Inborn errors of metabolism Flashcards
Inborn errors of metabolism
Single gene defects resulting in disruption to metabolic pathways
Consequence of IEM
- Toxic accumulation of substrates
- Toxic accumulation of intermediates from alternative metabolic pathways
- Defects in energy production/use due to deficiency of products
Alkaptonuria
Deficiency in homogentisic acid oxidase:
· Autosomal recessive disorder
· Urine turns black on standing (and alkalinisation)
· Black ochrontic pigmentation of cartilage & collagenous tissue (ochronosis)
· Congenital
Cystinuria
Mutations of SLC3A1 amino acid transporter gene (chromosome 2p) & SLC7A9 (Chromosome 19), causing defective transport of cysteine and other dibasic amino acids through epithelial cells of renal tubule and intestinal tract
· Autosomal recessive disorder
· Cysteine has low solubility in urine→formation of calculi in renal tract
Mechanisms of Inheritance
Autosomal Recessive Autosomal Dominant X-linked Co-dominant Mitochondrial
Autosomal recessive inheritance
- Both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy
- Consanguinity increases risk of autosomal recessive conditions
- Examples: cystic fibrosis, sickle cell disease
Autosomal dominant inheritance
- Rare in IEMs
- Examples: Huntington disease, Marfan’s, Familial hypercholesterolemia
X-linked inheritance
Recessive X linked conditions are passed through the maternal line
- Condition does appear in males
- Condition carried in females, but not usually expressed (because females have two copies of X chromosome). Female carriers may manifest condition→Lyonisation (random inactivation of one of the X chromosomes)
- Example: Haemophilia A, Duchenne, Muscular Dystrophy, Fabry’s Disease, Ornithine Carbomyl Transferase Deficiency
Dominant X linked conditions are passed on from either affected parent
-Affected father will only pass the condition to his daughters
-Affected mother can pass the condition to sons and daughters
-Example: Fragile X
There is no male to male transmission
Co-dominant inheritance
· Two different alleles of a gene are expressed, and each allele makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition
Example: ABO blood group, ⍺1AT deficiency
Mitochondrial inheritance
· Mitochondrial gene mutation
· Inherited exclusively from mother:
-Only the egg contributes mitochondria to the developing embryo
· Affects both male and female offspring
· E.g. MERRF- Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
· E.g. MELAS- Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
What is heteroplasmy?
presence of both normal and mutated mtDNA resulting in mitochondrial inherited disease
How does heteroplasmy arise?
When the mitochondria replicates, it is separate from the nucleus replicating. The mitochondria RANDOMLY segregates in the cells, and sometimes they will segregate with all wildtype, sometimes they will have a combination of wildtype and mutant, and sometimes they will contain all mutant mitochondria.
What does level of heteroplasmy determine?
· Distribution of the affected mitochondria, and thus level of heteroplasmy, determines presentation.
· Mitochondrial disease can vary in symptoms, severity, and age of onset.
Which organs are more commonly affected in mitochondrial diseases?
· High energy-requiring organs (e.g. brain, liver, kidneys) which are more frequently affected
Prevalence of inborn errors of metabolism
Individually rare
Collectively common
- cumulative frequency accounting for high mortality within the first year of life
significant contribution to the 1% of children of school age with physical handicap and the 0.3% with severe learning difficulties
What does presentation of IEM depend on?
Depends on:
- where the gene is and what the specific enzyme is
- age
Presentation of neonates with IEM
- neonatal presentation often acute
- often caused by defects in energy metabolism
>maple syrup urine disease
>tyrosinaemia
>OTC (urea cycle defect)
Clues for IEMs in neonates
- Consanguinity
- Family history of similar illness in siblings or unexplained deaths
- Infant who was well at birth but starts to deteriorate for no obvious reason (acute symptoms arising)
- symptoms present in the first week of life, when starting full milk feeds
Describe late-onset of IEM
- Late onset due to accumulation of toxic molecules
- Symptoms appear at adulthood
- Present with organ failure, encepalopathy, seizures
- Patients have residual enzyme activity allowing slower accumulation of toxins
IEMs in adults
- Wilson’s
- Haemochromatosis
Treatment for IEM
- dietary control/restrictions
- compound supplementation
- Newer drug and enzyme replacement therapy
- organ transplantation
Classification of IEM
Toxic accumulation:
> Protein metabolism disorder
> Carbohydrate intolerance (galactosaemia)
Deficiency in energy production/utilization:
> Fatty acid oxidation disorder
> Mitochondrial disorder
> Carbohydrate utilization/production disorder
Disorders of complex molecules involving organelles:
> lysosomal storage disorders (Fabry’s)
> Peroxisomal disorders (Zellwegers)
Symptoms of IEMs
Non-specific:
-poor feeding, lethargy, vomiting, hypotonia, fits
Specific:
- abnormal smell (sweet, musty, cabbage-like)
- cataracts
- hyperventilation 2º to metabolic acidosis
- hyponatraemia and ambiguous genitalia
- neurological dysfunction with respiratory alkalosis
Biochemical abnormalities in IEMs
- hypoglycaemia
- hyperammonaemia
- unexplained metabolic acidosis/ketoacidosis
- lactic acidosis
Clinical presentation of IEMs
- Cognitive decline
- Epileptic encephalopathy
- Floppy baby
- Exercise intolerant
- Cardiomyopathy
- Dysmorphic features
- Sudden unexpected death in infancy (SUDI)
- Foetal hydrops
How do we diagnose IEMs?
By laboratory investigations:
- routine tests
- specialist tests
- confirmatory tests
Routine laboratory investigations for IEMs
- Blood gas analysis
- Blood glucose
- Plasma ammonia
Specialist investigations for IEMs
- Plasma amino acids
- Urinary organic acids + orotic acid
- Blood acyl carnitines
- Blood lactate and pyruvate
- Urinary glycosaminoglycans
- Plasma very long chain fatty acids
Confirmatory investigations for IEMs
· Enzymology
>red cell galactose-1-phosphate uridyl transferase
>lysosomal enzyme screening
· Biopsy (muscle, liver)
· Fibroblast studies
· Mutation analysis- whole genome sequencing
Neonatal Screening: importance
Via new-born screening programmes:
- early identification of life-threatening disease in pre-symptomatic stage
- early initiation of medical treatment
- reduction of morbidity and mortality
Criteria for neonatal screening
· Condition should be an important health problem
· Must know incidence/prevalence in screening population
· Natural history of the condition should be understood
-there should be a recognisable latent or early symptomatic stage
· Availability of a screening test that is easy to perform and interpret
-acceptable, accurate, reliable, sensitive and specific
· Availability of an accepted treatment for the condition
-more effective if treated earlier
· Diagnosis and treatment of the condition should be cost-effective
Criteria for a good screening test
· Accurate and reproducible
· Cheap and produces rapid result
· Ethical
· Good statistical performance
-how well the diagnosis influences the test result (sensitivity and specificity)
-how well the test result predicts the diagnosis (positive and negative predictive values)
Newborn Blood Spot Screening
Taking blood spots for screening:
· Samples should be taken on day 5 (day of birth is day 0)
· All four circles on card need to be completely filled with a single drop of blood which soaks through to the back of the Guthrie card
