Fatty-Acid Oxidation Defects

Fatty Acids

• Under fasting conditions, fatty-acids are the stores used once 8-hour of carb derived glycogen is used up

  • Lipolysis: fatty acids get released into blood stream to be used by the body and converted into energy as Actyl-CoA and gluconeogenesis

  • Fatty acids can also produce ketone bodies via Bet-Oxidation to serve as energy for the BRAIN

• Fatty acids:

  • 3 acyl groups with attached glycerol group + carbon chain

  • Many fatty acids based upon the length of their carbon chain + the saturated double bonds

  • Most dietary fat stored as Palmaric acid (C16) or Stearic acid (C18)

Fatty-Acid Metabolism Pathways: C14-C18 transport step

Fatty acids needs to be converted to Acetyl-CoA

• C14-C18 Fatty acids → transport across plasma membrane via Long chain F.A transporter

• Converted to Actyl-CoA (But cannot enter inner mitochondrial membrane)

• Acyl-CoA + Carnitine → Acylcarnitine (of varying lengths) via CPT1 activity (TRANSPORT PREP STEP)

• Acyl Carnatine moved into inner membrane in exchange free cranatine out via CACT activity (TRANSPORT STEP)

• Acylycratine → Actyl CoA + Carnitine via CPTII activity (LIBERATION STEP)

Acyl-CoA can now enter into BETA OXIDATION

Fatty-Acid Metabolism Pathways: C14-C20 B-Ox

• Special Cleavage Steps: Only done for fatty acidsC14 or longer

• Acyl 2 carbon is cleaved from it via the Mitochondrial Trifunctional Protein

• the Acyl-2C’s liberated can then undergo Beta-Oxiadtion

  • Each turn liberated a 2C Acytl CoA group

Fatty-Acid Metabolism Pathways: C4-C12 B-Ox

• Smaller fatty acids can diffuse freely across all membrane of the cell + mitochondria: no need for the transporter or Beta-oxidation steps

  • Each turn liberated a 2C Acytl CoA group

Fatty Acid Oxidation Defects: Pathophysiology

• Defective utilization of Fatty Acids (Acyl groups) for energy

  • Rapid glycogen depletion→ hypoglycemia in fasting sate (can’t switch over to FA B-Ox to maintain blood glucose levels)

  • Deficiency of energy substrate for muscles and brain

    • Muscles: F.A → Acetyl-CoA for energy

    • Brain: F.A → Acetyl-CoA → Ketone bodies (ketogenesis step)

  • Accumulation of unmetabolized F.A in liver and muscle

    • Liver disease

    • Myopathy

    • Cardiomyopathy

Fatty Acid Oxidation Defects: Major Clinical phenotypes

Hypoketotic + hypoglycemic

• Glucose levels drop quickly, Ketone bodies made at low levels

  • Cognitive and developmental insults to the brain

• Body TRIES to breakdown F.A., but can’t convert smaller chunks to the 2-Acetyl-CoA via B Ox

  • F.A.s liberated into blood stream = buildup within muscle and liver → dysfunction

  Myopathy + Cardiomyopathy

  Hepatic failure/Liver dysfunction (Reye Syndrome)

• Maternal liver disease → affected fetus can create issue in the mother w F.A build up

Fatty Acid Oxidation Defects: Etiologies

• Disease of the Carnitine pathway:

  • primary: defects in the protein pathways

  • secondary: nutrition deficiencies

• Disease of Fatty Acid B-Oxidization

L-Carnitine Amino Acid

• Binds to Acyl (organic +inorganic) residues (F.A) in the blood and enables transport into cells + their elimination → (why we supplement with Carnitine in Organic Acidemias: for their elimination w carnitine)

  • Long chain (>C12) needs it to get their long “acyl” chains into the inner mitochondria membranes where “Digestion” step + B-Ox can occur

Sources: we can make a-little, but not enough on its own

• Diet: Milk + meat

• Reabsorption: Kidneys via Caratine trnasporter protien

Carnitine Testing

• Plasma Carnatine levles: Free, unbound and Acyl-Cartines (boudn to Fas and organic acids)

• Plasma Acyl Carnatine prolei: quantity the diffrent types of bound-caratine resdiues

Fatty Acid Oxidation Defects: Key Concepts

• All Autosomal Recessive

• Spectrum of Severity

• Phenotypes vary but always have

  • Hypoketotic + Hypoglycemia

  • Myopathy and/or Cardiomyopathy

  • Liver failure (Reye Syndrome)

    • SCIDs can ocure fruently: overnight fast casues sudden hypoglycemi even that kills them

Fatty Acid Oxidation Defects: Therapy

Acute Illness/Fastine

• IV Dextrose (immediate)

• Carnitine (some FOADs): overdrive membrane import of FA and remove excess FAs

• Monitor for

  • hypoglycemia

  • liver failure

  • Muscle breakdown

Chronic

• Avoid prolonged fasting

  • frequent feedings: CORNSTARCH (McArdles?)

• Supplment with Medium-Chain-Triglycrides (“MCT”) oil <C10 for some (not MCAD/SCAD) → doesn’t need transporter or Digestion steps before B-Ox

• Supplment with L-Cartine for some (not LCHAD)

• Avoid liver toxic or carantine lowerin medication (valproic acid, salicylates, some anethetics)

Overview of FAOD Clinical Issues

OCTN2 Deficiencey: Metabolism

• OCTN1 and OCTN2 transport Carnitine across plasma membrane

  • OCTN1: Primarily in liver

  • OCTN2: Primarily in Muscle + Kidney

• No OCTN2 = No carnitine = Long F.A.s don’t undergo B-Oxidation in the Muscle

  • Also: Kidney→ not enough Carnitine is re-absorbed and therefore too much excreted = very low levels of carnitine

OCTN2 Deficiency

• Also called Primary Carnitine Uptake Defiencey

Etiology

• SLC22A5 gene mutation→ reduced Carn. uptake by Kidney +muscle→ low blood and muscle Carn+ Acyl-Carn

Can also just be caused by LOW-Diet CARTNATINE

OCTN2 Deficiency: presentation

Forms: Severe Infantile, Mild Child/late Onset

• Infancy:

  • Hypoketotic hypoglycemia

  • Liver failure

• Child:

  • Myopathy + Cardio myopathy

  • Liver affects are less: when Carn is severe enough, B-Ox affected through whole body → but Child type, Carn is enough to avoid defieciny inthe liver but not the rest of the body

• Late

  • mild myopathy or asymptomatic

OCTN2 Deficiency: Diagnosis

NBS: Low C0 and Acyl-Carnitine levels (Low level of ALL the species) → NEED TO TEST MATERNAL LEVELS AS WELL

Confirmation

• Carnitine and Acyl-Carnitine levels

• Enzyme activity: Fibroblasts

• Molecular: finds 70%

OCTN2 Deficiency: Treatment and outcome

Treatment

• high-dose Carn

• Avoid fasting

• IV Dextrose

Outcome

• Good if treated before severe decompensation

CPT 1+2 Deficiency: Metabolism

• CPT 1 and CPT2 present at outer and inner mitochondrial membrane

  • CPT1: Outer Mito membrane → Acyl-Coa + Carnitine = Acylcarnitine

    • High Free-Carn levels

    • Low Acylcarnitine levels

  • CPT 2: Inner Mito membrane

CPT1A Deficiency

• CPT1A → Liver

• CPT1B → Muscle

• CPT1C→ Brain

CPT1A gene mutation→ Low hepatic longer chain acyl carntine

CPT1A Deficiency: presenation

Early onset

• Hypoketotic + hypoglycemic

• Liver fialure with Fasting/illnes

CPT1A Deficiency: Diagnosis

NB: Elevated free Carn (C0) + Low long chain F.A.s (C0:C16 ratio increased

Confirmation

• Carnatine and Acylcarnitine levels

• Enzyme: Skin + CVS/Amnio

• Molecular: >90%

CPT1A Deficiency: Treatment+ Outcome

Treatment

• Avoid fasting→ frequent feedings +

• IV dextrose when Ill

• Cornstarch

• MCT Oil

• High Carb/low-fat diet

Outcome

• Good if severe decompensations prevented

• Maternal liver disease reported with CPT1A offspring

CPT2 and CACT Deifiecnies

• Bothe present very similarly

• Once Acyl-Coa + Carnitine = Acylcarnitine, it must be brought through the inner mitochondrial membrane via Carnitine Acylcartine Translocase (CACT)

  • CACT: exchanges Acycl carnitine in, free carnatine out of the membrane

• Acylcarnatine needs to be reconverted to Acyl-Coa via Carnitine palmibly-transferase II

  • Acyl-CoA needs to be liberated before it can enter into B-Oxidation

    When CPT2 or CACT is deficient, Acyl carnitine generated via CPT1 cannot be used and BUILDS UP

CPT2 and CACT Pathophysilogy

CPT2 or CACT gene mutation→ increased levels of long chain acyl-carnitine

CPT2 and CACT Def: Presentation

Very rare condition where symptoms begin IN UTERO: some energy deficit that can create dysmoprhic features at birth

Neonatal:

• Hypoketotic

• Liver fialure

• Cardiomyopathy

• Dymorphic feautres /renal cyts

Later onset form:

• EXCERISE INDUCED MUOPATHY (build up of Creatine Phospho Kinase)

CPT2 and CACT Def: Diagnosis

NBS: Elevated C16 and or C18:1 ratio (long to short F.A. chain ratio)

Confirmation: Only way to differienate the two

• Carnitine and

• Enzyme activity: Skin, Muscle, CVS/Amnio

• Molecular: >95%

CPT2 and CACT Def: Treatment + Outcome

Treatment:

• Avoid fasting with frequent feeding and IV Dextrose when Ill

• Cornstarch,

• MCT oil

• Carnitine,

• High-carb/low-fat diet

Outcomes

• Neonatal: Lethal

• Infantile: Variable

• Late: Myopathy is mild if treated

Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficeny

• VLCAD Drives the initial steps of fatty acid beta oxidation for the long chain fatty acids (>C14)

VLCAD Deficiency: Pathophysiology

• ACADVL mutation → Deficient C14-20 B-oxidation

• Generally more mild, later onset, exercise

VLCAD Def: Presentation

Infant:

• Hypoketoitic hypoglycemia

• Liver failure

• myopathy

• cardiomyopathy

Child: Cardio myopathy

Late: *******EXCERCISE MYOPATHY: WAY MORE COMMON FORM *****

VLCAD Def: Diagnosis

NBS: Elevated C14:1 ratio and longer chain Acyl-carnitine

Confirmation:

• Carnatine and AC

• Enzyme activity: Skin, white blood cell, aminotic fluid

• Moelcualr: 85-93%

VLCAD Def: Treatment + Outcome

Treatment:

• Avoid fasting with frequent feeding and IV dextrose when ill

• Cornstarch

• MCT Oil

• +/- Carnitine

• High-carb/low-fat diet

Outcome

• good if treated before severe decompensation

Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency

• Most common FAOD and the first to be added to NBS

• the meatbolism of C8-C10 length acyl-CoA Fatty Acid groups

  • These can move freely acros the inner mitocondrial memebrane WITH OUT then eed for Carnatine complex (so no Acylcarantine needed

• Once inside,C8-C10 Acyl-CoAs → *****BETA OXIDATION via MCAD****→ C4-C6 AcylCoAs

MCAD Deficiency = C8-C10 Buildup in blood and tissue + C8 Octanoyl Acycl Carainatase (Toxic)

MCAD Def: Pathophysiolo

ACADM gene mutation → lowered C6-C10 Fatty acid B-Oxidation = build up of C8-C10 in tissues

MCAD Def: Presentation:

Typical presentation at 3-24months old with Fasting/Illness

• Hypoketotic hypoglycemic

• Liver disease

• Often Sudden Infant Death syndrome→ usually the first personation you will see (sleeping longer through the night, greater chance for fasting affects to kick in)

MCAD Def: Diagnosis

NBS: Elevated C8, lesser C6 and C10 : (C8 >C6/C10)

Confirmation

• Carnitine

• AC

• uAG

• Enzyme activity: Skin, WBC, amino/CVS

• Molecualr: 90%

MCAD Def: Treatment + Outcome

Treatment

• Fasting with Frequent feeding and IV dextrose when ill

• Cornstarch

• +/- Carnitine

• High carb/low-fat diet

• ****NO MCT OIL!!!!****

Outcome

• Good if treated before severe decompensation

• Maternal liver disease reported (AFLP/HELLP)

Short Chain Acyl-CoA (SCAD) Deficiency

• C4-C6 Acyl-CoAs are B-Oxidized by SCAD activity

• Much more MILD production of Acetyl-Coa (C1)

SCAD Def: Pathophysiology

ACADS gene mutation→ deficient C4 +C6 fatty acid B-Oxidation

SCAD Def: presentation

• Incidence is not well known: Most SCAD inididuals are ASYMPTOMATIC

• Possible NEONATAL form

  • Ketotic hypoglycemia: lood gluclose can be low, but can still produce KETONE BODIES for energy→ B-Ox can still be done on longer chains FAs to produce Acytl CoAs (stopping at C4-C6)

  • Myopathy

  • Lethargy

  • Sizures

SCAD Def: Diagnosis

NBS: Elevated C4: BUT other IEM (like Organic Acidemias) also high C4 → Urine Organic Acid profiles can distinguish

Confirmation

• Carnitine and AC

• Urine Organic Acid Profile

• Enzyme activity: Skin

• Molecular: 100%

SCAD Def: Treatment + Outcome

Treatment

• Avoid fasting with frequent high-carb feeding and IV dextrose when ill

Outcome

• Good if treated before severe decompensation

• Maternal liver disease reported (AFLP/HELLP)

Long-Chain HydroxyAcy-CoA l Dehydrogenase (LCHAD) or Tri-Function Protein Deficiency

• TFP is involved in the B-Oxidation of a number of long-chain FAs

  • when Deficient: inability to metabolize long chain Acyl-Coa molecules

LCHAD/TFP Def: Pathophysiology

LCHAD gene mutation:

CHAD/TFP Def: Presentation

Typical presentation in Infancy

• Hypoketotic hypoglycemia

• Myopathy

• Cardiomyopathy

• Liver deiase

  • c16-oh and c18 elevated = pigmented retinopathy + neuropathy, MANY SCIDS cases

CHAD/TFP Def: Diagnosis

NBS: Elvated C16-OH w

Confrimation

• Carnatine and AC

• Enzyme acitivty: Skin, WBC

• Molecular: HADHA gene

CHAD/TFP Def: Treatment + Outcome

Treatment

• Avoid fasting with frequent feedings and IV dextrose when ill

• Cornstarch

• MCT oil

• High-carb/low-fat diet

• ******NO CARNITINE ******

Outcome:

• Believed to be good if treated before severe decompensation

  • MOST PREVELANT FOAD found in Mom’s who devlope liver dysfunction with fetus’s thatare affected with FOAD