Inborn error of metabolism

2. Inborn Error of Metabolism
 Single gene mutations
 Alteration of primary protein structure
 Alteration of the amount of protein synthesized
 Mild to lethal

3. Inheritance:
• Most IEM…… autosomal recessive genetic traits
• Urea cycle disorder ornithine transcarbamylase
deficiency…….. X linked
• Some are mitochondrial inheritance

4. Metabolic disorders can be classified using a
variety of schemes based on:
 the clinical presentation
 the age of onset
 the tissues or organ systems involved
 the defective metabolic pathways

5. Classifications of IEM
Amino acids • Phenylketonuria- Homocystinuria - tyrosinemia
Lipidoses • Tay sach’s disease – Gaucher’s disease –
metachromatic leukodystrophy
carbohydrates • Galactosemia – fructose intolerance –
Glycogen storage disorders
Organic acidemia • Methylmalonic aciduria- propionic aciduria-
maple syrup urine disease
Transport disorders • Cystinuria cystinosis – hypercholesterlemia
(AD)
Peroxisomal
disorders
• Adrenoleukodystrophy – zellweger syndrome –
chondrodysplasia punctata
Lysosomal storage
disorders
• mucopolysaccaridosis
Urea cycle disorders
• Ornithine transcarbamylase deficiency-
arginosucciniase deficiency- carbamyl
phosphate synthetase deficiency
Metal metabolic
disorders
• Wilson’s disease – Menkes disease

6. Group 1
Anabolism/
catabolism
Lysosomal,
Peroxisomal,
glycosylation, and
cholesterol synthesis
defects
some Lysosomal
disorders can be
efficiently treated by
enzyme replacement
or substrate
reduction therapies
Group 2
intermediary
metabolism
Aminoacidopathies,
organic acidurias, urea
cycle disorders, sugar
intolerances, metal
disorders and
porphyrias
Acute or chronic
intoxications
Neonatal to adulthood
Most …. treatable
emergency removal of
the toxin by special diets,
extracorporeal
procedures, cleansing
drugs or vitamins
Group 3
energy production/
utilization
Cytoplasmic defects
encompass those affecting
glycolysis, glycogenosis,
gluconeogenesis,
hyperinsulinisms, and
creatine and pentose
phosphate pathways; the
latter are untreatable.
Mitochondrial defects
include respiratory chain
disorders, and Krebs cycle
and pyruvate oxidation
defects, mostly untreatable,
and
disorders of fatty acid
oxidation and ketone bodies
that are treatable

7. Clinical presentations:
• Pregnancy:
acute fatty liver of pregnancy- HELLP
syndrome………… long chain 3 hydroxy coenzyme
A dehydrogenase deficiency (LCHADD)

8. Clinical presentations:
• Sepsis like presentation
• Mental retardation
• Neurological impairment, Seizures,
Encephalopathy, tone abnormalities
• Sudden infant death
• Metabolic acidosis
• Hypoglycemia
• Liver dysfunctions
• Dysmorphic features
• Cardiac disease
• Hydrops fetalis
• Abnormal urine odor

10. Inborn Errors of Metabolism with hydrops
fetalis
• Lysosomal disorders:
- Mucopolysaccaridosis types I, IVA, VII
- Gaucher disease
- Nieman pick disease type c
- Farber disease
• Hematologic disorders:
- G-6-PD deficiency
- Pyruvate kinase defieciency
• Others:
- Neonatal hemochromatosis
- Respiratory chain disorders

12. Evaluation
• History, Family history:
parental consanguinity, unexplained neonatal
deaths
• Physical examination:
facial dysmorphism, cataracts, retinopathy,
structural brain anomalies, hypertrophic or dilated
cardiomyopathy, hepatomegaly, multicystic
dysplastic kidneys and myopathy.

14. Evaluation
Initial
Evaluation
CBC
Blood
glucose
Plasma
ammonia
Plasma
lactate,
pyruvate
Liver
functions
tests
Urine
reducing
substances
Urine
ketones
Electrolytes,
Ca, Mg

15. 2nd line
Evaluation
carnitine,
acylcarnitine
s, vLCFA
enzymes
Magnetic
resonance
imaging
(MRI)
Magnetic
resonance
spectrosco
py (MRS)
Plasma
aminoaci
d
analysisUrine
organic
acid
analysis
EEG
Mutation
analysis
CSF
aminoacid
analysis

16. PhenylketonuriaDisorder
1:15000Incidence
Autosomal recessiveInheritance
Phenylalanine hydroxylase (> 98 percent)
Biopterin metabolic defects (< 2 percent)
Metabolic error
Mental retardation, acquired microcephalyKey manifestation
Plasma phenylalanine concentrationKey laboratory test
Diet low in phenylalanineTherapy approach

18. Maple syrup urine diseaseDisorder
1:150,000Incidence
Autosomal recessiveInheritance
Branched-chain 3-keto acid
dehydrogenase
Metabolic error
Acute encephalopathy, metabolic
acidosis, mental retardation
Key manifestation
Plasma amino acids and urine organic
acids
Dinitrophenylhydrazine for ketones
Key laboratory test
Restriction of dietary branched-chain
amino acids
Therapy approach

20. Carbohydrate metabolism
GalactosemiaDisorder
1:40000Incidence
Autosomal recessiveInheritance
Galactose 1-phosphate
uridyltransferase (most common);
galactokinase; epimerase
Metabolic error
Hepatocellular dysfunction, cataractsKey manifestation
Enzyme assays, galactose and
galactose 1-phosphate assay,
molecular assay
Key laboratory test
Lactose-free dietTherapy approach

22. Glycogen storage disease, type Ia
(von Gierke's disease)
Disorder
1:100000Incidence
Autosomal recessiveInheritance
Glucose-6-phosphataseMetabolic error
Hypoglycemia, lactic acidosis, ketosisKey manifestation
Liver biopsy enzyme assayKey laboratory test
Corn starch and continuous overnight
feeds
Therapy approach

24. Fatty acid oxidation
Medium-chain acyl-CoA
dehydrogenase deficiency
Disorder
1:15000Incidence
Autosomal recessiveInheritance
Medium-chain acyl-CoA dehydrogenaseMetabolic error
Nonketotic hypoglycemia, acute
encephalopathy, coma, sudden infant
death
Key manifestation
Urine organic acids, acylcarnitines, gene
test
Key laboratory test
Avoid hypoglycemia, avoid fastingTherapy approach

26. Lactic acidemia
Pyruvate dehydrogenase deficiencyDisorder
1:100000Incidence
X linkedInheritance
E1 subunit defect most commonMetabolic error
Hypotonia, psychomotor retardation,
failure to thrive, seizures, lactic acidosis
Key manifestation
Plasma lactate
Skin fibroblast culture for enzyme
assay
Key laboratory test
Correct acidosis; high-fat, low-
carbohydrate diet
Therapy approach

28. Lysosomal storage
Gaucher diseaseDisorder
1:60,000; type 1–1:900 in Ashkenazi
Jews
Incidence
Autosomal recessiveInheritance
β-glucocerebrosidaseMetabolic error
Coarse facial features,
hepatosplenomegaly
Key manifestation
Leukocyte β-glucocerebrosidase assayKey laboratory test
Enzyme therapy, bone marrow transplantTherapy approach

30. Fabry's diseaseDisorder
1:80,000Incidence
X linkedInheritance
α-galactosidase AMetabolic error
Acroparesthesias, angiokeratomas
hypohidrosis, corneal opacities, renal
insufficiency
Key manifestation
Leukocyte α-galactosidase A assayKey laboratory test
Enzyme replacement therapyTherapy approach

32. Hurler's syndromeDisorder
1:100000Incidence
Autosomal recessiveInheritance
α-l-iduronidaseMetabolic error
Coarse facial features,
hepatosplenomegaly
Key manifestation
Urine mucopolysaccharides Leukocyte α-
l-iduronidase assay
Key laboratory test
Bone marrow transplantTherapy approach

34. Organic aciduria
Methylmalonic aciduriaDisorder
1:20000Incidence
Autosomal recessiveInheritance
Methylmalonyl-CoA mutase, cobalamin
metabolism
Metabolic error
Acute encephalopathy, metabolic
acidosis, hyperammonemia
Key manifestation
Urine organic acids Skin fibroblasts for
enzyme assay
Key laboratory test
Sodium bicarbonate, carnitine, vitamin
B12, low-protein diet, liver transplant
Therapy approach

36. Propionic aciduriaDisorder
1:50000Incidence
Autosomal recessiveInheritance
Propionyl-CoA carboxylaseMetabolic error
Metabolic acidosis, hyperammonemiaKey manifestation
Urine organic acidsKey laboratory test
Dialysis, bicarbonate, sodium benzoate,
carnitine, low-protein diet, liver transplant
Therapy approach

38. Peroxisomes
Zellweger syndromeDisorder
1:50000Incidence
Autosomal recessiveInheritance
Peroxisome membrane proteinMetabolic error
Hypotonia, seizures, liver dysfunctionKey manifestation
Plasma very-long-chain fatty acidsKey laboratory test
No specific treatment availableTherapy approach

40. Urea cycle
Ornithine transcarbamylase deficiencyDisorder
1:70000Incidence
X linkedInheritance
Ornithine transcarbamylaseMetabolic error
Acute encephalopathyKey manifestation
Plasma ammonia, plasma amino acids
Urine orotic acid
Liver (biopsy) enzyme concentration
Key laboratory test
Sodium benzoate, arginine, low-protein
diet, essential amino acids; dialysis in
acute stage
Therapy approach

41. Treatment
Prevent Catabolism:
Administration of calories is used in the treatment of
acute episodes to try to slow down catabolism.
Limit the Intake of the Offending Substance:
the basis of treatment in Galactosemia, fructose
intolerance and PKU.
Increase Excretion of Toxic Metabolites:
by exchange transfusion, peritoneal dialysis (PD),
hemodialysis, forced diuresis, using alternative
pathways for the excretion of toxic metabolites. For
example, carnitine is useful in the elimination of organic
acids in the form of carnitine esters. Sodium benzoate
and phenylacetate are useful in treating
hyperammonemia.

42. Enzyme Replacement Therapy:
Human alpha glucosidase enzyme (pompe’s disease)-
Laronidase (Aldurazyme) enzyme(MPS I)patients-
Fabry-specific enzyme replacement therapy (ERT) with
recombinant alpha-Gal A (Fabrazyme) is safe and
effective, Imiglucerase (Gaucher disease)
Increase the Residual Enzyme Activity:
B12 decreases the urinary levels of methyl malonate by
enhancing activity of Trans Cobalmin II
Reduce Substrate Synthesis:
Inhibition of substrate synthesis has been used as a
strategy for treating glycolipid Lysosomal storage
disease.

43. Replacement of the End Product:
Hypoglycaemia can be prevented by frequent feeds
during the day and continuous nasogastric feeding
at night, in infancy and early childhood. Raw
cornstarch (2 g/kg every six hours) has been shown
to be effective in preventing hypoglycaemia in older
children with glycogen storage disease type I as
well as decreasing the hyperlipidaemia,
hyperuricaemia, and lactic acidaemia

44. Transplantation and Gene Therapy:
For the last 25 years, hematopoietic cell
transplantation (HCT) has been used as effective
therapy for selected inborn errors of metabolism
(IEMs), mainly Lysosomal storage diseases and
Peroxisomal disorders. The main rational for HCT in
IEMs is based on the provision of correcting
enzymes by donor cells within and outside the blood
compartment

45. Prevention
Genetic counselling and prenatal diagnosis:
The samples required are chorionic villus tissue or
amniotic fluid. Modalities available are:
• 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.
Neonatal screening: tandem mass spectrometry

46. Selective screening for inborn errors of metabolism
by tandem mass spectrometry in Egyptian children:
A 5 year report
• A relatively high number of patients (203/3380 (6%))
were confirmed with 17 different types of IEMs.
Averages for age at diagnosis for different disorders
ranged from 2.5 months to 6.6 years with general
developmental delay and irreversible neurological
damage being the most common presenting features
(75.9% and 65.5%, respectively). Amino acid disorders
(127/203 (62.6%)), mainly phenylketonuria (100/203
(49.3%)), were the most encountered, followed by
organic acidemias (69/203 (34%)), while fatty acid
oxidation defects (7/203 (3.4%)) were relatively rare.
88% of patients were born t consanguineous parents.

47. References
• Talkad S. Raghuveer and et.al. Inborn Errors of
Metabolism in Infancy and Early Childhood: An
Update. American Family Physician j.2006:
17:1981-1990
• Atlas of Metabolic Diseases, 2nd edition
• Ananth N Rao, J Kavitha, Minakshi Koch and
Suresh Kumar V. Inborn Errors of Metabolism:
Review and data from a tertiary care center.
Indian Journal of Clinical Biochemistry, 2009: 24
(3) 215-222
• Anju Gupta. To Err is Genetics: Diagnosis and
Management of Inborn Errors of Metabolism
(IEM)

48. • Laila A. Selim and et.al. Selective screening for
inborn errors of metabolism by tandem mass
spectrometry in Egyptian children: A 5 year
report. Clinical Biochemistry 47 (2014) 823–828