Inborn errors of metabolism
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Transcript of Inborn errors of metabolism
INBORN ERRORS OF METABOLISM
Soumya Ranjan Parida Basic B.Sc. Nursing 4th year Sum Nursing College
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
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
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
Signs DisordersSkin abnormality- Perioral / perianal erruption Multiple carboxylase deficiency Increased pigmentation Adrenoleukodystrophy Angiokeratomas Fabry’s disease Xanthomas Hyperlipidemias Ichthyosis Refsum, Sjogren-Larsen syndrome Blond skin PhenylketonuriaHair abnormality Multiple carboxylase deficiency Menkes kinky hair diseaseDimorphic features Zellweger syndrome Gluteric aciduria type 2Hepatomegaly / HSM Niemann pick disease, Gaucher, GSDNeurological Symptoms Seen in many disordersOcular abnormalities - Cataract Zellweger syndrome, Galactosemia Heterochromia iris Zellweger syndrome Dislocated lenses Homocystinuria Retinitis pigmentosa Zellweger syndrome
Clinical pointers to neurometabolic disorders
Suspected Metabolic Disorder
Plasma NH3
High Normal
Blood ph & co2Blood ph & co2
normal normalAcidosis
No ketosis No ketosis Ketosis +/- lactic acidosis
Urea cycle defect Fatty acid oxidation defect
Organic acidemiaMitochondrial disorders
Metabolic disorders with abnormal urine odor
Inborn errors of metabolism Urine odor
Glutaric acidemia 2HawkinsinuriaIsovaleric acidemiaMSUDHypermethioninemiaMultiple coboxylase deficiencyOasthouse urine diseasePKUTrimethylaminuriaTyrosinemia
Sweaty feet, acridSwimming poolSweaty feet, acridMaple syrupBoiled cabbageTomca urinetHops-likeMousy or mustyRotting fishBoiled cabbage, rancid butter
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
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
Phenylalanine Tyrosine
4-OH-phenylpyruvate
Epoxide + cysteine
Homogentisic acid
Maleylacetoacetate
FumarylacetoacetateSuccinylacetoacetate
SuccinylacetoneFumarate Acetoacetate
Co2+H2o
PE
PP
PLPA
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, 23 Alcaptonuria 4 Hawkinsinuria5 Albinism
Methionine
Homocysteine Serine
Cystathionine
Homoserine Cysteine
Sulfate
α-ketobutyric acid
Propionic acid
Succinic
Co2+H2o
S-adenosylmethionine
S-adenosylhomocysteineBetain
FH4
MA Transferase
AH ohlase
CB synthase
Cystathionase
Sulphite oxidase
1 Methionemia2 Homocystinuria
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 synthaseASA lyase
Arginase
O aminotranferase+
NAG synthase
Urea cycle
Blood ph, HCO3
Acidosis No acidosis
Obtain organic acids
Obtain plasmaAmino 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
Citrullinemia Argininemia Arginosuccinic acidemia
HHH syndrome
OTC deficiency CPS or NAG
synthase deficiency
Than
Clinical apprach to Hyperammonia
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
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
OHCblTCװ
OHCblTCװ
OHCbl
TCװ
OHCbl+3
Cbl+2 MethylCblCbl+2Cbl+1Adensyl Cbl
MSUD MSUD MSUD
β Ketothiolase deficiency
Propionic acidemia
Methylmalonic acidemia
3-HMG aceduria
MMU+HCU
MMU+HCU
Refusal to feed,vomiting, acidosisdehydration, neutropenia, hypoglycemia
Ketosis No Ketosis or mild ketosis
No skin menifestations Skin menifestations
No odor Characteristic odor
1 Methylmalonic acidemia2 Propionic acidemia3 Ketothiolase deficiency
1 MSUD2 Isovaleric acidemia
Multiple carboxylase deficiency
1 3OH-3-methylglutaric aciduria2 Acyl CoA dehydrogenase deficiency3 HMG CoA synthase deficiency
Clinical approach to organic acidemia
Transporter OCNT2
CarnitineLong chain free fatty acid(C16-Pamitate)
Long chain free fatty acid(C16-Pamitate) Carnitine+
CPT1
CPT װ
TRANS
Carnitine cycleLC aceyl carnitine
LC fattyaceyl- CoA
Carnitine
VLCADLCAD
ETF
ETF-DH
TFP
2,3(C16-10)Enoyl CoA
C14-10 Aceyl CoA
Long chain β oxidation
MCADSCAD
ETF
ETF-DH
Hydratase
3-OH-ACDSCHAD
Thiolase
Short & medium chain β oxidation
Acetyl-CoA
HMG-CoA synthase
HMG-CoA lyase
Acetacetate
Β-HydroxybutyrateKetone 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-
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 gangliosidosisTay-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
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-GlcUDP-Gal
Lactate dehydrogenatePK
Enolase
Phosphoglycerate mutase
Phosphoglycerate kinase
G-3-P dehydrogenase
AldolaseAldolase
Phosphofructokinase
Phosphohexose isomerase
PhosphoglucomutaseGlucokinase Hexokinase
F-1,6-dptaseFructokinase
Glc-6-Pase
Galactokinase
G-1-PUT
UDP-Gal-epimerase
Galactilol
Galactoconic acid
GS
GS
Pa PbPaP
PbKa
PbKb
Oxaloacetate
Carboxylase
Carboxykinase
Glycogen, Galactose,Fructose disorders
Glucose
MucopolysaccharidosesNumber Eponym Enzyme Deficiency Stored
MPSClinical menifestations
MPS 1H
MPS 1SMPS1H/S
MPS 2MPS 3
MPS 4
MPS 6
MPS7
Hurler
ScheieHurler-Scheie
HunterSanfilippo A,B,C,D
Morquio A, B
Maroteaux-Lamy
Sly
α-L-Iduronidase
α-L-Iduronidase-
Iduronate sulfataseHepara-n- sulfatase,α-N-acetyl-glucosaminidase,α-glucosaminidase acetyltransferase,N- acetylglucosamine6-sulfatase,Galactose-6-sulfatase, β-GalactosidaseN-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 sameHyperactivity, mild somatic features, mental retardation, coarse hair, hirsuitism, sleep disorders
Odontoid hypoplasia, short trunk, IQ-N, Spleen-NIQ-N. Others same as 1
Same as 1
Mitochondria
SuccinylCoA +Glycine
ALA Synthase
ALA
PBG
HMB
Uro’gen 3Uro’gen1
Copr’ogen3Copr’ogen1 Proto’gen ix
Protoporphyrin Ix
Heam
ALA dehydratase
PBG deaminase
Uro’gen 3 cosynthase
Uro’gen decarboxylase
Copro’genoxidase
Proto’gen oxidase
ferrochelatase
ADP
AIP
CEP
PCTHEP
HCP
VP
EPP
Porphyrias
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