CHEMPATH: Metabolic disorders and screening (1+2) Flashcards
What are the inheritance types of metabolic disorders? Which abide by Mendelian inheritance?
- Chormosomal
- Polygenic
- Monogenic
Polygenic and monogenic mainly abide by Mendelian inheritance
What does OMIM stand for and what is its use?
Online Mendelian Inheritance in Man (OMIM)
- Constantly updated catalogue of metabolic conditions
- Most are autosomal and typically present at a young age with non-specific symptoms
- X linked is the next most common, then Y linked and mitochondrial
What are the causes of deficient enzyme activity?
- Lack of enzyme
- Reduced enzyme activity due to defects of…
- Post-translational modification
- Assembly
- Transportation
- Defects of co-factor activation
What are some commonly seen biochemical hallmarks of metabolic disorders?
- Lack of end-product
- Build-up of precursors
- Abnormal, often toxic metabolites (due to large amounts of substrate that does not usually react with the enzymes, starts reacting and producing toxic metabolites)
What is the criteria for screening for a metabolic condition (Wilson &Junger, 1968)?
- Important health problem
- Accepted treatment
- Facilities for diagnosis and treatment
- Latent or early symptomatic stage
- Suitable test or examination
- Test should be acceptable for population
- Natural history understood
- Agreed policy on whom to treat as patients
- Economically balanced
- Continuing process
What is the use of OMIM numbers?
Should be used when referring to any metabolic conditions as they may have several names
What is the pathophysiology of phenylketonuria?
- Phenylalanine hydroxylase (PAH) deficiency
- PAH converts phenylalanine into tyrosine
- If the enzyme is deficient, you get:
- Build-up of phenylalanine (toxic)
- Abnormal metabolites:
- Phenylpyruvate
- Phenylacetic acid (detected in urine)
How common is PKU? What are the clinical features?
~1 in 10,000
IQ <50 but no other physical symptoms
What investigations are used for diagnosing PKU and what is the management?
- Blood test for presence of phenylalanine
- NB: no gene test is available as over 400 different genes may be implicated in PKU
Management: dietary supplementation but must be started within the first 6 weeks of life otherwise it will not be effective at preventing complications.
What is the sensitivity and specificity of this test using measurement of a metabolite?
Sensitivity = true positive/total disease present
- Talking about those in whom the disease in present.
- Therefore if 48/50 then 96% sensitivity
Specificity = true negative/total disease absent
- Concerns those in whom the disease is absent
- In this example: 100/100 = 100%
What is the positive and negative predictive value of this test?
PPV = True positive/total positive found
- Only refers to positive tests (tells you if someone has the disease or if you can rule it out)
- 48/48 = 100%
NPV = True negative/total negative found
- Negative predictive value only refers to negative tests
- In this example 100/102 = 98%
What are the advantages and disadvantages of a lower cut-off for this test?
- Advantage - high sensitivity/no false negatives so no one with the disease will be missed
- Disadvantage - more false positives, lower positive predictive value
Which factor can have a big impact on the predictive value of a test?
Prevalence of the disease - high false positive rates with lower prevalence of disease and so low PPV.
From example:
- If instead of 50 disease present to 100 disease absent you’d have:
- 50 disease present to 49,950 disease absent.
- Assuming the specificity remains the same at 95%, you’d have 2,500 false positive for every 50 disease present
- PV+ve goes down to 2%
What is the test used to investigate for metabolic disorders in the newborn? When is it done?
5-8 days of life
- Heel prick test/Guthrie test
- Capillary blood from the posterior medial third of the foot is spotted onto a card.
How is the newborn heel prick test analysed?
- Sent to one of 17 UK Newborn Screening Laboratories Network labs
- Bloodspot punched out and blood sample eluted to measure phenylalanie etc
- PPV for PKU is ~80%
What is the incidence of congenital hypothyroidism? What are the causes and reasons for investigation by heel prick?
- Inherited in only 15% of cases; usually due to dysgenesis/agenesis of the thyroid glands
- Not always clinically detected
- Based on high TSH (in UK), started in 1970
- PPV ~ 60-70%
What did the National Screening Committee do to the Wilson and Jugner criteria?
Extended it to include 29 criteria including… ‘evidence from RCTs that the proposed screening would be effective in reducing mortality or morbidity’
When was sickle cell disease (OMIM 603903) added to the UK screening programme? What about CF and MCADD?
SCD - 2006
CF - 2007
MCADD - 2009
How common is CF and why was it added?
1 in 2500
Evidence that early intervention improves outcome
How many types of CF exist? What is the pathophysiology of CF? Which organs are affected and how?
6 classes of defects (image)
Pathophysiology:
Failure of Cl- to move from inside the epithelial cell into the lumen –> increased reabsorption of Na+/H2O –> viscous secretions –> ductule blockage –>
- Lungs - recurrent infection
- Pancreas - malabsorption, steatorrhoea, diabetes
- Liver - cirrhosis
What is measured in neonate blood tests to diagnose CF?
high blood immune reactive trypsin (IRT) if it is >70ng/ml in 3 bloodspots then DNA mutation detection panel is used etc.
What is the advatage and disadvantage of mass spectrometry in testing for metabolic diseases?
Advantage - from a single sample, many abnormal metabolites can be picked up
Disadvatage - testing for all diseases is rarely done as it is expensive and there may be no treatment
What is MCADD?
Medium chain Acyl-CoA dehydrogenase = fatty acid oxidation disorder
Added to newborn screening in 2009
What is the pathophysiology of MCADD?
Pathophysiology:
- The carnitine shuttle allows you to get fat into the mitochondria so that it can be broken down
- Fatty acid oxidation is a process of sequentially breaking down a fatty acid into smaller and smaller chains
- If MCAD is missing, you are NOT going to produce acetyl-CoA from fatty acids
- Acetyl-CoA is necessary in the TCA cycle to produce ketones, which spares glucose
- You use fat when you’re fasting or between meals, in order to spare your glucose stores
What is a classical presentation of MCADD? How is it diagnosed in the screening test? What is the management?
- MCAD deficiency is a classic cause of cot death – If a baby can’t break down fats, when they are not feeding, they will get massively hypoglycaemic and die
- Screening = measuring C6-C10 Acylcarnitine using tandem mass spectromerty
- Treatment = make sure the child NEVER becomes hypoglycaemic, and hence never becomes reliant on fats for energy
What is the cause of homocystinuria? What are the clinical features? Is screening done in the UK?
Homocystinuria = failure of remethylating homocysteine
Clinical features:
- Lens dislocation
- Mental retardation
- Thromboembolism
Possible inclusions for the UK new-born screening programme:
- Homocystinuria (amino acid disorder)
- Isovaleric acidaemia (organic acid disorder)
- Glutaric aciduria type I (organic acid disorder)
- Maple syrup urine disease (organic acid disorder)
- Long chain acyl CoA dehydrogenase deficiency (fatty acid oxidation disorder)
Case study:
24yo male, dehydration, N&V, no diarrhoea, disorientated, tactile hallucinations, salbutamol PRN, methandrostenolone & creatine supplement, cannabis, hx of ADHD
- Slight physical build, no signs of alcohol, afebrile, BP normal, pulse regular, GCS 15, no neck stiffness, normal speech, gait and power, U&Es, LFTs, FBC
- Prolonged clotting times
- PTT 28.5s (11-16s)
- APTT 47s (29-37s)
- INR 2.2 (0.9-1.2)
- Progression:
- 3/7 represented to A&E, acute confusion state and unable to give hx and disorientated in time, place, person
- Examination similar to first; new test results in image above
- Respiratory alkalosis
- An ammonia test was ordered (unusual test) which showed 10x the normal level
-
Advice from the hepatologist:
- DDx: Intracerebral bleed? Drug toxicity?
- Ammonia is probably a red herring
- Getting an ammonia sample is difficult – you need a free-flowing sample, that you then stick in ice and rush to the laboratory. However, this is unlikely to account for how high the ammonia result was
- Whilst the doctors were trying to diagnose the patient, he went on to develop cerebral oedema, experience seizures, become comatose and die 3 days later = the underlying diagnosis was a urea cycle defect
What is the purpose of the urea cycle? How many enzymes are in the urea cycle? How many defects are related to the urea cycle?
The urea acid cycle is responsible for: ammonia –> urea (ammonia is v toxic)
There are 7 enzymes in the pathway (each with documented disorders of metabolism in)
There are 3 other diseases that count as urea cycle defects:
Name 3 diseases that count as urea cycle defects.
- Lysinuric protein intolerance
- Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH)
- Citrullinaemia type III
All cause high ammonia.
What is the inheritance pattern of urea cycle defects?
These conditions are autosomal recessive (i.e. there is NOT usually a family history); with one exception:
Ornithine Transcarbamylase Deficiency (OTC) = X-linked
How does the body attempt to remove high ammonia? What can therefore be measured when suspecting urea cycle defects?
Body attaches an ammonium group to glutamate to make glutamine.
- Serum glutamine is HIGH in hyperammonaemia
- Serum amino acids in urea cycle will either be HIGH or ABSENT
- Urine orotic acid
What kind of indicators in the history can suggest urea cycle disorder?
- Long-term psychiatric disorders
- Patients may subconsciously reduce protein intake when younger because it made them ill –> “small build”
But uncommon affecting 1 in 30,000
How do you treat hyperammonaemia?
Remove ammonia (giving sodium benzoate, sodium phenylacetate, dialysis)
Reduce ammonia production by reducing protein diet
Which metabolic disorder can cause hyperammonaemia with respiratory alkalosis?
Urea cycle disorders
Which metabolic disorders can cause hyperammonaemia with metabolic acidosis (and a high anion gap)?
Organic acidurias
Define organic acidurias. Which amino acids are affected?
Defects within the complex metabolism of the branched chain amino acids:
leucine, isoleucine, valine
Describe the breakdown of leucine.
- To break down leucine, you break off the ammonia group (using transaminase) and you add a high energy protein group
- This produces a breakdown product called isovaleryl CoA
- The next step is the conversion of isovaleryl CoA by isovaleryl CoA dehydrogenase
Absence of isovaleryl CoA dehydrogenase can lead to isovaleric acidaemia.
In what form is leucine exported and excreted?
Molecules with high energy groups CANNOT traverse the membrane so they need to be converted into other molecules:
- Export from cell as:
- Isovaleryl carnitine
- Excrete as:
- 3OH-isovaleric acid (cheesy/sweaty smell)
- Isovaleryl glycine
What are the clinical features of organic acidurias?
In neonates:
- Unusual odour
- Lethargy
- Feeding problems
- Truncal hypotonia but limb hypertonia
- Myoclonic jerks
- Hypocalcaemia
- Neutropenia
- Thrombopenia
- Pancytopenia
AND metabolic acidosis hyperammonaemia (high anion gap from ammonia)
What is a chronic intermittent form of organic aciduria?
Reye syndrome
What are the features of Reye syndrome? What is a common cause?
- Reye syndrome – swelling of the LIVER and BRAIN
- Vomiting
- Lethargy
- Increasing confusion
- Seizures
- Decerebration
- Respiratory arrest
Commonly caused by salicylates (aspirin), antiemetics, and valproate.
What are the investigations for metabolic screen for Reye syndrome? Which does not need to be collected during the acute episode?
Collect during acute episode:
- Plasma ammonia
- Plasma/urine amino acid
- Urine organic acids
- Plasma glucose and lactate
Stays abnormal in remission:
- Blood spot carnitine profile
What condition results from defects in mitochondrial fatty acid beta-oxidation?
Hypoketotic hypoglycaemua, hepatomegaly and cardiomyopathy
(When hypoglycaemic, you should be able to make ketones from fatty acid breakdown unless there is a defect as above)
Which investigations can be used for detecting mitochondrial fatty acid beta-oxidation disorder?
Blood ketones
Urine organic acids
Blood spot acylcarnitine profile
Which conditions cause the following:
- hypoketotic hypoglycameia
- hypoketotic hyperglycaemia
- hyperketotic hypoglycaemia
- hyperketotic hyperglycaemia
- hypoketotic hypoglycameia - metabolic disease such as MCADD or paraneoplastic
- hypoketotic hyperglycaemia - HHS/HONK (T2DM)
- hyperketotic hypoglycaemia - starvation
- hyperketotic hyperglycaemia - DKA (T1DM)
Name 2 carbohydrate metabolic disorders.
Galactosaemias include:
- Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency
- Glycogen storage disorder type 1 AKA voc Gierke disease AKA glucose 6 phosphatase deficiency
How does gal-1-PUT deficiency present?
- Raised gal-1-phosphate = liver and kidney disease
- Presents with:
- D&V
- conjugated bili (ALWAYS pathological in paediatrics)
- hepatomegaly
- Hypoglycaemia
- Sepsis (gal-1-phos inhibits the immune response)
What is the consequence of gal-1-PUT deficiency in childhood?
High concentrations of Gal-1-phosphate build up which become a substrate for aldolase (found in eye lens) –> bilateral cataracts
What investigations are used to diagnose Gal-1-PUT deficiency? What is the treatment?
- High galactose in urine
- Red cell gal-1-PUT
Tx: avoid galactose (e.g. in milk)
What is the cause of von Gierke/glycogen storage disease type 1? What is the pathophysiology?
Glucose 6 phosphatase deficiency –>
Without this phosphatase, glycogen cannot be converted into glucose for energy as the phosphate from glucose-6-phosphate(or G1P) cannot be removed. Phosphate is a high energy group so it cannot get across a membrane.
Muscles and liver build up glycogen which cannot be liberated –> hypoglycaemia etc.
What are the clinical features of glycogen storage disorder type 1?
Glycogen cannot be liberated from organs and builds up…
Clinical features:
- Hepatomegaly
- Nephromegaly
- Hypoglycaemia
- Lactic acidosis (because lack of G6Pase causes oxidative stress and neutrophil apoptosis)
Who can be affected by mitochondrial metabolic disorders?
Any organ at any age with any type of inheritance
How does the type of DNA in mitochondrial disorders affect the onset of symptoms?
- mtDNA is small compared to nuclear DNA
- Heteroplasmy of mtDNA means that clinical manifestations become evident at a certain threshold of mutant DNA
mtDNA is maternally inherited but nucelar DNA also plays a huge role in mitochondrial function (the small amount of mtDNA could not account for all mitochondrial functions)
Which organs are most affected by mitochondrial disorders?
Defective ATP production most affects organs with a high energy requirement
- Brain
- Muscle
- Kidney
- Retina
- Endocrine
Give 3 examples of mtDNA disorders at different ages.
- Birth = Barth (cardiomyopathy, myopathy, neutropenia)
- 5-15yo = MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes)
- 12-30yo = Kearns-Sayre (chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia)
What investigation would you do for mitochondrial disorders?
- High lactate (alanine) – after periods of fasting (i.e. overnight) and before or after meals - in normal people, lactate should be lower after fasting but in mitochondrial disorders, this is the opposite
- CSF lactate/pyruvate – must be deproteinised at the bedside
- CSF protein - raised in Kearns-Sayre syndrome
- CK
- Muscle biopsy (looking for ragged red fibres)
- Mitochondrial DNA analysis (not useful in children as those presenting in children are usually due to nuclear DNA defects)
What is the pathophysiology of congenital disorders of glycosylation? How severe is it?
CDG = defect of post-translational protein glycosylation
Mortality is 20% in the first year
What are the clinical features of CDG and CDG type 1a?
CDG is a multisystem disorder…
- cardiomyopathy
- osteopenia
- hepatomegaly
- facial or other dysmorphia
CDG type 1a: abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction
What investigations can be done for CDG?
Tranferrin glycoforms measured in serum
What is the function of peroxisomes? What are peroxisomal disorders?
Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism that result in impairment of peroxisome function. In most cases, this results in neurologic dysfunction of varying extent (UpToDate)
Peroxisomes –> metabolism of very long chain fatty acids and biosynthesis of complex phospholipids
What are the clinical features of peroxismal disorders in neonates vs infants?
Neonates:
- severe muscular hypotonia
- seizure
- hepatic dysfunction includin mixed hyperbilirubinaemia
- dysmorphic signs
Infants:
- retinopathy –> early blindness
- sensorineural deafness
- hepatic dysfunction
- mental deficiency
- failure to thrive
- dysmorphic signs
- bony changes - large fontanelle which closes only after 1yo, osteopenia of long bones, calficied stippling especially in patellar region
What investigations are used for peroxismal disorders?
Very long chain fatty acid profile
What is the function of lysosomes? What is the pathophysiology of lysosomal storage disorders?
Lysosomes = cytoplasmic organelles containing enzymes for degradation of various saccharides and proteins. Defective enzymes –> progressive accumulation of partially degraded material –> distention of the cell, disruption of cellular function, and, sometimes, failure of active transport of small molecules from the lysosomes. (UpToDate)
Lysosomal storage disorders = defect in lysosomal metabolism or export of naturally occurring compounds –> accumulation of various glycosaminoglycans, glycoproteins, or glycolipids within lysosomes of various tissues –> organomegaly.
What are the clinical features of lysosomal storage disorders?
- Organomegaly (connective tissues, solid organs, cartilage, bone and nervous system)
- Dysmorphia
- Regression
What investigations are done for lysosomal storage disorders?
- Urine mucopolysaccharides and/or oligosaccharides
- Leucocyte enzyme activities
What is the treatment for lysosomal storage disorders?
Bone marrow transplant
Exogenous enzyme
