Table 2.

Genes of Interest in the Differential Diagnosis of Primary Pyruvate Dehydrogenase Complex Deficiency

Gene(s)DisorderMOIClinical Findings & Brain MRILaboratory Findings
Disorders assoc w/secondary PDCD that are phenotypically similar to primary PDCD
BOLA3
IBA57
ISCA1
ISCA2
NFU1
PMPCB 		Multiple mitochondrial dysfunction syndromes (OMIM PS605711)ARLeigh syndrome, seizures, spasticity, & mvmt disorder; unlike primary PDCD, MMDS is assoc w/optic atrophy, cardiomyopathy, leukodystrophy.Neonatal lactic acidosis; ↓ PDC enzyme activity in at least fibroblasts & skeletal muscle cells for some; unlike primary PDCD, MMDS is assoc w/↑ glycine & electron transport chain enzyme activity deficiencies.
ECHS1 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D)ARLeigh syndrome, long philtrum, & episodic dystonia; may be a complete phenocopy of primary PDCD 1; corpus callosum dysgenesis/agenesisLactic acidosis & & ↑ pyruvate (lactate:pyruvate ratio may be nl); unlike primary PDCD, ECHS1D may be assoc w/abnl acylcarnitine profile or ↑urine organic acid w/marked 2-methyl-2,3-dihydroxybutyric acid.
HIBCH 3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) (OMIM 250620)ARLeigh syndrome & long philtrum; corpus callosum dysgenesis/agenesisLactic acidosis & ↑ pyruvate (lactate:pyruvate ratio may be nl); unlike primary PDCD, HIBCHD may be assoc w/abnl acylcarnitine profile or urine organic acids.
LIAS Hyperglycinemia, lactic acidosis, and seizures (OMIM 614462)AREpileptic encephalopathy, lactic acidosisLactic acidosis & ↑ pyruvate (lactate:pyruvate ratio may be nl or ↑); ↓ PDC enzyme activity (muscle, fibroblasts); unlike primary PDCD, lipoic acid synthesis defects are assoc w/↑ glycine & electron transport chain enzyme activity deficiencies.
LIPT1 Lipoyltransferase 1 deficiency (LIPT1D; OMIM 616299)
LIPT2 Lipoyltransferase 2 deficiency (OMIM 617668)
SLC25A1 Mitochondrial citrate carrier deficiency (combined D-2- & L-2-hydroxyglutaric aciduria; OMIM 615182)ARUnlike primary PDCD, MCCD is assoc w/facial dysmorphism & apnea; intracerebral cysts.Neonatal lactic acidosis & ↑ 2-hydroxyglutaric acid
TPK1 Thiamine pyrophosphokinase deficiency (thiamine metabolism dysfunction syndrome 5 - episodic encephalopathy type; OMIM 614458)ARDevelopmental regression, ataxia, dystonia, & microcephaly; typically higher developmental achievement than in PDCD.↑ lactate & ↑ pyruvate; nl lactate:pyruvate ratio. Note: Treatable w/high dose thiamine 2
Other disorders (not assoc w/inhibition of PDCs) that are phenotypically similar to primary PDCD
~90
genes		Other Leigh syndromes (See Nuclear Gene-Encoded Leigh Syndrome Overview & mtDNA-Associated Leigh Syndrome & NARP.)AR
AD
XL
Mat		Dystonia & developmental regression; T2-weighted hyperintensity of the basal gangliaLactic acidosis. Note: Electron transport chain defects typically → nl pyruvate. If pyruvate is ↑, lactate:pyruvate ratio is > nl (>20) due to dysfunction of electron transport chain.
FBXL4 FBXL4-related encephalomyopathic mtDNA depletion syndrome ARLeigh syndrome & long philtrum; corpus callosum dysgenesis/agenesisLactic acidosis & ↑ pyruvate; hyperammonemia may be more striking than in primary PDCD.
PANK2 Pantothenate kinase-associated neurodegeneration (PKAN)ARDystonia, spasticity, dysarthria, intellectual impairment; "eye of the tiger" MRI sign (classic for PKAN) is absent in primary PDCD (Globus pallidus lesions in DLAT-PDCD resemble PKAN but DLAT-PDCD is not assoc w/eye of the tiger MRI sign.)Unlike primary PDCD, PKAN is assoc w/acanthocytosis & low/absent plasma pre-beta lipoprotein fraction.

AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; nl = normal; PDCD = pyruvate dehydrogenase complex deficiency; PDC = pyruvate dehydrogenase complex; XL = X-linked

1.
2.

From: Primary Pyruvate Dehydrogenase Complex Deficiency Overview

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