Inborn Errors of Metabolism Flashcards
- Who is the father of Inborn errors of metabolism and why?
Archibold E Garrod (1857-1936): Father of IEM – published/printed book ‘Inborn Errors of Metabolism’.
- What did Archibold propose in his book?
Proposed:
- Alkaptonuria (dark urine –> functional enzyme that breaks down AA’s phenylamine and tyrosine is missing)
- Cystinuria (high conc of cysteine in urine)
- Albinism (loss of pigment)
- Pentosuria (high conc of sugar xylitol (a pentose) in urine)
We’re all congenital, inborn and had the discontinuous distribution of a Mendelian Trait?
- What is meant by the term “inborn” mean
transmitted through the gametes
- What does “the discontinuous distribution of a Mendelian trait” mean?
- traits with only a few possible phenotypes that fall into discrete classes; phenotype is controlled by one or only a few genes and it doesn’t change throughout your life eg blood type
- Is Alkaptonuria caused by dominant or recessive genes?
•Autosomal recessive
- What is Alkaptonuria?
Homogentisic acid oxidase deficiency so cannot process amino acids e.g. tyrosine
- What are some signs/symptoms of Alkaptonuria?
•Urine turns black on standing (and alkalisation), arthritis and black ochronotic pigmentation of cartilage & collagenous tissue.
- Is Cystinuria recessive or dominant?
What is the prevalence of Cystinuria
autosomal recessive
1:7000.
- What mutation results in Cystinuria?
•Mutations of SLC3A1 amino acid transporter gene (Chr 2p) & SLC7A9 (Chr 19)• Mutations of SLC3A1 amino acid transporter gene (Chr 2p) & SLC7A9 (Chr 19)
- What is Cystinuria?
Defective transport of cystine and dibasic aa’s through epithelial cells of the renal tubule and intestinal tract
- Who came up with the one gene- one enzyme concept?
Beadle and Tatum in 1945 (Got a nobel prize for it in 1958)
- What is the one gene- one enzyme concept?
All biochemical processes in all organisms are under genetic control
These biochemical processes are resolvable into a series of stepwise reactions
Each biochemical reaction is under the ultimate control of a different single gene
- Using the one gene-one enzyme concept, what is the effect of a mutation of a single gene?
Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
- Summarise the one gene - one enzyme concept into one sentence?
each gene directly produces a single enzyme, which consequently affects an individual step in a metabolic pathway.
- Who invented the molecular disease concept and when ?
Pauling
1949
- What is the molecular disease concept?
- Work on haemoglobin in sickle cell disease - evidence that human gene mutations produce an alteration in the primary structure of proteins
- Inborn errors of metabolism are caused by mutations in genes which produce abnormal, non-functional proteins
- Following questions refer to Autosomal Recessive inheritance:
- What is the risk of getting the disease if both parents are carriers
- What increases the risk of autosomal recessive conditions
- What are some examples of autosomal recessive conditions?
o Both parents carry a mutation affecting the same gene - 1 in 4 risk each pregnancy
o Consanguinity increases risk of autosomal recessive conditions
o Examples: Cystic fibrosis, sickle cell disease
- Are autosomal dominant conditions rare or common in inborn errors of metabolism?
Rare
- What are some examples of autosomal dominant conditions?
Huntingdon disease,
Marfan’s
Familial hypercholesterolaemia
- The following questions refer to X Linked Recessive conditions
- Which line are they passed through (maternal or paternal)
- Will the condition be expressed in males or females
- Who will carry the mutation –> what is a consequence of this?
- Passed through maternal line
- Condition appears in males
- Female carry the condition but not usually expressed , however may manifest condition ( Lyonisation= random inactivation of ONE of the X chromosomes)
- Why is it more common for males to express X linked recessive disorders than females?
Recessive X-linked disorders tend to be more common in males, because it’s less likely that a female will get 2 copies of the recessive mutation.
- For Dominant X-Linked recessive who can it pass it on to sons/daughters?
- Can a father pass it on to his son?
passed on from either affected parent; fathers only pass the condition to daughters while mothers can pass the condition to both sons and daughters.
oNo male to male transmission (father only passes on Y chromosome)
- What are some examples of X-Linked Dominant conditions?
Fragile X (learning disabilities, speech impairment) Ornithine carbamoyl transferase deficiency (excess ammonia)
- What are some examples of X-Linked recessive conditions?
Haemophilia A (clotting factor issues , increased bleeding)
Duchenne muscular dystrophy (weakness and loss of muscles)
Fabry’s disease (lysosomal storage disorder)
- What is meant by “codominant” inheritance?
- Two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein.
- Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
- What are some examples of codominant inheritance?
ABO Blood group (eg parents A and B, child AB)
α1AT
- What is meant by “Mitochondrial “ Inheritance?
Which parent can pass on Mitochondrial inheritance and why?
• Mitochondrial gene mutations are exclusively inherited from mother and affects both male and female offspring.
o As only the egg contributes mitochondria to the developing embryo, only females can pass mutations to offspring and fathers cannot pass their mutations on.
- Two examples of mitochrondrial inheritance conditions are :
-MERFF
and
-MELAS
What do they stand for and what are the symptoms?
. MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes :seizures, headaches, brain function
- What affects the presentation of mitochondrial inherited conditions?
- Distribution of affected mitochondria determine presentation – diseases vary in symptoms, severity and onset.
- High energy-requiring organs more frequently affected
- There is a current debate on three parent babies- in 2017 what significant event occurred regarding this topic?
2017 – UK granted first licence to Newcastle fertility centre
- What is Heteroplasmy?
Cell contains varying amounts of normal mitochondrial DNA and also mutated mitochondrial DNA
- If individual cases of IEM are rare, why do they account for such a high mortality rate in the first year of life?
•There are many types of diseases of IEM that are individually rare (1:10,000 - 1:500,000) but these are collectively common and account for high mortality within the first year of life.
- Fill in the blank:
“ IEM pay a significant contribution to the *% of children of school age with physical handicap and the *% with severe learning difficulties.
1%
0.3%
- Its important to recognise IEM early on in sick neonates for treatment, how can we do this?
by newborn screening programmes
- What is the presentation of IEM in neonates?•
Neonatal presentation often acute and caused by defects in energy metabolism:
o Maple syrup urine disease (body cant break down branched amino acid, urine smells sweet) Tyrosinaemia (can’t breakdown tyrosine)
o OTC (urea cycle defect) – partial deficiency of enzyme for converting nitrogen into urea.
- What is the presentation of IEM in Adults?
Wilson’s disease (error of copper metabolism) or Haemochromatosis (iron overload).
- Most neonates with IEM are born at term with normal birthweight and no abnormal features, so when do symptoms present?
• Symptoms present frequently in the first week of life when starting full milk feeds
- What are some clues for IEM?
o Consanguinity or family history of similar illness in siblings or unexplained deaths.
o Infant who was well at birth but starts to deteriorate for no obvious reason.
- What can IEM non-specific symptoms be mistaken for?
Sepsis
- What are the non-specific symptoms of IEM?
Poor feeding, lethargy, vomiting, hypotonia, fits
- What are specific symptoms of IEM?
o Abnormal smell (sweet, musty, cabbage-like) and cataracts (opaque lens – blurred vision).
o Hyperventilation 2 degree to metabolic acidosis.
o Hypernatraemia (too much sodium) and ambiguous genitalia.
o Neurological dysfunction with respiratory alkalosis.
- What are some biochemical abnormalities seen in patients with IEM?
Hypoglycaemia, Hyperammonaemia, Unexplained metabolic acidosis/ketoacidosis or Lactic acidosis.
- What are some clinical scenarios seen in patients with IEM?
Cognitive decline, Epileptic encephalopathy (loss of cerebral function), Floppy baby (low muscle tone), Exercise intolerant, Cardiomyopathy, Dysmorphic features, Sudden unexpected death in infancy (SUDI), Fetal hydrops (fluid accumulation).
- What are the routine laboratory tests that would be given to a patient with IEM symptoms?
Blood gas analysis
Blood glucose
Plasma ammonia
- What specialist investigations could take place for a patient with IEM?
•Plasma amino acids, Urinary organic acids + orotic acid, Blood acyl carnitines, Blood lactate and pyruvate, Urinary glycosaminoglycans, Plasma very long chain fatty acids.
- What investigations can we do to confirm IEM?
- Enzymology
- Biopsy (muscle, liver)
- Fibroblast studies
- Mutation analysis – whole genome sequencing
- What do we investigate in an enzymology?
o Galactosemia: Red cell galactose-1-phosphate uridyl transferase (catalyses formation of galactose)
o Lysosomal enzyme screening
- How many babies are screened per year in the uk?
What is the importance of neonatal screening?
- UK >770000 babies screened/year
- Early identification of life-threatening disease in pre-symptomatic babies means medical treatment is initiated earlier - reduction of morbidity and mortality.
- What are Wilson and Jugners criteria for screening patients seeing as we cant screen for every disease?
- Conditions needs to be an important health problem and relatively prevalent (not extremely rare).
- Condition’s natural history should be understood – needs a recognisable latent or early symptomatic stage.
- Easy to perform/interpret screening test available- 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.
- What is the criteria for a good screening test?
• Accurate and reproducible, cheap and produces rapid result, ethical.
• Good statistical performance.
o How well the diagnosis influences the test result (sensitivity and specificity).
o How well the test result predicts the diagnosis (positive and negative predictive values).
- Initially, what did the newborn blood spot screen for?
- In 2015, what was it extended to include?
PKU and Congenital hypothyroidism
2015 - Cystic fibrosis, Haemoglobinopathies and Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- In England , from 2015 the newborn blood spot screening was extended to include 4 additional components - what are these?
Maple syrup urine disease (MSUD),
Homocystinuria (pyridoxine unresponsive) (HCU), Isovaleric acidaemia (IVA), Glutaric aciduria type 1 (GA1).
- How are newborn blood spots taken?
•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.
- Case Study:
Patient :
- Male infant
- Consanguineous parents
Symptoms:
•Strange, cabbage-like smell
-heart murmur (HM investigated but no abnormalities were found)
What initial investigations do you think should take place?
Test for Plasma amino acid and urine sugars
- Following from case study ^
Initial Investigations showed Tyrosine and Methionine present and urine sugars -gross galactosuria
Further investigations and result:
Galactosuria = formulae changed to lactose free Alanine aminotransferase (high) Aspartate transaminase (high), Glucose, Methionine and Tyrosine (high), Prothrombin time (very long), partial prothrombin time (very long).
A thin layer chromatography urine reducing sugars showed presence of galactose
Completed a plasma amino acid by HPLC
4 days after admission (4/52): Very ill, acidotic, grey, pyrexial (fever), gross ascites with distended abdomen and plasma albumin falls.
What does the baby have?
What treatment would be appropriate?
Acute Liver Failure
(Tyrosinaemia type 1)
•Treatment: iv dextrose, bicarbonate, antibiotics and FFP (fresh frozen plasma).
- What are 4 Possible metabolic causes for acute liver disease in neonate
Classical galactosaemia
Hereditary fructose intolerance
An organic acidaemia
Tyrosinaemia type 1
- What specifically happens in Tyrosinaemia type 1?
- Blockage/deficiency of fumarylacetoacetate hydrolase (FAH) causes abnormal tyrosine breakdown which results in accumulation of toxic metabolites such as succinyl-acetate (damages the liver and kidneys).
- Treatment stops the building up of these metabolites by stopping the pathway slightly higher up.
- Case Study:
• 15 year old male referred from local DGH to King’s College Hospital - Fulminant Hepatic Failure?
• History:
o Well in morning, went to bed (tired) and was woken up at dinner – walked downstairs, slumped on sofa, started shaking and lost consciousness – taken to a district general hospital where he had fluctuating consciousness with intermittent screaming but no focal neurological signs.
• On Examination:
o Sleepy but wakes up, orientated, slurred but appropriate speech (talked endlessly),
o No neurological signs, no hepatosplenomegaly, nor signs of chronic liver disease, scleral jaundice and normal heart and lungs.
• Initial Investigations (mostly normal reflected the liver damage starting to occur): transferred to liver centre hospital.
o Paracetamol + Salicylate screen negative so no overdose but NH3 was very high.
o Normal brain CT and CSF examination.
• Past Medical History:
o No friends, special needs school (behavioural and learning difficulties), decreased weight due to dieting, iron and vitamin supplements, large cheese (carbohydrate) intake of the day of collapse.
• Family History:
o Mother has nephritis and Mother’s brother died of Herpes simplex encephalitis 9 years ago.
• Further Investigations:
o Second line tests and ultrasound (looking at liver with mild splenomegaly): normal.
o EEG- diffuse encephalopathy of moderate severity.
o Liver biopsy - minimal hepatitic changes and focal fatty infiltration
o Organic acids by GCMS showed: Increased uracil and orotic acid excretion.
What diagnostic test can take place?
Whats the diagnosis?
oOrnithine transcarbamylase (OTC) low and Carbamylphosphate synthase within range
•Diagnosis: Block at OTC caused a build-up of ammonia as it is not oxidised in the urea cycle.
