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Long chain Hydroxy Acyl-CoA Dehydrogenase Deficiency

INTRODUCTION   

LCHADD is caused by a defect in the intramitochondrial b-oxidation of fatty acids. It can cause severe hypoketotic hypoglycemia, lethargy, liver dysfunction with hepatomegaly, clotting defect, metabolic acidosis, hyperammonemia cardiomyopathy, and sudden death.

PATHOPHYSIOLOGY  

The pathophysiological process begins with reduced glucose intake as a result of, a fasting state or increased energy needs from a catabolic state (infection, stress, fever, etc...) not sufficiently provided for by caloric intake. The resulting hypoglycemia leads to mobilization of free fatty acids (FFAs) which enter the mitochondria via the carnitine cycle. In the mitochondria, as shown in the diagram above, the fatty acids in the hydroxy form are normally oxidized to acetyl-CoA which is used to produce the ketones that can supply the energy needs to compensate for the lack of adequate glucose. A deficiency of LCHAD however, prevents this. The block at LCHAD also results in the accumulation of fatty acid intermediates that inhibit gluconeogenesis (thus preventing endogenous glucose production), have a toxic effect on the liver and produce metabolic (including lactic) acidosis. Muscle, particularly myocardium, requires a lot of energy and, therefore, becomes functionally impaired resulting in lethargy, hypotonia and cardiomyopathy.

PRESENTATION   

Affected infants and children usually present by 2 years of age and neonatal cases do occur.
LCHADD is frequently precipitated by intercurrent illnesses and may present with the following:
- Hypotonia and weakness
- lethargy
- hypoglycemia, with absense or 'trace' ketones
- seizures
- hepatomegaly with liver dysfunction (rarely liver failure or cirrhosis)
- coagulopathy
- cardiomyopathy
- 'Reye' like syndrome
- developmental delay
- peripheral neuropathy
- retinitis pigmentosa
- coma
- sudden death

Children or their sibs affected with fatty acid oxidation disorders have often been misdiagnosed as having Reyesyndrome or idiopathic cardiomyopathy; some who have died have also been labelled as SIDS deaths. Suchfamily history should be viewed as suspicious for FAOD.

NOTE that in the acute crises, patients can be seriously ill WITHOUT hypoglycemia, although typically FAOD crises are associated with hypoglycemia. At these times the urine typically tests 'absent' or 'small' for thepresence of ketones. Liver function tests may be mildly elevated; hyperammonemia and hyperuricemia areoften present during acute episodes.

DIAGNOSIS   

ASSESSMENT
Assess for cardiorespiratory stability, dehydration, fever, infection or any other physical stress or (e.g. surgery), as a potential precipitant for metabolic decompensation. Assess hepatic and neurological status.

INVESTIGATIONS
- On admission to the ER, a dextrostix should be obtained.
- If the patient is symptomatic, including lethargy
Obtain the following:
- Blood glucose
- Electrolytes, CO2 and blood gas
- Ammonia (1.5 ml blood in sodium-heparin tube (green top tube). Ammonia specimen must be immediately
  put on ice and walked to the laboratory. Delay in this process causes an artifactual elevation in ammonia).
- Lactate
- LFTs (AST, ALT, AlkPO4, bilirubin)
- Clotting studies (PT, PTTK)
- EKG and CXR for preliminary cardiac assessment. Cardiomyopathy is often present. If there is a past
  history of cardiomyopathy or current cardiac concerns, cardiology services should be notified immediately
  for emergency evaluation and input for management.
- All other relevant tests e.g. for infection, dehydration, other pathologies. If diagnosis unclear, obtain
  DURING THE ACUTELY SICK PHASE a newborn screening spot for tandem mass spectrometry, plasma
  amino acids and acyl carnitines (require 2 ml blood in green or red top tube) and urine for organic acids and
  acyl glycines. These will provide a diagnostic pattern of results.

THERAPY  

ER TREATMENT

1. If the patient is not hypoglycemic, is drinking oral fluids well and is mentally alert and oriented
    there is no need for emergent intravenous infusion. If the patient is acutely stressed however, high
    carbohydrate fluids (apple juice, Kool-Aid etc...) must be consumed PO frequently and glucose status
    monitored periodically. If ALL these criteria are not met, intravenous fluids containing 10% glucose should
    be used. This will not only prevent hypoglycemia but also counter catabolism by reducing lipolysis and the
    subsequent accumulation of toxic free fatty acid metabolites.

2. In the event of a low dextrostix or glucose value, lethargic or comatose
    - Insert an IV
    - Measure blood glucose, acid/base levels, and ammonia
    - Push D25W (2ml/kg)
    - Follow with a continuous 10% glucose infusion at 1.5x maintenance, to provide 7- 8mg/kg/min glucose.
    - If metabolic acidosis present, administer IV sodium bicarbonate (1 mEq/ml)

3. The use of L-carnitine in the treatment of longer chain fatty acid disorders remains controversial.
    Carnitine will bind fatty acyl-CoA compounds; theoretically it facilitates their excretion and 'neutralizes' the
    effect of the long chain fatty acid. However there are concerns about the safety of excessive long chain
    acyl-carnitines, especially their potential for inducing arrhythmia's. Where carnitine deficiency is not severe,
    it is probably advisable to avoid its use.

4. A cardiology assessment is necessary to properly evaluate a child with acute symptomatic LCHADD
   (specifically for heart failure or pericardial effusion).

5. Any precipitating factor (e.g. infection) for the metabolic crises should be treated aggressively to help
   minimize further catabolism.

ADMISSION
      -  Children stressed, symptomatic or unable to take fluids by mouth should be prophylactically given 10%
         dextrose at 1.2-1.5x maintenance infusion rates so that glucose remains >100mg/dl.
       - Blood glucose and acid/base status should be monitored regularly. If the child is physically stressed
         keep the blood sugar levels elevated (glucose levels should be kept between 120-170 mg/dl)

RECOVERY

LCHADD chronic management is complicated as many children take a significant amount of time (days to
weeks) to improve clinically even once their biochemical parameters have normalized. Particular problems
include improvement in mental status, hypotonia, hepatomegaly and cardiomyopathy. It is important to be
aware that despite therapy children with LCHADD have died or been left with chronic neurologic, cardiac and
hepatic problems. though the long term prognosis for children with LCHADD is unclear treatment can be
optimized by:

     - avoidance of fasting (this may include complex carbohydrate in the form of cornstarch supplementation to
       get through the night as the child gets older)
     - high carbohydrate/low fat intake
     - Early detection of physiologic stresses inc. infection, surgery with especial attention to REGULAR
       feedings/source of glucose AROUND the clock.
     - Regular review by cardiology and opthalmologic services. Note that the pregnant mother carrying a fetus
       with LCHADD is at risk for the HELLP syndrome (hemolysis, elevated liver enzymes and low platelets
       and should be closely followed up for counselling and antenatal care for future pregnancies as there will
       be a 25% risk of future pregnancies having an affected LCHADD fetuses.

Any questions about the patient or this protocol please call or have paged the Genetics/Metabolism
Fellow-on-call or, failing this, the Metabolic attending on call at your hospital or nearest pediatric tertiary
care center.

Additional information may be obtained via OMIM at http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?600890#TEXT