Inborn Errors Of Metabolism Flashcards
What are inborn errors of metabolism?
Single gene defects resulting in disruption to metabolic pathways
Can vary in age of onset and clinical severity
What are the effects of inborn errors of metabolism
Toxic accumulation of substrates
Toxic accumulation of intermediates from alternative metabolic pathways
Defects in energy production/use due to deficiency of products
Combination of above
What is Alkaptonuria?
Autosomal recessive disease
Congenital
Urine turns black on standing
Black ochrontic pigmentation of cartilage and collagen out tissue - ears and eye
Caused by Homogentisic acid oxidase deficiency
What is the molecular disease concept?
Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
What are the mechanisms of inheritance for inborn metabolic disease genes?
Autosomal recessive - most common
Autosomal dominant - rare in IEMs
X-linked
Mitochondrial
Describe the AUTOSOMAL RECESSIVE mechanism of inheritance.
Both parents carry mutation effecting the same gene
1 in 4 risk in pregnancy
Consanguinity (parents are blood related) increases risk of autosomal recessive conditions
Eg. Alkaptonuria
Describe the X LINKED mechanism of inheritance.
Passed through the maternal line
- condition appears in males
- condition carried in females
- lyonisation can occur (female carriers can express gene and manifest condition)
Eg. Fabry’s disease
Describe the MITOCHONDRIAL inheritance pathway.
Mitochondrial gene mutation
Inherited exclusively from mother
- only egg contributes mitochondria in developing embryo
- fathers do NOT pass on these disorders
Affects both make and female offspring
Eg. MERFF, MELAS
What is heteroplasmy?
Cell contains varying amounts of normal mtDNA and also mutated mtDNA.
How is the severity of mitochondrial disease determined?
the distribution of affected mitochondria determines presentation
Mitochondrial disease can vary in symptoms, severity, age of onset
High energy-requiring organs ore frequently effected
How common are inborn errors of metabolism?
Induvidually rare:
Collectively common:
- high mortality within first year of life
- significant contribution to children of school, age with physical handicap and severe learning difficulties
What are treat,emits available for inborn errors of metabolism?
Dietary control/restrictions
Compound supplementation
New drug/enzyme replacement.
Organ transplant
How is IEM classified into toxic accumulation?
Protein metabolism
- amino acids
- organic acids
- urea cycle disorders
Carbohydrate intolerance
How can IEM be classified into deficiency in energy production/utilisation?
Fatty acid oxidation
Carbohydrate utilisation/production
Mitochondrial disorders
How can IEM be classified into disorders of complex molecules involving organelles?
Lysosomal storage disorders
Peroxisomes disorders
How is IEM presented in Neonatal patients?
Often acute
Often caused by defects in carbohydrate intolerance and energy metabolism
How is IEM presented in late onset patients?
Due to accumulation of toxic molecules
- Patients have residual enzyme activity allowing slower accumulation of toxins
- symptoms appear at adulthood
- present with organ Faliure,seizures, encephalopathy
How is IEM detected in neonates?
Born at term with normal birth weight and no abnormal features.
Symptoms present frequently in the first week of life when starting full milk feeds.
Clues:
- consanguinity
- FH of similar illness in siblings or unexplained deaths
- infant who was well at birth and starts to deteriorate with no obvious reason.
Define consanguinity
Being from the same ancestor or being related
What are the clinical symptoms of neonatal IEM?
Poor feeding, lethargy, vomiting
Epileptic encephalopathy
Profound hypotonia (floppy baby)
Organmegaly
Dysmorphic features
Sudden unexpected death in infancy (SUDI)
What are the biological symptoms of neonatal IEM?
Hypoglycemia
Hyperammonaemia
Unexplained metabolic acidosis
Lactic acidosis
What are routine laboratory investigations to detect IEM?
Blood gas analysis
Blood glucose and lactate
Plasma ammonia
What are specialist investigations to detect IEM?
Plasma amino acids
Urinary organic acids + orotic acid
Blood acrylic carnitines
Urinary glycosaminoglycans
Plasma very long chain fatty acids
CSF tests
What confirmatory investigations can be done to confirm someone has IEM?
Enzymology
Biopsy (muscle, liver)
Fibroblast studies
Mutation analysis - whole genome sequencing
What is newborn screening?
Early identification of life threatening disease in pre-symptomatic babies
earlier initiation of medical treatment
Reduction of morbidity and mortality
What is the criteria for screening?
Must be important health problem
Must know Incidence or prevalence in screening population
Natural history of the condition should be understood
Availability of a screening test that is easy to perform and interpret
Availability of an accepted treatment for the condition
Diagnosis and treatment of condition should be cost effective.
How is a new born blood sport screening obtained?
Samples should be taken on day 5 from heal prick
All four circles on “Guthrie” card red to be completely filled with a single drop of blood which soaks through to the back of the card
Require a good quality bloodspot for analysis
What is Tyrosinaemia Type 1?
Genetic deficiency in FAH
FAH catalyses the final step in tyrosine metabolism
Increased byproduct succinylacetone leads to significant organ toxicity (liver and kidney)
How is Tyrosinaemia Type 1 treated?
Nitisinone (NTBC)
- inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
- early treatment achieves 90%> survival rate with normal growth.
Side effects: accumulation of tyrosine and Requires daily dietary restriction of tyrosine and precursor phenylalanine
What is ornithischians transcarbamylase deficiency? (OTC)
Urea cycle disorder
Symptoms range from mild to profound neuropschiatric manifestations
Eg. Seizures, ataxia
What can OTC cause?
Factors can trigger hyperammonaemic encephalopathy
- increased endogenous protein catabolism (eg. Fasting, trauma, infection)
- high protein
