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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