abundant free radical
superoxide anion
Presentation of IEM
- intoxication
- acute encephalopathy
- chronic encephalopathy
- acid based disturbances - energy deficit
- problems making
- problems using - complex molecule
key strategy in acute encephalopathy IEM
- stop catabolism; provide adequate calories
- dilute toxins and promote excretion with hydration
- hemodialysis if severe
common examples leading to chronic encephalopathy
PKU and homocystinuria
IEM categories that present as intoxications
- AA disorders
- Urea Cycle defects
- Organic acidurias
- Sugar intolerances
AA disorder labs
- plasma amino and urine OA
- metabolic acidosis with urine ketones
- increased AG
UCD labs
- +++ NH4 plasma
- minimal metabolic acidosis
- respiratory alkalosis
- no liver dysfunction
- no ketoacidosis
Organic aciduria labs
- metabolic acidosis w/ urine ketones
- NH4
- glycine
- abnormal urine OA
- increased AG
sugar intolerance labs
- NBS
- urine OA
- liver enzyme analysis
Order of energy use in fasting
- blood glucose
- breakdown glycogen
- FAO
- breakdown AA
Categories of energy deficit disorders
- FAO
- glycogen storage
- mitochondrial
Presentation of FAO
- hypoketotic hypoglycemia
- hypotonia
- cardiomyopathy
- SIDS
- Reyes
Presentation of glycogen storage
- hepatomegaly
- hypoglycemia
- lactic acidosis
- FTT
Presentation of mitochondrial disorder
- lactic acidosis
- seizure
- cardiomyopathy
- hypotonia/myopathy
- +/- hypoglycemia
Presentation of complex molecule disorders
- progressive dysmorphic/coarse facies
- severe bone dysplasia
- neurologic
Types of complex molecule defects
- lysosomal storage
- peroxisomal diseases
- intracellular trafficking and processing
- IE of cholesterol synthesis
what complex molecules do lysosomes deal with
- glycosaminoglycans
- glycoproteins
- gangliosides
- glycolipids
what complex molecules do peroxisomes deal with
- bile acid and plasmalogen synthesis
- oxidation of VLCFA
- degradation of phytanic and pipecolic acids
genetics of AA metabolis is normally what type?
single gene defects
PKU pathophys
- defect in phenylalanine hydroxylase
- AR
- gene 12q24.1
- +++ plasma phenylalanine
- +++ urine phenylpyruvic acid
treatment PKU
limit phenylalanine
some forms may benefit from biopterin and 5 hydroxytryptophan and dopa (biogenic amine precursors)
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
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
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
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
diagnosis of glutaric aciduria type 1
- urine OA: increased glutaric and 3-hydroxyglutaric acids
- low carnitine
treatment of glutaric aciduria type 1
- L - carnitine
- riboflavin
- diet
- IVF with glucose when ill
homocystinuria pathophy
- AR
- chr 21q
- cystathione beta-sythetase deficiency
- marfanoid
- NDI
- lens dislocation down
- atherosclerosis
treatment of homocystinuria
pyridoxine
low methionine diet
betaine - helps convert homocysteine back to methionine
nonketotic hyperglycinemia
- AR
- intractable seizures
- hiccups in utero
- Dx: increased glycineCSF : glycineplasma
- Tx: sodium benzoate may help decrease CSF glycine
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
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
fatty acid pathway
FAO major source of energy in skeletal muscle and heart
- FA conjugated to carnitine
- carnitine-FA transported across mitochondrial membrane
- released as an acyl-Coa
- catabolized in Beta oxidation
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
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
Galactosemia diagnosis
suspect with reducing substance in urine
definitive diagnosis is deficient GALT
if sugar intake causes hypoglycemia think ___
fructose 1,6 bisphosphate aldolase deficiency
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
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
Mucolipidosis
I. Cherry red spot myoclonus snydrome
2. I cell deficiency
3. Pseudohurler
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
peroxisomal disorders
Zellweger
infantile Refsum
neonatal adrenoleukodystrophy
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
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
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
