Inborn Errors of Metabolism Flashcards
Define Inborn Errors of Metabolism
Inborn Errors of Metabolism = Monogenic defects which disrupt metabolic pathways. A group of rare genetic disorders
IEMs can cause:
- Toxic accumulation of substrate
- Toxic accumulation of intermediates from other metabolic pathways
- Insufficient products = defects in energy production/use
-All of these together
What are the 4 IEM disorders which were studied by Garrod?
Alkaptonuria - homogentisic acid accumulates, autosomal recessive
Cystinuria - ↑ cysteine(aa) conc. in urine, autosomal recessive
Alibinism - Congenital absence of any pigmentation
Pentosuria - High xylitol(a pentose sugar) conc. in urine
These are all:
- Congenital(present at birth)
- Inborn (transmitted through gametes)
- Inherited
Describe Alkaptonuria and how it presents
Homogentisic acid oxidase deficiency
Autosomal recessive disorder
Urine turns black on standing/alkalinisation
Black ochronotic (accumulation of homogentisic acid in connective tissue) pigmentation of cartilage and collagenous tissue
Black material in articular cartilage + ligaments
What is the One-Gene, One-Enzyme concept ?
1-Gene, 1-Enzyme Concept: Mutation in 1 gene alters 1 enzyme, and therefore affects 1 biochemical reaction
Molecular disease concept: Gene mutn->Abnormal protein->Abnormal protein (causes IEMs)
- Genes control all biochemical processes (stepwise reactions)
- Each biochemical reaction is under the ultimate control of a different single gene
- Mutation of a single gene alters the cell’s ability to carry out a single primary chemical reaction
What is the Molecular Disease Concept?
Inborn errors of metabolism are caused by: Gene mutn->abnormal protein->abnormal protein function/activity
Diff. electrophoretic ability b/w healthy Hb + sickle cell anaemia Hb. Diff. number of ionisable aa residues in globin protein = diff molecular structure = sickling process.
Abnormal protein causes disease. Gene determines protein structure + functional activity
What are the different inheritance patterns?
Single gene disorders (IEM) inheritance patterns:
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
Using a accurate family history can establish
What is the autosomal recessive mechanism of inheritance?
Autosomal Recessive = Most common IEM mode of inheritance
Both parents carry a mutation which affects the same gene
Homozygotes have the disease
Heterozygotes = carriers
1 in 4 risk per pregnancy. Both parents are carriers
Consanguinity (the fact of being descended from the same ancestor, cousin-cousin marriage) increases risk of autosomal recessive conditions
E.g diseases: PKU(Phenylketonuria) Alkaptonuria, MCADD
What is the autosomal dominant mechanism of inheritance ?
These are rare in IEMS.
1 copy of a mutated gene from one parent causes the genetic condition.
50% chance of having an affected child
No carrier status
E.g: Marfans, Acute Intermittent Porphyria
What is the X-linked inheritance mechanism ?
Copy of gene on X-chr has the genetic mutation.
Recessive X-linked conditions always pass through the maternal line :
- Condition appears in males = more frequently affected
- Condition carried in females
Female carriers usually don’t express the disease but may manifest condition
(Lyonization - Random inactivation of one of the X chromosomes)
E.g: Fabry’s disease, Ornithine carbamoyl transferase deficiency.
X-chr of male comes from mother as mother has no Y chr. + there is no male-male transmission
What is Mitochondrial inheritance ?
Mitochondrial gene mutation = Mitochondria fail to produce enough energy for body to function
Mitochondria are Inherited exclusively from mother
- The egg will contribute mitochondria to the developing embryo
- Only females can pass on mitochondrial mutations to their children
Affects both male and female offspring. but affected male cannot pass on mitochondrial disorder
Example :
- MERFF (Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizure)
- MELAS(Mitochondrial encephalopathy with lactic acidosis and stroke like episodes
most mit. diseases are caused by mutations in mit DNA which is maternally inherited
What is Heteroplasmy?
Heteroplasmy = Each cell contains varying amounts of normal mt DNA and also mutated mtDNA
each cell contains 2 copies of every gene
most normal ppl have homoplasmic cells = their cells contain only normal mitochondrial DNA.
Ppl w maternally-inherited mit disease usually have heteroplasmic cells = cell contains some normal mit DNA + some mutated mit DNA
Heteroplasmy = symptoms, severity, age of onset of mit disorder vary greatly within family. symptoms appear when mutation affects much of the mitochondrial DNA
=mother w mit mutation will pass the mut onto her children but not all her children will become symptomatic. if children are symptomatic, disease that each child has varies depending on % of mutant mit DNA in each part of body
there is a threshold proportion of mutant mit DNA after which the cell can’t cope = disease. diff. threshold in diff tissues = some more sensitive to energy deficiency.
=infinite num of manifestations of mit disease = hard to diagnose accurately
Which types of organs are severely affected by Mitochondrial diseases?
High-energy-requiring organs are more frequently affected
Treatment of IEMs
- Dietary control/Compound supplementation
- Enzyme replacement therapy
- Drug therapy
- Organ transplant for damaged organs
How are IEM classified ?
Describe the 3 categories and subsections within them.
Toxic accumulation - toxic compounds accumulate: -Protein metabolism o Amino acids-PKU, tyrosinemia o Organic acids-propionyl acidaemia o urea cycle disorders -OTCD -Carbohydrate intolerance o galactosaemic
Deficiency in energy production/utilisation:
- Fatty acid oxidation -MCADD
- Carbohydrate utilisation/production-GSDS
- Mitochondrial disorders -MERFF
Disorders of complex molecules involving organelles:
- Lysosomal storage disorders e.g. Fabry’s
- Peroxisomal disorders e.g. Zellweger’s
What is the presentation of IEM?
Describe the two main categories of this.
Neonatal to adult onset depending on severity of metabolic defect
- Neonatal presentation often acute
- Often caused by defects in protein/carbohydrate intolerance and energy metabolism
Late onset is due to accumulation of toxic molecules
- Patients have residual enzyme activity allowing slower accumulation of toxins over time
- Symptoms appear at adulthood
e. g. adult onset lysosomal storage disorders - Present with organ failure, encephalopathy(Damage that affects the brain), seizures.
Describe neonates who are born with IEM.
What clues may be present to help diagnose them with IEM?
Neonates w IEM may be born at term with normal weight and no abnormal features.
Symptoms frequently present in the first week of life when starting full milk feeds - when normal metabolism starts to fail - cannot metabolise lactose
Clues:
Consanguinity
FH of similar illness in siblings/unexplained deaths
Infant who was well at birth but deteriorates for no clear reason
infants with errors in pathways involved in accessing stored energy appear well for prolonged time due to ongoing carb intake. but if sudden illness/changed diet/stop night feed = can’t access enough stored energy = hypoglycaemia/seizures
What symptoms will Neonates present with ?
Clinical :
- Poor feeding, lethargy ,vomiting (non-specific, mistaken for sepsis)
- Epileptic encephalopathy
- Hypotonia(floppy baby)
- Organomegaly
- Dysmorphic features
- SUDI-Sudden death
Biochemical abnormalities:
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic acidosis/ketoacidosis
- Lactic acidosis
What laboratory investigations can be carried out to diagnose IEM ?
Routine laboratory investigations :
- Blood gas analyisis
- Blood glucose and lactate
- Plasma ammonia
Specialist investigations:
- Plasma amino acids
- Urinary organic acids +orotic acid
- Blood acyl carnitines
- Urinary glycosaminoglycans
- Plasma very long chain fatty acids
- CSF tests - CSF lactate pyruvate, neurotransmitters
save urine/blood/CSF for further investiagtions
What are some confirmatory investigations which are carried out ?
Enzymology:
- Red cell galactrose -1 -phosphate uridyl transferase for galactosaemia
- Lysosomal enzyme screening for Fabry’s
Biopsy (Muscle,Liver, Skin) - to confirm high enzyme activity
Fibroblast studies
Mutation analysis - Whole genome sequencing
send off blood to enzymes lab for RBC, WBC + plasma enzymes analysis - analyse enzyme activity to confirm defect
-important to know full family history - mutation known to family?
What is Newborn screening and what can it lead to ?
First = PKU, bacterial inhibition test
Identify fatal IEM diseases in pre-symptomatic babies = start treatment early = ↓ morbidity+mortality
Screening to Detect PKU. Bacterial inhibition assay. Early knowledge of disorder = treat PKU by restricting aa phenylalanine. = reduced mental retardation
What is the criteria for screening?
-Condition should be an important health problem
-Must know incidence/prevalence in screening population (this may vary in different populations)
-Natural history of the condition should be understood
(recognisable latent/early symptomatic stage)
-Availability of a screening test that is easy to perform and interpret
(Acceptable,accurate,reliable,sensitive and specific, quick, simple, cheap, ethical)
-Availability of an accepted treatment for the condition
(More effective if treated earlier. evidence of benefits of early intervention)
-Diagnosis and treatment of the condition should be cost effective. - test + follow-up + therapy
What are the different new born spot screening programmes?
test multiple disorders from a single blood spot:
- PKU
- SCD
- Cystic fibrosis
- Congenital hypothyroidism
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- Maple syrup urine disease
- Homocystinuria
- Isovaleric acidaemia
- Glutaric aciduria type 1
How are samples taken for new born screening ?
Blood spots are taken on day 5 via a heel prick.
All 4 circles on ‘Guthrie’ card need to be filled with a drop of blood which soaks through to the back of the card.
UK National Screening Program Centre monitors screening
What are the possible metabolic causes for acute liver disease in neonate?
- Classical galactosaemia
- Hereditary fructose intolerance
- An organic acidaemia
- Tyrosinaemia type 1
- Urine organic acid analysis shows an increase in succinylacetone
What is Tyrosinaemia Type 1 ?
Genetic deficiency in fumarylacetoacetase (FAH)
Catalyses the final step in tyrosine metabolism
Increased byproduct succinylacetone leads to significant organ toxicity
(liver,kidney)
How can Tyrosinemia TYpe 1 be treated and what are the side effects of the treatment ?
Treatment -Nitisinone (NTBC)
- Inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
- Early treatment achieves >90% survival rate with normal growth, improved liver function and prevention of cirrhosis(severe liver scarring)
NTBC side effect is accumulation of tyrosine and requires dietary restriction of tyrosine and precursor phenylalanine.
Outline the metabolism of Tyrosine pathway
Check slide on Panopto
What is Ornithine Transcarbamylase deficiency ?
Urea cycle disorder
Symptoms range from mild to profound neuropsychiatric manifestations:
Ataxia, seizure, hyperammonaemic encephalopathy
Factors can trigger hyperammonaemic crisis:
Increased endogenous protein catabolism, infection ,fasting,trauma,steroid administration
High protein intake
Outline the Urea Cycle
Check slide on Panopto
Metabolism
complex biochemical processes
specific pathways
synthesis/catabolism of proteins, carbs, fats, complex molecules
Liver damage causes ………..
elevation of aa’s as they cannot be broken down (metabolised)
WATCH ‘CASES’ PANOPTO VID -
https://sgul.cloud.panopto.eu/Panopto/Pages/Viewer.aspx?id=00369073-9949-46d8-b705-ae2101101570&start=0