Differential Diagnosis

Disorders of Riboflavin Metabolism Disorders of riboflavin metabolism can mimic multiple acyl-CoA dehydrogenase deficiency (MADD) (both biochemically and clinically) or have overlapping phenotypic features with MADD and should be considered as the primary differential diagnoses. With frequent use of exome sequencing, it is postulated that many individuals diagnosed with MADD of unknown genetic etiology will be identified as having a genetic alteration associated with a disorder of riboflavin metabolism. Cellular uptake of riboflavin is mediated by the transmembrane proteins hRFVT1, hRFVT2, and hRFVT3 (encoded by SLC52A1, SLC52A2, and SLC52A3, respectively). Riboflavin is then converted to the coenzyme flavin mononucleotide by riboflavin kinase and then to flavin adenine dinucleotide (FAD) by FAD synthase (encoded by FLAD1). FAD is a cofactor for electron transfer by the ETF/ETFDH complex from oxidations of fatty acids and some amino acids to the electron transport chain in the inner mitochondrial membrane . If FAD biogenesis is deficient, electron transfer by the ETF/ETFDH complex is compromised, which can result in a clinical presentation mimicking that of MADD (as MADD is caused by impairment of the ETF-ETFDH complex itself; see ). summarizes disorders of riboflavin metabolism presenting as MADD or with overlapping phenotypic features with MADD that should be considered in the differential diagnosis. Table 2. Riboflavin Metabolism Disorders to Consider in the Differential Diagnosis of MADD

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"

Clinical Guidance

Avoid the following:

• Fasting, including periods of preparation and recovery from planned surgery or anesthesia

• Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

• Inadequate calories following vaccination. Vaccination is safe.

• Dehydration (risk for rhabdomyolysis and acute renal failure)

• High-fat, high-protein diet, including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet

• Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. However, a combination of low-dose propofol, fentanyl, and nitrous oxide was used successfully in an individual with MADD .

• Administration of intravenous intralipids during an acute metabolic crisis

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"

Therapies Under Investigation

There are few experimental therapies for MADD. Only a few case reports are available to support their utility:

• Sodium D,L-3 hydroxybutyrate (NaHB). Favorable outcome after ketone body treatment has been reported . Ketone bodies not only replace the missing endogenous energy supply but also provide building blocks for myelin synthesis in the brain. Hence, it may be helpful in re-myelination as well as cardiomyopathy .

• Bezafibrate. Bezafibrate is a hypolipidemic drug and an agonist of peroxisome proliferating activator receptor. It increases expression of several enzymes involved in mitochondrial fatty acid oxidation. Bezafibrate was reported to have favorable outcome on acylcarnitine profile in one affected individual and on skin fibroblasts from 12 people with MADD .

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"