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Paediatrics RACP written exam > Metabolic > Flashcards

Metabolic Flashcards

1
Q

Cherry red macula is seen in?

A

Tay-Sachs (hyperreflexic, macrocephaly) and Neimann-Pick (hyporeflexic)

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2
Q

Glutaric acidaemia type 1 can present with …?

A

Bilateral subdural haemorrhages, differential for NAI

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3
Q

Which urea cycle defect is not autosomal recessive?

A

Ornithine transcarbamyase (OTC) deficiency (X-linked)

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4
Q

Describe Farber’s disease

A
  • 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
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5
Q

Developmental delay, hypopigmentation (blond hair, blue eyes) and eczema

A

Phenylketonuria (PKU)

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6
Q

The mucopolysaccharidoses are a group of disorders caused by?

A
  • 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
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7
Q

What is the treatment of acute hyperammonemia?

A
  • Fluid, electrolytes, glucose (5-15%), and lipids IV
  • Sodium benzoate or sodium phenlyacetate infusion
  • Dialysis if above treatment fails
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8
Q

Unwell 2 day old neonate with hyperammonemia, respiratory alkalosis, normal blood glucose and normal anion gap?

A

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
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9
Q

Describe Pompe disease

A
  • 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
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10
Q

2 day olds with jaundice, hepatomegaly, poor feeding and vomiting. Investigation and diagnosis?

A
  • 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
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11
Q

An 18-month-old, gastroenteritis with diarrhoea and vomiting, brought to ED with reduced level of consciousness. Diagnosis?

A
  • 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
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12
Q

Describe maple syrup urine disease (MSUD)

A
  • 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
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13
Q

Describe phenylketonuria

A
  • 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.
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14
Q

Describe the process of glycolysis

A
  • 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
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15
Q

What is the role of GLUT?

A
  • Glucose transporters, helps get glucose from the bloodstream into cells
  • Insulin acts on GLUT to increase uptake of glucose
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16
Q

Describe the process of gluconeogenesis

A
  • 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
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17
Q

What is glycogenolysis?

A
  • 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
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18
Q

What two processes can the liver use during times of fasting to make glucose?

A
  • 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)
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19
Q

What is the role of lactate dehydrogenase?

A
  • Converts lactate into pyruvate, so pyruvate can undergo gluconeogenesis to form glucose in times of fasting
  • This makes an NADH molecule
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20
Q

What is the major form of glucose storage in the body?

A
  • 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
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21
Q

How is fructose intolerance diagnosed?

A

Via hydrogen breath test

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22
Q

Describe Tay Sachs disease

A
  • 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
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23
Q

Describe glutaric acidaemia (GA1)

A
  • 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.
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24
Q

Raised anion gap metabolic acidosis

A
  • > 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)
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25
Q

Respiratory alkalosis in metabolic disease is consistent with?

A

Hyperammonemia

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26
Q

Anterior beaking of vertebrae is seen in?

A

Mucopolysaccharidosis

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27
Q

Pancytopenia, hepatosplenomegaly, hip pain (osteonecrosis of the femoral head)

A
  • Gaucher disease
  • Lysosomal storage disorder
  • Beta-glucocerebrosidase deficiency
  • Anaemia and thrombocytopenia, splenomegaly
  • Treatment with enzyme replacement therapy
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28
Q

Encephalopathy, dystonia, macrocephaly. Triggered by fever.

A

Glutaric aciduria type 1. Treatment: low lysine diet, carnitine, emergency regime

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29
Q

Discuss the acylcarnitine profile

A
  • 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
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30
Q

What are the tests used in investigating metabolic disease?

A
  • Urine organic acids
  • Plasma amino acids
  • Acylcarnitine profile
  • Urine glycosaminoglycans - diagnosis of MPS only
  • Urine tandem metabolic screen (urine AA and OA)
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31
Q

Hypoglycemia, low cortisol, slightly tanned

A

Adrenal insufficiency (Addison’s)

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32
Q

Discuss glycogen storage diseases

A
  • 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)
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33
Q

Mildly ketotic hypoglycemia with severe lactic acidosis indicates?

A
  • 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)
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34
Q

Hypoketotic hypoglycaemia with normal free fatty acids

A
  • Abnormal fatty acid oxidation
  • MCAD deficiency - medium chain acyl CoA dehydrogenase deficiency
  • Impaired gluconeogenesis
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35
Q

Hypoglycaemia with low ketones and low free fatty acids

A
  • Due to high insulin which stops catabolism and counter-regulatory hormones
  • Hyperinsulinism
  • Key clues: glucose requirements to maintain BSL > 3.5 = >10mg/kg/min
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36
Q

How much glucose do children usually need for the brain?

A

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

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37
Q

Describe the normal starvation response

A
  • 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
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38
Q

Normal pattern of hypoglycaemia

A
  • 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.
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39
Q

What conditions are associated with impaired fasting tolerance at:

  • 0-2 hrs
  • 2-6 hrs
  • 6-12 hrs
  • 12-24 hrs
A
  • 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
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40
Q

Permanent ketosis is pathognomonic for …?

A

SCOT deficiency = succinyl-coA-3-oxoacid CoA transferase deficiency
= disorder of ketone metabolism

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41
Q

Discuss idiopathic ketotic hypoglycaemia

A
  • 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
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42
Q

What is the pathophysiology of idiopathic ketotic hypoglycaemia?

A
  • 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
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43
Q

Management of idiopathic ketotic hypoglycaemia?

A
  • 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
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44
Q

Causes of hypoglycaemia with and without acidosis?

A
  • 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
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45
Q

Metabolic acidosis with raised anion gap, high ammonia, encephalopathy…?

A

Organic acidaemia:

  • Methylmalonic acidaemia
  • Propionic acidaemia
  • Present in infancy, progress to coma and death if untreated
  • Often present prior to Guthrie results
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46
Q

What are the investigations and treatment for organic acidemias?

A
  • 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
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47
Q

Discuss holocarboxylase synthase deficiency

A
  • 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
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48
Q

How do we investigate for and treat urea cycle defects?

A
  • 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
49
Q

Encephalopathy, normal gas and ammonia, elevated ketones, increased leucine, isoleucine, valine…?

A

Aminoacidopathy = maple syrup urine disease

50
Q

What is the investigation and treatment for MSUD?

A
  • Ix: urine organic acids (branch chain ketoacids) and amino acid profile
  • Tx: stop feeds, IV dextrose 8mg/kg/min CHO, insulin
  • Chronic: MSUD formula (no leucine, isoleucine, valine), protein restriction, calories for growth, liver transplant
51
Q

What is the treatment for phenylketonuria?

A
  • Phenylalanine hydroxylase (not funded in NZ, cofactor for enzyme, may mean can have normal diet)
  • Protein restriction
  • PKU formula (has no phenylalanine in it)
  • High carb/energy foods
52
Q

Lumbar kyphosis, hypotonia, developmental delay, recurrent ear infections, snores. Positive urine glycosaminoglycans

A
  • Mucopolysaccharidosis
  • T1 = Hurlers, Scheie = AR
  • T2 = Hunters = X-linked
53
Q

What is the treatment for MPS1?

A
  • Hurlers disease
  • Enzyme replacement therapy - laronidase
  • HSCT - cross correction
  • High transplant-related morbidity, outcome greatly improved if <2.5y age
54
Q

7yo boy with mild developmental delay, new regression in behaviour and lower limb spasticity?

A
  • X-linked adrenoleukodystrophy
  • Diagnosed via VLCFA accumulation
  • Abnormal MRI - myelin instability
  • Hyperpigmentation
  • Oxidative stress and damage
  • Tx: HSCT - inhibits the advancing demyelination if administered early
55
Q

What is the role of the peroxisome?

A
  • Makes bile acids and plasmalogens

- Breaks down phytanate, pristanate, and VLCFAs

56
Q

X-linked adrenoleukodystrophy vs metachromatic leukodystrophy on MRI

A

Metachromatic also has corpus callosum involvement on MRI, whereas X-linked only posteriorly involved

57
Q

Hypotonia, large fontanelle, hepatomegaly, mild transaminitis, blindness

A

Peroxisomal disorders e.g. Zellweger syndrome

58
Q

What is the role of mitochondria?

A
  • Generation of ATP via oxidative phosphorylation (mitochondrial respiratory chain)
  • Generation of reactive oxygen species
  • Intracellular calcium homeostasis
  • Role in programmed cell death
  • “battery of our cells”
59
Q

Metabolic acidosis, high anion gap, mild-mod ammonia, high urinary ketones…?

A

Organic acidaemia (propionic acidemia, methylmalonic acidemia, glutaric acidemia)

60
Q

Metabolic acidosis, normal anion gap, normal ammonia…?

A

Aminoacidopathy (MSUD, PKU, homocystinuria)

61
Q

High ammonia, normal anion gap respiratory alkalosis…?

A

Urea cycle disorder (OTC, citrullinemia, argininosuccinic aciduria)

62
Q

Propionic acidemia vs methylmalonic acidemia

A
  • Both cause metabolic acidosis
  • PA - defect in propionyl CoA carboxylase, elevated 3-OH propionic acid (UOA), elevated C3 acylcarnitine (NBS), elevated glycine (PAA)
  • MA - defect in methylmalonyl CoA mutase, elevated methylmalonic acid (UOA), elevated C3 acylcarnitine (NBS), elevated alanine and glycine (PAA)
63
Q

Discuss Glutaric Acidemia type 1 (GA)

A
  • Organic acidemia that doesn’t present with metabolic acidosis, commonly has normal metabolites
  • Defect in enzyme glutaryl CoA dehydrogenase
  • “cerebral” organic acidemia
  • Microencephalic macrocephaly
  • Dystonia and movement disorder with febrile illness (catabolic crisis causing injury to basal ganglia)
  • Doesn’t usually present in neonatal period
  • Bilateral subdural haematomas, ddx NAI
  • High urine glutaric acids
64
Q

What is the most common inborn error of amino acid metabolism?

A

PKU - phenylketonuria

65
Q

What is the cause and presentation of PKU?

A
  • Low phenylalanine hydroxylase enzyme (converts phenylalanine to tyrosine), therefore high phenylalanine and low tyrosine levels
  • Elevation of phenylalanine leads to permanent brain injury and dysfunction
  • Fair skin and hair, light sensitivity, eczema, hair loss
  • If untreated: ID, musty/mousy odour, epilepsy 50%, eye abnormalities
  • MRI brain may show demyelination and volume loss
66
Q

What is the treatment for PKU?

A
  • Start ASAP, lifelong
  • Dietary restriction of phenylalanine, supplementation of tyrosine
  • Supplements: essential amino acids, vitamins and minerals
  • Tetrahydrobiopterin (BH4) supplementation
  • Test phenylalanine levels monthly
67
Q

What effects can maternal PKU have on the fetus?

A
  • IUGR, microcephaly
  • Intellectual disability
  • Dysmorphism, congenital heart disease
  • Pre-conception counselling very important + monitoring phenylalanine levels
68
Q

Discuss features, diagnosis, and management of homocystinuria

A
  • Aminoacidopathy
  • Intellectual disability, Marfan-like, ectopia lentis (down), osteoporosis, not flexible, thrombosis/CVA
  • Decrease in cystathionine b-synthetase, leads to elevated homocysteine in plasma and urine
  • Elevated methionine on NBS and PAA
  • Tx: dietary restriction of methionine, Betaine (helps decreased homocysteine levels), aspirin, B12/folic acid/pyridoxine supplementation
69
Q

What is the function of the urea cycle?

A

To dispose of toxic ammonia from the deamination of amino acids, by converting it to non-toxic urea for renal excretion

70
Q

Discuss Fabry disease

A
  • Lysosomal storage disorder
  • X-linked, alpha-galactosidase deficiency
  • Neuropathic pain hands and feet, recurrent abdo pain, hypohydrosis, poor exercise tolerance and corneal opacities
  • Angiokeratomas and telangiectasia 2nd decade, in groin and periumbilical area
  • Symptoms are usually present by 10 years of age but the diagnosis is often delayed
  • Can develop proteinuria and ESRF, CVA in adults
71
Q

Discuss possible presentations of MCAD

A
  • Lethargy, vomiting, low GCS
  • Sudden infant death syndrome
  • Reye’s syndrome
72
Q

How can children with long chain fatty acid oxidation disorders present?

A
  • Cardiomyopathy and hypoglycaemia

- Rhabdomyolysis

73
Q

What is the management of MCAD?

A
  • Impaired gluconeogenesis therefore avoid fasting
  • Supplement with carnitine. Dextrose during acute episodes.
  • Carbohydrate snacks at bedtime
  • 25% of babies die before results of Guthrie
74
Q

What are possible complications of galactosemia (even if treated early)

A
  • Tremors
  • Learning difficulties
  • Speech and language issues
  • Ovarian failure requiring oestrogen replacement in adolescence
75
Q

Discuss galactokinase deficiency

A
  • Similar to galactosemia but without systemic complications
  • Only develop cataracts
  • Treatment with dietary restriction of galactose
76
Q

Newborn with hypoglycaemia, lactic acidosis, hyperuricemia, hyperlipidaemia, neutropenia, hepatomegaly, doll-like face (fatty cheeks), thin extremities…?

A
  • Von Gierke disease (glycogen storage disease type 1)
  • Deficiency in glucose-6-phosphate enzyme, inability to release free glucose from glycogen - accumulation in liver causes hepatomegaly
  • Lactic acidosis due to inability of gluconeogenesis
  • Ix: glucagon administration produces no hyperglycaemic response, requires genetic testing
  • Tx: older children cornstarch keeps BSL stable 4-6h, younger children require continuous NGT feeds to sustain BSL, especially overnight
77
Q

How does GSDI (Von Gierke disease) present?

A

Hypoglycaemia, lactic acidosis, hyperuricemia, hyperlipidaemia, neutropenia, hepatomegaly, doll-like face (fatty cheeks), thin extremities

78
Q

Strenuous exercise leading to muscle cramps, high CK, myoglobinuria?

A
  • McArdle disease (GSDV)

- DDx: exercise-induced rhabdomyolysis

79
Q

Discuss McArdle disease?

A
  • GSDV
  • Develop muscle cramps, raised CK, myoglobinuria post strenuous exercise, “2nd wind”
  • Due to myophosphorylase enzyme deficiency
  • Treatment: avoid strenuous exercise to avoid rhabdomyolysis, give oral fructose/glucose to improve exercise tolerance
80
Q

Discuss hereditary fructose deficiency

A
  • Deficiency of fructose 1,6 bisphosphate aldolase
  • AR, initially healthy infant who presents age 4-6m when fructose introduced into diet
  • Develop jaundice, vomiting, lethargy, seizures, irritability post fructose intake e.g fruit
  • Positive urinary reducing substances
  • Tx: avoid all sucrose, fructose, sorbitol
81
Q

Discuss fructokinase deficiency

A
  • Asymptomatic, present with fructosuria

- No treatment necessary

82
Q

What are mucopolysaccharidosis disorders and their features?

A
  • Hurler syndrome, Hunter syndrome, SanFilippo syndrome
  • Progressive conditions due to accumulation of lysosomes (mucopolysaccharides, sphingolipids, oligosaccharides)
  • Hepatosplenomegaly, bony deformities, developmental regression, sensory loss (hearing and vision), coarse facial features
83
Q

Discuss the key differences between Hunter, Hurler, SanFilippo, and Morquio syndromes

A
  • Hurler (MPSI) - AR, alpha-L-iduronidase deficiency, melanocytic naevi, corneal clouding
  • Hunter syndrome (MPSII) - X-linked, iduronate 2 deficiency, pearly papules, normal eyesight
  • SanFilippo syndrome (MPSIII) - AR, visceral and bony manifestations less prominent
  • Morquio syndrome (MPSIV) - skeletal problems, corneal clouding
84
Q

What are the types of lysosomal storage disorders?

A
  • Mucopolysaccharidosis
  • Tay Sachs, Fabry’s disease, Gaucher disease type 1
  • Krabbe’s disease, Pompe disease, Wolman syndrome
  • Batten disease
85
Q

Name the different glycogen storage disorders

A
  • GSDI - Von Gierke disease
  • GSDII - Pompe disease (also lysosomal storage issue)
  • GSDV - McArdle disease
86
Q

Discuss Wolman syndrome

A
  • Lysosomal acid lipase deficiency (lysosomal storage disorder)
  • Poor feeding, FTT
  • High lipids and triglycerides
  • Bilateral adrenal calcifications on CT scan
87
Q

Discuss Krabbe’s disease

A
  • Lysosomal storage disorder
  • Galactosylceramidase deficiency
  • Increasing muscle tone, profound irritability, seizures, vision loss, developmental regression
88
Q

Discuss Zellweger syndrome

A
  • Peroxisomal disorder, VLCFA oxidation defect
  • Involves all organs of the body
  • Dysmorphic facies, prominent forehead, seizures, liver disease
  • Bone involvement, hypotonia, hearing and vision deficits
  • Ix: plasma VLCFAs
  • MRI brain: leukodystrophy (abnormal myelination)
  • Usually fatal in infancy
89
Q

What are examples of peroxisomal disorders?

A
  • Zellweger syndrome

- X-linked adrenoleukodystrophy

90
Q

Discuss adrenoleukodystrophy

A
  • X-linked, peroxisomal disorder
  • Due to deficiency in peroxisomal oxidation of VLCFAs
  • Developmental regression age 4-11y, new-onset spasticity, behavioural issues, seizures
  • Hyperpigmentation gums
  • Adrenal failure typically in school-aged boys (low Na and BP)
  • MRI: white matter T2 hyperintensity in occipital and parietal regions
  • Tx: HSCT - inhibits the advancing demyelination if administered early
91
Q

Discuss MELAS

A
  • Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
  • Present with developmental delay, weakness, headache, stroke-like presentation
  • Short-stature, cardiac disease, hearing loss, endocrinopathy, exercise intolerance, neurodegenerative disease
  • CSF protein is often increased
  • MRI: may show cortical atrophy with infarct-like lesions in both cortical and subcortical structures, basal ganglia calcifications, and ventricular dilatation
92
Q

Discuss Kearns-Sayre syndrome

A
  • Mitochondrial disorder due to defective phosphorylation
  • Cardiac conduction abnormalities
  • Cardiomyopathy
  • Lactic acidosis
  • Progressive external ophthalmoplegia
  • Can treat with pacemaker, vitamins, but no cure for disease
93
Q

Discuss metachromatic leukodystrophy

A
  • AR, white matter disease
  • Deficiency of arylsulfatase A (ASA), which is required for the hydrolysis of sulfated glycosphingolipids
  • Late infantile form most common: 12-18m of age with irritability, inability to walk, and hyperextension of the knee, causing genu recurvatum
  • Involves central and peripheral NS, UMN and LMN signs, cognitive and psychiatric signs
  • Deep tendon reflexes are diminished or absent
  • Gradual muscle wasting, weakness, and hypotonia
  • As the disease progresses develop nystagmus, myoclonic seizures, optic atrophy, and quadriparesis
  • Death in the first decade of life
94
Q

When would you see ragged red fibres?

A
  • MERRF - mitochondrial disease with myoclonic epilepsy and ragged red fibres
  • Mutation in mitochondria resulting in lack of ATP
  • Muscle weakness, diplopia, fatigue
  • Muscle biopsy: ragged red fibres
  • High lactate and CK
  • Seizures, ataxia
  • Tx: mitochondrial supplements
95
Q

Discuss Leigh disease

A
  • Mitochondrial encephalomyopathy
  • Progressive degenerative disorder, become apparent during infancy: feeding + swallowing problems, vomiting, and FTT
  • Delayed motor and language milestones, generalised seizures, weakness, hypotonia, ataxia, tremor, pyramidal signs, and nystagmus
  • Intermittent respirations with sighing or sobbing - suggest brainstem dysfunction
  • External ophthalmoplegia, ptosis, retinitis pigmentosa, optic atrophy, and decreased visual acuity
  • MRI: bilateral symmetric areas of low attenuation in basal ganglia and brainstem
  • Elevations in serum lactate levels are characteristic
  • Hypertrophic cardiomyopathy, hepatic failure and renal tubular dysfunction can occur
96
Q

Discuss Batten disease

A
  • Most common type of neuronal ceroid lipofuscinoses (NCLs), juvenile
  • Inherited lysosomal storage disorder
  • Symptoms usually start after age 5 - initially progressive visual loss, retinal pigmentary changes, often results in an initial diagnosis of retinitis pigmentosa
  • Subsequent progressive dementia, seizures, motor deterioration, and early death
97
Q

What are some mitochondrial disorders?

A
  • MELAS
  • MERRF (myoclonic epilepsy with ragged red fibres)
  • Leigh disease
  • Kearns Sayre disease
98
Q

What conditions can cause a high ammonia?

A
  • Urea cycle disorders (respiratory alkalosis)
  • Organic acidemias (metabolic acidosis with high anion gap)
  • Falsely elevated: tourniquet, inappropriate sample handling
99
Q

What is the key finding in hyperinsulinism and fatty acid oxidation disorders?

A

Lack of ketones - hypoketotic hypoglycaemia

100
Q

What are the causes of high lactate?

A
  • Ischaemia, poor tissue perfusion
  • Hypoxia
  • Haemolysis
  • MELAS, Kaerns Sayre
  • Von Gierke disease (GSDI)
101
Q

Which conditions are you checking for when you send urine organic acids?

A
  • Organic acidemias (e.g. methylmalonic acidemia, propionic acidemia)
  • Aminoacidopathies (e.g. MSUD, PKU, homocystinuria)
  • Fatty acid oxidation disorders (e.g. MCAD)
  • Most sensitive when patient is in catabolic state e.g. fasting/illness
102
Q

Elevation of which acylcarnitines are seen in IEOM?

A
  • C3 or C5 in some organic acidemias

- C6 to C10 in MCAD

103
Q

Cause of isolated large liver?
+ chronic liver disease?
+ large spleen?
+ large spleen + chronic liver disease?

A
  • Large liver = GSD
  • Liver + CLD = tyrosinemia type 1, galactosemia, some GSD (III, IV), UCD
  • Liver + spleen = Gaucher, Niemann Pick A (neuro), B (lungs), osteopetrosis
  • Liver + spleen + CLD = tyrosinemia, Wolman, Niemann Pick C
104
Q

Glycogen storage type 1 A vs B

A 
A = normal neutrophils
B = neutropenia, ulcers, gut disease - GCSF
105
Q

Discuss GLUT-1 transporter disorder

A
  • Presents with developmental delay, seizures, microcephaly
  • Low CSF glucose: serum glucose
  • Cannot transport glucose in to brain
  • Caused by mutations in the SLC2A1 gene
  • Tx: ketogenic diet - provides more fuel for the brain, improves developmental outcome
106
Q

Discuss tyrosinemia, including treatment

A
  • Aminoacidopathy
  • Accumulation of tyrosine leads to liver (hepatitis, jaundice) and kidney disease, Rickets, risk of HCC due to liver cirrhosis
  • Type 1 - increased succinylacetone on UOA
  • Nitisinone (inhibitor of tyrosine catabolism), special low protein pasta and bread, tyrosine and phenylalanine-free formula daily
107
Q

Niemann Pick A vs B vs C

A
  • A: early onset disease, hepatosplenomegaly, severe brain disease
  • B: lungs
  • C: supranuclear gaze palsy
108
Q

Which IEOM are not detected on Guthrie screening?

A

Lysosomal storage disorders

109
Q

Discuss Rett syndrome

A
  • X-linked dominant, affected boys die after birth, MECP2 gene mutation
  • First symptoms 6-18m age
  • Developmental regression, stereotypical movements, flapping hands, autistic behaviours
  • Periods of hyperventilation
  • Normal HC at birth, then progressive microcephaly
  • Seizures, scoliosis
  • Tx: supportive, anticonvulsants
110
Q

These amino acids are elevated in which conditions?

  • Phenylalanine
  • Leucine
  • Tyrosine
  • Homocysteine
A
  • PKU - brain damage, treat with protein restriction
  • MSUD - present with coma, bloods usually normal
  • Tyrosinaemia - liver disease, jaundice, kidney disease
  • Homocysteinuria - Marfan-like, ID, ectopia lentis down, thrombus risk
111
Q

Where do organic acids come from, and what are some examples?

A

Breakdown product of amino acids. e.g. lactate, ketones, acetic acid, glutaric acid, malenic acid

112
Q

How do we test for lysosomal disorders?

A

White cell enzymes, urine GAGs

113
Q

What is the role of the lysosome?

A

Recycling and digestion centre of cell. If errors then the material is not broken down and you develop congestion of cells and organs

114
Q

What are examples of lysosomal disease groups?

A
  • Mucopolysacharidosis - Hunter, Hurler, SanFillipo
  • Sphingolipids - Tay Sachs, Sandhoff
  • Leukodystrophy - metachromatic, Krabbe
  • Liver/spleen/blood - Gaucher, Neimann Pick
  • Fabry
115
Q

Non ketotic hyperglycinemia can present with?

A
  • “hiccups” in utero = seizures
  • Most common metabolic issue in Maori
  • Elevated CSF: plasma glycine ratio
116
Q

Child with developmental delay and Addison’s disease?

A

Think X-linked adrenoleukodystrophy

117
Q

Discuss Lesch-Nyhan syndrome

A
  • X-linked recessive
  • Build up of uric acid as unable to recycle purines
  • Hyperuricaemia
  • Inc uric acid secretion in urine - precipitates and crystaises - urate stones
  • Urate crystal deposits in kidney (nephropathy), joints (gout), subcutaneously (chalky tophi lumps)
  • Leads to low dopamine in brain - behavioural issues, GDD, hypotonia, dystonia, chorea, finger biting and head banging
  • Ix: hyperuricaemia, HGPRT gene mutation
    Tx: allopurinol, benzos
118
Q

Discuss Niemann Pick disease

A
  • Build up of sphingomyelin in lysosomes (lipid-laden appearance, foam cells)
  • A: early onset, HSM, weak, hyporeflexia, cherry red macula, ILD and resp failure, fatal by age 3
  • B: less severe, no neuro, splenomegaly, low plts and WCC, ILD
  • C: supranuclear gaze palsy

Paediatrics RACP written exam (18 decks)

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