Approach To Inborn Errors Of Metabolism Flashcards
Classification of IEM
Based on substate / organelle
1. Small molecule disease (Intoxication)
- Aminoacidopathies (urea cycle enzyme defects, maple syrup urine disease)
- Organic acidopathies
- Organelle disease (Making and breaking complex molecules)
- Lysosomal
- Peroxisomal
- Glycosylation
- Cholesterol synthesis defect
- Congenital disorders - In-between (Energy insufficiency + Making and breaking complex molecules)
- Fatty acid disorders
- Glycogen storage disorder
- Mitochondrial disorder
- Lactic acidosis
Based on clinical features:
1. Neurological deterioration
- can present as intoxication (acute encephalopathy), making and breaking complex molecules (chronic encephalopathy, developmental regression)
2. Acid-base disorders
3. Cardiac disorders / myopathies
4. Hypoglycaemia
5. Liver disease
6. Storage / Dysmorphism / Hydrops
Effect of IEM
Transport proteins across membrane:
1. Cystinuria
2. Lysinuric protein intolerance
3. HHH syndrome (Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome)
Accumulation of substrate:
1. Maple syrup urine disease (Leucine)
Excessive secondary substrate (due to diversion to secondary pathway):
1. Propionic acid
Deficiency of product:
1. Glucose
Secondary inhibition:
1. Succinyl acetone (tyrosinaemia) and prophyria
Small molecule vs Organelle disease
Small molecule disease:
- Onset: Sudden, acute
- Course: Remission + Relapse
- Physical findings: Non-specific
- Investigation: Specific pattern in “Metabolic screen”
- Histopathology: Non-specific
- Response to treatment: Brisk
Organelle disease:
- Onset: Gradual
- Course: Progressive
- Physical findings: Characteristic
- Investigation: No specific pattern
- Histopathology: Characteristic
- Response to treatment: Poor (but changing)
Metabolic emergencies
- Intoxication
- Typically a term newborn who after a symptom free period (∵ not yet ingest food + time needed to accumulate toxin) suffer a progressive course leading to lethargy, feed refusal, vomiting, tachypnea, autonomic instability, motor automatism, apnea, seizure, coma, respiratory arrest
- Intoxication from a small molecule:
—> Ammonia
—> Leucine (a BCAA)
—> Organic acid (toxic)
DDx:
- Infection
- Heart failure
- Drug intoxication (in baby / mother)
- CNS disease
- Energy insufficiency (Disorder of energy metabolism)
—> Hypoglycaemia
—> Lactic acidosis
- Collapse, drowsy, LOC (not a lot of autonomic instability, cerebral edema, neurological deterioration vs Intoxication)
- Organ failure due to interruption of normal energy sources
—> Glucose (Most organs, obligatory RBC)
—> Fat / Ketones (Brain, Heart)
- Disorders of:
—> Glycogenolysis
—> CHO utilisation
—> Gluconeogenesis
—> Ketogenesis
Amino acid metabolism
A.A.
—> NH3 —> Urea cycle
or
—> Organic acid —> Krebs cycle —> Electron transport chain
Ammonia
Play a part in:
- Urea cycle defects (most common) (Alkalosis)
- Some other amino acid disorders
- Organic acidaemias (most common) (Acidosis)
- Fatty acid oxidation defects (Normal / Acidosis)
- Energy / Mitochondrial disorders (Acidosis (∵ anaerobic respiration))
Measure in:
- Any patient with unexplained lethargy / altered sensorium
Most common cause of abnormal NH3:
- Suboptimal technique / processing specimen
—> Be quick in obtaining specimen, minimise blood stasis / muscle manipulation
—> Keep on ice, transport STAT to lab
Normal range:
- Term neonate: <=100 mmol/L
- Preterm neonate: <=150 mmol/L (IEM: ~>200)
- Well infant and beyond: <=40 mmol/L (IEM: ~>100)
Organic acidaemia vs Urea cycle disorder
Organic acidaemia:
- pH: Low
- HCO3: Low
- pCO2: Low (secondary hyperventilation)
Urea cycle disorder:
- pH: High (ammonia a potent respiratory stimulator —> respiratory alkalosis)
- HCO3: Low (secondary metabolic compensation)
- pCO2: Low
Urea cycle defect
- Alkalosis
- ↑NH3
- ↓Urea
- ↑/↓ Citrulline (depends on proximal / distal pathway defect)
- Orotic acid (if OTC deficiency: Secondary substrate accumulation)
2 pathways of cycle:
1. Mitochondrial (Proximal pathway)
2. Extra-mitochondrial (Distal pathway)
Locating defect by Patterns of amino acid changes:
1. Citrulline (Low indicate proximal pathway defect, High indicate distal pathway defect)
NB:
- OTC deficiency: X-linked disorder, Poor prognosis
Organic acidaemia
Measure urine organics (not blood ∵ kidney will concentrate organic acid —> easier to measure):
- 3OH proprionic acid
- Tiglic acid
- Tiglylglycine
- Propionylglycine
- Methylcitrate
Organic acid:
- Intermediate metabolite for metabolism of amino acid + fatty acid
- Cause primary / secondary metabolic effects (e.g. enzyme inhibition of NAGS by Propionic acid —> NAGS inhibited —> ↑NH3, Glycine cleavage enzyme inhibition —> ↑Glycine)
- Measured directly via urine organic acid
- Measured indirect via Acylcarnitines
Acylcarnitines:
- Carnitines: transporter for excretion
- Carrier of organic acid
- ↑ during organic acidaemia
Glutamine, Glycine:
- Carrier of organic acid for excretion
- Non-specific to enzyme defect
- ↑ during organic acidaemia
Maple syrup urine disease:
- Affect enzyme high up in pathway —> Leucine, Isoleucine, Valine accumulation (BCAA: toxic to body)
Isovaleric acidaemia:
- Isovaleric CoA accumulation
- Sweaty feet odour
Methylmalonic acidaemia:
- Methylmalonyl CoA accumulation
Investigations of Intoxication defects
- CBC
- Organic acid toxic to bone marrow —> BM depression —> Pancytopenia - LFT
- Blood gas
- Alkalosis —> Urea cycle defect
- Acidosis —> Organic acidaemia - Anion gap
- Na, Cl, HCO3 - Glucose
- Lactate
- Urine for Ketone
- Plasma ammonia
- Plasma amino acid
- Urine orotic / arginosuccinic acid
- Urine organic acid
- Acylcarnitine
Treatment of hyperammonaemia (only need to know principle)
Emergency:
1. Stop protein
- Stop giving milk
- But not prolonged ∵ body will run into catabolism —> cause secondary deterioration
- Reduce catabolism
- 10% Dextrose +/- Insulin / Lipid (for more balanced energy level) - Remove NH3
- Alternative pathway (Sodium Benzoate / Phenylbutyrate —> help excretion of nitrogen group)
- Extracorporeal detoxification (HDF > HF > HD (not PD), indicated when encephalopathy / NH3 >300) - Replenish urea cycle intermediate, carnitine / glycine in organic acidaemia
- Arginine, Citrulline, Carbaglu
- Carnitine - Promote urinary excretion
- Forced diuresis
Hypoglycaemia
- Overutilisation of glucose
- Excessive removal (e.g. Hyperinsulism)
- Insufficient alternative (e.g. Fatty acid oxidation defect —> needing to utilise glucose instead) - Underproduction of glucose
- Gluconeogenesis (e.g. GSD type 1)
Timing of hypoglycaemia:
Phase 1: Post-prandial <2.5 hours after meal
- Hyperinsulism
- Hereditary fructose intolerance (cannot be metabolised, CHO utilisation defect)
Phase 2: Short fast 2.5-12 hours after meal
- Glycogenolysis defects
- Gluconeogenesis defects
Phase 3: Medium to long fast >12 hours after meal
- Gluconeogenesis defects
- Mostly fatty acid oxidation defects with hypoketosis (Low ketone (worse than high ketone since brain cannot even use ketone for energy))
- Ketotic hypoglycaemia with major ketosis (High ketone)
Fatty acid oxidation defect
Long chain fatty acyl CoA (16-18 Carbon)
—> with help of Carnitine
—> go into Mitochondrial via mitochondrial membrane
—> Carnitine recycled by enzymes
—> Long chain fatty acyl CoA
—> Long chain β-oxidation enzymes will come to metabolise
—> Carbon chain of fatty acid shorten
—> Medium chain fatty acyl CoA
—> Medium chain β-oxidation enzymes will come to metabolise
—> Short chain fatty acyl CoA
—> Short chain β-oxidation enzymes will come to metabolise
—> End product: Acetyl CoA
—> Acetyl CoA form Ketone
(Medium chain fatty acyl CoA do not require carnitine for transportation)
Hyperinsulinism vs FAO defect
Triglyceride —(Glycolysis via Glucagon / Epinephrine action (Insulin inhibit Glycolysis))—> Free fatty acid + Glycerol
—> Free fatty acid (FFA) —(FAO)—> Ketone (3HOB)
—> Glycerol —> Glucose
FFA / 3HOB ratio <3 —> Hyperinsulinism
FFA / 3HOB ratio >3 —> FAO defect
Investigations for Hypoglycaemia
FAOD:
1. True glucose
2. Urine ketones
3. Urine organics
4. Acylcarnitines
5. FFA/3HOB ratio
Endocrine disorders:
6. Insulin
7. Cortisol
8. GH
Glycogen storage disease:
9. Lactate
10. NH3
11. Urate
12. Lipids
13. LFT
14. CK
Glycogen storage disease
Glycogen:
- Stored in liver and muscle
- Highly branched glucose polymer (1,4 / 1,6-linkage) —> good for storage (animal starch every 10-12 molecules vs plant starch)
- Act as glucose reservoir
- Independent pathways synthesis / breakdown
Storage of glycogen:
- Glycogen synthase (1,4-linkage) —> deficiency —> GSD type 0
- Debrancher enzyme (1,4 transferase + 1,6 glucosidase) —> deficiency —> GSD type 3
- Brancher enzyme (1,6-linkage) —> deficiency —> GSD type 4
Glycogen degradation:
- Phosphorylase kinase (activate Glycogen phosphorylase) —> deficiency —> GSD type 9
- Glycogen phosphorylase (break glycogen into Glucose 6 phosphate) —> deficiency —> GSD type 5/6
- Glucose 6 phosphate translocase (transport Glucose 6 phosphate into ER) —> deficiency —> GSD type 1b
- Glucose 6 phosphatase (break Glucose 6 phosphate into Glucose) —> deficiency —> GSD type 1a
Clinical features:
- Doll like face
- Large liver
- Liver problems / Muscle problems (depend on subtype)
Secondary effects of GSD1
- Glucose 6 phosphate —X—> Glucose
- Glucose 6 phosphate —> Glycolysis instead
—> Pyruvate —> Lactate —> Lactic acidosis
—> Pyruvate —> Acetyl CoA —> Malonyl CoA —> ↑Lipids (↑Cholesterol + Triglyceride)
—> ↑Lactate —> Occupy transporter in kidney tubules —> ↑Urate
Treatment of Hypoglycaemia
- Prevention of hypoglycaemia
- Secondary metabolic derangements (e.g. high urate, deranged LFT)
- Regular meal / snacks
- Overnight NG / PG feeds
- Uncooked cornstarch (Difficult to digest —> constant supply of glucose)
- Regular monitoring of long term complications (e.g. growth problems, hepatosplenomegaly, adenoma in liver, high cholesterol, high urate, deranged muscle function)
Lactic acidosis
Lactate:
- Weak acid
—> Should not affect pH unless >5
—> Occasional need HCO3
- Elevated alanine / urate: Secondary markers
—> Less likely to be affected by sampling
- Maybe worsened by excess glucose
Formation of Lactate:
- Pyruvate + NADH + H —> Lactate + NAD
Lactic acidosis:
Secondary causes:
1. Sampling errors
2. Sepsis
3. Left heart outlet obstruction
4. Gut ischaemia
5. Seizure
6. Drugs
Metabolic:
Primary
1. Pyruvate defects (causing Pyruvate accumulation)
- Pyruvate dehydrogenase (PDH) deficiency
- Pyruvate carboxylase (PC) deficiency
2. Mitochondrial ETC defects (causing NADH accumulation)
Secondary
1. Defects in gluconeogenesis
Organelle disease
- Lysosomal storage disorders
- Storage cells +/- Organomegaly - Peroxisomal disorders
- Failure to thrive
- Developmental delay
- Seizures
- Multisystem disease - Mitochondrial disorders
- Lactic acidosis
- Myopathy
- CNS disease - Synthetic defects
- CDG syndrome
- SLO
- Menkes
- Sjogren-Larssen
Summary
Issues with Inborn errors:
- Individually rare: 1 in 50-100000
- But relatively common as a group: >500 conditions and counting
- Early recognition + treatment is often life-saving
Consider metabolic causes:
- Exaggerated response to intercurrent illness
- A condition resembles an intoxication but without a history of ingestion / exposure
- A condition resembles an infection but no organism is isolated
- Unexpectedly poor response to treatment of an illness presumed to be acquired
- Similar condition in a sibling / cousin
- Catastrophic illness in the newborn
- Acute encephalopathy of any kind, esp. recurrent
- Developmental regression
- Hypoketotic hypoglycaemia
- Recurrent liver failure (Reye syndrome)
- Storage syndrome
Approach to Hypoglycaemia (SpC Paed E-learning: Common Endocrine Problems)
- Is it really hypoglycaemia?
- Symptomatic?
- Recheck H’stix + Confirm with blood taking (random blood glucose) - Why hypoglycaemia? (Rmb Hypoglycaemia is NOT a Dx!)
- Get relevant history
- Check critical samples before giving D10 - Treatment of hypoglycaemia
Hypoglycaemia:
—> Ketotic
——> ↑Lactate —> ↑G6Pase deficiency, F-1,6-Pase deficiency
——> ↑Ketone —> Normal, Ketotic hypoglycaemia, Debrancher enzyme deficiency, GH deficiency, Cortisol deficiency
—> Non-ketotic
——> ↓FFA, ↓Ketone —> Hyperinsulinism, HI mimickers (Neonatal hypopituitarism, Drug-induced, Insulinoma, Anti-insulin / Insulin receptor Ab, Beckwith-Wiedemann syndrome)
——> ↑FFA, ↓Ketone —> Fatty acid oxidation defects
Hormonal defense against Hypoglycaemia
Step 1: Insulin suppression
- When BS falls below normal post-absorptive mean of 4.9mM
- If Hyperinsulism —> Hypoglycaemia at this stage
Step 2: Glucagon secretion + Activation of sympathoadrenal system (Adrenaline release)
- When BS falls to 3.6-3.9mM
—> Glycogenolysis
- If Glycogen storage disease —> NOT hypoglycaemia until this stage
Step 3: Cortisol + Growth hormone secretion
- When BS falls <3.6mM
- Important to maintain BS during prolonged fasting
- If GH / Cortisol deficiency —> NOT hypoglycaemia until this stage
Metabolic defence against Hypoglycaemia
Post-absorptive stage: Liver
- Glycogenolysis: Release glucose from breakdown of stored glycogen
- Gluconeogenesis: From gluconeogenic amino acids e.g. alanine (recycling of lactate)
Prolonged fasting: Liver, Adipose tissue
- Restriction of glucose utilisation to the brain + a few glycolytic tissue e.g. RBC
- Adipose tissue: Lipolysis release glycerol (gluconeogenic) + FFA (alternative substrate in muscle)
- Liver: convert FFA to ketones (alternative substrate in brain)
History + P/E of Hypoglycaemia
- Age at presentation
- Neonatal / Infancy: Persistence, Glucose requirement
- Toddlers / Small children: Drugs (urine toxicology), Child abuse - Antenatal history including Intrauterine / Perinatal stress causing Hyperinsulinism
- LGA (∵ GDM —> hyperinsulism)
- IUGR (causing hyperinsulism)
- SGA - Maternal history of pregnancy + delivery
- GDM
- Diabetic mother
- HELLP syndrome caused by FAO disorder - Time relationship with feeding
- Post-prandial: Dumping syndrome
- Hypoglycaemia after short vs long fasting - Associated features
- Micropenis in male: Hypopituitarism
- Midline defect: Cleft
- Big tongue + body asymmetry (Beckwith-Wiedemann syndrome)
- GERD, Post-fundoplication: Dumping syndrome
Treatment of Hypoglycaemia
If conscious:
- Glucose 0.2g/kg given by mouth (i.e. D20 1ml/kg, D10 2ml/kg, Polycal 10% 2ml/kg)
If unconscious / oral not tolerated:
- IV Dextrose bolus: IV D10 2ml/kg over 20mins
- Followed by IV D10 + 1/2 NS (D20 250ml mixed with NS 250ml) at full maintenance
Close monitoring of H’stix: Repeat in 30mins, Q1H x2 —> Q3H if stable
Adrenal insufficiency
Causes:
1. Panhypopituitarism
2. CAH
3. Chronic steroid exposure (Chronic GC therapy >10-14 days (HC equivalent >5mg/m2/day))
Steroid cover:
- Severe stress (e.g. GA, shock, major trauma, repeated emesis, dehydration, decrease GC) —> HC 100mg/m2/dose x1 (max 100mg) —> 100 mg/m2/day in 4-6 divided doses
- Moderate stress (e.g. febrile illness) —> HC 50 mg/m2/dose x1 (max 100mg) —> 50 mg/m2/day in 4-6 divided doses
- IV to Oral conversion = 1:1
T1DM
- Not obese, No acanthosis nigricans (evidence of insulin resistance), Evidence of ketosis (no insulin to suppress ketosis)
Diagnosis of T1DM:
- RG >11 + Evidence of persistence (HbA1c >6.5%, Hyperglycaemic symptoms, Persistently high glucose)
- No need OGTT
History:
- Polyuria, Polydipsia, Polyphagia
- Weight loss
Physical examination:
- General condition, alertness
- Hydration status
- Acanthosis nigricans
- BMI
Investigations:
1. RG
2. Ketone (BOHB)
3. Blood gas (for acidosis)
4. Insulin + C-peptide
5. HbA1c + Fructosamine
6. Anti-islet cell Ab
7. TSH, fT4, Anti-Tg, Anti-TPO Ab
8. Fasting full lipid profile
9. Urine for ketone (bedside)
10. MSU for R/M + C/ST
11. Celiac panel if Caucasian: Anti-tTG IgA + Anti-tTg IgG
12. LRFT, CaPO4, Mg, Amylase
13. CBC
Diabetic ketoacidosis
- Hyperglycaemia, Blood glucose >11
- Metabolic acidosis HCO3 <15
- Ketosis (Ketone in urine / blood)
Degree of DKA:
- Mild: HCO3 10-15, alert
- Moderate: HCO3 5-10, alert to drowsy
- Severe: HCO3 <5, stupor / coma
S/S:
- Vomiting
- Fatigue
