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Paediatric Biochemistry > Overview of Inborn Errors of Metabolism > Flashcards

Overview of Inborn Errors of Metabolism Flashcards

1
Q

How do Genetic Defects occur?

A

Can affect any point of the many elements that control the structure, binding and transcription of the protein

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2
Q

What are some examples of major categories of IEMs?

A
  • Organic acid(aemia)
  • Amino Acid
  • Purines and Pyrimidines
  • Urea Cycle disorders
  • Fatty Acid oxidation disorders
  • Disorders of carbohydrate metabolism
  • Congenital disorders of glycosylation
  • Mitochondrial / respiratory chain disorders
  • Peroxisomal
  • Lysosomal
  • Disorders of creatine biosynthesis
  • Disorders of biogenic amine metabolism
  • Sterol and bile acid metabolism
  • Disorders of cobalamin absorption, transport and metabolism
  • Disorders of Folate metabolism and transport
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3
Q

What are some mechanisms of disease of IEMs?

A
  • Accumulation of a toxin.
  • Energy deficiency
  • Deficient production of essential
  • Metabolite / structural component
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4
Q

What are some examples of accumulation of toxin?

A
  • Ammonia accumulates in patients with urea cycle defects
  • Porphyrins accumulate in the porphyrias
    • Presents in symptoms of mental disease, pain in acute porphyria
    • In sensitive porphyria, there is accumulate in the post cursors after PBG and make skin sensitive and acute porphyria is accumulation before PBG
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5
Q

What are some examples of energy deficiency in causing IEMS?

A
  • Galactosaemia: If energy cannot be generated from galactose in early life
  • Glycogen storage disorders: If glycogen cannot be developed again,
  • Brain cannot use free fatty acids due to blood brain barrier. Free fatty acids are used to form ketones which can be used by the brain. The brain uses ketones in the fasting mode over the glucose.
  • Red blood cells can only use glucose for energy which is used to keep its shape. It cannot use free fatty acids due to lack of mitochondria so can lyse if there is low glucose
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6
Q

What are some examples of Deficient production of molecules essential in IEMs?

A

Defects of neurotransmitter syndrome.

  • Enzyme 31.2: aromatic L-amino acid decarboxylase deficiency. Leads to lack of dopamine and serotonin

Congenital disorder of Glycosylation

  • Group of rare genetic disorders characterized by defects in one of the many enzymes, transporters, or other functional proteins, required for the synthesis and processing of glycoconjugates.
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7
Q

What is the clinical presention of congenital disorders of glycosylation?

A

Broad spectrum including:

  • Mental retardation
  • Structural abnormalities of the central nervous system
  • Cardiac defects
  • Physical malformations
  • Peripheral neuropathies, etc
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8
Q

What are metabolic pathways involved with energy metabolism?

A
  • Glycolysis
  • Pentose phosphate pathway
  • Glycogen metabolism
  • Kreb’s cycle
  • Respiratory chain
  • Triglyceride mobilisation
  • Fatty acid oxidation
  • Ketone body metabolism
  • Gluconeogenesis
  • Galactose metabolism
  • Amino acid catabolism
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9
Q

What are the factors of Clinical Heterogenity in Inborn Errors of Metabolism?

A
  • Genetic variability of lesions, most disorders are multi-allelic
  • Variability of other aspects / components of metabolism
  • Environment (Diet, Drugs, Infection)
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10
Q

What randon x-inactivation in females?

A
  • X chromosome can be inactivated
  • Process cannot be selected or switched back on. This means you can have favourable or unfavourable expression of the X
  • Process occurs early in embryology
  • Significant variability of phenotype of X related disease in females e.g. the urea defect OTC deficiency
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11
Q

How can OTC defects present in pregnancy?

A
  • Involution in Pregnancy
  • Can occur during a massive protein load leading to hyperammonaemia
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12
Q

How can Inborn Errors of Metabolism (IEM) Diagnosed?

A

Pre-symptomatic Screening

  • whole population, neonatal bloodspot screening
  • selected groups

Investigation of Symptomatic Individuals

  • test body fluids for abnormal metabolites
  • measure enzyme activities
  • DNA analysis, NGS panels
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13
Q

How is neonatal screening conducted in the UK?

A
  • Phenylketonuria
  • MCAD deficiency
  • MSUD
  • IVA
  • GA1
  • Hcys
  • Hypothyroidism
  • Cystic fibrosis
  • Sickle disease
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14
Q

What are some presentations of inborn errors of metabolism?

A
  • Acute: medical emergency?, hypoglycaemia, hyperammonaemia, metabolic acidosis
  • Chronic: more difficult, need to decide how many investigations to pursue
  • Specific clinical features that immediately suggest a disorder or group
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15
Q

What are some conditions that present acutely in IEMs?

A
  • Metabolic acidosis - Propionic acideamia
  • Hypoglycaemia - MCAD
  • Hyperammonaemia - OTC deficiency
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16
Q

What are some conditions that present chronically in IEMs?

A
  • Mental retardation - Sanfilippo syndrome
  • Developmental delay - OTC def (usually girls)
  • Recurrent seizures - GLUT 1 deficiency
17
Q

What are some conditions that present with with specific or unique clinical signs in IEMs?

A
  • Lens dislocation (defect in collagen) - Homocystinuria
  • Self-harming behaviour - Lesch-Nyhan disease (uric acid accumulation)
  • Cherry red spots in the macula - Tay Sachs
  • Renal stones - Cystinuria
  • Cardiomyopathy - Barth syndrome
  • Sparse brittle hair - Menkes
18
Q

What are metabolic investigations used in the initial screen for disease with low threshold of suspicion?

A

Urine

  • Organic acids
  • Amino acids
  • Sugar Chromatography
  • Oligosaccharides
  • Mucopolysaccharides

Blood

  • Amino acids
  • Acylcarnitines

Increasing use of NGS panels or whole exome sequencing as frontline investigation

Metabolomic profiling, i.e. sensitive high-resolution mass spec analysis giving rise to large profile of analytes

19
Q

How Does metabolomics work?

A
  • Metabolite extraction then high sensitivity mass spectrometry for data acquisition. The information is expressed in a number of different way.
  • Bioinformatic pathways are then used to find patterns. The pathway is then analysed and reconstructed
20
Q

What are the benefits for diagnosis for Metabolomics?

A
  • Treatment, improve prognosis
  • Identify cause of clinical problem
  • Genetic counselling
  • IEM act as models for other disorders
21
Q

How are IEMs treated?

A
  • Manipulate diet to reduce substrate load, e.g. PKU
  • Drugs that bind toxic metabolites or reduce their concentration e.g. alternative pathway drugs for hyperammonaemia in urea cycle defects
  • Substrate depletion, e.g. miglustat in Gaucher disease
  • Enzyme inhibitors, NTBC in tyrosinaemia type 1
  • Enzyme replacement (Bone marrow transplant, SCID, ERT, e.g. in lysosomal storage disorders)

Paediatric Biochemistry (31 decks)

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