Table 5.

Genes of Interest in the Differential Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency

Gene(s)DiffDx DisorderMOIFeatures of DiffDx DisorderDistinguishing Features
BCKDHA
BCKDHB
DBT 		Maple syrup urine disease (MSUD) types 1 & 2 ARAge 12-24 hrs. Maple syrup odor in cerumen, ↑ plasma concentrations of BCAAs 2 & allo-isoleucine, & generalized disturbance of plasma amino acid concentration ratios
Age 2-3 days. Ketonuria, irritability, & poor feeding
Age 4-5 days. Deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, & stereotyped movements (e.g., "fencing" & "bicycling")
Age 7-10 days. Possible coma & central respiratory failure
  • DLD deficiency causes MSUD type 3 & can typically be differentiated from MSUD types 1 & 2 by the presence of severe lactic acidosis, α-ketoglutarate excretion in urine, & liver involvement in DLD deficiency
  • The maple syrup odor frequently assoc w/MSUD types 1 & 2 is not typically assoc w/DLD deficiency.
BOLA3
IBA57
LIAS
LIPT1
NFU1 		Defects in lipoic acid metabolism (OMIM 605711, 614299, 614462, 615330, 616299)ARNeonatal lactic acidosis & a biochemical phenotype similar to DLD deficiency 3Unlike DLD deficiency, children w/defects in lipoic acid metabolism (except LIPT1 deficiency) have ↑ glycine in body fluids.
DLAT
DLD
PDHA1
PDHB
PDHX
PDK3
PDP1 		Primary pyruvate dehydrogenase complex deficiency AR
XL 4		Most commonly presents w/neurologic impairment, hypotonia, structural brain abnormalities, & lactic acidosis w/a normal lactate:pyruvate ratio 1While clinical findings & preliminary lab values are similar, DLD deficiency is often also assoc w/: (a) defective αKGDH w/↑ urine α-ketoglutarate & (b) BCKDH complex dysfunction w/↑ plasma BCAAs & urine branched-chain ketoacids.

αKGDH = α-ketoglutarate dehydrogenase; AR = autosomal recessive; BCAA = branched-chain amino acid; BCKDH = branched-chain α-ketoacid dehydrogenase; DD = developmental delay; DiffDx = differential diagnosis; DLD = dihydrolipoamide dehydrogenase; MOI = mode of inheritance; PDH = pyruvate dehydrogenase; XL = X-linked

1.
2.

Leucine, isoleucine, and valine

3.

Lipoic acid is the essential cofactor attached to the E2 subunits of BCKDH, αKGDH, and PDH as well as to the H protein of the glycine cleavage system (see Glycine Encephalopathy) [Cameron et al 2011, Mayr et al 2011, Navarro-Sastre et al 2011, Ajit Bolar et al 2013, Haack et al 2013, Soreze et al 2013, Tort et al 2014].

4.

PDHA1- and PDK3-related primary pyruvate dehydrogenase complex deficiency (PDCD) are inherited in an X-linked manner. Primary PDCD caused by pathogenic variants in DLAT, DLD, PDHB, PDHX, or PDP1 is inherited in an autosomal recessive manner.

From: Dihydrolipoamide Dehydrogenase Deficiency

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