Juan M. Pascual and Salvatore DiMauro
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 (spongio-sis) 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.
PYRUVATE DEHYDROGENASE DEFICIENCY
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
Neonates with pyruvate dehydrogenase complex (PDC) defects may present with severe aci-dosis 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 later during the first year of life with Leigh disease. The clinical manifestations can be indistinguishable from forms caused by respiratory chain disorders (see Chapter 188).
FIGURE 159-1. Pyruvate dehydrogenase deficiency in a 10-month-old girl. T2-weighted MRI images showing axial sections at the level of the thalamus (left) and of the centrum semiovale (right). Severe cortical atrophy (predominantly in the frontal lobes and Sylvian opercula), white matter underdevelopment (more pronounced in the occipital lobes) and increased water content, and agenesis of the corpus callosum are characteristic features.
Milder variants can present during infancy, childhood, or even adulthood with episodic cere-bellar ataxia, which may occur spontaneously, be precipitated by carbohydrate intake, or occur in conjunction with mild infections. Dystonic attacks and progressive peripheral neuropathy may occur. Lactic acidosis is usually not found during testing of these patients, but mild postprandial hyperlactatemia may occur.4 The diagnosis of these disorders requires measurements of lactate and pyruvate in plasma and cerebrospinal fluid (lactate:pyruvate ratio < 15); analysis of amino acids in plasma (hyperalaninemia) and of organic acids in urine (lactic, pyruvic acids); and neurora-diological investigations, including magnetic resonance spectroscopy to detect lactate. Enzymatic analysis of fibroblast PDH activity is usually performed, and molecular diagnosis is available. A ketogenic diet together with thiamine supplementation can afford substantial benefit in responsive cases.5 Dichloroacetate is sometimes temporarily used to enhance lactate clearance.
PYRUVATE CARBOXYLASE DEFICIENCY
Pyruvate carboxylase (PC) deficiency is an autosomal recessive disease due to mutation of the PC gene, which is located in chromosome 11. PC catalyzes the conversion of pyruvate to oxaloacetate when abundant acetyl-CoA is available, thus replenishing Krebs cycle intermediates in the mitochondrial matrix. The enzyme is bound to biotin. PC is involved in gluconeogenesis, lipogenesis, and neurotransmitter synthesis.6 PC deficiency presents with three degrees of phenotypic severity:
1. An infantile form (A) with moderate lactic acidosis, mental and motor deficits, hypotonia, pyramidal tract dysfunction, ataxia, and seizures leading to death in infancy. Episodes of vomiting, acidosis, and tachypnea can be triggered by metabolic imbalance or infection.
2. A severe neonatal form (B), presenting as severe lactic acidosis, hypoglycemia, hepatomegaly, depressed consciousness, and severely abnormal development. Abnormal limb and ocular movements are common findings. Brain MRI reveals cystic periventricular leukomalacia. Hyperammonemia with mild hypercitrullinemia, high lactate-to-pyruvate ratio, paradoxical postprandial ketosis, and low glutamate comprise a very suggestive metabolic profile, mostly due to depletion of intracellular aspartate and oxaloacetate. Early death is common.
3. A rare benign form (C) causes episodic acidosis and moderate mental impairment compatible with survival and near-normal neurological performance. A variety of mutations have been identified, some of which significantly impair PC activity.7 Enzymatic analysis of fibroblast PC activity can be performed, followed by genotyping. Dietary modification with triheptanoin (a triglyceride) supplementation has been attempted to increase acetyl-CoA and anaplerotic propionyl-CoA.8 Liver transplantation has also been performed.9
DISORDERS OF THE KREBS CYCLE
Several tricarboxylic acid enzymes are susceptible to mutations that cause severe mitochondrial dysfunction inherited as autosomal recessive traits. Defects of aconitase, the E3 component of the alpha-ketoglutarate dehydrogenase complex (also shared by the pyruvate dehydrogenase complex); succinate dehydrogenase (SDH, also part of the mitochondrial respiratory chain and known as complex II); and fumarase (fumarate hydratase, FH) are collectively associated with profound encephalopathy and excretion of specific metabolic precursors and by-products.10 The manifestations are pleomorphic. In the case of SDH, mutations of subunit A cause Leigh syndrome (or optic atrophy in the elderly), while mutations in subunits B, C, and D are associated with paraganglioma, and mutations in subunits B and D are associated with pheochromocytoma and severely reduced tumor SDH activity. FH mutations, which cause structural brain malformations, dysmorphic facial features, and neonatal polycythemia,11 are independently associated with uterine and cutaneous leiomyomas and with papillary renal cell cancer. However, the SDH-and FH-related tumors are inherited in an autosomal dominant fashion.12 E3 (dihydrolipoamide dehydrogenase) deficiency, a “crossroads” disorder, causes accumulation of pyruvate and branched-chain amino acids in plasma and excretion of branched-chain alpha-keto acids in urine.13Succinyl-CoA synthetase complex defects presenting early in life as Leigh syndrome associated with mitochondrial depletion have been described recently. These patients present with an accumulation of succinyl carnitine and mild methylmalonic aciduria (see Chapters 156 and 176).
MITOCHONDRIAL TRANSPORTER DISORDERS
Mitochondria store and utilize a variety of energetic compounds that travel the outer and inner organelle membranes through specific transporters. The adenosine nucleotide (ATP and ADP) translocator (ANT1), the malate/aspartate shuttle, the voltage-dependent anion channels (VDAC), the carnitine transporters,14 and the recently identified pyruvate transporter15,16 are important representatives of an expanding class of molecules increasingly implicated in human disease states. For example, autosomal dominant ANT1 mutations destabilize mitochondrial DNA maintenance, causing multiple mitochondrial DNA (mtDNA) deletions that manifest as progressive external ophthalmoplegia and facioscapulohumeral muscular dystrophy, whereas recessive mutations cause congenital heart defects, cataracts, and lactic acidosis.17