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RACP METABOLICS > Metabolica > Flashcards

Metabolica Flashcards

1
Q

OTC?

A

Ornithine transcarbamylase deficiency

Urea cycle defect

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2
Q

Hyper ammonia?

A

In urea cycle state indicates catabolism
Sodium benzoate:
Combines win glycine to form hippuric acid which the kidneys then excrete

Treat by returning to anabolic:
Low protein feeds
Lipids
Sugar

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3
Q

Most common CF mutation?

A

66% is CFTR Delta F 508 (Cystic Fibrosis Transmembrane conductance regulator protein
DELETION of phenylalanine at Amino Acid 508
Chloride Channel
CLASS 2 - MISFOLDED, Can’t make it to cell surface
Correctors like lumacaftor or tezcaftor help it fold and get to surface

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4
Q

Micropenis causes in neonate?

A

Stretched penile length <2.5SD = <1.9cm
Hormonal abnormality after 14/40
Hypogonadotrophic hypogonadism - GNRH deficiency (Prader Willi, Kallmann, Lawrence Moon-Biedel)
Hypergonadortophic hypogonadism - primary testicular failure
Idiopathic

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5
Q

Congential PanHypo Pit Symptoms?

A 
Micropenis (Low FSH/LH)
Optic Atrophy
Midline defects
Poor Growth
Hypoglycaemia (Low ACTH/GH)
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6
Q

Difference between 5 Alpha Reductase and Androgen Insensitivity?

A

5AR is Autosomal recessive, can’t convert testosterone into DHT, effects XY Genotype with variable phenoytype and virilisation at puberty.

Androgen Insensitivity effects XY genotype, X-Linked recessive, cryptorchidism, absent uterus, feminization at puberty

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7
Q

Homocystinuria?
Prevalance
Symptoms
Pathophys

A

1:300,000 - More in Ireland/Germany/Norway/Qatar (1:1800)

//
Ectopia lentis - Free floating anterior lens - MYOPIC
Marfanoid - reduced flexibility
Learning difficutlies, thrombosis, chest wall deformties, osteoperosis
//
Methionine -> Cysteine via homocysteine
High plasma/urine homocysteine
CBS (Cystathionine beta-synthase) enzyme Pyridoxine-dependent 
GIVE Pyriodoxine and FOLATE
Or Low methionine diet
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8
Q

What is inappropriate ketosis?

A

Ketones (beta-hydroxybutyrate of <2.5) when hypoglycaemic is EITHER:

Hyperinsulinism (which suppresses formation)
OR
Fatty Acid Oxidation defect (not mobilising)

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9
Q

MCAD

A 
Medium Chain Acyl0CoA Dehydrogenase deficiency
-
HYPOGLYCAEMIA and HYPOKETONEMIA
(Carnitine deficiency, fatty acid transportation defects, defects of beta oxidation enzymes)
MCAD is most common
Low BSL
Low Carnitine (free + total)
Low Ketones
Elevated FFA
Urine - Dicarboxylic acids, acylglycine)
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10
Q

Treatment for PKU?

A 
Phenylketonuria
Low Phenylalanine (protein) diet
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11
Q

Findings in SEPTIC OPTIC DYSPLASIA?

A

Optic nerve hypoplasia
Optic chiasm hypoplasia
Absent septum pallucidum
Pituitary stalk hypoplasia

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12
Q

Clues to a mitochondrial disorder?

A

Tissues with an energy requirement effects (Brain/Skeletal Muscle/Heart)
Abnormal brains
Raised creatinine Kinase
Raised Lacate

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13
Q

3 MethylGlutaconic Aciduria

-Types?

A

Type 1 - Super Rare
Type 2 BARTH Syndrome - TAZ Gene, Xlinked, taffazzin portine, cardiolipin abnormalities - Cardiomyopathy, Skeletal Myopathy, Neutropaenia, FTT
Type 3 - COSTEFF syndrome 0 Opthal and neuro
Type 4 - Catarcts, Neurtopaeniua, Epilepsy
Type 5 - Cardiomyopathy, cerebellar ataxia, testicular dysgenesis

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14
Q

GLUT 1 Deficiency?

Gene
Product
Symptoms

A 
Gene is SLC2A1 on 1p34.2
Solute Carrier Family 2 , member 1
GLUT 1 Product
Glut 1 across blood brain barrier
Low CSF glucose cf. paired serum glucose
Causes 
Seizures age <4 yr
Developmental delay
Paroxysmal exertional dyskinesia
TREAT with KETO DIET
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15
Q

Propionic Acidemia?

A

Organic acidemia - defect in fatty acid oxidation
Deficinecy of propionyl-CoA carboxylase
If catabolic can have acute metabolic deompensation
Ax with metabolic stroke - bilateral infarcts to basal ganglia due to toxi metabolites causing endothelial injury

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16
Q

Three broad patterns of metabolic illness?

A

Intoxication
Energy Metabolism
Complex molecules

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17
Q

Describe intoxication in regards to metabolic disorders

A

Placental unit can detoxify, therefore unlikely dysmorphic/congenital injury
Subsequent toxin accumulates (Amino acid to NH3, Organic Acidemia, Translation), or CHO Toxin (Galactose/Fructose) or Fat Toxin
Related to trigger
Occur due to cytoplasm or mitochondrial defect
Treatable with sugar 8-10 mg/kg/min

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18
Q

Describe energy metabolism defect in regards to metabolic

A

Failure to utilise CHO or Fat for energy - KREB Cycle related (All roads lead to Rome)
Defect worst for high energy organs (Brain, Liver, Muscle, Heart (Which also prefers ketones))
May be congenital as placenta can’t supply cellular energy
Damage to structures with scarring/cysts

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19
Q

Describe Complex molecule metabolic disorders

A

Problem with complex molecules - peroxismoe, lysosome, golgi apparatus, endoplasmic reticulum, protein glycosylation

Complex, multisystem, dysmorphic
Less likely to have liver derangement than Intox or Energy metabolism
Rarely treatable

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20
Q

If sick enough for an LP - Think Metabolic?

A

And DO AN AMMONIA

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21
Q 
If not responding to standard treatment?
And tachypnoea
Respiratory alkalosis
Feeding difficulty
Hypotonia
What might you think?
A

THINK METABOLIC

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22
Q

Altered mental state, tachypnoea -

THINK?

A

Hyperammonemia

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23
Q

Ketoacidosis and an unexplained anion gap?

A

Organic acidemia or disorder of gluconeogenesis

24
Q

Ketones present in neonate?

A

Abnormal - Think organic acidemia or gluconeogenic defect

25
Q

Ketones NOT present when hypoglycaemic?

A

Abnormal - Hyperinsulinism OR

Disorder of beta oxidation of fats

26
Q

What presenting clue to a metabolic crisis?

A

Poor feeding/vomiting - to dehydration
Lethargy/altered consciousness - to coma
Appear ‘septic’
Tachypnoea - hyperammonemia, or metabolic acidosis
Abnormal neurological examination - due in nature to disorder:
Ataxia, Diffuse hypotonia/hypertonia, twictching, seizure
PHx of BRUE, or severe illness in response to gastro etc.

27
Q

What presenting biochemical clues for metabolic crisis?

A 
Metabolic acidosis
Lactic acidemia/acidosis
Increased anion gap
Hyperammonemia
Hypoglycemia
KETONES - High (organic acidemia) or inappropriately low (fatty acid oxidation defects)
28
Q

What late signs of metabolic crisis?

A 
Apnoea
Bradycardia
Seizures
Hypothermia
Multi organ dysfunction
Suddeny Death
29
Q

Metabolic conditions that may present with sudden death (and hence masquerade as SIDS?)

A

Fatty acid oxidation
Disorders of carnitine transport/metabolism
Urea cycle defect
Organic acidemia
Disorders of pyruvate metabolism
Oxidative phosphorylation
Carbohydrate disordes (galactosemia, hereditary fructose intolerance, glycogen storage disease, disorder of gluconeogenesis)

30
Q

In setting of catabolism - which IEM may be triggered?

A

Defects in catabolic pathways - TREATABLE
Glycogen storage disease 1, or gluconeogenesis

Fatty acid beta-oxidation defects
Carnitine transport disorder
Ketogenesis defects

Amino acid disorders
Organic acidemia

31
Q

What defines a metabolic crisis?

A

Metabolic disorder associated with acute CLINICAL and BIOCHEMICAL decompensation

32
Q

Catabolic cascade? AKA triggers for catabolism?

A

Prolonged fasting
Infection
Surgery
Steroid therapy
Vaccination (fever and increased metabolic rate)
Neonatal physiology (Newborns lose weight, they are all catabolic)
Excess protein intake ***

33
Q

How does protein differ from other metabolic disorders?

A

EXCESS intake alone can trigger AA degradation pathways and crisis without corresponding catabolic state

34
Q

Biochemical profile of organic acidemia in NEONATE?

A 
pH LOW
Bicarbonate LOW
Anion gap HIGH
Ammonia elevated
Urinary KETONES elevated
Bone marrow suppression
35
Q

Diet related causes of metabolic trigger

A

Excess Protein - Urea cycle defect or acidemia
Galactose - galactosemia - cataracts + jaundice
Fructose - herediatry fructose intolerance

36
Q

Hereditary Fructose Intolerance - Fructose load leads to:

A

Post prandial hypoglycaemia

37
Q

Glycogen storage disease - Von Gierke

Clinical Vignette?

A 
Distended abdomen
Weight loss
Difficulty sleeping >3 hours
Mild transaminase rise
With trigger at FEVER 6/12
Hypoglycaemia, mild metabolic acidosis, HCO3 - 15, lactate 3.6, elevated transaminases, Urine pH 6.5 - aka not very good acidification - Renal Tubular Acidosis develops with metabolic liver disease “renal fanconi” syndrome
38
Q

Glycogen store length?

A

10-12 hours, gluconeogenesis kicks off early

39
Q

Fatty Acid oxidation- time to kick in post fasting?

A

10-12 hours

40
Q

Gluconeogenesis time to effect?

A

Starts within hours but ramps up to full speed by 10 hours, (muscles and RBCs) eventually spares muscles after ~ 24 hours and just RBC

And also fatty acid oxidation as ketone fuels

41
Q

Glycogen Storage Disease Type 1 - Biochemical Abnormalities

A

GLUCONEOGENESIS FINAL PATHWAY - Glycogen metabolism + Gluconeogenesis - GLUCOSE 6 PHOSPHATASE (G6Pase)
Low sugar, body catabolic
Glycogen instead of being converted to glucose, accumulates as G6P, which tricks liver, to paradoxically behaves anabolically - Elevated lactate/pyruvate/triglycerides
Inhibited ketones (lower than expected) (As Trigs being made)
Elevated FFA
- Xanthoma
Elevated glycogen in liver (hepatomegaly)

42
Q

4 Metabolic Crisis Questions?

A
  1. Is the patient sick (infections/stress/vaccine/fever/surgery)?
  2. Is the patient eating too much protein?
  3. Is the patient having a food that is toxic for them? (Protein, galactose, fructose)
  4. When are symptoms in relation to food (glycogen storage disorder, gluconeogenesis, fatty acid ox)
43
Q

Biochemical pathways - which tests in acute metabolic diseases?

A

Crisis are either: Intoxication OR Energy Metabolism

Proteins - NH3 Urea Cycle
Organic acids - organic acidemia
Therefore:
Order - ammonia, pH, anion gap need bicarb, Cl vs. N + K

//
CHO disorders:
Herediatry fructose intolerance, can’t convert to glucose
Fructose sequesters phosphate F1P - liver failure with LOW ATP state
F1,6 bisphosphatase inhibits gluconeongenesis without interfering with glycogen
ORDER Glucose (LOW), Lactate (HIGH) (accumulates at end)
//
Fatty Acids - Fatty acids oxidise to acetyl-coa then ketones produced
Order Ketones (LOW) (Urine, First Pass post presentation) with Glucose
To support fatty acid oxidation defect

THEREFORE:
Ammonia
Electrolytes
Blood Gas
Glucose
Lacate
Urinalysis (Ketones)
44
Q

Method of tachypnoea in urea cycle disorder?

A

Ammonia is a RESPIRATORY STIMULANT
Low CO2 drives by respiratory alkalosis ALKALOTIC STATE
Body compensates by dumping HCO3 - compensatory ‘metabolic acidosis’

45
Q

Body wastes HCO3 (diarrhoea or renal)

How does body compensate?

A

Compensation is retaining chloride

Gives a NON ANION GAP ACIDOSIS

46
Q

Causes of raised ammonia?

A

Urea cycle primary
OR
Urea cycle can be impacted on a secondary

47
Q

Metabolic Crisis in organic acidemia changes in LFT and FBE?

A

Raised transaminases

Neutropaenia and thrombocytopaenia

48
Q

Metabolic Crisis Shopping list:

LEVEL 1
LEVEL 2

A 
Gas
Electrolytes
Ammonia
Urinary Ketones
LFT
FBE
Glucose
Lactate
//
Level 2 - to CONFIRM
Metabolic Screen 
Blood AA Amino Acids 
Urine OA Organic Acids
Blood AC Acyclcarnitines
49
Q

How do metabolic confirmatory tests work, what effects them?

A

BLOOD AA
Urine or CSF occasionally
Acute Specimens more likely diagnostic
Nutritional status, age of patient

URINE OA
GAS MS - detects organic metabolites - intermediates of energy metabolism and fatty acid oxidation

Tandem Mass Spec for Acyclcarnitine
Sort by mass
Smashed , resorted
Carnitine bound metabolites - aka acylcarnitine

Carnitine binds long chain fat, escorts into mitochondria
But fickle - will bind to organic acids and fatty acids too
And if you mass spec for carnitine, then mass spec again - u get what carnitine is bound to (and what is therefore hanging about)

50
Q

Regarding metabolic algorithims - What information necessary if metabolic acidosis?

A

Consider ketosis
Consider sugar
Consider lactate

In order to differentiate: Organic acidemias, glyogen storage disease, defects in gluconeogenesis, fatty acid oxidation, multiple carboxylase deficiency, mitocondrial

51
Q

Regarding metabolic algorithims - what information for hyperammoniaemia

A

Consider Ketoacidosis
Consider presence of significant liver disease
Consider response to glucose if liver disease

Primary respiratory alkalosis - ? Urea Cycle Defect
Primary Liver disease
Primary metabolic acidosis - ?Organic acidemia with inhibition of UC, ?Valproic acide inhibiting urea cycle, or sick ++ with perfusion or aponea leading to MAcidosis overtaking RespAlkalosis
Or with nil liver disease or resp alkalosis or ketoacidosis - Fatty Acid Oxidation

52
Q

Regarding metabolic algorithms - what information for hypoglycaemia

A

What is the character of hypoglycaemia?
Persistent = Hyperinsulinism/endocrine
Post feeding = Hereditary fructose intolerance, or galactosemia with liver injury or hyperinsulinism
If with fasting consider hepatomegaly or not
If nil hepatomegaly assess ketones (fatty acid ox vs. ketotic hypoglycemia/MCAD)
If hepatomegaly assess duration of fast to genearte lacetmia (GSD1 vs. fatty acid ox, gluconeogensis def)

53
Q

Glycogen storage disease

What sorts?

A

All Glycogen enzyme issues - All autosomal recessive
GSD 1 - Von Gerkes “Jerky” factory - Glucose-6-phosphatase, final step to create glucose in gluconeogenesis and glycogenolysis - LACTIC ACIDOSIS, due to downstream pyruvate buildup, hypoglycaemia -> seizures, High triglycerides, hepatomegaly, gout/uric acid
GSD 2 - Pompe disease “Pompei volcano” - Lemon Acid Maltase deficiency, LYSOSOMAL, Alpha 1,4,glucosidase, HCM, cardiomegaly, hepatomegaly, respiratory distress, Limb girdle weakness, hypotonia, PAS stain pink from lysosomes, big tongue
GSD 3 TREE- Cori “Quarry” - debranching enzyme/delimit
GSD 5- HIVE McArdle - Hurdler - Glycogen phsophorylase - muscle breakdown (Muscle cramps with excercise) - Myoglobinuira - skeletal muscle injury, arrythmias due to electrolyte changes - hyperkalemia - “2nd wind phenomenon”- increased blood flow compensates

54
Q

Compare and contrast GSD2’s two forms

A

Infantile form - little/no enzyme - Cardiac involvement - HCM, large tongue, large liver
Juvenile form - reduced enzyme - adolescent or later onset

Both AR, lysosomal build up glycogen, PROXIMAL (Girdle) limb weakness, diaphragm weakness
GAA gene
Alglucosidase alfa - Gene Therapy

55
Q

Farber disease?

A 
Farber’s Lipogranulomatosis
Hoarse/weak cry
Lipogranulomas under skin
Swollen painful joints
- AR, abnormal lipid metabolism which accumulates

RACP METABOLICS (1 decks)

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