in born errors ofmetabolism

1. Dr G.Rajkumar MD
Professor of Paediatrics
CHRI
APPROACH TO A CHILD WITH
INBORN ERRORS OF
METABOLISM

2. OBJECTIVES
• What are IEMs?
• Categories
• When to suspect?
• History and clinical pointers
• Metabolic presentation
• Differential diagnosis
• Emergency and long term management
• Expanded newborn screening

3. WHAT ARE IEMS?
Monogenic disorders primarily Autosomal Recessive
resulting from deficiency of:
‐ A critical enzyme in the intermediary pathways of
carbohydrate, protein and lipid metabolism
or
‐ A co‐factor which is responsible for activation of an
apoenzyme in the same pathways

4. WHAT ARE IEMS?
Clinical effects result from:
Lack of the product
Accumulation of immediate and remote precursors/ toxic
byproducts
Secondary metabolic consequences

5. IEMS: A FORMIDABLE CHALLENGE
Number and Complexity
Diverse clinical manifestations
Mimic many common pediatric illnesses including
sepsis, encephalopathy
Limited availability of lab services
Emergency and long term care
Counseling

6. CATEGORIES OF IEM
•Carbohydrate
‐ Oxidative phosphorylation (OXPHOS) disorders
‐ Glycogen storage disorders, Galactosemia
•Protein
‐ Urea cycle disorders
‐ Organic acidemias
‐ Aminoacidopathies
•Lipids
‐ Fatty acid oxidation disorders (FAOD)
‐ Disorders of carnitine transport

7. CATEGORIES OF IEM
•Lysosomal storage disorders (LSD):
‐ Mucopolysaccharidosis (MPS), sphingolipidosis
• Peroxisomal disorders
•Mitochondrial disorders

8. WHEN TO SUSPECT IEM?
CLINICAL POINTERS ‐ HISTORY
• Developmental delay (DD), regression, mental
retardation (MR)
• Refractory seizures
• Encephalopathy
• Rapid breathing (Acidotic)
• Failure to thrive, episodic vomiting
• Unusual body odours
• Life threatening illnesses following seemingly minor infections
• Consanguinity, family history of sibling deaths,
DD/MR, seizures

9. ABNORMAL URINARY ODOURS
Disorder Odor
Phenylketonuria Musty Musty
Maple Syrup Urine Disease
(MSUD)
Maple syrup or burnt sugar
Isovaleric acidemia, Glutaric
acidemia type 2
Sweaty feet
Multiple carboxylase deficiency Cat urine

10. IEM Abnormal odor
Maple syrup urine disease (MSUD) Maple syrup
Isovaleric acidemia or glutaric acidemia type II Sweaty feet
Cystinuria and tyrosinemia type I Sulfur
Tyrosinemia type I Boiled cabbage
Trimethylaminuria or dimethylglycine dehydrogenase
deficiency
Old fishy
Multiple carboxylase deficiency (MCD) Cat’s urine
Phenylketonuria Mousy

11. WHEN TO SUSPECT IEM?
CLINICAL POINTERS ‐ EXAMINATION
•Cataract, corneal clouding, cherry red spot
•Micro/ Macrocephaly, coarse facies
•Alopecia, intertrigo
•Hepatomegaly, liver dysfunction
•Splenomegaly
•Abnormal CNS examination
•Skeletal deformities

12. IEM should be considered in the differential diagnosis of any sick neonate
along with common acquired causes such as sepsis, hypoxic-ischemic
encephalopathy, duct-dependant cardiac lesions, congenital adrenal
hyperplasia and congenital infections.
Clinical pointers towards an underlying IEM include
Deterioration after a period of apparent normalcy
Parental consanguinity
Family history of unexplained neonatal deaths
Rapidly progressive encephalopathy and seizures of unexplained cause
Severe metabolic acidosis
Persistent vomiting
Peculiar odor (urine, cerumen)
Acute fatty liver or HELLP (hemolysis, elevated liver enzymes & low
platelet counts) during pregnancy: seen in women carrying fetuses with
long-chain-3- hydroxyacyl-coenzyme dehydrogenase deficiency
(LCHADD).

13. Encephalopathy with or without metabolic
acidosis:
• Encephalopathy , seizures, and tone abnormalities are predominant
presenting features of
Organic acidemias,
Urea cycle defects and
Congenital lactic acidosis.
• Isolated intractable seizures are prominent in pyridoxine
dependency, pyridoxal phosphate dependency, folinicacid
responsive seizures, and glucose transporter 1 deficiency

14. Acute liver disease
• Jaundice alone- Gilbert syndrome, Criggler-Najjar syndrome
• Hepatic failure (jaundice, ascites, hypoglycemia, coagulopathy)-
Tyrosinemia, galactosemia, neonatal hemochromatosis, glycogen storage
disease type IV.
• Neonatal cholestasis: alpha-1 antitrypsin deficiency, Niemann-Pick
disease type C.
• Hypoglycemia: persistent and severe hypoglycemia may be an indicator
of an underlying IEM. Hypoglycemia is a feature of galactosemia, fatty
acid oxidation defects, organic acidemias, glycogen storage disorders and
disorders of gluconeogenesis

15. Dysmorphic features:
• Peroxisomal disorders,
• Pyruvate dehydrogenase deficiency,
• Congenital disorders of glycosylation (CDG), and
• Lysosomal storage diseases.
• Some IEMs may present with non-immune hydrops fetalis;
these include lysosomal storage disorders and CDG.

16. IEM Facial features
Zellweger syndrome (absence of peroxisomes) Large fontanelle, prominent forehead, flattened
nasal bridge, epicanthal folds and hypoplastic
supraorbital ridge
Pyruvate dehydrogenase deficiency Epicanthal folds, flattened nasal bridge, petite
nose with anteverted alae nasi, long philtrum
Glutaric aciduria type II Macrocephaly, high forehead, flattened nasal
bridge, short anteverted nose; genitourinary
abnormality of hypospadias in males, aural
anomalies and rocker bottom feet
Smith-Lemli-Opitz syndrome (cholesterol
biosynthetic defect)
Epicanthal folds, flat nasal bridge, syndactyly,
cataracts and genital abnormalities
Congenital glycosylation disorders Inverted nipples and lipodystrophy
Lysosomal storage disorders, Coarse facies

17. Cardiac disease:
• Cardiomyopathy is a prominent feature in some IEM including
• Fatty acid oxidation defects,
• Glycogen storage disease type II and
• Mitochondrial electron transport chain defects.

18. CLINICAL POINTERS TO DIAGNOSE IEM
Feature Disorder
Eye
Cataract
Corneal clouding
Cherry red spot
Galactosemia
MPS: Hurler, Scheie, Morquio ,
Maroteaux‐Lamy syndrome
Tay‐Sachs, Niemann Pick
Skin ‐ Alopecia, intertrigo
Hair – Coarse, kinky
Biotinidase deficiency
Menkes kinky hair disease
Hepato ± splenomegaly LSD: MPS, sphingolipidosis, GSD
Hepatomegaly & liver dysfunction Galactosemia, tyrosinemia, GSD
Cardiomyopathy LSD, GSD, FAOD, mitochondrial
disorders

19. WHEN TO SUSPECT IEM?
LAB POINTERS
• Metabolic acidosis
• Wide anion gap
• Hyperammonemia
• Hypoglycemia:
• Urine Ketones (Ketotic/ non ketotic)
• Urine Reducing substances (Positive/ Negative)
• Lactic acidosis
• Altered liver function

20. CASE ILLUSTRATION
• A 6 month old male, 2nd order, born of non consanguinity,
admitted for diarrhoea and dehydration
• H/O Sibling death with suspected encephalopathy
• No developmental delay/ failure to thrive
• O/E: Moderate dehydration, rapid breathing, drowsy
• Hepatomegaly, firm, span 8cm

21. CASE ILLUSTRATION: INVESTIGATIONS
• GRBS: 45 mg/dl; Urine ketones: Positive
• ABG: pH 7.09, pCO2 14.8,BE – 23.6, HCO3 4.5
• Metabolic acidosis
• Anion gap 33 ‐ Wide
• NH3 328 μg/dl (N: 25‐94) ‐ Hyperammonemia
• Lactate 28.8 mg/dl (N:2.5‐20) – Lactic acidosis
• FINAL DIAGNOSIS – ORGANIC ACIDEMIA

23. Suspected Metabolic Disorder

25. DEFINITIVE DIAGNOSIS
• Blood: Tandem mass spectrometry for acyl carnitine,
organic acids
• Plasma and urine amino acids (quantitative)
• Urine organic acids by chromatography
• Specific metabolite assays
• DNA mutation analysis
• Enzyme assays on skin fibroblasts or blood cells
Diagnosis is important not only for treatment and prognostication but
also for genetic counselling and antenatal diagnosis in subsequent
pregnancies.

26. DIFFERENTIAL DIAGNOSIS
•Sepsis:
‐ Can mimic, precipitate and complicate IEM
‐ Galactosemia – predilection for E coli sepsis
‐ Negative CRP and blood culture in a rapidly
deteriorating infant should alert to possible IEM
•Reye encephalopathy
‐ An important differential for Fatty Acid Oxidation Disorders with
hepatomegaly, hypoglycemia, hyperammonemia and
hepatic dysfunction

27. Investigations
• Metabolic investigations should be initiated as soon as the
possibility is considered.
• The outcome of treatment of many IEM especially those
associated with hyperammonemia is directly related to the
rapidity with which problems are detected and appropriate
management instituted.

28. First line investigations (metabolic screen):
The following tests should be obtained in ALL babies with suspected IEM.
1) Complete blood count: (neutropenia and thrombocytopenia seen in
propionic and methylmalonic academia)
2) Arterial blood gases and electrolytes
3) Blood glucose
4) Plasma ammonia (Normal values in newborn: 90-150 µg/dl or 64-107
µmol/L)
5) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)
6) Liver function tests
7) Urine ketones
8) Urine reducing substances.
9) Serum uric acid (low in molybdenum cofactor deficiency).

29. Acidosis Ketosis Lactate Ammonia Diagnosis
-- + -- __ Maple syrup urine disease
+ +/- -- __ Organic aciduria
+ +/- + +/- Lactic acidosis
-- -- -- + Urea cycle
-- -- -- __ Non-ketotic
hyperglycinemia , sulfite
oxidase deficiency,
peroxisomal,
Phenylketonuria,
galactosemia

30. Second line investigations (ancillary and
confirmatory tests)
These tests need to be performed in a targeted manner, based on presumptive diagnosis
reached after first line investigations:
1) Gas chromatography mass spectrometry (GCMS) of urine- for diagnosis of
organic acidemias.
2) Plasma amino acids and acyl carnitine profile: by tandem mass spectrometry
(TMS)- for diagnosis of organic acidemias, urea cycle defects, aminoacidopathies
and fatty acid oxidation defects.
3) High performance liquid chromatography (HPLC): for quantitative analysis of
amino acids in blood and urine; required for diagnosis of organic acidemias and
aminoacidopathies.
4) Lactate/pyruvate ratio- in cases with elevated lactate.

31. 5) Urinary orotic acid- in cases with hyperammonemia for classification of urea
cycle defect.
6) Enzyme assay: This is required for definitive diagnosis, but not available for
most IEM’s.
Available enzyme assays include: biotinidase assay- in cases with
suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia);
and .
GALT (galactose 1-phosphate uridyl transferase) assay- in cases with
suspected galactosemia (hypoglycemia, cataracts, reducing sugars in urine).

32. 7) Neuroimaging: MRI –
Zellweger syndrome has diffuse cortical migration and sulcation abnormalities.
Agenesis of corpus callosum has been reported in Menke’s disease, pyruvate
decarboxylase deficiency and nonketotic hyperglycinemia.
Maple syrup urine disease (MSUD): brainstem and cerebellar edema
Propionic & methylmalonic acidemia: basal ganglia signal change
Glutaric aciduria: frontotemporal atrophy, subdural hematomas
8) Magnetic resonance spectroscopy (MRS): may be helpful in selected disorders
E.g. lactate peak elevated in mitochondrial disorders, leucine peak elevated in
MSUD.
9) Urine for alpha-aminoadipic semialdehyde, - elevated in pyridoxine dependent
seizures. (test not available in India yet).

33. 10)Electroencephalography (EEG): some EEG abnormalities may be
suggestive of particular IEM; e.g. comb-like rhythm in MSUD, burst
suppression in NKH and holocarboxylase synthetase deficiency.6
11) Plasma very long chain fatty acid (VLCFA) levels: elevated in
peroxisomal disorders.
12) Mutation analysis when available.
13) CSF aminoacid analysis: CSF Glycine levels elevated in NKH

34. Precautions to be observed while collecting
samples
1. Should be collected before specific treatment is started or feeds are
stopped, as may be falsely normal if the child is off feeds.
2. Samples for blood ammonia and lactate should be transported in ice
and immediately tested. Lactate sample should be arterial and should
be collected after 2 hrs fasting in a preheparinized syringe.
Ammonia sample is to be collected approximately after 2 hours of
fasting in EDTA vacutainer. Avoid air mixing. Sample should be free
flowing.
3. Detailed history including drug details should be provided to the
lab. (sodium valproate therapy may increase ammonia levels).

35. Aims of treatment
1. To reduce the formation of toxic metabolites by decreasing substrate
availability (by stopping feeds and preventing endogenous catabolism)
2. To provide adequate calories
3. To enhance the excretion of toxic metabolites.
4. To institute co-factor therapy for specific disease and also empirically if
diagnosis not established.
5. Supportive care- treatment of seizures (avoid sodium valproate – may
increase ammonia levels), maintain euglycemia and normothermia, fluid,
electrolyte & acid-base balance, treatment of infection, mechanical
ventilation if required.

36. MANAGEMENT GOALS
• Prevention of formation of toxic metabolites
• Removal of toxic metabolites
• Increase activity of deficient enzyme by co‐factor
therapy (Mega vitamins)
• Addition of deficient substrate
• Supply essential nutrients/ disease specific diet

37. MANAGEMENT: EMERGENCY
• ABC
• Correction of hypoglycemia and maintenance of
blood sugars to suppress gluconeogenesis
• Correction of acidosis: IV Sodium bicarbonate with
serial ABGs
• Carnitine supplementation
• Broad spectrum antibiotics including anaerobic cover

38. HYPERAMMONEMIA – MANAGEMENT
• Hemodialysis for rapid reduction
• Decrease production: I.V. Arginine HCl
• Promote excretion: I.V. sodium benzoate and sodium
phenyl acetate
• Calories: carbohydrate/ lipid; reintroduction of
protein after 48 hours restricted to 1 g/kg with 50%
essential amino acids
• Avoid valproate, steroids

39. Vitamin Dosage/ day Indications
Biotin 10 ‐ 50 mg Holo-carboxylase deficiency
Biotinidase
Riboflavin 100 mg Glutaric aciduria
Electron Transport Chain defects
Thiamine 300 mg MSUD
Pyruvate met defects
Mitochondrial
Vit B12 1 ‐ 2 mg Methyl malonic acidemia
Homocystinuria
Pyridoxine 50 – 100 mg Pyridoxine Dependent seizures
Homocystinuria

40. DIET MANAGEMENT
•Restriction of proteins: 6% of total energy
•Restriction of substrates which accumulate
‐ Homocystinuria: Methionine
‐ PKU: phenylalanine
•Special diets:
‐ PKU, MSUD, galactosemia
•Replacement of deficient nutrients
‐ Homocystinuria: cystein

41. Prevention
1) Genetic counselling and prenatal diagnosis: Most of the IEM are
single gene defects, inherited in an autosomal recessive manner,
with a 25% recurrence risk.chorionic villus tissue or amniotic
fluid.
Modalities available are:17
• Substrate or metabolite detection: useful in phenylketonuria,
peroxisomal defects.
• Enzyme assay: useful in lysosomal storage disorders like Niemann-
Pick disease, Gaucher disease.
• DNA based (molecular) diagnosis: Detection of mutation in
proband/ carrier parents is a prerequisite.

42. 2) Neonatal screening: Tandem mass spectrometry is used in some
countries for neonatal screening for IEM.
Disorders which can be detected by TMS include
Aminoacidopathies ( phenylketonuria, MSUD, Homocystinuria,
Citrullinemia, Argininosuccinic aciduria, hepatorenal tyrosinemia),
Fatty acid oxidation defects ,
Organic acidemias (glutaric aciduria, propionic acidemia,
methylmalonic
acidemia, isovaleric acidemia).
The appropriate time for collection of samples is between 1 and 3
days of life.

43. EXPANDED NEWBORN SCREENING
• Pre‐symptomatic detection of newborns that
includes several IEM
• Originated with the development of the ‘‘Guthrie
test’’ for detecting phenylketonuria
• Dried Blood Spots: Heel prick blood at 48‐72 hours of
age on absorbent paper (Guthrie card) and analyzed
by tandem mass spectrometry

44. IEMS ARE:
• Individually rare but collectively have an incidence of 1 in 5000
• Presentation can occur at any age, even in adulthood
• Increasingly a primary/ differential diagnosis especially in infancy
• “Index of suspicion” ‐ The most difficult step in diagnosis is
considering the possibility!

45. Do’s and Don’t’s
1) Don’t think of IEM as rare, exotic and untreatable disorders.
2) Think of IEM in sick newborns in parallel with other common
conditionssuch as sepsis. The signs and symptoms are usually non
specific such as lethargy, poor feeding and vomiting.
3) Observe the precautions as explained while collecting and storing
samples
4) Even if the chances of survival appear bleak, every attempt must
be made to reach a diagnosis so that parents can be guided for
future pregnancy.