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Surprisingly, the number of energy metabolism disorders compatible
with life is still expanding, and their manifestations are reaching truly
pleomorphic proportions. Collectively, these disorders spare no
organ or tissue and can mimic many of the diseases routinely encountered
by primary care clinicians. In addition to the well-known role of
energy metabolism enzymes in balancing the flux of high-energy bonds
inside cells and the supply of fuels to them, some also seem to
serve multiple roles. For example, mutations in some pyruvate metabolism
enzymes impair axonal migration but can also alter craniofacial
configuration. Many mutations are linked to selective neuronal necrosis
and apoptosis and to edema (spongiosis) of the cerebral white matter;
paradoxically, most cause enhanced excitation and epilepsy and result
in increased neuronal energy demands. These unexpected manifestations
probably occur because flux through energy metabolism pathways sustains
the synthesis and recycling of neurotransmitters and other signaling
molecules by groups of neural cells. Consequently, the brain usually
bears the full burden of these diseases, but cardiac and skeletal
muscles, liver, and kidney are also frequently involved.
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Defects in the pyruvate dehydrogenase (PDH) complex are a frequent
cause of lactic acidosis. PDH is a large mitochondrial matrix enzyme complex
that catalyzes the oxidative decarboxylation of pyruvate to form
acetyl-CoA, nicotinamide adenine dinucleotide (NADH), and CO2. Symptoms
vary considerably in patients with PDH complex deficiency, and almost
equal numbers of males and females are affected, despite the location
of the PDH E1 alpha subunit gene (PDHA) in the X chromosome, a paradox explained
by selective female X-inactivation.1 Thus, the
phenotype of PDH deficiency is dictated by mutation severity (especially
in males) and by the pattern of X-inactivation in females.2 Dozens
of PDHA1 mutations have been identified. In addition, there are
patients harboring mutations in the E1 beta subunit, the E2 dihydrolipoyl transacetylase
segment of the complex, the E3 (dihydrolipoamide dehydrogenase)
subunit, the E3-binding protein, the lipoyl-containing protein X,
and the PDH phosphatase (eTable 159.1).3
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Neonates with pyruvate dehydrogenase complex (PDC) defects
may present with severe acidosis caused by progressive lactate and
pyruvate accumulation, hypotonia, microcephaly, partial or total
agenesis of the corpus callosum (see Fig. 159-1),
and dysmorphic features similar to those seen in fetal alcohol syndrome.
The acidosis is refractory to treatment, but thiamine pyrophosphate and
dichloroacetate are often administered. If these infants survive
this initial phase, they have severe neurological impairment and
often die by about 3 years of age. Some children present ...