Pyruvate dehydrogenase complex deficiency (PDCD)
General description
Pyruvate dehydrogenase complex deficiency (PDCD) represents one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism, characterized by impaired conversion of pyruvate to acetyl-coenzyme A and subsequent disruption of cellular energy production.
Genetic defects in PDCD predominantly involve mutations in the X-linked PDHA1 gene, which encodes the E1α subunit and accounts for approximately 77% of all cases. The remaining cases result from mutations in autosomal recessive genes encoding other complex components: PDHB (E1β subunit), DLAT (E2 subunit), DLD (E3 subunit), and PDHX (E3BP).
Clinical manifestations and disease spectrum
The clinical presentation of PDCD demonstrates remarkable heterogeneity, with manifestations ranging from fatal severe neonatal lactic acidosis to later-onset neurological disorders that may not become apparent until adulthood.
Four distinct clinical phenotypes have been identified through systematic analysis. The first group comprises patients with neonatal encephalopathy accompanied by severe lactic acidosis, typically presenting at birth with life-threatening metabolic decompensation. The second phenotype involves non-progressive infantile encephalopathy, characterized by developmental delays but without ongoing neurological deterioration. The third group manifests as classic Leigh syndrome with progressive basal ganglia involvement and characteristic neuroimaging findings. The fourth phenotype presents as relapsing ataxia with intermittent episodes of incoordination, particularly during periods of illness or stress.
MR spectroscopy
Characteristic spectroscopic findings include elevated lactate peaks at 1.33 ppm, supporting the laboratory diagnosis of lactic acidosis, along with pyruvate elevation at 2.37 ppm and alanine peaks at 1.5 ppm. These metabolic alterations reflect the underlying biochemical dysfunction and anaerobic metabolism characteristic of PDCD. Additional spectroscopic findings may include reduced N-acetylaspartate (NAA) peaks indicating neuronal loss or dysfunction, with normal creatine levels providing internal reference standards.
References
- Barnerias, Christine, et al. "Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis." Developmental Medicine & Child Neurology 52.2 (2010): e1-e9.
- Savvidou, Antri, et al. "Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency—Results from a nationwide population‐based study." Journal of Inherited Metabolic Disease 45.2 (2022): 248-263.
- Mew, Nicholas Ah, et al. "MRI features of 4 female patients with pyruvate dehydrogenase E1 alpha deficiency." Pediatric neurology 45.1 (2011): 57-59.
Abnormalities of the corpus callosum
The corpus callosum malformations range from complete agenesis to partial agenesis with absence of posterior portions, and hypoplasia with thinning of the commissural fibers.
Ventriculomegaly
The ventricular enlargement typically demonstrates asymmetric patterns affecting the lateral and third ventricles while characteristically sparing the fourth ventricle. This asymmetric distribution pattern helps differentiate PDCD from other causes of hydrocephalus and provides important diagnostic specificity.
Associated findings include ventricular septations and periventricular cystic lesions that reflect both developmental abnormalities and secondary destructive changes.
Cortical malformation
Developmental cortical malformations include polymicrogyria, abnormalities of cortical gyration, and neuronal migration defects that indicate disrupted embryonic brain development.
White matter lesion
White matter involvement manifests as delayed myelination and in some cases, leukoencephalopathy with cystic degenerations.
Leigh syndrome-like lesions
Leigh syndrome-like lesions appear as bilateral symmetric hyperintensities on T2-weighted images involving the globus pallidus, putamen, caudate nucleus, thalamus, and brainstem.