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LIPIDS & LIPID DISORDERS 1

Classification
  Biochemical
  Clinical
Pathology

Lipids
  General

Also see
  Carbohydrates

From: R Brian Sommerville

Lipids: General

  • Basic molecules: Fatty acids
    • Fatty acid definitions
      • Short chain: 4 to 8 carbons (C4 - C8)
      • Medium chain: C8 – C12
      • Long chain: C12/C14 - C20: Examples
        • Palmitic: C16
        • Stearic: C18
        • Linoleic: C18
        • Oleic: C18; Abundant in PN myelin
      • Very long chain (VLC): > C22
  • Lipid in muscle
    • Abundance: 0.2% of muscle fiber
    • Location: Type 1 > Type 2 muscle fibers
  • Fatty acids: Metabolism
  • Lipids (Fatty acids) as energy source
    • Energy production: General
      • Common tissues: Skeletal & Cardiac muscle
      • Lipids used especially during fasting & prolonged exercise
      • Acute lipid oversupply
        • Inhibits glucose oxidation
        • Mitochondria
          • Preferentially switch from Carbohydrate to Fatty Acid utilization
    • Heart; Kidney: 1° (Fatty acids)
    • Skeletal muscle
      • Uses circulating fatty acids during
        • Postprandial period
        • Fasting & Exercise
      • Requires: Carnitine
        • Carnitine sources: Liver synthesis (~ 25% of requirements); Diet (Meat)
        • Carnitine storage: 98% in skeletal muscle
        • Carnitine in neonates: Low levels
      • Steps in fatty acid metabolism
    • Brain: Ketones may be used
  • Disease testing
    • Plasma total and free carnitine levels
      • Frequently lowered in FAO disorders
      • Levels always decreased in carnitine transporter deficiency
    • Urinary organic acid profile
      • Most often normal or non-specific in adult FAO diseases
      • MADD: Abnormal excretion of
        • 2-hydroxyglutaric acid
        • ± Acylglycine derivatives
    • Acylcarnitine profile (Plasma or Blood)
      • Most sensitive analysis for FAO disorders
      • More sensitive
        • After prolonged fast (> 12 h in adults)
        • During acute decompensation

Fatty Acid Transport
Cytoplasm→Mitochondria


From MW King
  • Fatty acids: Activated in cytoplasm to Acyl CoA
  • Acyl CoA transport: Through mitochondrial membranes
  • Fatty acid-CoA in mitochondria is substrate for β-oxidation

Fatty Acid Oxidation

Carnitine Palmitoyltransferase 2 Carnitine Acylcarnitine Acyl-CoA dehydrogenase, very long-chain Trifunctional protein, Subunit A Trifunctional protein, Subunit B Acyl-CoA dehydrogenase, short-chain Acyl-CoA dehydrogenase, medium-chain Acyl-CoA dehydrogenase, long-chain Electron transfer flavoprotein L-3-Hydroxyacyl-CoA dehydrogenase, short chain 3-Ketoacyl-CoA thiolase, Medium chain

Lipid droplets in Muscle fibers: Large

Lipid Droplet

Lipid disorders: Biochemical classification



Lipid Myopathies: Clinical classification


Disorder Gene
(Common
mutation)
Clinical, Other Muscle
  Lipid
Acylcarnitine
  Increase & Other
Carnitine
Weakness, Fixed
Carnitine deficiency SLC22A5
  (OCTN2)
Cardiomyopathy +++
Type 1
Normal Very low
SCAD ACADS
(Arg171Trp
Gly209Ser)
Ophthalmoplegia - Butyrylcarnitine (C4)
Ethylmalonic aciduria
 
Multiple acyl-CoA
  dehydrogenase (MAD)
ETFA CoQ10 deficiency +
Type 1
All lengths Low
Multiple acyl-CoA
  dehydrogenase (MAD)
ETFDH GI: Vomiting ++
Type 1
All lengths Low
Neutral lipid storage
  + Ichthyosis
(NLSDI)
ABHD5 Hepatomegaly +++
Type 1 & 2
Normal
Leukocyte
  lipid vacuoles
Normal
Neutral lipid storage
  + Myopathy
(NLSDM)
PNPLA2 Cardiomyopathy +++
Type 1 & 2
Normal
Leukocyte
  lipid vacuoles
Normal
Rhabdomyolysis ± Exercise intolerance & Cramps
CPT II deficiency CPT2
(Ser113Leu
413delAG)
  ± Long chain Normal
VLCAD ACADVL Cardiomyopathy ± Long chain Mildly low
Short-chain 3-hydroxyacyl-CoA
  dehydrogenase (SCHAD)
HADH Hepatic
Hypoclycemia
  Hydroxybutyrylcarnitine Normal
Mitochondrial trifunctional
  protein (MTP) A
HADHA Polyneuropathy ± Long-chain
Dicarboxylic &
  3-Hydroxyacylcarnitines
Low
Mitochondrial trifunctional
  protein (MTP) B
HADHB Cardiomyopathy
Hepatic
± Long-chain
Dicarboxylic &
  3-Hydroxyacylcarnitines
Low
Medium chain 3-ketoacyl-CoA
  thiolase (MCKAT)
  Hepatic
Hypoglycemia
  3-Hydroxybutyric acid
C12-C16 dicarboxylic
  acids, unsaturated
 
Medium-chain acyl-CoA
  dehydrogenase (MCAD)
ACADM
(Lys304Glu)
Hepatic ± Medium chain
Acylglycines
Low
Phosphatidic acid
  phosphatase
LIPIN1   ± Normal Normal

Lipid Biochemistry


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References
1. Neuromuscular Disorders 2010;20:693–700, J Clin Med 2018;7(12)

3/25/2021