APPROACH TO

INBORN ERRORS OF METABOLISM

CHAIRPERSON : GUIDE :
Dr. Ajay Gaur Dr .Satvik Bansal
MD, PhD, FIAP M.D AssociateProfessor
Professor & HOD Department of Paediatrics
Department of Paediatrics GRMC Gwalior
GRMC Gwalior
PRESENTED BY :
Dr. Vineela Naravaram
Junior Resident
Department of Paediatrics
GRMC Gwalior
INTRODUCTION
 Inborn errors of metabolism ( IEM) are disorders in which there is a block at
some point in the normal metabolic pathway .
 IEM occur due to mutations in DNA
Enzyme

Receptor
DNA
Transport vehicle
which code for
Specific protein
Membrane pump

Structural element

 Mostly inherited in Autosomal Recessive manner

 Incidence upto 1 in 2497 to 1 in 1300
PATHOGENESIS

Enzyme/
cofactor
PRECURSOR SUBSTRA
PRODUCT
S TE

Alternate
metabolic pathway

TOXIC
METABOLITE
CLASSIFICATION OF IEM
Two classification systems were developed :
 Based on nosology (ICIMD) : ( Ferreira et al)
 Based on pathogenesis : ( Saudubray et al)
BASED ON
PATHOGENESIS

GROUP 1 GROUP 3
GROUP 2
INTOXICATION STORAGE
ENERGY FAILURE
DEFECTS DISORDERS

• MITOCHONDRIAL ENERGY
DEFECTS : • Peroxisomal
• Amino acid Pyruvate dehydrogenase disorders
disorders defects, FAOD • Lysosomal storage
• Organic acidemia • CYTOPLASMIC ENERGY disorders
• Urea cycle defects DEFECTS : • Congenital disorders
• Galactosemia Defects of gluconeogenesis of glycosylation
ICIMD : 24 categories 124 groups 1450 disorders
APPROACH TO INBORN ERRORS OF
METABOLISM
WHEN TO SUSPECT IEM ??
• Family H/0 Of consanguinity , sibling deaths of unexplained causes
• Sudden infant death syndrome ( MCAD deficiency )
• H/O period of normalcy Lethargy, poor feeding , and abnormal body
movements
• Symptoms that accompany starting or changes in diet
• Children with refractory seizures
• Recurrent unexplained vomitings
• Diminished exercise intolerance
• Developmental delay or regression of milestones
• Ambiguous genitalia : CAH
• Unusual odour of urine
• Persistent diarrhoea
APPROACH TO IEM
 ANTENATAL HISTORY :
• Acute fatty liver , HELLP syndrome : LCHAD deficiency
• Decreased fetal movements and arthrogyropsis : Glycogen storage type IV
• Increased fetal movements : metabolic seizures ( Pyridoxine dependant seizures , non
ketotic hyperglycinemia)
• Ante natal scan findings :
HYDROPS CORPUS ANTENATAL PERVENTRICUL OTHERS
FETALIS CALLOSUM VENTRICULOM AR CYST
AGENESIS EGALY
• Mucopolysaccha • Pyridoxine • Zellweger • PDH • Renal cyst
ridosis type IV , dependant spectrum deficiency, ( Glutaric
VII seizures, disorder, • Pyruvate aciduria
• Sphingolipidosis • Non – • Multiple carboxylase type 2)
• Zellweger ketotoc carboxylase deficiency • VACTERL
syndrome hyperglyci deficiency • (Mitochondr
nemia, ial
respiratory
chain
defects)
APPROACH TO IEM
 PHYSICAL EXAMINATION :
• DYSMORPHIC FACIES

Zellweger syndrome Mucopolysaccharidosis Smith – lemli – Opitz Glutaric

aciduria

syndrome type 2
 Head circumference :

Macrocephaly Microcephaly
Mitochondrial respiratory Glutaric acidemia type 1
chain dfects
Cobalamin metabolism Canavans disease
disorders
Smith- lemli – opitz
syndrome
Microcephaly Macrocephaly
 Macroglossia :
• Glycogen storage disorders type : Pompe disease
• Mucopolysaccharidosis
 Hair :
• Alopecia : Multiple carboxylase deficiency
• Steely or kinky hair : Menke s disease
• Trichorrhexis nodosa : Arginosuccinic aciduria
APPROACH TO IEM
 Eyes :

Corneal Cataracts Dislocated Cherry red Bull eye Retinitis

clouding lens spots maculopathy pigmentos
a

• Mucolipidosis • Classical • Cystathionine GM1 • Methylmalonic • Peroxisomal

• Mucopolysacc galactosemia ꟕ-synthase gangliosidosis acidemia disorders
haridois • Peroxisomal deficiency Tay Sachs • Homocystinuri • Abetalipopro
• Steroid disorders • Molybdenum disease a type c teinemia
sulfatse • Lowe oculo cofactor Farbers disease
deficiency cerebrorenal deficiency Galactosialidosis
• Tyrosinemia syndrome Niemann pick
type 2 disease
APPROACH TO IEM
 Skeletal dysplasias and Dysostosis multiplex :

• Mucopolysaccharidoses
• Mucolipidosis
• Galactosialidosis
• Peroxisomal disorders
• Disorders of cholesterol
synthesis
 Skin :
Thick skin Desquamating , Ichthyosis
vesiculobullous
lesions
• Mucopolysaccha • Acrodermatitis • Gauchers
ridoses enteropathica disease type
• Mucolipidoses • Hartnup disorder 2
• Porphyrias • Steroid
sulfatase
APPROACH TO IEM
 HEPATOMEGALY  HEPATOSPLENOMEGALY

• Disorders of fructose and • Mucopolysaccharidoses

galactose metabolism. • Niemann-Pick disease
• Glycogen storage disorders • Sphingolipidosis
• Disorders of Gluconeogenesis • Farber disease
• FAOD
• Urea cycle defects

 DYSTONIA :

• Gauchers disease type 1

• Glutaric acidemia type 1
• Krabbe disease
• Crieggler vnajjar syndrome
APPROACH TO IEM
IEM WITH PECULIAR URINE ODOUR PERSISTENT
DIARRHOEA
URINE ODOUR METABOLIC DISORDER CAUSES
Maple syrup , Burnt sugar Maple syrup urine disease
Glucose- galactose
Musty or Mousey Phenylketonuria malbsorption
Cat urine Multiple carboxylase Congenital lactase deficiency
deficiency
Rotten fish Trimethylaminuria Congenital chloride deficiency

Boiled cabbage , Rancid Tyrosinemia type 1

Acrodermatitis enteropathica
butter
Boiled cabbage Hypermethioninemia
Abetalipoproteinemia
Sulfur Cystinuria
Classical galactosemia
Swimming pool Hawkinsinuria
APPROACH TO IEM
MAJOR ORGAN SYSTEMS INVOLVEMENT :
 CNS :
• Deterioration in level of consciousness : Metabolic acidosis , Hyperammonemia, Hypoglycemia
• Seizures :
Pyridoxine dependant epilepsy, Pyridoxine – phosphate responsive epilepsy
Biotinidase deficiency
• Hypotonia :
Mitochondrial diseases
Zellweger syndrome
Glycine encephalopathy
Sulfite oxidase / Molybdenum cofactor deficiency
• Apnea : MSUD , Urea cycle disorders , FAOD
• Strokes : MELAS , Homocystinuria
• Developmental delay , Regression of milestones
• Dystonia
APPROACH TO IEM
 LIVER DYSFUNCTION : LIVER
DYSFUNCTION

Hepatomegaly with
Cholestatic jaundice Liver failure
hypoglycemia

Inborn errors of bile Galactosemia

Glycogen storage acid metabolism
disease

Zellweger
syndrome FAOD

Fructose 1,6
bisphophstase
deficiency Alpha – 1 Hereditary
antitrypsin fructose
deficiency intolerance
APPROACH TO IEM
 CARDIAC DYSFUNCTION : ENDOCRINE
DYSFUNCTION :
• FAOD  Congenital Hypothyroidism
• Glycogen storage disorder : Congenital adrenal
Type 2 : Pompe disease hyperplasia
Type 3 : Debranching enzyme Adrenoleucodystrophy
deficiency Hyperinsulinemic
• Lysosomal storage disorders : hypoglycemia
Fabry disease
Mucopolysaccharidosis
• Mitochondrial respiratory chain
disorders

 HAEMATOLOGICAL :
• Anaemia, leucopenia , Thrombocytopenia : Organic acidemia
• Transcobalamin deficiency , Gastric IF deficiency : mimics leukaemia
APPROACH TO IEM
MANAGEMENT OF IEM :
 Initial investigations : Laboratory findings that
Complete blood count with differential prompt metabolic workup :
Serum Glucose • Hypoglycemia
Arterial blood glucose GALAK • Metabolic acidosis
Plasma lactate • Lactic acidosis
Plasma Ammonia • Hyperammonemia
Blood and urine ketones • Ketosis
RFT, LFT , Se electrolytes
Urine reducing substances , pH
INTERPRETATION BASED ON GALAK INVESTIGATIONS
APPROACH TO IEM
APPROACH TO HYPOGLYCEMIA

HYPOGLYCEMIA

Without
With ketosis
ketosis

High Normal High Normal

lactate lactate lactate lactate

• Organic • FAO • Hyperinsulinis

• FBP ase
acidemia defect m
deficiency
• GSD type 1 • Adrenal • HMG Co A • HMG CoA
• Mitochondrial insufficienc lyase synthetase
diseases y deficiency deficiency
 APPROACH TO IEM METABOLIC
ACIDOSIS
With ketosis Without Ketosis

NH3 Normal NH3 High lactate Normal lactate

High Normal High Normal

lactate Glu N Glu
lactate lactate lactate

• PC Organic FAOD
def Glu N Glu Glu N Glu PDH Renal
•
cidemia HMG
HCS
deficie tubular
def Co A
ncy acidosis
• FBP ase lyase
def • PC def Organic Organic
• GSDType • HCS def acidemia acidemia
1 • Mitocho Adrenal MSUD
• Mitochon ndrial insufficie Ketolysis
drial d/s ncy defcts
d/sc
 APPROACH TO IEM
Hyperammonemia

Metabolic acidosis No acidosis

Organic LOW/N
Lactate GLUTAMINE
acids in GLUTAMINE
urine , Acyl
carnitine
CITRULLINE CITRULLINE

Organic
PC CITRIN OROTI
acidemia /
FAOD deficiency DEFICIENCY C ACID
LEVEL
ASA LEVEL

HIGH CPS DEF

OTC DEF. CAVA DEF
ARG DEF HIGH LOW
HHH ASAL DEF. ASAS DEF
 REFRACTORY
SEIZURES
NH3 , ABG - N

GALAK – Abnormal
(FAOD,UCD,OA,MSUD) IV Pyridoxine
Controlled Uncontrolled
PDS Trial of P5P/FA
AASA/Pipecolic Not controlled
acid PPNPO/FA
responsive
CSF : Plasma seizures
Glucose ratio N
<0.5 Plasma and
GLUT CSF AA
Serine Low CSF
Glycine and CSF : plasma
syn Glycine ratio
serine
defct

• Molybdenum <0.08 > 0.08

cofactor def
• Sulfite
oxidase def
NKH
MANAGEMENT OF IEM
SPECIALIZED INVESTIGATIONS :
 TMS -Tandem Mass spectrometry
 GCMS – Gas Chromatography Mass Spectrometry : Urine Organic acid analysis
 Plasma Amino-acid analysis
 Plasma carnitine and acyl carnitine levels : FAOD
 VLCFA : Peroxisomal disorders
 Homocysteine : Homocystinuria
 Urine guanidino acetate : Disorders of Creatine metabolism
 Cholesterol , Triglycerides : Glycogen storage disorders, Smith – lemli – opitz syndrome
 Transferrin isoelectric focussing : Congenital disorders of glycosylation
 Lactate / Pyruvate ratio : PDH , PC Deficiency , Mitochondrial disorders
 Specific enzyme assays : Storage disorders
 CSF glucose , lactate and aminoacids
 DNA based studies for molecular analysis
MANAGEMENT OF IEM
 IMAGING :
USG : for hydrops fetalis , Hepatomegaly , Hepatosplenomegaly ( storage disorders)
Echo, ECG , X- Ray : cardiac involvement – Pompes disease , Fabrys disease
MRI , MRS :

PA – edema in Corpus callosum MSUD – Double ZS -

basal ganglia agenesis swan appearance Polymicrogyria

GENETIC TESTS :
CMA ( Chromosomal microarray)
WES ( Whole exome sequencing)
WGS ( Whole genome sequencing)
MANAGEMENT IN IEM
 PRENATAL DIAGNOSIS :
INDICATIONS :
• Previously effected child
• Carrier parents – Autosomal recessive
• A woman is known to be a carrier or is at risk of being a carrier of a X-
linked recessive disease
• Abnormalities such as fetal hydrops or visceromegaly
HOW TO DO ??
CVS / Amniocentesis – for enzyme activity or genotyping
Substrate or metabolite profiling in the amniotic fluid supernatant
TREATMENT OF IEM
 PRINCIPLES OF TREATMENT OF IEM :
Increase enzyme
activity

A B C D
Decrease
Substrate E Increase Provide
deficient
availability disposal metabolites
of toxic

F metabolites
Treatment of IEM
ACUTE METABOLIC CRISIS :
 SUPPORTIVE THERAPY :
• Temperature maintainence
• Airway , Breathing : Ventilation
• Circulation : Shock – Avoid Ringer lactate and other hypotonic fluids
• Hypoglycemia
• Dyselectrolytemia
• Sepsis :
Galactosemia : E. coli sepsis
Multiple carboxylase deficiency : Candida sepsis
Metronidazole
Organic acidemia : PA , MMA : Gut bacteria s/b eradicated :
Neomycin
• Metabolic acidosis : IV Sodium bicarbonate
TREATMENT IN IEM
 Specific therapy :
SUBSTRATE REDUCTION THERAPY :
 Immediate discontinuing feeding – main source of protein and lipid
 Calorie intake : 20 % - Glucose infusion
 FAOD : Intralipid infusion avoided
MCAD deficiency : MCT supplementation avoided
 Breast milk after 24 – 48 hrs except : Galactosemia , VLCAD
 Protein should never be with held > 24 – 48 hrs of life - break down of endogenous
proteins
 Protein is started with 25% of requirement with gradual increment.
 Special formula consisting of EAA’s WITHOUT THE OFFENDING AMINOACID is
initiated.
 At discharge – quantified amount of BM and special formula
TREATMENT IN IEM
 MEDICATIONS :
Metronidazole - OA (Organic acid from odd chain fatty acid )
Triheptanonin – Long chain FAOD
Nitosinone ( NTBC ) – Tyrosinemia type 1Nitosinone
PROVISION OF DEFICIENT METABOLITE : ELIMINATION OF TOXIC
METABOLITES
• Glucose deficient : Adequate
• IV Hydration
dextrose infusion
• Carnitine ( organic acidemias)
• L- Carnitine : Carnitine uptake
• Sodium benzoate ( UCD)
defect , Organic acidemias
• Glycine ( Isovaleric acidemia)
• Urea cycle defects : L- Arginine
• Hemodialysis /CVVH
( except Argininemia), L- Citrulline
• Peritoneal dialysis
• Pyridoxine dependant seizures –
• DVET
Pyridoxine
TREATMENT IN IEM
INCREASE IN ENZYME ACTIVITY :
 Organic acidemias :
Biotin ( PA) , Vitamin B12 ( MMA)
 Aminoacidopathy :
Thiamine ( 300 mg / day ) in MSUD
 Congenital Lactic acidosis :
Thiamine 300 mg / day in MSUD
Ribofalvin ( 100 mg / day)
Coenzyme Q (5 – 15 mg/day) in Respiratory chain defects
ROLE OF LIVER TRANSPLANTATION
Urea cycle defects - > 90 % 5 year
survival
Tyrosinemia - > 95 % survival
Organic acidemia

GENE THERAPY
 DIET MANAGEMENT IN IEM
CONDITION PRINCIPLE INFANTS < 6 ON FOLLOW- MONITORING
MONTHS UP
MSUD Natural Breast milk Vegetarian Leucine levels
protein source (30 – 50 %) + diet + MSUD < 200 µmol/L
+ syn MSUD formula formula
( leu , Val , Iso)
Tyrosinemia Protein except NTBC + Breast NTBC + 200 – 600
type 1 Tyrosine milk + Vegetarian µmol/L
Tyrosinemia diet +
formula Tyrosinemia
formula
UCD Natural Natural Vegetarian Ammonia ,
protein + High protein + diet Glutamine <
energy source( AAMD formula 1000 µmol/L
Synth protein
MCAD Avoid fasting Frequent Vegetarian
feeding diet
Galactosemia Lactose free Soya milk- Lactose free Galactose-1
diet based formula diet phosphate
BM – C/I
DIET MANAGEMENT IN NEWBORN AT RISK OF IEM
 WHAT ARE SCREENED FOR ??
 NEW BORN SCREENING : A. PROTEIN METABOLISM
DISORDERS
COMPONENTS OF NEWBORN SCREENING PROGRAM :
• New born screening test Amino acid disorders
• Follow up of patient with abnormal Organic acidemias
results Urea cycle defects
• Diagnostic evaluation
• Disease management in true
B. LIPID METABOLIC AND
positives KETOGENESIS DISORDERS
• Continuous evaluation and
improvement of the newborn Carnitine uptake defects
screening system CPT I & II deficiency
PROCEDURE : MCAD
LCHAD
VLCHAD
HMG CoA lyase deficiency
OTHERS :

Biotinidase deficiency
Galactosemia
TAKE HOME MESSAGE

 IEM are individually rare , but collectively common.

 High index of suspicion is essential for the diagnosis

 Algorithm approach helps to clinch the diagnosis

 Estimation of ammonia and baseline investigation in any sick

neonate increase the detection rate.
REFERENCES
 Nelson Textbook of Paediatrics : Volume 1 : Edition 22
 Piyush gupta Text book of Pediatrics
 Cloherty and Stark’s Manual of Neonatal Care : Second edition
 AIIMS NICU protocol
 Schillaci L-AP, DeBrosse SD, McCandless SE. Inborn errors of metabolism with
acidosis: Organic acidemias and defects of pyruvate and ketone body
metabolism. Pediatr Clin North Am. 2018;65(2):209–230.
 Summar ML, Mew NA. Inborn errors of metabolism with hyperammonemia: Urea
cycle defects and related disorders. Pediatr Clin North Am. 2018;65(2):231–246.
 Weinstein DA, Steuerwald U, De Souza CFM, Derks TGJ. Inborn errors of
metabolism with hypoglycemia: Glycogen storage diseases and inherited
disorders of Gluconeogenesis. Pediatr Clin North Am. 2018;65(2):247–265.