Fatty Acid Oxidation Disorders

Question 1

What condition is NOT part of the
Newborn screening?

A) Pompe disease (GSD type II)
B) Classic Galactosemia
C) MCAD deficiency
D) Hereditary fructose intolerance
E) Primary carnitine deficiency

Answer 1

D

Question 2

What are the ranges for short-long chain fatty acids?

Answer 2

Very long chain: > C21
Long chain fatty acids: C13-C21
Medium chain: C6-C12
Short chain: < C6

Question 3

What are the 3 main classes of esters of fatty acids?

Answer 3

Fatty acids are found as 3 main classes of esters: triglycerides (most common),
phospholipids, and cholesterol esters

Question 4

What happens in the beta oxidation pathway?

Answer 4

Beta oxidation is a spiral pathway:

• Each turn of the spiral involves 4 steps
  and shortens the acyl-CoA by 2 carbons
• Dehydrogenation reactions linked with
  FAD and NAD
• The enzymes for long chain substrates
  are membrane-bound

Question 5

What is the inheritance pattern of fatty acid oxidation disorders? What can we see in these conditions?

Answer 5

Autosomal recessive

• All can present with hypoketotic
  hypoglycemia
• Major role in energy production during fasting

Question 6

Primary Carnitine deficiency

Answer 6

Gene: SLC22A5

• Low free and total carnitine
• Not treated cardiomyopathy and arrhythmia
• NBS: Can be missed because mother transfer the carnitine to baby through the placenta
• Mother with condition risk of sudden death, false positive NBS. DNA testing child and mother
• DNA used to miss. C.-149G>A 5’ UTR for a KOZAK sequence 20% of pathogenic variants

Question 7

Where do we get carnitine from?

Answer 7

Meat – so diet, but can be supplemented. Common deficiency during pregnancy, especially in vegetarian mothers

Question 8

Carnitine transporter deficiency

Answer 8

• Common in Faroe Islands
• Genetic founder effect (variant p.N32S)
• Young individuals with sudden death
• Long QT syndrome and cardiac arrhythmia

Question 9

CPT1A deficiency

Answer 9

• Activation of carnitine
• Isoforms A liver
• Fasting induced hepatic encephalopathy, hypoglycemia, liver failure, failure to thrive
• Diagnosis: elevated carnitine level with low C16, C18 (increase C0/(C16+C18)). Free carnitine normal or high level.
• Can be detected by NBS, DNA testing

Question 10

What is management for CPT1A deficiency?

Answer 10

• Therapy
• Severe, low fat diet, MCT oil/triheptanoin
• Monitor liver function tests
• Carnitine level Normal in plasma and
  abnormal in RBC
• Isoform B heart and skeletal muscle
• Isoform C brain p.R37C AD spastic paraplegia-73

Question 11

Carnitine acylcarnitine translocase
deficiency CACT

Answer 11

Gene: SLC25A20

• Present arrythmia
• Diagnosis increased C16, C18, C18:1, C18:2, low C0
• Therapy: fasting avoidance, low fat diet, MCT oil

Question 12

Common manifestations of fatty acid oxidation disorders

Answer 12

See table

Question 13

What genes are associated with fatty acid oxidation disorders?

Answer 13

See table

electron transfer defects, low yield

Question 14

True or false: VLCAD is part of NBS

Answer 14

True; confirm with molecular testing right after abnormal biochemical testing

Question 15

CPT2 deficiency

Answer 15

• Rhabdomyolysis
• Muscle cramps and myoglobinuria
• Very rare, except myopathic form
• Lethal neonatal with congenital anomalies
• Severe infantile, hypoglycemia, seizures, cardiomyopathy, arrhythmias
• Diagnosis: increased C16, C18, C18:1, C18:2 in plasma
• Therapy: avoidance of fasting, MTC oil/triheptanoin, sugary drinks with exercise
• Monitor: ALT, AST, CK, ACP, F/T carnitine
• Myopathic good prognosis
• Late-onset, missed in NBS

Question 16

VLCADD

Answer 16

*Gene: ACADVL

• Detected on NBS but can be missed
• ACP: high C16:1, C14:2, C14:1, C18:1, C12:1
• F&T carnitine: sometimes low.
• UOA: variable dicarboxylic aciduria.
• Elevated CK, LFTs
• Ammonia can be elevated
• Fibroblast and leukocyte enzyme activity also available.

Question 17

What are clinical findings in VLCADD?

Answer 17

Cardiomyopathy, arrythmia
Sudden death
Seizures, lethargy, coma
Intermittent rhabdomyolysis, muscle cramps, exercise intolerance
Nausea or vomiting, hepatomegaly, ‘Reye’ like syndrome
Hypoketotic hypoglycemia

Question 18

LCHADD or TFPD

Answer 18

Genes: HADHA and HADHB

• Detected on NBS
• ACP: elevated C16-OH +/- and C18:1-OH
• F&T carnitine: sometimes low.
• UOA: variable dicarboxylic aciduria, 3-OH saturated and unsaturated fatty acids.
• Elevated CK, LFTs
• Ammonia, uric acid can be elevated
• LCHAD is part of a trifunctional protein (TFP).
• Mutations can abolish all 3 functions or only
  LCHAD activity.
• TFP is composed of 4 alpha and 4 beta
  subunits. The alpha has LCHAD activity

Question 19

What are clinical findings of LCHADD or TFPD?

Answer 19

Sudden death
Seizures, peripheral neuropathy
Hypotonia and weakness
Retinitis pigmentosa
Hepatomegaly with liver dysfunction, ‘Reye’ like syndrome
Hypoketotic hypoglycemia, coagulopathy
Lethargy, coma, developmental delay
Severe cardiomyopathy

*Mom’s with HELLP syndrome - check fetus for LCHADD

Question 20

MCADD

Answer 20

Gene: ACADM

• Most common fatty acid oxidation disorder
• Detected on NBS
• ACP: elevated C6, C8, C10:1
• Elevated CK, LFTs

Question 21

What are clinical findings or MCADD?

Answer 21

Lethargy, coma
Sudden death
Seizures
Hypoketotic hypoglycemia

Question 22

SCHADD

Answer 22

Gene: HADH

• Detected on NBS but can be missed
• Elevated LFTs
• ACP: high C4-OH
• F&T carnitine: sometimes low.
• UOA: 3-hydroxyglutaric, DCA

Question 23

What are clinical findings of SCHADD?

Answer 23

Lethargy, coma
Sudden death
Seizures, encephalopathy
Hypoketotic hypoglycemia
Hepatomegaly, hyperinsulism

Question 24

Electron Transfer Defect Syndrome:

Answer 24

MADD

Question 25

MADD

Answer 25

Genes: ETFA, ETFB, ETFDH * Glutaric acidemia type 2 * Detected on NBS but can be missed * ACP: ↑ C4 + C5, C6, C8, C10, C12 * F&T carnitine: sometimes low. * UOA: Ethylmalonic, glutaric, 2-hydroxyglutaric, DCA * Elevated LFTs * Neonatal onset: exclude riboflavin deficiency, DNA testing ETFA> ETFB> ETFDH. * Late onset * Therapy: avoid fasting, prompt treatment infection, low fat diet, ketones, riboflavin (100-300 mg/day)

Question 26

What are clinical findings of MADD?

Answer 26

Cardiomyopathy, arrythmia Lethargy, coma Intermittent rhabdomyolysis, muscle cramps, exercise intolerance Sudden death Seizures, encephalopathy, lethargy, coma Hypoketotic hypoglycemia Hepatomegaly

Question 27

What is treatment of FAODs?

Answer 27

* Frequent feeds if tolerating * Infusion D10 at 1.5x maintenance * Oral or IV carnitine if low (caution) * Avoid intralipids and propofol, valproic acid * Diazoxide for hyperinsulism * Triheptanoin for VLCAD, LCHADD, TFD * MCT oil for VLCAD, LCHADD, TFD

Question 28

Treatment of nonketotic hypoglycemia

Answer 28

* Dextrose infusion: 5-10 mg/kg/min adjust to maintain glucose > 75mg/dl. * Control hyperammonemia * Reduction of fever to < T 38 C * IV carnitine: controversial * IV antibiotics if needed

Question 29

Avoidance of fasting for FAODs

Answer 29

* 1st year of life: not over 1 hour per kilogram of baby’s body weight up to 8 hours. – 0-4 months: 4 hours – 5-8 months: one additional hour per month. * If breastfeeding back up milk. * Older children and adults: 8-12 hours. * Cornstarch – Start: 1 year of age if symptoms – Dosage: 1g/kg/d

Question 30

Treatment for rhabdomyolysis for FAODs

Answer 30

* Dextrose infusion * Full hydration * Diuresis with possible alkalinization of the urine * If life-threatening consider intubation, ventilation, and paralysis to decrease muscle work * Dialysis if severe kidney failure

Question 31

Diet for FAODs

Answer 31

* Reduced the percentage of fat intake depending on condition and age * Tritheptanoin aka Dojolvi is a triglyceride with 3 medium-chain odd-carbon fatty acids (C7). Bypass the enzymatic defects associated with the LC-FAODs to provide energy and acetyl-CoA. * MCT oil is present in multiple formulas and foods * Avoid essential fatty acid deficiency due to restrictions

Question 32

Triheptanoin treatment

Answer 32

* Dojolvi is a triglyceride with 3 medium-chain odd-carbon fatty acids (C7). * Anaplerotic effect via propionyl-CoA production and conversion to succinyl-CoA. * Recommended target daily Dojolvi dose is up to 35% of daily caloric intake, divided into 4 or more doses per day and given with a meal or snack.