Fatty Acid Oxidation Disorders Flashcards
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
D
What are the ranges for short-long chain fatty acids?
Very long chain: > C21
Long chain fatty acids: C13-C21
Medium chain: C6-C12
Short chain: < C6
What are the 3 main classes of esters of fatty acids?
Fatty acids are found as 3 main classes of esters: triglycerides (most common),
phospholipids, and cholesterol esters
What happens in the beta oxidation pathway?
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
What is the inheritance pattern of fatty acid oxidation disorders? What can we see in these conditions?
Autosomal recessive
- All can present with hypoketotic
hypoglycemia - Major role in energy production during fasting
Primary Carnitine deficiency
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
Where do we get carnitine from?
Meat – so diet, but can be supplemented. Common deficiency during pregnancy, especially in vegetarian mothers
Carnitine transporter deficiency
- Common in Faroe Islands
- Genetic founder effect (variant p.N32S)
- Young individuals with sudden death
- Long QT syndrome and cardiac arrhythmia
CPT1A deficiency
- 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
What is management for CPT1A deficiency?
- 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
Carnitine acylcarnitine translocase
deficiency CACT
Gene: SLC25A20
- Present arrythmia
- Diagnosis increased C16, C18, C18:1, C18:2, low C0
- Therapy: fasting avoidance, low fat diet, MCT oil
Common manifestations of fatty acid oxidation disorders
See table
What genes are associated with fatty acid oxidation disorders?
See table
electron transfer defects, low yield
True or false: VLCAD is part of NBS
True; confirm with molecular testing right after abnormal biochemical testing
CPT2 deficiency
- 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
VLCADD
*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.
What are clinical findings in VLCADD?
Cardiomyopathy, arrythmia
Sudden death
Seizures, lethargy, coma
Intermittent rhabdomyolysis, muscle cramps, exercise intolerance
Nausea or vomiting, hepatomegaly, ‘Reye’ like syndrome
Hypoketotic hypoglycemia
LCHADD or TFPD
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
What are clinical findings of LCHADD or TFPD?
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
MCADD
Gene: ACADM
- Most common fatty acid oxidation disorder
- Detected on NBS
- ACP: elevated C6, C8, C10:1
- Elevated CK, LFTs
What are clinical findings or MCADD?
Lethargy, coma
Sudden death
Seizures
Hypoketotic hypoglycemia
SCHADD
Gene: HADH
- Detected on NBS but can be missed
- Elevated LFTs
- ACP: high C4-OH
- F&T carnitine: sometimes low.
- UOA: 3-hydroxyglutaric, DCA
What are clinical findings of SCHADD?
Lethargy, coma
Sudden death
Seizures, encephalopathy
Hypoketotic hypoglycemia
Hepatomegaly, hyperinsulism
Electron Transfer Defect Syndrome:
MADD
MADD
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)
What are clinical findings of MADD?
Cardiomyopathy, arrythmia
Lethargy, coma
Intermittent rhabdomyolysis, muscle cramps, exercise intolerance
Sudden death
Seizures, encephalopathy, lethargy, coma
Hypoketotic hypoglycemia
Hepatomegaly
What is treatment of FAODs?
- 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
Treatment of nonketotic hypoglycemia
- 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
Avoidance of fasting for FAODs
- 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
Treatment for rhabdomyolysis for FAODs
- 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
Diet for FAODs
- 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
Triheptanoin treatment
- 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.
