10 Questions
What is the main rationale for hematopoietic cell transplantation (HCT) in IEMs?
To provide correcting enzymes by donor cells within and outside the blood compartment
What is the recommended dosage of raw cornstarch for preventing hypoglycaemia in older children with glycogen storage disease type I?
2 g/kg every six hours
What type of tissue or fluid is required for prenatal diagnosis of IEMs?
Chorionic Villous tissue or Amniotic fluid
What is the purpose of enzyme replacement therapy (ERT)?
To provide correcting enzymes
What is the recurrence risk of IEMs if the diagnosis is known and confirmed in the index case?
25%
What is the name of the technique used in some countries for neonatal screening of IEMs?
Tandem mass spectrometry
What type of disorders can be detected by tandem mass spectrometry?
Aminoacidopathies, fatty acid oxidation defects, and organic acidemias
What is one of the limitations of using tandem mass spectrometry for neonatal screening?
Difficulty in interpretation of abnormal test results
What is the mode of inheritance of most IEMs?
Autosomal recessive
What is the goal of genetic counselling in IEMs?
To provide prenatal diagnosis for subsequent pregnancies
Study Notes
Anabolism
- Anabolism is the set of metabolic pathways that construct molecules from smaller units, requiring energy.
Inborn Errors of Metabolism (IEM)
- IEMs occur due to mutations in DNA, affecting specific proteins such as enzymes, receptors, transport vehicles, or membrane pumps.
- Examples of mechanisms in IEM:
- Precursor → Enzyme AB → A → Enzyme BC → B → End Product C
- Abnormal metabolic pathway → Toxic Metabolite D
- Inborn errors of metabolism can be divided into three pathophysiological diagnostic groups:
- Group 1: Anabolism/Catabolism
- Group 2: Intermediary Metabolism (Urea cycle disorders, some lysosomal disorders)
- Group 3: Energy Production/Utilization (Mitochondrial defects, respiratory chain disorders, Krebs cycle and pyruvate oxidation defects)
Classification of IEM
-
- Carbohydrate metabolism
-
- Organic acid metabolism
-
- Lipid metabolism
-
- Protein metabolism
-
- Amino acid metabolism
-
- Mitochondrial fatty acid oxidation
Approach to IEM
- Suspecting inborn errors:
- Symptoms accompanying diet changes
- Seizures
- Developmental delay
- Recurrent vomiting
- Unusual urine odor
- Parental consanguinity
- Family history of inborn errors
- Investigations:
- First-line tests
- Second-line tests (ancillary and confirmatory tests): - Gas chromatography mass spectrometry (GCMS) - Plasma amino acids and acyl carnitine profile by Tandem mass spectrometry (TMS) - High-performance liquid chromatography (HPLC) - Lactate/pyruvate ratio - Urinary orotic acid test - Enzyme assay - Neuroimaging (MRI) - Magnetic resonance spectroscopy (MRS) - Electroencephalography (EEG) - Plasma very long chain fatty acid (VLCFA) levels - Mutation analysis - CSF amino acid analysis
Treatment of IEM
- Aims of treatment:
- Reduce toxic metabolite formation
- Provide adequate calories
- Enhance toxic metabolite excretion
- Supportive care
- Long-term treatment:
- Dietary treatment (protein restriction)
- Replacement of end products
- Enzyme replacement therapy (ERT)
- Transplantation and Gene Therapy
- Hematopoietic cell transplantation (HCT)
Prevention
- Genetic counselling and prenatal diagnosis:
- Autosomal recessive inheritance
- 25% recurrence risk
- Prenatal diagnosis available for subsequent pregnancies
- Neonatal screening:
- Tandem mass spectrometry (TMS)
- Detects amino acidopathies, fatty acid oxidation defects, and organic acidemias
- High sensitivity but low specificity
Test your knowledge on anabolism, the metabolic pathways that build molecules from smaller units by requiring energy, and inborn errors of metabolism (IEM) caused by mutations in DNA coding for specific proteins.
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