A predetermined protocol with specific algorithms that achieves a prompt diagnosis of long chain fatty acid oxidation disorder (LCFAOD) may translate into better management of the acute metabolic crisis, according to an article recently published in the European Journal of Human Genetics

“As such, differential diagnosis of FAOD remains important, to initially recognize symptoms and later to account for possible normal biochemical testing that may occur when blood samples are collected from patients not in catabolism,” the authors wrote. 

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This review and viewpoint article based its conclusions on 10 different publications regarding LCFAOD and other fatty acid oxidation diseases. The result is 3 different algorithms, including a proposed screening, diagnosis, and management according to the age group. 

For example, in patients of 2 years of age or under, hypoketotic hypoglycemia, hyperammonemia, hepatic failure, cardiac symptoms or diseases, and/or congenital malformations such as neuronal migration defects and renal cysts should raise suspicion for LCFAOD. 

Other clinical presentations with less specific symptoms, including hypotonia, failure to thrive, and motor or language delay without a clear cause, may also be suggestive of mitochondrial fatty acid oxidation disorders. Moreover, fatty liver during pregnancy and HELLP syndrome are noteworthy maternal history elements. 

Once identified a fatty acid oxidation disorder is a possible diagnosis, determining the levels of free and total carnitine is the first step, followed by the plasma lactate, lactate/pyruvate ratio, and another laboratory testing, finalizing in DNA tests as the definite diagnostic tool. 

Regarding children of 2 to 11 years of age, severe hypoketotic hypoglycemia and cardiac symptoms are the most common presentations. After drawing an acylcarnitine profile, the next step depends on whether the patient has an abnormal riboflavin characteristic profile and free carnitine levels. If the acylcarnitine profile is normal, plasma lactate or creatinine kinase levels should be assessed depending on the clinical picture of each patient.  

Finally, in individuals 11 years or above, exercise intolerance is the most frequent presenting symptom. If the acylcarnitine profile is abnormal, the algorithm is similar to that for patients between 2 and 11 years of age. On the other hand, for all patients with a normal acylcarnitine profile but positive ketones, drawing the plasma levels of creatinine kinase is the best next step. 

“Through the reduction of hospitalization rates due to acute metabolic decompensations, prompt and accurate referrals will also reduce burdens on local hospitals and associated costs to patients who do not receive appropriate treatment,” the authors concluded. 


Vianey-Saban C, Fouilhoux A, et al. Improving diagnosis of mitochondrial fatty-acid oxidation disorders. Eur J Hum Genet. Published online January 5, 2022. doi:10.1038/s41431-022-01260-1