Metabolic Flashcards
Cherry red macula is seen in?
Tay-Sachs (hyperreflexic, macrocephaly) and Neimann-Pick (hyporeflexic)
Glutaric acidaemia type 1 can present with …?
Bilateral subdural haemorrhages, differential for NAI
Which urea cycle defect is not autosomal recessive?
Ornithine transcarbamyase (OTC) deficiency (X-linked)
Describe Farber’s disease
- Also known as Farber’s lipogranulomatosis
- Hoarse or weak cry, lipogranulomas and swollen, painful joints, hepatomegaly, developmental delay
- Rare autosomal recessive condition caused by abnormal lipid metabolism. Lipids accumulate abnormally throughout the body, especially around the joints
Developmental delay, hypopigmentation (blond hair, blue eyes) and eczema
Phenylketonuria (PKU)
The mucopolysaccharidoses are a group of disorders caused by?
- Absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans
- Glycosaminoglycans accumulates in cells, blood, and tissues
- Results in permanent, progressive cellular damage which affects physical appearance, physical abilities, organ and system functioning and usually development
What is the treatment of acute hyperammonemia?
- Fluid, electrolytes, glucose (5-15%), and lipids IV
- Sodium benzoate or sodium phenlyacetate infusion
- Dialysis if above treatment fails
Unwell 2 day old neonate with hyperammonemia, respiratory alkalosis, normal blood glucose and normal anion gap?
Urea cycle defect e.g.
- OTC deficiency (ornithine transcarbamylase deficiency, high glutamine/ornithin/alanine, low citrulline, high urine orotic acid)
- Or classic citrullinemia (ASA deficiency, high citrulline)
- Argininosuccinic aciduria (ASA lyase deficiency, high argininosuccinic acid)
- Need amino acid profiles to distinguish between types of urea cycle defects
Describe Pompe disease
- Glycogen storage disease type II (GSDII) with defect in lysosomal metabolism
- AR inherited deficiency of the enzyme acid α-glucosidase (GAA), which hydrolyzes glycogen to glucose
- Hypertrophic cardiomyopathy in infants
- Skeletal and respiratory muscle weakness, hypotonia, areflexia
- Raised CK
- Enzyme replacement with recombinant human GAA has improved survival, and cardiac/resp/motor function
2 day olds with jaundice, hepatomegaly, poor feeding and vomiting. Investigation and diagnosis?
- Galactosaemia
- Children present after commencing feeds with jaundice, hepatomegaly and vomiting, E.Coli sepsis
- Cataracts are not present initially. On newborn screening
- Deficiency in GALT enzyme (galactose-1-phosphate uridyltransferase) leads to an increase in galactose and galactose-1-phosphate. Accumulates in liver and eyes causing jaundice + cataracts
- GALT level not useful if RBC transfusion in past 3/12
- Usually positive reducing substances in the urine
- Treatment: elimination of galactose from diet for life
An 18-month-old, gastroenteritis with diarrhoea and vomiting, brought to ED with reduced level of consciousness. Diagnosis?
- Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) typically presents in children aged 18m-3y during a period of stress (usually a virus).
- Children younger than this usually feed so frequently that it masks the disorder.
- The treatment is to avoid prolonged periods of fasting.
- Ix: Acylcarnitine profile
Describe maple syrup urine disease (MSUD)
- Presents day 3-5
- Poor feeding and vomiting during the first week of life
- Seizures, hypertonicity, loss of moro, periods of flaccidity, can be mistaken for sepsis/meningitis
- Death from cerebral oedema without treatment
- Hypoglycaemia, ketosis and ketonuria, unremarkable bloods otherwise; occ metabolic acidosis with increased anion gap
- Branched chain a-ketoacid dehydrogenase deficiency
- Raised leucine, isoleucine, valine, alloisoleucine
- Leucine smells like maple syrup
Describe phenylketonuria
- Picked up on Guthrie, otherwise progressive developmental delay is the most common presentation
- Untreated children in later infancy may have vomiting, seizures, eczema, mousy odour, mental retardation and behavioural disorders.
- The fair skinned colouring is due to tyrosine deficiency.
Describe the process of glycolysis
- Glucose broken down to form 2 x pyruvate molecules ( no organelles or oxygen required)
- This produces energy in the form of 2 x extra ATP + 2 x NADH (these then enter electron transport chain, to make 3 ATP each)
- Pyruvate enters mitochondria (needs oxygen) to enter Krebs cycle = extra 30 x ATPs
- Glucose -> glucose-6-phosphate via addition of phosphate molecule from glucokinase (liver + pancreas) and hexokinase (all cells)
- Insulin increases glycolysis, glucagon decrease glycolysis
What is the role of GLUT?
- Glucose transporters, helps get glucose from the bloodstream into cells
- Insulin acts on GLUT to increase uptake of glucose
Describe the process of gluconeogenesis
- The process of making glucose from amino acids (broken down muscle), lactate, and glycerol (broken down triacylglycerides)
- Mainly occurs in liver, can occur in kidney + intestines
- Essentially the opposite of glycolysis. Use ATP to turn pyruvate (from lactate and amino acids) into glucose
What is glycogenolysis?
- Extra glucose (leftover after glycolysis) is stored in liver and muscle cells in the form of glycogen
- This can be utilised via process of glycogenolysis to produce glucose. This helps for around 12-24 hours of fasting
- Glucagon (from pancreas) stimulates liver cells to break down glycogen. This produces free glucose into bloodstream
- Epinephrine stimulates skeletal muscle cells to break down glycogen. This produces G6P which undergoes glycolysis to make energy
What two processes can the liver use during times of fasting to make glucose?
- Gluconeogenesis and glycogenolysis
- Gluconeogenesis makes glucose from amino acids, lactate, glycerol. Can keep going, main process of making glucose after 12 hours of fasting
- Glycogenolysis converts glycogen into glucose (good for 12-24 hrs fasting)
What is the role of lactate dehydrogenase?
- Converts lactate into pyruvate, so pyruvate can undergo gluconeogenesis to form glucose in times of fasting
- This makes an NADH molecule
What is the major form of glucose storage in the body?
- Glycogen in the liver and skeletal muscle cells.
- Glycogen synthesis is stimulated by insulin.
- Glycogen is utilised during periods of fasting via the process of glycogenolysis which is stimulated by glucagon and epinephrine
How is fructose intolerance diagnosed?
Via hydrogen breath test
Describe Tay Sachs disease
- Lysosomal storage disorder that presents after 3 months with regression of gross motor skills and weakness, exaggerated startle reflex or myoclonic seizures
- Macrocephaly due to accumulation of GM2 ganglioside in the brain. Beta-hexosaminidase A deficiency
- Hypotonia, hyperreflexia (c.f. Niemann Pick Disease is hyporeflexic), seizures, visual disturbance
- Cherry red macula. No visceromegaly
- Inc in Ashkenazi Jew population
- Death by age 4 but can have late-onset forms
Describe glutaric acidaemia (GA1)
- Present like sepsis, may have associated infection and fever
- Metabolic decompensation with ketoacidosis, hyperammonemia, hypoglycaemia, and encephalopathy.
- Can cause bilateral subdural haemorrhages
- 25% present with dystonia (these children are often diagnosed with cerebral palsy)
- Rarely presents in the newborn period
- Can develop oro-facial dyskinesia
- Microencephalic macrocephaly is typical and if present at birth, can be the earliest sign.
- Cam develop normally if they are treated with L-carnitine and a low-protein diet when initially diagnosed through newborn screening.
Raised anion gap metabolic acidosis
- > 20
- Exclude tissue hypoxia = lactic acidosis
- Exclude diabetes = ketones
- Think: organic acidaemia, disorders of gluconeogenesis, mitochondrial/Kreb cycle
- Tests: ammonia, glucose, ketones
(less likely to be low anion gap apart from organic acidemias presenting with renal tubular acidosis and bicarb loss)
Respiratory alkalosis in metabolic disease is consistent with?
Hyperammonemia
Anterior beaking of vertebrae is seen in?
Mucopolysaccharidosis
Pancytopenia, hepatosplenomegaly, hip pain (osteonecrosis of the femoral head)
- Gaucher disease
- Lysosomal storage disorder
- Beta-glucocerebrosidase deficiency
- Anaemia and thrombocytopenia, splenomegaly
- Treatment with enzyme replacement therapy
Encephalopathy, dystonia, macrocephaly. Triggered by fever.
Glutaric aciduria type 1. Treatment: low lysine diet, carnitine, emergency regime
Discuss the acylcarnitine profile
- Fatty acids (from lipids) form complex with coenzyme A = acyclCoA
- Transported by carnitine into mitochondria
- Makes an acylcarnitine and free coenzyme A - enters Kreb cycle and forms ketones
- Chopped up by enzymes (MCAD and LCAD) to make free coenzyme A
What are the tests used in investigating metabolic disease?
- Urine organic acids
- Plasma amino acids
- Acylcarnitine profile
- Urine glycosaminoglycans - diagnosis of MPS only
- Urine tandem metabolic screen (urine AA and OA)
Hypoglycemia, low cortisol, slightly tanned
Adrenal insufficiency (Addison’s)
Discuss glycogen storage diseases
- Hepatomegaly, proximal weakness, short stature/poor growth
- Ketotic hypoglycemia due to abnormal glycogenolysis - increased lactate (due to shunting) and triglycerides
- Avoid catabolism - regular daytime feeds, emergency plan when unwell, may need continuous overnight feeds or cornstarch
- Ix: raised CK, raised cholesterol and triglycerides
- Muscle phenotypes Pompe (II) and McArdle (V)
Mildly ketotic hypoglycemia with severe lactic acidosis indicates?
- Gluconeogenesis disorder, fructose 1-6 bisphosphatase deficiency
- F16BP is a key enzyme in gluconeogenesis from food
- Hypoglycemia develops when glycogen reserves are limited
- Disease begins before 2 years of age
- Can be hypoketotic (as acetylCoA is diverted into Krebs cycle to metabolise pyruvate rather than making ketones)
Hypoketotic hypoglycaemia with normal free fatty acids
- Abnormal fatty acid oxidation
- MCAD deficiency - medium chain acyl CoA dehydrogenase deficiency
- Impaired gluconeogenesis
Hypoglycaemia with low ketones and low free fatty acids
- Due to high insulin which stops catabolism and counter-regulatory hormones
- Hyperinsulinism
- Key clues: glucose requirements to maintain BSL > 3.5 = >10mg/kg/min
How much glucose do children usually need for the brain?
4-6mg/kg/min.
50% of glucose is used by the brain.
Brain can use ketones and lactate, but lack of these and hypoglycaemia = high risk of brain damage
Describe the normal starvation response
- Initially have glucose from food. As this decreases then glycogenolysis begins (breakdown of glycogen for glucose).
- Then gluconeogenesis starts - production of glucose from lactate, alanine, and fructose
- Then get fatty acid oxidation which causes production of acetlyCoA and ketones
Normal pattern of hypoglycaemia
- Low glucose
- Insulin suppressed
- Cortisol and growth hormone normal or elevated
- Fatty acids mobilised and acetlyCoA then ketones are produced
- If inc ketones but no FFA then cannot take up into cell. If inc FFA but no ketones then FA oxidation disorder.
What conditions are associated with impaired fasting tolerance at:
- 0-2 hrs
- 2-6 hrs
- 6-12 hrs
- 12-24 hrs
- 0-2 hrs: hyperinsulinism
- 2-6 hrs: glycogen storage diseases
- 6-12 hrs: disorders of gluconeogenesis
- 12-24 hrs: fatty acid oxidation or GH/cortisol deficiency
Permanent ketosis is pathognomonic for …?
SCOT deficiency = succinyl-coA-3-oxoacid CoA transferase deficiency
= disorder of ketone metabolism
Discuss idiopathic ketotic hypoglycaemia
- Exaggerated starvation response e.g. at 12-13 hours
- Presents between 18m and 7y
- Recurrent episodes of hypoglycaemia and ketonuria often during intercurrent illness
- Seizures may occur, neurological sequelae are rare
- Low BSL, inc ketones and FFA
- Low BSL responds quickly to PO or IV glucose
- Work-up normal
- Improves with age, rarely seen after puberty
What is the pathophysiology of idiopathic ketotic hypoglycaemia?
- Unknown
- Significant decrease in glycogenolysis without a compensatory increase in gluconeogenesis
- Limitation in availability of gluconeogenic amino acid alanine
- Increased dependency on gluconeogenesis when younger as glycogen stores rapidly depleted during fasting
Management of idiopathic ketotic hypoglycaemia?
- Avoidance of prolonged fasting, especially in presence of illness
- May need cornstarch at night if have ketones in morning
- Diagnosis of exclusion of other IEM and endocrine disorders
Causes of hypoglycaemia with and without acidosis?
- No acidaemia
- Low ketones + FFA = hyperinsulinism
- Low ketones, inc FFA = FAO defects
- Acidaemia
- Inc lactate = gluconeogenesis defects
- Inc ketones = ketotic hyperglycaemia, GH or cortisol deficiency, glucogenoses
Metabolic acidosis with raised anion gap, high ammonia, encephalopathy…?
Organic acidaemia:
- Methylmalonic acidaemia
- Propionic acidaemia
- Present in infancy, progress to coma and death if untreated
- Often present prior to Guthrie results
What are the investigations and treatment for organic acidemias?
- Ix: urine organic acids, plasma amino acids (elevated glycine), and acylcarnitine profile
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, lipid, insulin, L-carnitine (helps to detoxify chemicals and into urine), no protein
- Hydroxocobalamin B12 trial after critical samples taken (co-factor)
Chronic:
- Calories, protein restriction, L-carnitine (binds to and helps excrete organic acids), amino acid supplement formula
- Metronidazole, cycled to reduce intestinal flora (stop propionyl acid formation by gut bacteria)
- Liver +/- kidney transplantation
Discuss holocarboxylase synthase deficiency
- Carboxylase deficiency, unable to use biotin
- Alopecia, rash, immunodef, lethargy, poor feeding, seizures
- Metabolic acidosis, high anion gap, lactic acidosis
- Ix: urine organic acids and acylcarnitine profile
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, insulin, L-carnitine
- High dose biotin for Samoan variant (much more severe in Samoan population)
- Chronic: biotin, calories, ER, L-carnitine
How do we investigate for and treat urea cycle defects?
- Ix: urine organic acids (orotic acid for OTC) and amino acid profile. High ammonia without acidosis, low urea
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, lipid, insulin, ammonia scavengers
- Chronic: protein restriction, calories for growth, strict ER, sodium benzoate/phenylbutyrate (mop up nitrogen and excrete it from body, don’t work well in neonates)
- Phenylbutyrate, arginine, citrulline
- Liver transplant
Encephalopathy, normal gas and ammonia, elevated ketones, increased leucine, isoleucine, valine…?
Aminoacidopathy = maple syrup urine disease