Inborn Errors of Metabolism Flashcards
What are IEMs, inheritance pattern
Groups of diseases from inherited genetic defects leading to abnormal metabolism
Inheritance: AR most common, X-linked, mitochondrial
Symptoms can be due to:
- intoxication of substrates
- intoxication of metabolites
- deficiency of products
General diagnosis of IEMs
Mutation analysis
Enzyme reaction rate
- most direct measurement of functional defect using enzyme assay
- BUT: requires living tissues/cells; fibroblast culture (skin biopsy) or blood cells also possible
- BUT: few labs do this (difficult to standardise)
==> use as last resort only
Amount of metabolites
- e.g. using tandem mass spectrometry to analyse length of C chains in fatty acid oxidation reaction (normally all should breakdown to C2)
Amount of side products
Clinical presentations of IEM
Small molecule pathways e.g. a.a.
= ACUTE
–> any age, usually young
–> vomiting, LOC, epilepsy, liver failure etc.
–> metabolic acidosis, organic aciduria
–> sudden infant death (usually due to co-incidental illness that precipitates defect)
Large molecule pathways e.g. glycogen
= CHRONIC
–> usually during childhood
–> developmental delay, epilepsy, neurological symptoms
–> organomegaly depending on site of storage; also affect organelle (lysosomal storage disease)
Investigations: Who, When
Who?
- FHx of similar illness or unexplained infant death
- Previous Hx of similar illness in patient or unexplained metabolic derangement
- Hx of change of diet before the attack
- Abnormal growth or development
- Feeding difficulties, early after birth
- liver, neurological symptoms
When?
- EARLY
- at onset of deterioration, before any treatment given
(metabolite changes may only be obvious when under stress/high demand)
Investigations: What
Urine dipsticks
- glucose and ketone
Urine
- reducing substances screen e.g. galactose
- metabolic screening e.g. organic acids
Serum
- NH3, amino acid profile (urea cycle)
- Lactate (mitochondrial resp chain)
- Glucose, free carnitine/acylcarnitine (FAOD)
Biopsy (rarely done): skin, liver, muscle
Classical Galactosaemia: pathogenesis, clinical presentations, diagnosis, treatment
Rare in Chinese (1/410,000); 1/60,000 in caucasians
Pathogenesis:
- Gal-1-P uridyl transferase deficiency i.e. GALT (normally converts Gal-1-P to UDP-gal with side product of galacitol)
==> accumulation of Gal-1-P –> toxic to liver, kidney and CNS
==> accumulation of galacitol –> osmotic agent - cataract
Clinical presentations:
- within 1st wk after birth, after milk
- CNS: vomiting, irritability, convulsion
- Liver: failure, high bili
- Kidney: failure (tubular defects)
- Eye: cataract (if untreated for 1 yr)
Other DDx: hereditary fructose intolerance, tyrosinaemia type I
Diagnosis:
- +ve reducing substances in urine (galactose) during milk feeding –> must get sample early!
- confirmatory => enzyme activity of GALT or mutation analysis of GALT gene
Treatment:
- dietary restriction: soy based milk and dairy product avoidance
- growth monitoring
- cataract screening
Possible end-results of defects and examples
A–>B with side product C
1) when B is ATP e.g. beta oxidation of fatty acids –> energy deficit and hypoglycaemia
2) side product C is toxic e.g. organic aciduria such as PKU or glutaric aciduria, amino acidopathy such as tyrosinaemia –> brain, liver, kidney toxicity
3) when A is toxic e.g. NH3 –> urea cycle defects
4) lactate accumulation/acidosis e.g. mitochondrial respiratory chain defects (pyruvate can’t convert to ATP) –> various syndromic disorders e.g. MELAS
5) accumulation of A e.g. storage diseases such as mucopolysaccharidosis, glycogen storage diseases
Fatty acid oxidation purpose, transport into mitochondria
Normal function of beta oxidation:
- TG –> fatty acids –> ketone bodies
- required as energy source (emergency supply and specific source in skeletal muscle and cardiac muscles
Carnitine acyltransferase (CPT1) at outer mitochondrial membrane –> binds acyl CoA to carnitine so fatty acid can be transported to mitochondrial matrix –> acyl CoA and carnitine released by CPT2 in matrix
Acyl CoA enters beta oxidation spiral –> 2 carbons removed at a time (specific enzymes for long/medium/short chain fatty acids)
Medium chain acyl CoA dehydrogenase deficiency (MCAD) - main presentations, biochemistry, measurement
MC FAOD in caucasians (1/40-80 carriers)
MC identifiable cause in Reye’s and SIDS (sudden infant death syndrome)
AR disorder
Main features:
- HYPOKETOTIC HYPOGLYCAEMIA after longer fasting periods e.g. vomiting –> rapidly depleted glycogen stores with defective fatty acid oxidation
- encephalopathy (toxic fatty acid related compounds), lethargy/confusion/coma (due to hypoBG)
- normoglycaemia between attacks, absent symptoms when patient is well
Biochemistry:
- reduced total carnitine
- exertion of dicarboxylic acid (C6-C10)
- excretion of C6-C10 acyl-carnitine
- excretion of glycine conjugates (alternative oxidation of fatty acid intermediates; combines with acylcarnitine and excreted)
Diagnosis:
- tandem mass spectrometry –> abnormal acyl-carnitine patterns – elevated C8 levels (more than C6/C10)
Treatment:
- moderate fat restriction (medium chain TGs) and avoid prolonged fasting
- glycine supplement (during crisis –> bind to acyl CoA to excrete)
- L-carnitine supplement
- dextrose infusion if decompensation/during attack
FAOD in Chinese
MCAD very rare
More common:
- primary carnitine deficiency
- glutaric aciduria II (inhibition of electron transfer flavoprotein)
- carnitine translocase deficiency
==> many have good outcome but some defects may develop cardiomyopathy (except translocase deficiency)
Primary Carnitine Deficiency (PCD): pathogenesis, typical presentation and complications, treatment, prognosis
Pathogenesis
- affect OCTN2 transporter on mitochondrial membrane required for active uptake of carnitine
- -> heart and skeletal muscles have high demand for fatty acid oxidation ==> arrhythmia, CARDIAC ARREST
- -> kidney tubule uses transporter to reabsorb carnitine ==> excessive carnitine in urine
Typical presentation:
- hypoketotic hypoBG (like other FAOD(
- metabolic crisis when under stress e.g. URTI
- accumulation of toxic intermediates
Treatment:
- high dose carnitine infusion, then oral
- supportive, avoid long chain fatty acids
Prognosis: normal survival on LIFE LONG TX (otherwise risk of sudden cardiac death), little side effects of carnitine
Maternal PCD
Phenotype with presentation in adulthood
- mother has disease but asymptomatic and well (mild phenotype; S467C mutation)
- baby undergoes newborn screening and found low carnitine
Generally well without treatment
Glutaric Acidaemia Type I (no need details): pathogenesis, presentation, investigations, treatment, outcomes
Glutaryl-CoA dehydrogenase deficiency (accumulation of glutraryl-CoA which is converted to glutaric acid)
Presentation:
- big head, acute CNS events with seizure, hypotonia with marked head lag
- usually from 2mths-4yrs old; found with newborn screening (NBS)
Investigations:
- urine glutaric acids
- MRI: frontotemporal atrophy
- confirmatory: fibroblast culture for enzyme deficiency
Treatment:
- low but adequate protein intake (esp tryptophan, lysine)
- carnitine supplement
Aim to avoid metabolic crisis before puberty (lower risk after puberty)
Outcomes:
- no NBS = Dx at metabolic crisis = long term survival with major neurological defects
- NBS = Dx at birth = avoid metabolic crisis = no neurological disease
Urea cycle defects: normal function, MC enzyme deficiency, inheritance, presentations, male vs female, investigations, treatment
Normal function: detoxification of ammonia (NH3) and generation of arginine
Ornithine Transcarbamylase deficiency most common
- mitochondrial enzyme
- carbamyl phosphate + ornithine –> citrulline
- X linked disease
Presentations:
- CNS toxicity of NH3 (astrocyte glutamine accumulation = swelling = cerebral oedema) –> vomiting, drowsiness, LOC, seizure, brain damage
- abdominal pain
- male: usually 1st wk after birth; very severe
- female: most likely carrier and asymptomatic; those with symptoms are mild and onset when a few years old (e.g. provoked by high protein diet, drugs such as valproate)
Investigations:
- plasma ammonium: normal <20 mcmol/L; 50-80 = non-specific illness; >100 = likely urea cycle defects
(–> DDx of hyperNH3 –> organic acidaemia, liver disease, Reye’s)
Treatment:
- dietary protein restriction
- arginine supplements
- NH3 carrier to increase excretion e.g. Na benzoate
Large molecule diseases: presentation, types of diseases
Presentation
- CHRONIC, onset late in childhood
- organomegaly, neurological, developmental delay, convulsions
Many enzymes involved in synthesis and lysis of glycogen – principally liver and muscle storage
Glycogen storage diseases (13 types)
- glycogenolysis enzyme defects
- primarily liver storage (hepatic form) –> GSD 1,3,6,9
- muscular form –> GSD 2,3,5,7
