Pyruvate Dehydrogenase Complex Deficiency (PDHCD) is a
mitochondrial disease that leads to lactic acidosis without hypoglycemia.
Pyruvate Dehydrogenase Deficiency.
The exact incidence is unknown, but several hundred
cases have been described.
All the components of the pyruvate
dehydrogenase complex are encoded by nuclear genes and are synthesized in
the cytoplasm before being transported into the mitochondria. Most of these
genes are autosomal, but the E1α subunit gene has been mapped to
Xp22.3. Hence, most cases of pyruvate dehydrogenase complex deficiency are
X-linked with more severe consequences in males than in heterozygous
females; the frequency, however, is the same for both genders.
Pyruvate dehydrogenase (PDH) is an enzyme complex
consisting of three catalytic subunits, pyruvate dehydrogenase (E1, a
tetramer), dihydrolipoamide acyltransferase (E2, a monomer), and
dihydrolipoamide dehydrogenase (E3, a dimer), and two cofactors, thiamine
pyrophosphate and lipoic acid. A sixth component, previously named X-protein
and recently renamed E3-binding protein (E3-BP), has been found to be
mutated in a few patients. The enzyme complex converts pyruvate—after it
enters the mitochondria—into acetyl-CoA, one of two essential substrates
(oxaloacetate being the other) in the production of citrate. PDHCD therefore
leads to a limited production of citrate and because citrate is the first
substrate in the tricarboxylic acid (citric acid or Krebs) cycle, the cycle
is blocked and other metabolic pathways need to be stimulated to produce
acetyl-CoA. Nevertheless, the decreased level of energy substrates (ATP)
primarily affects the CNS, because brain acetyl-CoA is synthesized almost
exclusively from pyruvate. The most common deficiency involves the E1
subunit, a heterotetramer consisting of two alpha and two beta subunits with
the defect located on the alpha subunit (E1alpha), which contains several
serine phosphorylation sites and seems to be involved in the regulation of
the whole complex. Mutations in E2, E3, and E3-BP are less often the cause
for PDHCD. The enzyme defect causes more pyruvate to be metabolized to
lactate and leads to lactic acidosis.
The combination of an otherwise unexplained lactic
acidosis with early-onset neurological disease and structural brain
anomalies should always include PDHCD in the differential diagnosis. In
addition to pyruvate carboxylase deficiency, defects in the mitochondrial
chain of electron transport or in gluconeogenesis should be considered.
However, lactic acidosis in the absence of hypoglycemia does not match with
a defect in gluconeogenesis, whereas a defect in the mitochondrial
respiratory chain would also affect other organ systems, such as muscle,
heart, liver, and kidneys. In contrast to a respiratory chain defect, the
blood lactate/pyruvate ratio in PDHCD is normal and both lactate and
pyruvate decrease after fasting. Specific enzyme assays are available to
measure the total PDH activity, as well as that of the individual components
of the enzyme complex. However, measured residual enzyme activity does not
always correlate with the clinical picture.
The range of clinical expression is wide and has
four different ways of presentation: fatal infantile lactic acidosis,
psychomotor retardation, progressive ...