Table 2.

Genes of Interest in the Differential Diagnosis of Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Gene(s)DisorderMOIFeatures of Disorder
Clinical characteristicsLaboratory findings
Disorders of fatty acid beta-oxidation
ACADS Short-chain acyl-CoA dehydrogenase (SCAD) deficiency ARClinically benign biochemical phenotype 1Acylcarnitines demonstrate ↑ of C4-acylcarnitines (butyrylcarnitine), distinguishing this disorder from MCAD deficiency.
ACADVL Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency ARMay present similarly to MCAD deficiency w/hypoketotic hypoglycemia, liver dysfunction, & liver failure, but is clinically distinct w/presence of significant rhabdomyolysis & cardiomyopathy not seen in MCAD deficiency.Plasma acylcarnitines demonstrate ↑ of C14-, C14:1-, C16-, & C16:1-acylcarnitines, distinguishing this disorder from MCAD deficiency.
EFTA
EFTB
ETFDH 		Multiple acyl-CoA dehydrogenase deficiency (MADD)ARComplex disorder w/presentations ranging from neonatal w/complex congenital abnormalities & dysmorphism to hypoketotic hypoglycemia, cardiomyopathy, & rhabdomyolysis in later-onset presentations.
  • Acylcarnitines demonstrate variable ↑ of C4-, C5-, C5DC-, C6-, C8-, C10:1-, C12-, C14-, C14:1-, C16-, C16:1-, C16-OH-, C16:1-OH-, C18-, C18:1-, C18-OH-, & C18:1-OH-acylcarnitines.
  • ↑ of diagnostic biochemical markers may incl glutaric acid, 3-hydroxyisovaleric acid, lactic acid, medium- & long-chain dicarboxylic acids, & glycine species such as isovalerylglycine, isobutyrylglycine, & 2-methylbutyrylglycine.
  • Ketone bodies incl acetoacetic acid & 3-hydroxybutyric acids are minimal or undetectable, distinguishing this disorder from MCAD deficiency.
HADHA
HADHB 		Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency / trifunctional protein (TFP) deficiency ARMay present similarly to MCAD deficiency w/hypoketotic hypoglycemia, liver dysfunction, & liver failure, but are clinically distinct w/presence of significant rhabdomyolysis & cardiomyopathy as well as peripheral neuropathy & retinopathy not seen in MCAD deficiency.Plasma acylcarnitines demonstrate ↑ of C16-OH-, C16:1-OH-, C18-OH-, & C18:1-OH-acylcarnitines, distinguishing these disorders from MCAD deficiency.
Carnitine transport disorders
SLC22A5 Systemic primary carnitine deficiency (carnitine uptake defect)ARBroad clinical spectrum; may present w/decompensation similar to MCAD deficiency (hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, ↑ liver transaminases, & hyperammonemia triggered by fasting or common illnesses) or w/childhood myopathy, pregnancy-related low stamina, cardiac arrythmia, or fatiguePlasma total & free carnitine levels are low, distinguishing this disorder from MCAD deficiency.
CPT1A Carnitine palmitoyltransferase (CPT) 1A deficiency ARDoes not present w/cardiomyopathy or skeletal myopathyPlasma total & free carnitine levels are ↑, w/↓ levels of long-chain acylcarnitines & an ↑ C0/(C16+C18) ratio, distinguishing this disorder from MCAD deficiency.
CPT2 Carnitine palmitoyltransferase (CPT) II deficiency ARIn addition to the more commonly known adult form, persons may develop a severe infantile hepatocardiomuscular form of the disorder.Plasma acylcarnitine analysis demonstrate ↑ of C16-OH-, C16:1-, C18-, & C18:1-acylcarnitines, distinguishing this disorder from MCAD deficiency.
SLC25A20 Carnitine-acylcarnitine translocase (CACT) deficiency ARMay be clinically indistinguishable from CPT II deficiencyMay be biochemically indistinguishable from CPT II deficiency; CACT deficiency & CPT II deficiency have identical ↑ of C16-OH-, C16:1-, C18-, & C18:1-acylcarnitines, distinguishing both from MCAD deficiency.
Other causes of a Reye-like syndrome (selected examples)
ALDOB Hereditary fructose intolerance ARFollowing dietary exposure to fructose, sucrose, or sorbitol, symptoms of nausea, vomiting, & abdominal distress as well as chronic growth restriction / failure to thrive manifest.Following dietary exposure to fructose, sucrose, or sorbitol, hypoglycemia, lactic acidemia, hypophosphatemia, hyperuricemia, hypermagnesemia, & hyperalaninemia can present.
ARG1
ASL
ASS1
CPS1
NAGS
OTC
SLC25A13
SLC25A15 		Urea cycle disorders (NAGS, CPS1, OTC, ASS1, ASL, ARG1, ORNT1, & citrin deficiencies)AR
XL 2		Can be assoc w/acute neonatal encephalopathy w/hyperventilation & hypothermia, Reye-like syndrome, migraines, recurrent vomiting, protein avoidance, or unexplained "cerebral palsy"More significant hyperammonemia & normal plasma acylcarnitine profile, distinguishing this disorder from MCAD deficiency.

AR = autosomal recessive; ARG1 = arginase; ASL deficiency = argininosuccinic aciduria; ASS1 deficiency = citrullinemia type I deficiency; CPS1 = carbamoylphosphate synthetase I; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; NAGS = N-acetylglutamate synthase; ORNT1 = ornithine translocase; OTC = ornithine transcarbamylase; XL = X-linked

1.

Most infants with SCAD deficiency identified through newborn screening have remained well, and asymptomatic relatives who meet diagnostic criteria have been reported. Thus, SCAD deficiency is now viewed as a clinically benign biochemical phenotype rather than a disease.

2.

OTC deficiency is inherited in an X-linked manner; deficiencies of NAGS, CPS1, ASS1, ASL, ARG1, ORNT1, and citrin are inherited in an autosomal recessive manner.

From: Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

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