Clinical suspicion of inborn errors of metabolism should arise with parental consanguinity, positive family history, unexplained sibling deaths, or recurrent issues like hypoglycemia, acidosis, or encephalopathy. Initial screening tests available in India can help identify aminoaciduria, organic acidemias, or fatty acid oxidation defects while definitive testing requires samples not readily available, like fresh tissue, to analyze specific enzyme activities. Managing treatable conditions like hereditary fructose intolerance or some organic acidemias can improve outcomes.

2. Clinical suspicion of
metabolic liver disease
• Parental consanguinity
• Positive family history
• Sibling deaths
Sudden unexplained /
Neuropsychiatric illness/
Seizure disorder/ Myopathies

3. Inborn errors ± Liver involvement
Aminoaciduria 21-70%
Incidence in SE Asia
Organic acidemia 12-51% 1:2000-9300 live births
Fatty Acid Ox Defects 7-27%
Condition Incidence/ live births in West Treatable
Hereditary Fructose Intolerance 1:20,000 yes
Galactosemia 1:40,000-60,000 yes
Cong dis of Glycosylation 1b 1:40,000 (Danish) yes
Wolman’s ds 1:50,000 no
Gauchers 1:100,000 yes
Primary hyperoxaluria 1:120,000 yes
Niemann-Pick Type C 1:150,000 no
Neonatal Hemochromatosis NA yes
Bile acid synthetic defects NA yes

4. Persisting into adulthood
Children Adults
Presenting for the first time
Family history
Diet history
Past history

5. Hereditary Fructose Intolerance
Infant on breast milk

6. Screening Definitive
(available in India) (not available in India)
Aldolase B
Urine (enzyme assay);
Non- glucose reducing Labs. to develop in India,
substances + tissue based
 Liver <15% of normal,
best liver biopsy sample
 Small Intestine
(in presence of coagulopathy)
Liver Bx: “Fructose holes” in EM Gene mutations (20) in 9q

7. Niemann-Pick Disease
Type A Type B Type C (important)
(neuronopathic) (non-neuronopathic)
Deficiency of enzyme – Cholestrol trafficking
Sphingomyelinase effect
(Detection in WBC, fibroblasts) Not related to enzyme
Neurological Respiratory Liver (45-65%) ±
Liver: rare Liver: rare Neurological
 Neonatal cholestasis (20-30%) with splenohepatomegaly
Rarely decompensation and liver failure
 Older children (50-70%) : Splenohepatomegaly with
cirrhosis /portal hypertension
 Liver adenomas (rarely)

8. Splenohepatomegaly with liver disease
Bone marrow: Foam cells
Condition Enzymatic defect Hallmark
GM1 gangliosidosis B- galactosidase Dysostosis
multiplex, cherry
red spot
Gaucher types I,II, III B- glucoronidase
Niemann Pick A and B Sphingomyelinase
Niemann Pick C Cholesterol and Vertical
lipid trafficking ophthalmoplegia
defect ataxia
Wolman ds / Cholestrol Acid estrase Adrenal
ester storage ds calcification

9. Screening Definitive
(available in India) (NOT available in India)
Bone marrow/Liver Filipin testing
histology : foam cells (Accumulation of intracytoplasmic
(D/D: Gauchers, Wolman, unesterified cholesterol)
GM1 gangliosidosis) To develop in India
Plasma chitotriosidase
20-30X elevated than Enzyme analysis
normal not to be done
(also abnormal (cholesterol trafficking defect)
in Gauchers)
Available in India
Gene mutations (2)

10. Intracytoplasmic unesterified cholesterol

11. Wolman’s disease
Stormy
onset
First 2 weeks of life
Death
3-6mo

12. Supportive Definitive Definitive
(available in India) (NOT available
in India)
Hypertriglyceridemia Enzyme assay: Gene
Hypercholestrolemia Acid Lipase mutations
(<10% of normal) 10q
Foamy Histiocytes in WBC, skin fibroblasts (LIPA gene)
BM/Liver
Antenatal Diagnosis
(vacuolated
chorionic villous sampling
hepatocytes) (<12 weeks) Aut. Recessive

13. Congenital Disorders of Glycosylation
CDG 1a CDG 1b (IMPORTANT) Other types
Hypoglycemia
Neurological Recurrent thrombosis/ No Liver /GI
Dysmorphism Coagulopathy manifestations
(inverted nipples, (imbalance in pro- and anti-
abnormal pads of fat, coagulant factors) Neurological/
almond shaped eyes) Protein losing enteropathy Musculo-skeletal
and/or
Rarely liver Congenital hepatic fibrosis no Rx
Transaminitis (moderate)
Cirrhosis / Liver Failure
Death by 2 yrs, no Rx Begins in infancy
Oral Mannose (100-150 mg/kg/dose 5 times a day) ?Cryptogenic
May survive into adulthood Liver disease

14. Congenital Disorders of Glycosylation
Mannose-6-phosphate isomerase
Phosphomannomutase 2
Biosynthesis of the Lipid-Linked Oligosaccharide and Localization of the
Early Glycosylation Defects.
Square: N-acetylglucosamine; circle: mannose; rhomb: glucose

15. Specific Definitive
Supportive (NOT available in (NOT available in
India) India)
Quantitative :
Serum Enzyme assay:
Small bowel histology chromatographic
in patients with GI carbohydrate Phosphomannose
symptoms: deficient transferrin Isomerase (1b)
assay
Villous atrophy (x10-20 fold) Phosphomanomutase
Lymphangiectasia (Ia)
Qualitative:
Isoelectric focusing WBC, liver
of serum transferrin -
cathodal shift
Most commonly used
Antenatal diagnosis

16. Non-ketotic hypoglycemia
± High CPK
± Developmental delay
FAOD

17. Fatty Acid Oxidation Defects
Screening Definitive
(available in India) (NOT available in India)
Quantitative Fatty acid analysis
Hypoketotic / Non-ketotic C8-10 in MCAD
hypoglycemia (in majority) C14-18 in LCHAD
C14 in VLCAD
GCMS: Urinary organic acid and
acylglycine assay (available) Enzyme activity in cultured skin
Tandem MS: Plasma carnitine and fibroblasts or muscle biopsy
acylcarnitine assay (available) Carnitine def. also
•Very low levels reaching zero:
primary carnitine def
•25-50% reduction: Other FAOD

18. Respiratory Chain Defects
Available in India

19. Definitive Tests Sample Availability
in India
Ragged red fiber Muscle Yes
(Histology)
Analysis of oxygen Liver, muscles, fibroblasts No
consumption fresh biopsy specimens
Polarographic studies required (5-10gm)
Enzymatic activity of Frozen samples No
respiratory chain (liver, kidney, myocardium)
complexes larger tissue (open
surgical in most centers)
Mt DNA deletions and Muscle No
mutations

20. Organic acidemia
Condition Features Specific Treatment
Propionic acidemia None
Liver failure
Methylmalonenic Pancreatitis Vitamin B12 1mg/day
acidemia (MMA) (13mo-9y)
Neutropenia
Isovaleric acidemia Glycine 250mg/kg
Low Protein diet
Carboxylase Reye syndrome, Biotin 20-50mg/day
deficiency Skin exfoliation
HMG CoA Lyase def Reye syndrome None
Beta ketothiolase def Fatty liver None

21. Organic acidemia
Condition Urine Ammonia Lactate Glucose
ketones
Propionic acidemia Very High normal High/Nl/
Methylmalonenic ++++ (>100µM) Low
acidemia (Massive)
Isovaleric acidemia
Carboxylase ++ High Very High normal
deficiency
HMG CoA Lyase Absent High/Nl High Low
def
Beta ketothiolase ++ High/Nl normal Low
def

22. Organic acidemia
Diagnosis
Urinary organic acid GCMS: Screening
Enzyme levels fibroblasts: definitive

23. Courtesy: Dr Moinak Sarma

24. Urea Cycle
Defects
Intermittent
Child/Adult

26. Investigations Available
in India
Amino acid analysis by GCMS Urine Yes
Screening Plasma
Enzyme levels (confirmatory)
• Carbomyl Phosphatase Fresh liver
deficiency Type 1 tissue in
• Ornithine transcarbamylase liquid No
•N acetyl Glutamate synthetase nitrogen
deficiency Comment
• Arginino succinic synthetase Difficult
• Arginino succinic Lyase Fibroblast
deficiency
• Arginase RBC

27. Treatment of urea cycle disorders

28. Bile Acid Synthetic Defects
Supportive Definitive
(Not available in India)
Plasma bile acid profile
(low or absent cholic or
chenodeoxycholic acid,
Increased intermediary metabolites)
Low or normal GGT
Fast Atom Bombardment
NCS, Rickets,
Tandem Mass Spectrometry –
no pruritus
Urinary bile acid metabolites

29. Negative for Bile acid disorder

30. Primary Hyperoxaluria
Infancy (20%) Childhood (>50%) Adults (20%)
90% Recurrent Occ. stones
Nephrocalcinosis urolithiasis
20% Nephrolithiasis Often UTI
20% Recurrent UTI
ESRD 80% at diagnosis Nearly all by 3rd
50% by 3yr decade
Recurrence after renal transplant
Death by 5yr

31. Screening Definitive
(not available in India)
Imaging
Stones/ nephrocalcinosis Liver biopsy: AGT activity
RFT, GFR
50%-70%: undetectable levels
30%-50%: substantial residual
24 hr urine oxalate
+ compounds:
Glycolate Gene mutations
L-Glycerate

32. Normal values
Disease 24 hr Oxalate excretion 24hr L-Glycerate excretion
mmol/1.73m2/d mmol/mmol creat
Primary I >1 6-28
Primary II 0.5-1.0 >28

33. Summary of investigations

34. Disease Diagnosis Sample India
Herediary Aldolase B Liver tissue (best)
Not available
fructose- intol. (enzyme assay) Small bowel bx. Important ,
treatable
Niemann-Pick Filipin testing Staining of skin Not available
Disease Type C fibroblasts Histopathologist
Wolman’s Acid Lipase WBC ( cheaper), Available
disease Fibroblasts (Sandor)
Antenatal : yes
CD Isoelectric serum transferrin Not available
Glycosylation focusing -cathodal shift
1b Screening, Important ,
not specific treatable
Enzyme not feasible

35. Disease Diagnosis Sample India
FAOD Screening Blood and urine Sandor, Neogen
(TMS/GCMS)
Confirmatory Enzymes skin Not available
fibroblasts
Organic aciduria Screening Blood and urine Sandor, Neogen
(TMS/GCMS)
Confirmatory Enzymes skin Not available
fibroblasts
Urea cycle Screening Blood and urine Sandor, Neogen
defects (TMS/GCMS)
Enzymes skin Not available
Confirmatory fibroblasts LTx…
Bile acid Bile acid profile Blood and urine Not available
synthetic defects and metabolites Develop…
treatable

36. Disease Diagnosis Sample India
Primary Screening – 24hr urine Sandor, Neogen
hyperoxaluria oxalate & glycolate
Confirmatory Liver AGT activity Not available
• GAL-1-PUT
Galactosemia • Epimerase RBC Available
Not widely
Tyrosinemia Succinylacetone Urine available
Develop…
treatable

37. Sample Collection Storage
Blood for TMS 5-7ml heparin tube 4-8°C
centrifuge Do not freeze
Blood for enzyme 7-8ml 4-8°C
assay Do not freeze
Urine 10-15ml Freeze
1-2ml for filter paper
strip
Skin 2x4mm 4-8°C
(upper arm) Do not freeze
(Do not use betadine)
Transport in Gel packed Thermocol box
….Discussion
Reach Lab in 2-3 days

38. Recurrent Recurrent
unexplained (high Recurrent
hypoglycemia anion gap) acidosis encephalopathy
+ ketosis No jaundice
CNS Liver
Heart
Hypoglycemia
Hyperammonemia
Non-ketotic Abnormal urine
Very high odour Rest normal
hypoglycemia
lactate
L/P ratio >20
High CPK
Organic acidemia Urea cycle defect
RCD FAOD