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Paediatric Biochemistry > Glycogen Storage Disorders > Flashcards

Glycogen Storage Disorders Flashcards

1
Q

What are Glycogen Storage Disorders?

A
  • Inherited disorders that affect the quantity and/or the quality (structure) of glycogen stored in tissue
  • Overall affects 1 in 25,000 (Europe/USA)
  • Mainly diagnosed in first few years of life
  • Testing mainly through genetics, only 1 UK lab offers biochemical testing
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2
Q

What is the presentation of Glycogen Sorage Disorders?

A
  • Hepatomegaly and fasting hypoglycaemia are presenting features of GSD affecting the liver
  • Muscle cramps and exercise intolerance are features of GSD affecting muscle
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3
Q

What is Glycogen?

A
  • Secondary energy store for the body
  • Stored by forming 1-4 linked straight chains with branches formed by 1-6 links
  • Store of glucose in a readily accessible form without imposing an osmotic load on the cell
  • 2 main storage sites liver (35%) and muscle (60%). Some also stored in brain, intestine and kidneys
  • Can be mildly elevated in the neonatal period
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4
Q

Describe glycogen metabolism

A

Synthesis

  • Priming - Glycogenin
  • Elongation - Glycogen synthase
  • Branching - Glycogen branching Enzyme

Degradation

  • Shortening of straight chains - Phosphorylase
  • Removal of branch points - Debrancher
  • Whole sale degradation - Acid a-glucosidase

Transport and utilisation

  • Glycolysis - PFK etc.
  • Release from cells - Glucose-6-phosphatase
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5
Q

What are Hepatic GSDs examples?

A
  • GSD I: glucose-6-phosphatase or transport systems in ER
  • GSD III: debranching enzyme
  • GSD IX a, b , c: liver phosphorylase b kinase (PBK)
  • GSD VI: liver phosphorylase
  • GSD IV: branching enzyme
  • GSD 0a: glycogen synthase
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6
Q

What are Muscle GSDs?

A
  • GSD II: acid a-glucosidase
  • GSD V: muscle phosphorylase
  • GSD VII: muscle phosphofructokinase
  • GSD IX: Muscle isoforms of PBK

Rare

  • GSD X: phosphoglycerate mutase
  • GSD XII: Aldolase A
  • GSD XIII: β-enolase
  • GSD XIV: Phosphoglucomutase
  • GSD XV: Glycogenin deficiency
  • Phosphoglycerate kinase deficiency
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7
Q

What are rare muscular forms of GSDs?

A

*

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8
Q

What are Routine biochemistry investigation of GSDs?

A
  • U+E
  • LFTs
  • Clotting
  • Glucose
  • (Free Fatty Acids, Beta-Hydroxybutyrate, insulin, c-peptide, Ammonia)
  • Lactate
  • CK
  • Cholesterol and triglycerides
  • Urate
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9
Q

What are the samples used for Enzyme analysis?

A
  • 5- 10 mL lithium Heparin whole blood. To be received within 24 hours of collection
  • Blood spot
  • Liver biopsy snap frozen
  • Muscle biopsy snap frozen
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10
Q

What are features of GSD Type 1 (von Gierke)?

A
  • 1:58,000 newborns - rare, 25% of GSDs diagnosed
  • Types A and B
  • Glucose-6-Phosphatase deficiency (type a)
  • Terminal step in both gluconeogenesis and glycogenolysis
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11
Q

What is the routine biochemistry findings of GSD Type 1 (von Gierke)?

A
  • ↓ Glucose
  • ↑ Urate
  • ↑ Transaminases
  • ↑ ↑ ↑ Lipeamia
  • Glucose challenge
  • ↑ Lactate
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12
Q

How is diagnosis of GSD type 1 (von Gierke)?

A
  • DNA analysis preferred to enzyme analysis – 2 common mutations (~50%) for each type but >65 and >80 described.
  • Enzyme analysis only indicated if genetics unclear. Type 1a frozen muscle biopsy and Type 1b fresh liver biopsy (requires sacrifice of a rabbit).
  • Histology finding of elevated liver glycogen. Upregulation of glycogen synthase due to increased [G-6-P]
  • No clear genotype/phenotype correlation
  • Monitor AFP, urate, proteinuria
  • 1b – increased risk of inflammatory bowel disease and osteopenia
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13
Q

What are features of GSD 2 (Pompe)?

A
  • Autosomal recessive disease whereby there is a partial or complete deficiency acid α-glucosidase.
  • Progressive storage of glycogen in the lysosomes, leading to rupture of the lysosome and subsequent cellular damage
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14
Q

What are symptoms of GSD 2 (Pompe)?

A

Infantile form

  • Presents within the first 6 months
  • Severe hypotonia
  • Progressive cardiomyopathy,
  • Respiratory and feeding difficulties.
  • Rapidly fatal if left untreated.

Adult or late onset form

  • Presents with a milder disease progression with little or no cardiac involvement.
  • Muscle weakness and respiratory insufficiency are common clinical presentations.
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15
Q

What is the Diagnosis and treatment of GSD type 2?

A

Investigation

  1. Blood spot enzyme analysis
    • Measure activity at both acidic and neutral pH and ± acarbose
    • Use ratio of acid/neutral and ± acarbose
  2. White cell assay used to confirm adult onset and difficult cases
  3. Histology vacuolated lymphocytes

Treatment

  • Through enzyme replacement therapy
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16
Q

How is cross reactive immunogenic material measured?

A

Measure if any enzyme being made

  • Uses antiGAA Ab
  • Band present CRIM +ve - Straight to ERT
  • Absent bands CRIM –ve - Immune modulation prior to ERT
  • Rapid turnaround time ~72 hours
  • Second antibody to b-Actin
  • Checks for sample degradation
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17
Q

What is GSD Type 3 (Cori)?

A

Deficiency of glycogen debranching enzyme (AGL)

2 phenotypes

  • 3a liver and muscle
  • 3b liver only
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18
Q

What are 2 functions of glycogen debranching enzyme (AGL)?

A
  • Transfer of 3 glucose residues from a branch point to a non reducing end
  • Cleavage of the a-1,6- linkage liberating glucose

Stored Glycogen in GSD III is short chained and highly branched

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19
Q

What are routine biochemical findings in GSD type III (Cori)?

A
  • ↓ Glucose
  • Amino acids ↓Ala, Leu, Val
  • ↑ Transaminases
  • ↑ Cholesterol
  • Glucose challenge
  • ↑ Lactate
20
Q

How is diagnosis of GSD III made?

A

Enzyme analysis in blood for GSD 3a

  • Measure glycogen content and leucocyte debrancher activity
    • Glycogen content elevated, debrancher low/ND
    • Assay requires phosphorylase limit dextran(PLD). PLD is glycogen that has been digested down to branch points by phosphorylase. Not commercial available needs to be made in house

GSD 3b requires finding of low liver debrancher activity with normal muscle activity

21
Q

What are features of GSD type IV (Andersen) and polyglucosan body disease?

A

Defect in Glycogen branching enzyme

  • Adds the branches into the glycogen molecule
  • Removes 7 units from the non reducing end
  • Links them to a glucose unit 3 residues from a reducing end via and alpha 1-6 bond
22
Q

What are symptoms of GSD Type 4?

A

Infantile presentation

  • Failure to thrive
  • Hepatomegaly
  • Progressive liver disease
  • Cirrhosis
  • Death age 4-5
23
Q

How is diagnosis of GSD Type 4 made?

A
  • WBC and liver enzymology
  • ND/ ↓ ↓
24
Q

What are symptoms of Plyglucosan Body Disease?

A

Prenatal-adult presentation

  • (cardio)myopathy
  • Neurogenic bladder
  • Gait difficulties
25
How is diagnosis of GSD type 4 made?
* WBC and Muscle enzymology * ↓ /↓N * EM studies
26
What is the deficiency of GSD type V (McArdle’s)?
Muscle phosphorylase deficiency
27
How does GSD type V (McArdle's) present?
* Exercise intolerance with 2nd wind * Muscle cramps * Fatigue * Rhabdomyolysis Typically diagnosed in 2nd/3rd decade
28
What is the Routine biochemistry findings of GSD type V (McArdle’s)?
* ↑ ↑ ↑ CK * ↑Urate (Serum) * Myoglobinuria **Forearm exercise test** * Flat lactate response * ↑NH3
29
How is GSD type V (McArdle’s) genetically investigation?
**Using hotspot mutation analysis.** * 2 common mutations in European populations: p.R50X and p.G205S **Histopathology of muscle biopsy** * Negative staining for myophosphorylase * Increased PAS staining for glycogen **Muscle biochemistry used for VUS and confirmation of attenuated forms**
30
How the forearm exercise test conducted?
* IV in Dominant antecubital Vein * Draw base line base line lactate and NH3. Keep on ice process quickly * Squeeze ball MAXIMALLY for 1minute * Collect bloods for lactate and NH3 at 1, 2, 4 6 and 10 minutes
31
What is the defect of GSD type IV (Hers)?
Deficiency of **Liver phosphorylase isoform** * 1% of GSDs rare (1:65-80,000)
32
How does GSD type IV (Hers) present?
**Can be asymptomatic** Presents with: * Hepatomegaly * Mild hypoglycaemia * FTT
33
How is **GSD type IV (Hers) diagnosed?**
* Molecular genetics * **Enzyme analysis on liver biopsy.** White cell assay for phosphorylase unreliable to presence of muscle isoform
34
What are features of GSD type IX?
* 30% of GSDs cases are type IX. 75% are x-linked * Diagnosis complicated by presence of other isoforms in blood. Muscle Isoforms cannot be detected in blood * Liver isoforms presents with mild hypoglycaemia, hepatomegaly. IXc can be more severe with fibrosis and cirrhosis * Muscle forms present with exercise induces cramps and pain
35
How is GSD type IX diagnosed?
* Measure PBK, active phosphorylase, total phosphorylase and glycogen * Ratio of phosphorylase a/ total phosphorylase more sensitive indicator of disturbance than PBK activity
36
What are features of GSD type VII (Tauri)?
Deficiency of **Muscle Phosphofructokinase** * Rare GSDs
37
How does GSD type VII (Tauri) present?
* Exercise intolerance * Muscle cramps * Fatigue * Rhabdomyolysis * No 2nd Wind * Compensated haemolytic anaemia
38
39
How is GSD type VII diagnosed?
1. **Molecular genetics PFKM** 2. **Enzyme activity on muscle biopsy** 3. **RBC PFK activity (in development)** * Uses ratio of activity at 2 concentrations of ATP * Liver isoform more sensitive to substrate inhibition
40
What are features of GSD type 0?
**GSD 0a GYGS2** * Liver isoform **GSD 0b GYGS1** * Muscle isoform * Small No. of cases ?3
41
What is the childhood presentation of GSD type 0?
**GSD 0a GYGS2** * No storage of excessive quantities of glycogen * No hepatomegaly * Fasting hypoglycaemia with ketosis **GSD 0b GYGS1** * Abnormal BP on exercise * Hypertrophic cardiomyopathy * Muscle fatigability
42
How is GSD type 0 diagnosed?
**GSD 0a GYGS2** * Molecular genetics * Liver assay **GSD 0b GYGS1** * Molecular genetics
43
What is the enzyme defect, inheritance, and clinical presentation of GSD Type X?
* **Enzyme:** Phosphoglycerate mutase * **Inheritance:** AR * **Clinical presentation:** Myopathy and cramps upon exercise and Histology finding of tubular aggregates
44
What is the enzyme defect, inheritance, and clinical presentation of GSD Type XII?
* **Enzyme:** Aldolase * **Inheritance:** AR * **Clinical presentation:** Haemolytic anaemia and Myopathy and cramps upon exercise
45
What is the enzyme defect, inheritance, and clinical presentation of GSD Type XIII?
* **Enzyme:** Enolase * **Inheritance:** AR * **Clinical presentation:** Myopathy and cramps upon exercise. Rhabdomylosis and myoglobinuria
46
What is the enzyme defect, inheritance, and clinical presentation of Phosphoglycerate Kinase?
* **Enzyme:** Phosphoglycerate Kinase * **Inheritance:** AR * **Clinical presentation:** Haemolytic anaemia and Myopathy and cramps upon exercise

Paediatric Biochemistry (31 decks)

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