Inborn errors of metabolism

Inborn errors of metabolism

1. INBORN ERRORS OF METABOLISM
Soumya Ranjan Parida
Basic B.Sc. Nursing 4
th
year
Sum Nursing College

2. INBORN ERRORS OF METABOLISM
Introduction –
Inborn errors of metabolism are a group of metabolic disorders
caused by deficiency of an enzyme required for the formation of a
protein or for catalyzing a biochemical reaction in body.
IEM are divided into six subgroups –
1 Aminoacidurias
a) Disorders of aminoacid metabolism
b) Urea cycle defects
c) Disorders of fatty acid oxidation
d) Disorders of organic acids
2 Disorders of carbohydrate metabolism
3 Lysosomal storage defects
4 Peroxisomal disorders
5 Endocrine disorders
6 Miscellaneous diseases

3. Diagnostic approach to neurometabolic disorders
When to suspect IEM
History of unexplained deaths in the neonatal period
Parental consanguinity
In the neonatal period –
Lethargy, poor feeding, persistent vomiting, intractable seizures,
tachypnea, floppyness, unusual body/ urine odor, failure to thrive
Always r/o sepsis and HIE
On examination –
Skin and hair changes,
Hepatomegaly,
Jaundice,
Hypotonia,
Unexplained neurological signs and coma,
Ambiguous genitalia

4. Diagnostic approach to neurometabolic disorders
Older children –
- Recurrent episodes of sensorial derangement,
- Vomiting, hypotonia,
- Hypoglycemia and acidosis
- Unexplained development delay with or without seizures,
- Mental retadation,
- Organomegaly,
- Coarse facies,
- Cataract,
- Dislocated lenses,
- Chronic skin lesions,
- Abnormal hair and urine color,
- FTT

5. Signs Disorders
Skin abnormality-
Perioral / perianal erruption Multiple carboxylase deficiency
Increased pigmentation Adrenoleukodystrophy
Angiokeratomas Fabry’s disease
Xanthomas Hyperlipidemias
Ichthyosis Refsum, Sjogren-Larsen syndrome
Blond skin Phenylketonuria
Hair abnormality Multiple carboxylase deficiency
Menkes kinky hair disease
Dimorphic features Zellweger syndrome
Gluteric aciduria type 2
Hepatomegaly / HSM Niemann pick disease, Gaucher, GSD
Neurological Symptoms Seen in many disorders
Ocular abnormalities -
Cataract Zellweger syndrome, Galactosemia
Heterochromia iris Zellweger syndrome
Dislocated lenses Homocystinuria
Retinitis pigmentosa Zellweger syndrome
Clinical pointers to neurometabolic disorders

6. Suspected Metabolic Disorder
Plasma NH3
High
Normal
Blood ph & co2
Blood ph & co2
normal normalAcidosis
No ketosis No ketosis Ketosis +/-
lactic acidosis
Urea cycle defect
Fatty acid
oxidation defect
Organic acidemia
Mitochondrial disorders

7. Metabolic disorders with abnormal urine odor
Inborn errors of metabolismUrine odor
Glutaric acidemia 2
Hawkinsinuria
Isovaleric acidemia
MSUD
Hypermethioninemia
Multiple coboxylase deficiency
Oasthouse urine disease
PKU
Trimethylaminuria
Tyrosinemia
Sweaty feet, acrid
Swimming pool
Sweaty feet, acrid
Maple syrup
Boiled cabbage
Tomca urinet
Hops-like
Mousy or musty
Rotting fish
Boiled cabbage, rancid butter

8. Laboratory investigations
Blood investigations –
TLC, DLC, blood sugar, serum electrolytes, serum
ammonia, lactate and pyruvate, liver enzymes and ABG.
Urine metabolic screen –
Ph, ketones, odor, reducing substances, special urine
tests such as Fecl3, DNPH, nitropruside and
toluidine blue spot test, chromatography

9. Management
Empirical management –
•Stop oral feeds
•Start IV fluids
•Co-factor therapy
•Correct dehydration,acidosis, dyselectrolytemia
•Provide cardiorespiratory support
•Start specific therapy
•Peritoneal dialysis
•Hemodialysis
•Exchange blood transfusion

10. Phenylalanine Tyrosine
4-OH-phenylpyruvate
Epoxide + cysteine
Homogentisic acid
Maleylacetoacetate
FumarylacetoacetateSuccinylacetoacetate
Succinylacetone
Fumarate Acetoacetate
Co2+H2o
PE
PP
PL
PA
PAG
4-oH PA
Glutamine
DOPA
Dopamine
NE E
DOPA
DOPAquinone
Melanin
ohlase
ohlase
Tyrosinase
Aminotransferase
Dioxygenase
Dioxygenase
HA oxidase
Isomerase
ohlase
Hawkinsine
1 PKU 2 Tyrosinemia 1, 2
3 Alcaptonuria 4 Hawkinsinuria
5 Albinism

11. Methionine
Homocysteine
Serine
Cystathionine
Homoserine Cysteine
Sulfate
α-ketobutyric acid
Propionic acid
Succinic
Co2+H2o
S-adenosylmethionine
S-adenosylhomocysteine
Betain
FH4
MA Transferase
AH ohlase
CB synthase
Cystathionase
Sulphite oxidase
1 Methionemia
2 Homocystinuria

12. Ornithine
Citrulline
Argininosuccinic acid
Arginine
Carbamyll phosphate
NH3+co2+ATP
Glutamate Glutamine
+
Phenylacetic acid
Glycine + Benzoyl CoA Hippurate
Glutamic acid
Acetyl CoA
N-Acetyl-glutamic acid (NAG)
CPS
OTC
ASA synthase
ASA lyase
Arginase
O aminotranferase
+
NAG synthase
Urea cycle

13. Blood ph, HCO3
Acidosis No acidosis
Obtain
organic acids
Obtain plasma
Amino acidosis
Specific amino
acid elevation
No specific amino
acic elevation
Obtain urine
orotic acid
High Normal or low
Obtain plasma citruline
Low
Normal or elevated
Organic
acidemia
CitrullinemiaArgininemia
Arginosuccinic
acidemia
HHH
syndrome
OTC
deficiency
CPS or NAG
synthase deficiency
Than
Clinical apprach to Hyperammonia

14. Treatment of hyperammonemia
•Provide adequate calories, fluid and electrolytes
•Give priming dose of following –
•To be added to 20 ml/kg of 10% glucose and infuse with in 1-2
hours
Sodium benzoate 250mg/kg
Sodium phenylacetate250mg/kg
Arginine hydrochloride 200-600mg/kg
•These compounds are prepared as 1-2% solution for IV use
•Higher doses are needed for Citrullinemia and argininsuccinic
aciduria
•Continue infusion of above following the priming doses
•Initiate peritonial or hemodialysis if above treatment fails

15. Valine Isoleucine Leucine
2-Ketoisovaleric acid 2- Keto-3-methylvaleric acid 2-Ketoisocaproic acid
Methacrylyl-CoA Tiglyl-CoA Methylcrotonyl-CoA
Methylmalonyl-CoA Methylactoacytal-CoA Methylglutaconyl-CoA
D-Methylmalonyl-CoA Propionyl-CoA 3-OH-3-CH3gluterul-CoA
L-Methylmalonyl-CoA
Succinyl-CoA
CO2+H2O
Acetoacetic acid+Acetyl CoA
Acetone
OHCbl
TCװ
OHCbl
TCװ
OHCbl
TCװ
OHCbl+3
Cbl+2 MethylCbl
Cbl+2
Cbl+1Adensyl Cbl
MSUD
MSUD
MSUD
β Ketothiolase deficiency
Propionic acidemia
Methylmalonic
acidemia
3-HMG aceduria
MMU+HCU
MMU+HCU

16. Refusal to feed,vomiting, acidosis
dehydration, neutropenia, hypoglycemia
Ketosis No Ketosis or
mild ketosis
No skin menifestations Skin menifestations
No odor Characteristic odor
1 Methylmalonic acidemia
2 Propionic acidemia
3 Ketothiolase deficiency
1 MSUD
2 Isovaleric acidemia
Multiple carboxylase
deficiency
1 3OH-3-methylglutaric
aciduria
2 Acyl CoA dehydrogenase
deficiency
3 HMG CoA synthase
deficiency
Clinical approach to organic acidemia

17. Transporter OCNT2
Carnitine
Long chain free fatty acid(C16-Pamitate)
Long chain free fatty acid(C16-Pamitate)Carnitine+
CPT1
CPT װ
TRANS
Carnitine cycle
LC aceyl carnitine
LC fattyaceyl- CoA
Carnitine
VLCAD
LCAD
ETF
ETF-DH
TFP
2,3(C16-10)
Enoyl CoA
C14-10 Aceyl
CoA
Long chain
β oxidation
MCAD
SCAD
ETF
ETF-DH
Hydratase
3-OH-ACD
SCHAD
Thiolase
Short & medium chain
β oxidation
Acetyl-CoA
HMG-CoA synthase
HMG-CoA lyase
Acetacetate
Β-Hydroxybutyrate
Ketone synthesis
HMG-CoA
LC aceyl carnitine
Enoyl CoA
3-OHaceyl-CoA
3-Ketoaceyl-CoA
C8-4 Aceyl-CoA
Medium chain fatty acid
Leucine
TCA cycle
Respiratory chain
e-

18. Gal—Nacgal—gal—glc—ceramide
NANA
Gal—Nacgal—gal—glc-ceramide
NANA
NAcgal—gal—glc-ceramide

NANA
Gal—glc-ceramide
NANA
Gal—glc-ceramide
Glc-ceramide
ceramide Sphingosine+fatty acid
PC-ceramide
SO4
Gal--ceramide Gal-ceramide
Neurominidase
Sialidosis
GM1 gangliosidosis
Gm1 gangliosidosis
β-Hexosaminidase
GM2 gangliosidosis
Tay-sachs,Sandhoff
Lactosylceramide β-galoctsidase
Gm1 gangliosidosis, Krabbe disease
Glucosylceramide β-galoctsidase
Gaucher disease
Sufatide sulfatase
Metachromaticleukodytrophy Krabbe disease
Lactosylceramide
β-galoctsidase Ceramidase
Farberdisease
Sphingomyelinase
Niemann-Pick disase
Lipidoses

19. Gly
Gly
GlyGly
BrancherDebrancher
Glc-1-P
Glc-6-P
F-6-P
F-1,6-P2
Glyceraldehyde-3-P
1,3-Biphosphonate
3-Phosphoglycerate
2-Phosphoglycerate
Phosphoenolpyruvate
Pyruvate Lactate
Mitochondria
GLUT2
GLUT2
Fructose
Galactose
Gal-1-P
Glucose
FructoseF-1-P
DHA-P
GLUT2
GLUT2
Trans-
locase
RPR
Glc-6-P
Glucose
Glycogen
Glucose
α--Glucosidase
UDP-Glc
UDP-Gal
Lactate dehydrogenate
PK
Enolase
Phosphoglycerate mutase
Phosphoglycerate kinase
G-3-P dehydrogenase
AldolaseAldolase
Phosphofructokinase
Phosphohexose isomerase
Phosphoglucomutase
Glucokinase Hexokinase
F-1,6-dptase
Fructokinase
Glc-6-Pase
Galactokinase
G-1-PUT
UDP-Gal-epimerase
Galactilol
Galactoconic acid
GS
GS
Pa Pb
PaP
PbKa
PbKb
Oxaloacetate
Carboxylase
Carboxykinase
Glycogen, Galactose,
Fructose disorders
Glucose

20. Mucopolysaccharidoses
Number Eponym Enzyme Deficiency Stored
MPS
Clinical menifestations
MPS 1H
MPS 1S
MPS1H/S
MPS 2
MPS 3
MPS 4
MPS 6
MPS7
Hurler
Scheie
Hurler-Scheie
Hunter
Sanfilippo
A,B,C,D
Morquio A, B
Maroteaux-
Lamy
Sly
α-L-Iduronidase
α-L-Iduronidase
-
Iduronate sulfatase
Hepara-n- sulfatase,
α-N-acetyl-
glucosaminidase,
α-glucosaminidase
acetyltransferase,
N- acetylglucosamine
6-sulfatase,
Galactose-6-sulfatase,
β-Galactosidase
N-Acetylgalactosamine-4-
sulfatase
β-Glucuronidase
DS,HS
DS,HS
-
DH, HS
HS
KS
DS
DH, HS
MR,CHD, corneal clouding, coarse
facies, dysostosis multiplex, HSM,
hydrocephalus, joint stiffness hearing
loss.
Intelligence, life spanand stature are
normal. Others same as above
-
Intelligence-N. Others same
Hyperactivity, mild somatic features,
mental retardation, coarse hair,
hirsuitism, sleep disorders
Odontoid hypoplasia, short trunk, IQ-N,
Spleen-N
IQ-N. Others same as 1
Same as 1

21. Mitochondria
SuccinylCoA
+
Glycine
ALA Synthase
ALA
PBG
HMB
Uro’gen 3Uro’gen1
Copr’ogen3
Copr’ogen1 Proto’gen ix
Protoporphyrin Ix
Heam
ALA dehydratase
PBG deaminase
Uro’gen 3
cosynthase
Uro’gen
decarboxylase
Copro’gen
oxidase
Proto’gen
oxidase
ferrochelatase
ADP
AIP
CEP
PCT
HEP
HCP
VP
EPP
Porphyrias

22. THANKS