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Metabolics Flashcards

1
Q

Aminoacidopathies

A

Unable to metabolise amnio acids
Does not cause sig acidosis and hypoglycaemia
Amino acids toxic to organs
Ix: serum/urine/CSF amino acids

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2
Q

PKU

A

Aminoacidopathy- normal bloods
Defect in phenylalanine hydroxylase - cannot break down phenylalanine to tyrosine
Excess phenylalanine causes neurotoxicity
AR
Presents 6-8 months with developmental delay, seizures, vomiting, eczema
“Musty” smell, light colouring
Rx: low phenylalanine diet

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3
Q

MSUD

A

Aminoacidopathy- normal bloods
Inability to break down branch chain amino acids- leucine, isoleucine, valine
(BCAAs make up 20% of dietary protein)
Leucine toxic to brain- presents ~10 days with encephalopathy/coma

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4
Q

Tyrosinaemia I

A

Aminoacidopathy- normal bloods
Enzyme block causes high levels of succetylacetone - toxic to liver
Presents ~ 6 months with liver disease
Treatment blocks the enzyme above the block
Hypoglycaemia

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5
Q

Tyrosinaemia II

A

Aminoacidopathy- normal bloods

Tyrosine toxic to skin and cornea- keratitis and keratosis

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6
Q

Organic acidopathies

A

Organic acid- a carbon-containing compound containing an acidic group- breakdown products of amino acids

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7
Q

Organic acidopathies

  • What are organic acids
  • Ix
  • Clinical features
  • Organs affected
A

Organic acid- a carbon-containing compound containing an acidic group- breakdown products of amino acids
Transaminases remove the amino group from amino acids, making organic acids
Ix: Urine organic acids or acylcarnitine profile
Tend to cause severe acidosis, ketosis, hypoglycaemia, hyperammonaemia, elevated lactate
Particularly affect brain (comatose, hypertonic, seizures), liver (hepatitis)
Mx:
Cease protein intake, commence carnitine (buffers Acyl-CoA metabolites), 10% dextrose or SMOF, ammonia scavengers, renal replacement therapy

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8
Q

Methylmalonic acidaemia

A

Organic acidopathy

Bad outcome

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9
Q

Proprionic acidaemia

A

Organic acidopathy
Bad outcome- proprionic acid very neurotoxic
Metabolic stroke, esp bilateral basal ganglia

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10
Q

Isovaleic acidaemia

A

Organic acidopathy
Sweaty feet smell
Better outcome than other organic acidaemias

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11
Q

Lysosomal storage disease

  • What are lysosomes
  • Clinical features
  • Ix
A

Cell organelle- break down cellular waste production
Initially normal children who over months-years develop symptoms- developmental regression, seizures (no acute crises)
Ix: urinary GAGs (glycosaminoglycans), measure lyosomal enzymes in blood (white cell enzymes)/ liver/muscle/skin biopsy

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12
Q

Mucopolysaccharidoses

A

Lysosomal storage disease
Type 1- Hurler
Type 2- Hunter (X linked- rest are AR)
Type - Sanfilippo
Type 4- Morquio (non-neurological, hyper-extensible)
Coarse facial features, short stature, developmental delay/cognitive impairment
Respond early to BMT

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13
Q

Tay-Saches, Sandhoff

A

Lysosomal storage disease
- Sphingolipidosis
May have very early normal development, but usually severe developmental regression by a few months of age, hypotonic and cherry-red spot on retina but otherwise normal examination
Late onset Tay Sachs- teenager with psychosis

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14
Q

Leukodystrophy

A

Lysosomal storage disease - Sphingolipidosis
Eg. Metachromatic leukodystrophy, Krabbe disease
Impaired motor function (white matter disease) similar to CP, later cognitive decline and dementia
BMT

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15
Q

Gaucher disease

A

Lysosomal storage disease - Sphingolipidosis
Symptoms due to bone marrow and organ infiltration
Splenomegaly, hepatomegaly, bone marrow supression- more chronic presentation than leukaemia, pathological fractures
10x greater risk of Parkinsons disease
Good response to enzyme replacement therapy

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16
Q

Neimann Pick

A

Lysosomal storage disease - Sphingolipidosis
Liver and brain
Variable presentation- isolated hepatomegaly, developmental regression
FBC with histiocytes

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17
Q

Fabry disease

A

Lysosomal storage disease - Sphingolipidosis
MC in total, but more common in adults
Renal failure, cardiomyopathy, pain (esp in children), strokes

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18
Q

Urea cycle disorders

- What does the urea cycle do

A

Urea cycle converts nitrogen waste products (ammonia) in to urea
Ix: very high ammonia, can then measure specific chemicals involved in urea cycle
Rx: restrict protein to minimum needed to grow
Ammonium scavengers0 sodium benzoate, sodium phenylbutyrate, L-arginine, Carbaglu (NAGS)
Provide deficient metabolites eg. arginine, citrullinine
In a crisis- haemofiltration/ haemodialysis

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19
Q

Ornithine transcarbamylase

A

Urea cycle disorder- MC
X linked- severe in boys, mild in girls
Classical- encephalopathy/coma in the first week of life
50% mortality with neonatal presentation, 75% of survivors die in childhood

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20
Q

Fatty acid oxidation disorders

A

Production of ketones (and reducing substances) once glycogen stores run out
Hypoketotic hypoglycaemia, hyperammonaemia, lactic acidosis
Cardiomyopathy
Rhabdomyolysis with significant exercise
Acute hepatomegaly/liver injury
Ix: acylcarnitine profile
Rx: glucose 10% acutely, carnitine supplementation (mops up acyl-coA), avoidance of fasting

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21
Q

MCAD

A

Fatty acid oxidation defect- MC
1/40 carriers in Aus
AR- ACADM gene missense mutation
Hypoketotic hypoglycaemia during periods of fasting
Less unwell after age 3-4 -better glycogen stores
Well otherwise

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22
Q

VLCAD

A

Fatty acid oxidation defect

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23
Q

Carnitine palmitoyl transferase (CPT)

A

Fatty acid oxidation defect

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24
Q

LCHAD

A

Fatty acid oxidation defect

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25
Mitochondrial disorders
Respiratory chain- oxidative phosphorylation Elevated lactate Any Sx in any organ at any age Affects high energy organs- brain, heart, muscles, eyes, liver, pancreas, renal tubules Adult combinations of rhabdomyolysis with minor exercise, IDDM, renal disease, ophthalmoplegia and ptosis, deafness Ix: lactic acid, organic acids, moelcular mtDNA
26
Leigh
Infant with strokes in the basal ganglia- dsytonia, spasm, variable consciousness level MRI- T2 hyperintensity in basal ganglia
27
MELAS
Metabolic encephalopathy, lactic acidosis, stokes
28
Peroxisomal disorder
Peroxisome breaks down, and makes things eg. cell membranes | Ix: elevated VLCFA
29
Adrenoleukodystrophy
Peroxisomal disorder X-linked Younger child- behaviour eg. ADHD, Addison's disease, vision changes, 50% Addison's disease in males = ALD Ix: VLCFA MRI: T2 hyperintensity in white matter bilaterally BMT
30
Zellwegger syndrome
Peroxisomal biogenesis disorder Neonate with poor tone, large anterior fontanelle, tall forehead with bitemporal narrowing, poor feeding, dysmorphic Abnormal brain MRI Screen with VLCFAs
31
Refsums disease
Peroxisomal disorder Progressive disorder- rash, abnormal movements, retinitis pigmentosa, anosmia Elevated phytanic acid
32
Glycogen storage disorders
Hepatomegaly (develops), hypoglycaemia with ketosis after a shorter period of fasting FTT, short stature, hepatitis, liver adenoma/HCC, cherubic face, renal disease Type 1-9- all AR except 9 (XL) Lower the number, the more severe, the more intensive feeding required Elevated lactate, elevated ketones
33
Pompe disease
Glycogen storage disease II Neonate with hypotonia and cardiomyopathy- significant cardiomyopathy Weakness, areflexia
34
McArdle
Glycogen storage disease V | Muscle phenotype- sore muscles with minor exertion
35
Metabolic differentials for an unwell neonate (5)
``` Organic aciopathies- MMA, PA Aminoaciopathies- MSUD Urea cycle disorders Galactoasaemia Mitochondrial ```
36
Metabolic differentials for hypoglycaemia in an older child (not a neonate) (3)
Fatty acid oxidation disorder Glycogen storage disorder Mitochondrial
37
Metabolic differentials for developmental regression
``` Lysosomal storage disease Mitochondrial Peroxisomal- ALD Urea cycle disorders (not OTC) MSUD (mild), PKU Organic acidamia Other genetic- CDG, Retts, Alexander, VWM ```
38
Galactosaemia
Calactose-1-phosphate uridyl transferase deficiency- inability to break down galactose GALT gene Unwell neonate- day 7-8 Jaundice, hepatomegaly, vomiting, hypoglycaemia, seizures, FTT E. coli sepsis Classic galactosaemia assoc with hypergonadrotrophic hypogonadism and learning difficulties
39
Metabolic differentials hepatomegaly/hepatitis
``` Tyrosinaemia Galactosaemia GCS Lysosomal storage disease Neimann-Pick C Mitochondrial ```
40
Metabolic differentials seizures/microcephaly in a neonate
``` Non ketotic hyperglycinaemia- Maori Pyridoxine responsive seizures GLUT-1 transporter Creatine synthesis/transporter Sulfite oxidase Menkes Folate disorders ```
41
Main disorders detected on NNST
``` CF- IRT Congenital hypothyroidism - TSH MCAD- octanoyl carnitine PKU- phenylalanine levels Galactosaemia- galactose levels ```
42
Reasons for false negative on NNST- CF
NNST only detects ~50% of cases ``` IRT only elevated in 95% infants with CF Only top 10% IRTs of each batch sent for genetic testing Uncommon mutations missed No pancreatic involvement Mec ileus ```
43
Reasons for false NNST tests- hypothyroidism
``` Patients with a small amount of functioning thyroid tissue which later fails Pituitary disease (will not have high TSH) Monozygotic twins- transfusion of euthyroid blood TSH transiently elevated in LBW and prem neonates, or falsely low due to immaturity of HPT axis TSH surge first 24-48 hours of life- if test is done too early ```
44
False negative for PKU on NNST
If testing done <48 hours (not enough exposure to phenylalanine in diet)
45
False result for galactosaemia on NNST
<24 hours milk feeds- false neg | Immediately post feed- false pos
46
Babies who need repeat NNST
LBW <1500g and prem - Repeat after 2/52 if >1000g, after 4/52 if <1000g Sick infants not on enteral feeds- repeat after 24 hours on enteral feeds Same sex twins- repeat 2/52 after birth Transfusion- collect just prior to transfusion, and again after 2/52
47
Counter-regulatory hormones used in glycogenolysis
Adrenaline, glucagon (insulin suppresses)
48
Counter-reguatory hormones used in proteolysis
Cortisol (insulin suppresses)
49
Counter-regulatory hormones used in lipolysis
GH, cortisol, adrenaline (insulin suppresses)
50
Lipolysis
Triglyerides = glycerol + fatty acids Glycerol --> gluconeongeneis Fatty acids --> fatty acid oxidation
51
Hyperinsulinism
= >10mg/kg/min glucose requirement Hypoglycaemia should be assoc with decreased insulin, increased glucagon/cortisol/GH/adrenaline Hyperinsulinism suppresses all counter-regulatory hormones, therefore suppresses mechanisms of fuel generation = low glucose, low fatty acids, low ketones Any detectable insulin in the presence of BGL<2.6 is abnormal
52
Congenital disorders of glycosylation - Genetics - Ix - Clinical features
AR Ix: Transferrin isoforms Wide variety of symptoms: Hyperinsulinism, coagulation disorder, hypotonia, big ears, abnormal fat pads
53
Glutamate dehydrogenase hyperinsulinaemia
2nd MC HI Children become hypoglycaemic after eating protein (leucine) Hyperinsulinism and hyperammonaemia
54
Glycogen storage disease type 1
AKA glucose-6-phosphatase deficiency High lactate and hypoglycaemia (late block in glycogenolysis- shunts to lactate) Most severe GSD- may need cont PEG feeds Type 1b- assoc with neutropenia, impaired wound healing Present in the first weeks of life
55
Dumping syndrome
In children with GI pathology eg short gut syndrome, rapid uptake of nutrient from the GI triggers a rebound hyperinsulinism
56
How does ammonia caise encephalopathy
Ammonia binds glutamate in the brain to form glutamine- has an osmotic effect causing cerebral oedema Also direct effects on neurotransmitters
57
DDx rhabdo
FAOD (not MCAD) GSD- McArdle, Pompe Mitochondrial
58
LIPN1 deficiency
Intercurrent febrile illness - cell membranes become 'leaky' CK >100 000 K very high 33% die due to cardiac arrhythmia
59
Malignant hyperthermia
AD RYR1 gene mutation in >50% Provoked by volatile anaesthetics + depolarising muscle relaxants = muscle contractions, tachycardia, metabolic acidosis, hyperthermia Central core myopathy is allelic with MH
60
Lactate:pyruvate ratio- normal
Glycogen storage disorders Disorders of gluconeogenesis Pyruvate dehydrogenase deficiency
61
Lactate:pyruvate: high
Mitochondrial disorders | Shock/sepsis
62
Energy utilisation for hours fasting, and disorders assoc with hypoglycaemia during this time - 0-2 hrs - 2-6 hrs - 6-12 hrs - 12-24 hrs
0-2: glucose = hyperinsulinism 2-6: Glycogen = GSD 6-12: Gluconeogenesis = GSD 0, disorders of gluconeogenesis 12-24: b-oxidation of fatty acids = FOAD, GH/cortisol deficiency
63
How to calculate glucose requirement (in mg/kg/min)
% glucose x mL/kg/day / 144
64
Where is glycogen stored
Liver (main source of that is used to maintain BGL) and kidney (minor stores for BGL) Muscles- most glycogen stored here, but only used to supply muscles with glucose
65
Fructose-1,6-bisphosphatase deficiency
Disorder of gluconeongenesis Hypoglycaemia, hepatomegaly +/- liver disease, ketoacidosis, FTT Triggered by fructose
66
Hereditary fructose intolerance
Disorder of gluconeogenesis Aldose B deficiency Hypoglycaemia, hepatomegaly +/- liver disease, ketoacidosis, FTT Triggered by fructose
67
What does carnitine do
Cotransporter- helps LCFA and VLCFA in to mitochondria for b-oxidation (MCFA can pass through without help)
68
Reye syndrome
Rapidly progressive encephalopathy + liver toxicity Often shortly after viral infection eg. influenza, varicella 90% cases assoc with aspirin use Can also be due to IEM Hypoglycaemia, hyperammonaemia
69
Glycolysis
Process of converting glucose to pyruvate
70
Menkes
X linked Serum copper and ceruloplasma Seizures, developmental delay, hypotonia Kinky hair

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