Pyruvate dehydrogenase complex deficiency …

Jirair Bedoyan MD PhD FACMG

Neurogenetic Disorders

Updated 05.28.2024
Expires For CME 05.28.2027

Pyruvate dehydrogenase complex deficiency

Author: Jirair Bedoyan MD PhD FACMG

See Contributor Disclosures

Editor: Barry Wolf MD PhD

Pyruvate dehydrogenase complex deficiency

In This Article

Quick Link

Introduction

Overview

Pyruvate dehydrogenase complex deficiency is an inborn error of mitochondrial energy metabolism caused by partial or total inactivation of the mitochondrial matrix multienzyme pyruvate dehydrogenase complex. Pyruvate dehydrogenase complex is the gateway for the oxidative metabolism of carbohydrates, catalyzing the four-step oxidative decarboxylation of pyruvate (the end-product of glycolysis) to acetyl-CoA (the primary substrate for the tricarboxylic acid cycle) with concomitant reduction of NAD⁺ to NADH, which directly provides electrons for the mitochondrial respiratory chain.

Key points

	• Pyruvate dehydrogenase complex deficiency is a mitochondrial disorder of carbohydrate oxidation that mostly affects the brain and leads to an energy deficit.
	• Pyruvate dehydrogenase complex deficiency is a major cause of primary lactic acidemia with high morbidity and mortality.
	• The disorder has an incidence of about 1 in 40,000 live births annually in North America.
	• It is the second most common genetically resolved mitochondrial disorder entry in the North American Mitochondrial Disease Consortium Registry of over 2100 participants.
	• Pathogenic or likely pathogenic variants in over 38 genes result in enzymatic pyruvate dehydrogenase complex deficiency, but those due to X-linked PDHA1 constitute at least 75% of affected cases, with about 60% of those due to missense substitutions.
	• Individuals with pyruvate dehydrogenase complex deficiency are subclassified into at least three groups depending on the gene responsible for the disease, with significant clinical management consequences. Individuals with pathogenic or likely pathogenic variants in PDHA1, PDHB, DLAT, PDHX, and PDP1 fall in the primary-specific group.
	• The clinical presentation is variable and ranges from fatal congenital lactic acidosis and brain malformations in newborns and early infancy, to global developmental delay and failure to thrive, to relatively mild or intermittent ataxia, exercise-induced episodic paroxysmal dystonia, or neuropathy compatible with normal cognitive function and long-term survival.

Historical note and terminology

Key points

	• Individuals with pyruvate dehydrogenase complex deficiency were first described in 1970.
	• The NAD-dependent pyruvate dehydrogenase complex is a highly regulated mitochondrial matrix multienzyme complex crucial for carbohydrate oxidation for energy production, but with other moonlighting roles in cell-cycle progression and cellular differentiation and proliferation.
	• Multiple cofactors are needed for the catalytic and optimal enzymatic activity of pyruvate dehydrogenase complex.
	• Many NAD-dependent dehydrogenase complexes are structurally and functionally similar to pyruvate dehydrogenase complex but require different substrates and result in different products for each complex.
	• Pyruvate dehydrogenase complex appears to be localized near the inner mitochondrial membrane-bound complex I of the mitochondrial respiratory chain, and cardiolipin within the inner mitochondrial membrane is also required for optimal pyruvate dehydrogenase complex activation.

Pyruvate dehydrogenase complex deficiency was first described in 1970 in a 9-year-old boy with an intermittent combined cerebellar and choreoathetoid movement disorder determined to be due to an inherited defect in pyruvate decarboxylase (aka, the initial step in the catalytic oxidative decarboxylation of pyruvate to acetyl-CoA by pyruvate dehydrogenase complex) (10). Pyruvate dehydrogenase complex deficiency has been referred to as pyruvate dehydrogenase deficiency, although this designation more specifically refers to the E1 subunit of the pyruvate dehydrogenase complex. To date, over 500 cases of pyruvate dehydrogenase complex deficiency have been reported.

The mitochondrial multienzyme pyruvate dehydrogenase complex irreversibly catalyzes the oxidative decarboxylation of pyruvate (a 3-carbon alpha-keto acid) into acetyl-CoA as the primary substrate for the tricarboxylic acid cycle.

General structural organization of mitochondrial NAD-dependent multienzyme alpha-ketoacid dehydrogenase complexes with alpha-ketoacid and acyl-CoA as ...

Pyruvate and acetyl-CoA are the substrate and product, respectively for pyruvate dehydrogenase complex (PDC). E3 binding protein (E3BP) – the product of PDHX and specific to PDC, is not depicted. E3, dihydrolipoamide dehydrogen...

Pyruvate dehydrogenase complex is comprised of four core catalytic subunits (E1α, E1β, E2, and E3 encoded by PDHA1, PDHB, DLAT, and DLD, respectively) and a structural protein (E3BP encoded by PDHX). The proteins are directed to the mitochondria, where each of their mitochondrial targeting sequences is endogenously clipped off to generate their respective mature proteins. The E1 enzyme is a symmetric dimer of heterodimers (αβ/α’β’, 152.3 kDa) composed of two subunits each of E1α (a 361 aa mature protein of 40.2 kDa) and E1β (a 329 aa mature protein of 35.91 kDa). Full and dynamic structural models of pyruvate dehydrogenase complex, including binding of the linking arms to the surrounding E1, E2, and E3 subunits via their binding domains, are described (79; 29). Pyruvate dehydrogenase complex function also depends on four cofactors (coenzyme A, CoA; covalently bound lipoate; thiamine pyrophosphate, aka thiamine diphosphate; and flavin adenine dinucleotide).

Pyruvate dehydrogenase complex activity is highly regulated: phosphorylation sites (three serine amino acids) on E1α are regulated by a set of kinases (pyruvate dehydrogenase kinases) and phosphatases (pyruvate dehydrogenase phosphatases), which interact with lipoyl domains on E2 and E3BP, and are important in inactivation (phosphorylation by kinases) and activation (dephosphorylation by phosphatases) of pyruvate dehydrogenase complex (27). The lipoate cofactor is required for catalysis by multiple mitochondrial alpha-keto acid dehydrogenase complexes, including pyruvate dehydrogenase complex, and plays a critical role in stabilizing and regulating pyruvate dehydrogenase complex function (75). Pyruvate dehydrogenase complex is also glutathionylated on E2, and this glutathionylation decreases reactive oxygen species production when pyruvate is being oxidized, whereas depletion of glutathione leads to increased reactive oxygen species production from pyruvate dehydrogenase complex (21; 51). Glutathione reductase regulates the reversible glutathionylation, which is important for pyruvate dehydrogenase complex activity (51). Sirtuin 4 regulates pyruvate dehydrogenase complex function through its lipoamidase activity that cleaves the lipoyl moiety from E2 (44). Defective biosynthesis or mitochondrial transport of co-factors (eg, thiamine) or substrates (eg, pyruvate) can also result in functional pyruvate dehydrogenase complex deficiency (76). End-product inhibition is yet another mechanism for regulating pyruvate dehydrogenase complex. The Ki of acetyl-CoA for end-product inhibition of pyruvate dehydrogenase complex is 5 to 10 μM, which is much lower than the Ki of propionyl-CoA (3 to 4 mM) (08; 69; 31), implying that propionyl-CoA has significantly lower affinity for pyruvate dehydrogenase complex than acetyl-CoA. The mitochondrial phospholipid cardiolipin is localized within the inner mitochondrial membrane and plays an important role in mitochondrial bioenergetics; it is also required for optimal pyruvate dehydrogenase complex activation (41). Furthermore, alpha-keto acid dehydrogenase complexes, including pyruvate dehydrogenase complex, are localized near the inner mitochondrial membrane-bound complex I of the mitochondrial respiratory chain, thus suggesting direct coupling of oxidation of specific alpha-keto acids and generation of NADH for transfer of electrons to the mitochondrial respiratory chain via complex I (58). Furthermore, pyruvate dehydrogenase complex can translocate from the mitochondria to the nucleus (in a manner still unclear) during cell-cycle progression, generating a nuclear pool of acetyl-CoA from pyruvate and increasing the acetylation of core histones important for S phase entry as well as expression of damage-response genes among others (82; 80). Therefore, pyruvate dehydrogenase complex is a highly regulated mitochondrial matrix multienzyme complex crucial for carbohydrate oxidation for energy production, but with other moonlighting roles in cell-cycle progression and cellular differentiation and proliferation.

Other mitochondrial alpha-keto acid (aka, 2-oxoacid) dehydrogenase complexes structurally and functionally similar to pyruvate dehydrogenase complex where dysfunction results in human disease include: the alpha-ketoglutarate dehydrogenase complex (with the 5-carbon alpha-keto acid alpha-ketoglutarate as substrate), which results in alpha-ketoglutarate dehydrogenase complex deficiency; the branched-chain alpha-keto acid dehydrogenase complex (with 5- and 6-carbon alpha-keto acids namely alpha-ketoisovalerate, alpha-keto-3-methylvalerate and alpha-ketoisocaproateas substrates), which results in maple syrup urine disease; and the alpha-ketoadipate dehydrogenase complex (with the 6-carbon alpha-keto acid alpha-ketoadipate as substrate), which results in alpha-ketoadipate dehydrogenase complex deficiency.

Clinical manifestations

Presentation and course

	• Onset is broad--from fetal, neonatal, and infantile to late-onset in children and adults.
	• Clinical presentation and clinical course are heterogeneous.
	• Brain anomalies are common in pyruvate dehydrogenase complex deficiency, including cerebral atrophy or hypoplasia, ventriculomegaly and ventricular asymmetry, corpus callosum abnormalities, bilateral basal ganglia, or midbrain or brainstem lesions.
	• Individuals with pyruvate dehydrogenase complex deficiency are subclassified into at least three groups, depending on the gene responsible for the disease and with significant clinical management consequences.
	• Variable pyruvate dehydrogenase complex enzymatic testing sensitivity and variability between cell and tissue types used in testing have important diagnostic and management implications.
	• The age at diagnosis appears to be the best predictor of survival and cognitive outcome for individuals with pyruvate dehydrogenase complex deficiency.

The age of pyruvate dehydrogenase complex deficiency presentation ranges from fetal, neonatal, or infantile to late-onset in children and adults. The clinical presentation of pyruvate dehydrogenase complex deficiency is highly variable and ranges from fatal congenital lactic acidosis and congenital brain abnormalities, including ventriculomegaly (35% to 85%), corpus callosum abnormalities (15% to 55%) and Leigh syndrome (12% to 25%), to global developmental delay and failure to thrive, to relatively mild or intermittent ataxia, exercise-induced episodic paroxysmal dystonia or ataxia, Guillan Barre-like syndrome, or peripheral neuropathy with normal cognitive function and long survival (64; 65; 59; 32; 17; 53; 15; 71; 67). Muscular hypotonia (46% to 89%), developmental delay (57% to 83%), epilepsy (16% to 57%), and microcephaly (49%) are other common findings in patients with pyruvate dehydrogenase complex deficiency (64; 65; 32; 17; 53). Visual and eye movement impairments, including cortical blindness at one extreme to intermittent exotropia or esotropia at the other, as well as hearing impairments, have been reported. Age at diagnosis appears to be the best predictor of survival and cognitive outcome in those affected with pyruvate dehydrogenase complex deficiency (17). About 4% of patients with pyruvate dehydrogenase complex deficiency have normal brain imaging (CT or MRI) findings (53). Several vignettes highlight the clinical overlap and unique features of the various subclasses of pyruvate dehydrogenase complex deficiency (Table 1).

Typical neonatal or infantile presentation of pyruvate dehydrogenase complex deficiency is characterized by hypothermia, respiratory distress or failure, vomiting, metabolic and lactic acidosis, delayed motor development, poor linear growth or weight gain, intellectual disability, speech delay, and neurologic findings (eg, lethargy, apathy, hypotonia, pyramidal and extrapyramidal signs, ataxia, or seizures). Brain anomalies can be noted. Blood or CSF lactate and pyruvate are elevated with normal lactate to pyruvate (L/P) ratio (reference range: 10 to 20), differentiating primary pyruvate dehydrogenase complex deficiency from primary mitochondrial disorders, such as those due to electron transport chain dysfunction where L/P ratios are generally elevated. Fasting, intercurrent illness, excessive exercise, or other metabolic stressors may result in metabolic decompensation with a variable degree of metabolic and lactic acidosis and movement anomalies requiring emergent attention and management. The specific management approach depends on the patient and their specific disease. In most cases, polytherapy with ketogenic diet or intralipid, thiamine supplementation, dichloroacetate, bicarbonate or buffering agents for metabolic acidosis, riboflavin supplementation, L-carnitine supplementation if on ketogenic diet, or antiepileptic medications for seizure control constitute the management approach for individuals with pyruvate dehydrogenase complex deficiency. Sugar-free versions of supplements and medications are necessary for individuals on ketogenic diet to maintain adequate ketosis. Molecular genetic confirmation of the pyruvate dehydrogenase complex deficiency diagnosis is necessary for best management choices and outcome. Suspected cases of pyruvate dehydrogenase complex deficiency with enzymatically confirmed low pyruvate dehydrogenase complex activity by cell- or tissue-based assays should also have confirmatory molecular genetic testing completed before the start of high-fat interventions, such as ketogenic diet or intralipid. Use of ketogenic diet or intralipid therapy in newborns and infants with pyruvate dehydrogenase complex deficiency subclass other than primary-specific pyruvate dehydrogenase complex deficiency may be ineffective or even fatal (see Table 1) (20; 05; 72). Management approaches and emergency protocol (for primary-specific pyruvate dehydrogenase complex deficiency) for families are detailed in the Management section of this article.

Table 1. Newborn and Infant Pyruvate Dehydrogenase Complex Deficiency Presentation Vignettes: Diagnostic Approaches and Intervention Impacts

Case		1	2	3
Sex		Female	Female	Male
Clinical presentation		13-month-old with generalized hypotonia and developmental delay (nonverbal). Brain MRI showed paucity of white matter with thin corpus callosum and patchy enhancement of caudate and lentiform nuclei (globus pallidum and putamen) bilaterally, elevated blood lactate, and pyruvate. (L/P: 15, normal)	Day-of-life 28 ex-33 weeks preterm newborn. Brain MRI showed dysgenesis of the corpus callosum, ventricular septal defect, cleft palate, and elevated blood lactate. She later developed necrotizing enterocolitis.	Full-term newborn with generalized hypotonia. Brain MRI showed generalized cortical thinning and hyperintensities of white matter, elevated blood lactate, and pyruvate. (L/P: 19-23, normal)
Pyruvate dehydrogenase complex activity	Lymphocytes Fibroblasts	Normal Low	Normal Low	Low Normal
Alpha-ketoglutarate dehydrogenase complex activity	Fibroblasts	Not done	Low	Normal
E3 activity	Fibroblasts	Normal	Normal	Normal
Diet		Started ketogenic diet at age 24 months. Now on ketogenic diet intermittently.	Intralipid only on day-of-life 32	KetoCal® (ketogenic diet 3:1) on day-of-life 29
Age at death		Living	42 days	39 days
Genetic etiology (status at diagnosis)		PDHA1 Heterozygous c.225G>T, p.E75D (novel)	LIAS c.544C>T, p.R182X/c.354G>C, p.W118C (both novel)	ECHS1 c.836T>C,p.F279S/c.8C>A,p.A3D (novel/known)
Immunoblot analysis using fibroblasts		Not done	* Absent pyruvate dehydrogenase complex E2	Significantly reduced short-chain enoyl-CoA hydratase (below the limit of quantification)
Pyruvate dehydrogenase complex deficiency type		Primary-specific	Primary-generalized	Secondary
Reference		(72)	This review	(05)
* Alpha-ketoglutarate dehydrogenase complex E2 component was also absent.

Prognosis and complications

The age at diagnosis appears to be the best predictor of survival and cognitive outcome in those affected with pyruvate dehydrogenase complex deficiency (17); thus, early identification and diagnosis of pyruvate dehydrogenase complex deficiency are crucial (07; 87). Females have better survival, but surviving females are more severely affected than males (17; 53). Death among severe newborn and infantile patients with pyruvate dehydrogenase complex deficiency are generally about 40%, 60%, and 90% for those younger than 3 months, younger than 1 year, and younger than 4 years of age, respectively (17).

Neuroimaging findings

Notable brain anomalies in individuals with pyruvate dehydrogenase complex deficiency determined by CT or MRI include cerebral atrophy or hypoplasia (common); leukoencephalopathy, ventriculomegaly and ventricular asymmetry (common); periventricular cystic lesions or intraventricular septations (occasional); corpus callosum anomalies, including partial to complete agenesis (common); absent septum pellucidum, bilateral basal ganglia, and midbrain or brainstem T2-weighted hyperintense lesions or cystic cavitations (common); Leigh-like lesions with predominant involvement of globus pallidus and bilateral stroke-like lesions; mega cisterna magna; hypoplastic cerebellum or cerebellar vermian anomalies, lesions or absence; and optic nerve hypoplasia (03; 01; 17; 53; 66; 67).

1H MRS findings can include increased lactate peaks in sampled frontal white matter, basal ganglia, and midbrain structures.

Biological basis

Etiology and pathogenesis

	• Pyruvate dehydrogenase complex deficiency is a mitochondrial disorder of carbohydrate oxidation resulting in energy deficit.
	• Pyruvate dehydrogenase complex deficiency does not modify cytosolic NADH/NAD⁺ ratio, which is reflected in a normal L/P ratio in blood and CSF, distinguishing this disorder from other primary causes of lactic acidosis, such as those due to primary mitochondrial disorders resulting from mitochondrial respiratory chain dysfunction where L/P ratio is elevated.
	• Most cases of pyruvate dehydrogenase complex deficiency are due to disease-causing variants in PDHA1.
	• Most E1α amino acids resulting in disease when replaced are solvent inaccessible (“buried”) within the 3D E1 structure, impacting the structure and function of pyruvate dehydrogenase complex when replaced.
	• About 30% of buried E1α disease-causing missense variants are involved in subunit-subunit interface contacts.

General structural organization of mitochondrial NAD-dependent multienzyme alpha-ketoacid dehydrogenase complexes with alpha-ketoacid and acyl-CoA as ...

Pyruvate formed from cytosolic glycolysis crosses the outer mitochondrial membrane, probably via a voltage-dependent anion channel, and then is actively transported across the inner mitochondrial membrane by the mitochondrial pyruvate carrier. Oxidative decarboxylation of cytosolic malate by malic enzyme also produces pyruvate. Once within the mitochondrial matrix, pyruvate can be oxidized into acetyl-CoA by pyruvate dehydrogenase complex or carboxylate to oxaloacetate by pyruvate carboxylase, the latter being an early step in gluconeogenesis. Functional defect in pyruvate dehydrogenase complex results in elevated pyruvate within the cytoplasm, where it can be converted to alanine via a transamination reaction by alanine transaminase or to lactate by lactate dehydrogenase. Elevated lactate inhibits the first step in proline metabolism by proline oxidase, resulting in proline elevation (38). Lactate production yields less than one tenth of the ATP derived from complete glucose oxidation via the tricarboxylic acid cycle. Disease-causing variants in the primary genes associated with low pyruvate dehydrogenase complex activity result in pyruvate dehydrogenase complex deficiency by interfering with pyruvate flux and energy production from carbohydrate oxidation with resultant lactic acidemia, hyperpyruvicemia, hyperalaninemia, and hyperprolinemia aggravated with consumption of carbohydrate. Unlike in primary mitochondrial disorders where the blood lactate to pyruvate (L/P) ratio is high (usually greater than 25), in pyruvate dehydrogenase complex deficiency, the L/P ratio both in blood and CSF is usually normal, ranging from 10 to 20. Defective pyruvate dehydrogenase complex deficiency with reduced acetyl-CoA production results in decreased production of reducing equivalents in the form of NADH and, thus, decreased ATP through the mitochondrial respiratory chain and, consequently, an energy deficit.

Focus on primary-specific pyruvate dehydrogenase complex genes. Loss of primary pyruvate dehydrogenase complex enzymatic function may occur from loss of mRNA expression, subunit instability, or loss or reduction of functional activity of various primary pyruvate dehydrogenase complex-associated gene products (Table 2), which could, in part, be due to partial or complete deletion of the specific gene. Most cases of pyruvate dehydrogenase complex deficiency (at least 75%) are due to pathogenic or likely pathogenic variants in PDHA1, with over 130 nonduplicate disease-causing variants reported (42; 63; 59; 32; 19). Males and females with somatic mosaicism in PDHA1 have been reported (18). E1α null variants are likely lethal as none have been identified in males, except in a mosaic state (18). A few large rearrangements have been identified, such as a large intragenic 4.2 kb deletion covering part of intron 5 to part of intron 9 (g.10,145_14,371 del 4,227) (11). Most cases of pyruvate dehydrogenase complex deficiency due to PDHA1 (about 75%) are due to de novo disease-causing variants, whereas about 25% are due to inheritance from a carrier “asymptomatic” mother. About half of all nonduplicate E1α disease-causing missense variants (DMVs) are found within exons 5 to 7 (19). About 85% of E1α DMVs are solvent-inaccessible (“buried”), and about 30% of buried E1α DMVs are involved in subunit-subunit interface contact (19). Arginine (R) replacements constitute about 40% of all the E1α DMVs (72; 19). Recurrent replacements of mature proteins R234, R273, and R349 (aka, p.R263, p.R302, and p.R378) together predominate among all arginine replacements (53; 19). Certain E1α DMVs show sex predominance. For example, mature E1αR273 replacements to histidine (p.R302H) or cysteine (p.R302C) show female predominance (95%) (72; 19). About 10% of E1α DMVs are due to recurrent mature R349 replacements (mature R349H or R349C; p.R378H or p.R378C, respectively), exhibiting an average 20% to 25% of control mean in vitro fibroblast-based pyruvate dehydrogenase complex activity (72; 19). Mature E1α R349 replacements disrupt proper subunit-subunit interface contact and cooperative networks with other subunit residues and form a pocket in 3D E1 structure (37; 19; 24). Molecular dynamic simulations show that E1α DMVs influence the E1 active sites allosterically by altering the information flow and cooperative networks (24).

Disease-causing variants in PDHB are a rare cause of pyruvate dehydrogenase complex deficiency (52; 76; 19). An individual has been reported with dysregulation of the ubiquitin-proteasome system resulting in E1β instability and, thus, pyruvate dehydrogenase complex deficiency but without a molecular defect in PDHB (26).

Disease-causing variants in other primary-specific genes, such as DLAT (28; 47), PDP1 (43; 14; 06), and PDHX (12; 46; 33) are reported. A founder PDHX p.R446* variant is known in the European Roma population (in Bulgaria, Romania, Slovakia, and Hungary) (33).

Activating mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene, another primary-specific gene, causes X-linked dominant Charcot-Marie Tooth disease (CMTX6). The underlying pathogenic cause of peripheral neuropathy in these individuals is reduced pyruvate flux due to hyperphosphorylation of pyruvate dehydrogenase complex (36; 56).

Primary-specific pyruvate dehydrogenase complex gene variants constitute 80% to 90% of all cases of pyruvate dehydrogenase complex deficiency (76; 72).

Epidemiology

	• The incidence of pyruvate dehydrogenase complex deficiency is at least 1 in 40,000 live births annually in the United States.
	• Pyruvate dehydrogenase complex deficiency due to PDHA1 constitutes at least 75% of affected cases, with about 60% of those due to missense substitutions.
	• Certain amino acid ratios (Ala/Leu, Ala/Lys, Pro/Leu, (Ala+Pro)/Leu, or (Ala+Pro)/(Leu+Lys) or their combinations are highly sensitive (90% or greater) for identifying patients with pyruvate dehydrogenase complex deficiency.

Two studies found the incidence of pyruvate dehydrogenase complex deficiency to be about 1 in 40,000 live births annually in the United States (07; 87). The study from Ohio was a prospective study completed in a 1-year period, with newborn screening dried blood spot data of alanine and proline included (07); the second study from Pennsylvania was a retrospective study that reviewed 11 years of medical records at a major medical center (87). Certain amino acid ratios, such as Ala/Leu, Ala/Lys, Pro/Leu, (Ala+Pro)/Leu, or (Ala+Pro)/(Leu+Lys) or their combinations, are highly sensitive (90% or greater) but not specific (75% to 85%) for identifying patients with pyruvate dehydrogenase complex deficiency (07; 87). Second-tier molecular testing of dried blood spots for primary-specific pyruvate dehydrogenase complex deficiency genes (or at least PDHA1) would increase newborn screening specificity for this disorder and exclude other disorders, such as other primary mitochondrial disorders not on newborn screening. The estimated prevalence of pyruvate dehydrogenase complex deficiency in the United States is about 2,000 cases, but only about 50% of those are confirmed diagnostically (SAOL Therapeutics data, December 2023).

Pyruvate dehydrogenase complex deficiency due to chromosome X-linked PDHA1 constitutes at least 75% of affected cases, with about 60% of those due to missense substitutions (17; 53; 76; 05; 07; 19). Pyruvate dehydrogenase complex deficiency due to primary-specific genes (PDHA1, PDHB, DLAT, PDHX, PDP1, and PDK3) constitute 80% to 90% of all cases with pyruvate dehydrogenase complex deficiency (76; 72).

Differential diagnosis

•	Pathogenic or likely pathogenic variants in more than 38 genes are associated with enzymatic pyruvate dehydrogenase complex deficiency, presenting in many cases with overlapping clinical and biochemical features to primary-specific pyruvate dehydrogenase complex deficiency.
•	Facial features characteristic of fetal alcohol syndrome can be observed in some individuals with pyruvate dehydrogenase complex deficiency.

Associated or underlying disorders

Patients with pyruvate dehydrogenase complex deficiency are subclassified into at least three different groups (primary-specific, primary-generalized, and secondary pyruvate dehydrogenase complex deficiency) with important clinical consequences (05; 72). Although pathogenic or likely pathogenic variants in more than 38 genes cause functional (enzymatic) pyruvate dehydrogenase complex deficiency, the overwhelming majority (80% to 90%) of affected individuals are subclassified into primary-specific pyruvate dehydrogenase complex deficiency (due to variants in either PDHA1, PDHB, DLAT, PDHX, PDP1, or PDK3), with at least 75% due to PDHA1 pathogenic or likely pathogenic variants. This fact has important and practical diagnostic and therapeutic implications and is crucial for the prospect of future implementation of pyruvate dehydrogenase complex deficiency newborn screening. Impairment (or lack) of cofactors (eg, thiamine pyrophosphate), substrate (eg, pyruvate), complex component modifications (eg, by lipoylation or glutathionylation), and pyruvate dehydrogenase complex regulators (eg, pyruvate dehydrogenase phosphates and their regular and PD kinases) also result in pyruvate dehydrogenase complex deficiency. A list of known, possible, and potential molecular etiologies of impaired human pyruvate oxidation is shown in Table 2.

Table 2. Subclassification of Pyruvate Dehydrogenase Complex Deficiency and Other Pyruvate Metabolism-Related Disorders (currently known, possible, and potential molecular etiologies of impaired pyruvate oxidation)

Enzyme, complex, disorder, function, or pathway	Gene (OMIM #)
	Known	Possible	Potential
Primary-specific pyruvate dehydrogenase complex deficiency
Pyruvate dehydrogenase complex	DLAT (608770) PDHA1 (300502) PDHB (179060) PDHX (608769)
Pyruvate dehydrogenase phosphatases (including their regulator)	PDP1 (605993)	PDP2 (615499) PDPR (617835)
Pyruvate dehydrogenase kinases	PDK3 (300906)	PDK1 (602524) PDK2 (602525) PDK4 (602527)
Primary-generalized pyruvate dehydrogenase complex deficiency *
Multiple alpha-keto acid dehydrogenases (eg, branched-chain alpha-keto acid dehydrogenase complex, alpha-adipate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex)	DLD (238331)
Thiamine and thiamine pyrophosphate transporters	SLC19A2 (603941) SLC19A3 (606152) SLC25A19 (606521)
Thiamine pyrophosphokinase	TPK1 (606370)
Pyruvate carrier (mitochondrial)	MPC1 (614738)
Lipoate metabolism	LIAS (607031) LIPT1 (610284) LIPT2 (617659) SIRT4 (604482)
Mitochondrial iron-sulfur cluster proteins or their production/biogenesis (including cysteine desulfurase)	BOLA3 (613183) FDX1L (614585) FDX2 (614585) GLRX5 (609588) IBA57 (615316) ISCA1 (611006) ISCA2 (615317) ISCU (611911) LYRM4 (613311) NFS1 (603485) NFU1 (608100) NUBPL (613621)
Mitochondrial proteases or peptidases	LONP1 (605490) PMPCB (603131)
Regulation of glutathionylation			GLRX2 (606820)
Secondary pyruvate dehydrogenase complex deficiency *
Fatty acid oxidation	ECHS1 (602292)
Branched-chain amino acid metabolism	ECHS1 (602292) HIBCH (610690)
Tricarboxylic acid cycle	SUCLA2 (603921) SUCLG1 (611224) SUCLG2 (603922)
Phosphoenolpyruvate carboxykinase (cytosolic and mitochondrial)	PCK1 (614168) PCK2 (614095)
Mitochondrial bioenergetics/pyruvate dehydrogenase complex regulation	TAZ (300394)
Mitochondrial citrate carrier deficiency (combined D-2- and L-2-hydroxyglutaric aciduria)	SLC25A1 (190315)
Disorders with overlapping phenotype to pyruvate dehydrogenase complex deficiency that may or may not be associated with functional (enzymatic) pyruvate dehydrogenase complex deficiency
Other Leigh syndromes	Approximately 90 genes
Pyruvate carboxylase deficiency	PC (608786)
Glutamate oxaloacetate transaminase (mitochondrial)	GOT2 (138150)
Pantothenate kinase-associated neurodegeneration	PANK2 (606157)
FBXL4-related encephalomyopathic mtDNA deletion syndrome	FBXL4 (605654)
(05; 07) * Pathogenic or likely pathogenic variants in ECHS1, LYRM4, NFS1, SUCLA2, and TAZ are also involved in secondary 3-methylglutaconic aciduria via the “acetyl-CoA diversion pathway,” resulting in acetyl-CoA accumulation in the mitochondrial matrix (34). Elevated acetyl-CoA (end-product of pyruvate dehydrogenase complex reaction) in the mitochondrial matrix can act as an end-product inhibitor of pyruvate dehydrogenase complex (Ki of acetyl-CoA 5 to 10 μM), resulting in elevated alanine or proline with elevated Ala/Leu, Ala/Lys, (Ala+Pro)/Leu and (Ala+Pro)/(Leu+Lys) ratios (unpublished data). - Most of the above-noted “possible” and “potential” genes in this table noted as associated with functional pyruvate dehydrogenase complex deficiency have been shown in animal models and have not yet been identified as causative of human disease. - Genes underlined are on the Invitae (38-gene) Pyruvate Metabolism and Related Disorders Panel for testing. - PDHA1, PDK3, and TAZ are X-linked genes, and pyruvate dehydrogenase complex deficiency due to disease-causing variants in these genes exhibits an X-linked inheritance pattern with phenotypic variability in females due to X-inactivation. The remaining genes associated with pyruvate dehydrogenase complex deficiency show an autosomal recessive inheritance pattern.

Acquired disorders

Acquired disorders in the differential diagnosis of primary pyruvate dehydrogenase complex deficiency include:

Dietary thiamine deficiency. Dietary thiamine deficiency may develop in children who are critically ill for other reasons, resulting in an acquired decrease in pyruvate dehydrogenase complex activity and biochemical findings of elevated lactate and pyruvate (with normal ratio) similar to individuals with primary pyruvate dehydrogenase complex deficiency (48).

Fetal alcohol syndrome. Facial features characteristic of fetal alcohol syndrome include a short nose, long and smooth philtrum, and thin upper lip as well as primary microcephaly; such features are similar to those seen in pyruvate dehydrogenase complex deficiency. Furthermore, alcohol-induced CNS insult results in midline anomalies, such as agenesis of the corpus callosum, also commonly seen in pyruvate dehydrogenase complex deficiency. High acetaldehyde concentrations result from chronic alcoholism due to enhanced ethanol oxidation by induction of cytochrome P-450 2E1 (CYP 2E1) and concomitant reduction in aldehyde dehydrogenase activity. Hard and colleagues show that acetaldehyde impairs pyruvate dehydrogenase complex activity by a mixed inhibition-type mechanism, implicating acquired decreased pyruvate dehydrogenase complex activity in the developing fetus exposed to alcohol and, consequently, fetal alcohol syndrome (25).

Diagnostic workup

Key tests and procedures

	• Cultured skin fibroblasts are the most sensitive cells to measure pyruvate dehydrogenase complex enzymatic activity and confirm the pathogenicity of variants of uncertain significance in pyruvate dehydrogenase complex deficiency-associated genes.
	• Target-based single or multiple gene testing or exome or genome sequencing approaches are used for molecular genetic confirmation of suspected pyruvate dehydrogenase complex deficiency.
	• Establishing thiamine-responsiveness of the specific PDHA1 or PDHB disease-causing variant allows for greater management flexibility.
	• In the future, clinical transcriptomics, proteomics, and epigenetics testing would be needed to help identify and confirm the pathogenicity of rare disease-causing variants in pyruvate dehydrogenase complex deficiency-related genes.

Establishing the diagnosis. A diagnostic algorithm for pyruvate dehydrogenase complex deficiency has been recommended, and the reader is referred to Figure 2 in the 2017 article by Shin and colleagues (72).

Quantitative analysis of plasma amino acids, urine organic acids, and blood lactate and pyruvate are the most important laboratory tests for the initial recognition of pyruvate dehydrogenase complex deficiency in an individual. Metabolic and lactic acidosis, as well as keto acidosis, are initially observed. In contrast to pyruvate carboxylase deficiency, fasting hypoglycemia and hyperammonemia are not expected features of pyruvate dehydrogenase complex deficiency. Blood lactate, pyruvate, alanine, and proline can be intermittently normal when measured after an overnight fast but characteristically increased after a dietary intake of carbohydrates. Specific plasma amino acid ratios, such as Ala/Leu, Ala/Lys, Pro/Leu, (Ala+Pro)/Leu, and (Ala+Pro)/(Leu+Lys) and their combinations, are highly sensitive (90% or greater, depending the specific ratio or combination ratios used) but only 75% to 85% specific for identifying individuals with pyruvate dehydrogenase complex deficiency (07; 87). Often, plasma amino acids may be reported normal, but the specific amino acid ratios (noted above) could suggest pyruvate dehydrogenase complex deficiency.

Functional (enzymatic) diagnosis of pyruvate dehydrogenase complex deficiency is established in a proband with supportive metabolic analyte findings, such as elevated blood lactate and pyruvate with normal lactate to pyruvate (L/P) ratio, elevated blood alanine and often proline, Ala/Leu ≥4.0, Ala/Lys ≥3.0, Pro/Leu ≥3.0, (Ala+Pro)/Leu ≥6.5, and (Ala+Pro)/(Leu+Lys) ≥2.5, and typical brain anomalies, by measuring low pyruvate dehydrogenase complex enzyme activity in cultured fibroblast cells from skin biopsy, WBC lymphocytes, or skeletal muscle tissue (Table1) (72). Pyruvate dehydrogenase complex activity can be measured at low and high thiamine pyrophosphate concentrations to identify thiamine-responsive pyruvate dehydrogenase complex deficiency. It is important to know the limitations of clinical enzymatic testing (ie, its sensitivity and variability with patient sex, cell or tissue type used, and passage number used in assays) because this has important diagnostic and management implications (72).

A molecular genetic diagnosis of pyruvate dehydrogenase complex deficiency is established in a proband with supportive metabolic analyte findings and typical brain anomalies, by identifying a single pathogenic variant (or likely pathogenic variant) in an X-linked gene such as PDHA1 associated with pyruvate dehydrogenase complex deficiency (as heterozygous or hemizygous in a female or male, respectively) or biallelic pathogenic or likely pathogenic variants in other pyruvate dehydrogenase complex deficiency-associated genes by molecular genetic testing (Table 2).

Notably, the turnaround time in receiving test results varies among laboratories and should be considered when determining the order and type of testing. Frequently, both types of testing are ordered together or sequentially, especially if one of the test results is ambiguous or insufficient to establish pyruvate dehydrogenase complex deficiency diagnosis.

Biochemical diagnosis. Assaying pyruvate dehydrogenase complex in cultured fibroblasts in cases where the underlying genetic etiology is PDHA1 (most common) is highly sensitive irrespective of sex; 97% (95% confidence interval [CI]: 90%-100%) and 91% (95% CI: 82%-100%) in females and males, respectively (72). In contrast to fibroblast-based testing, lymphocyte- and muscle-based testing are not sensitive (36% [95% CI: 11%-61%, p=0.0003] and 58% [95% CI: 30%-86%, p=0.014], respectively) for identifying known pyruvate dehydrogenase complex-deficient females with pathogenic PDHA1 variants (72). The sensitivity and variability of pyruvate dehydrogenase complex activity testing using cultured fibroblasts, WBC lymphocytes, or skeletal muscle tissue for other pyruvate dehydrogenase complex deficiency-associated genes remain to be thoroughly evaluated.

Molecular diagnosis. Per ACMG/AMP variant interpretation guidelines, the terms “pathogenic variant” and “likely pathogenic variant” are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making (62).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which genes are likely involved, whereas comprehensive genomic testing does not.

If primary lactic acidosis and pyruvate dehydrogenase complex deficiency are suspected based on biochemical (elevated lactate and pyruvate with normal L/P ratio and specific amino acid ratios and their combinations) and clinical phenotype (brain anomalies and neurodevelopmental findings), a multigene panel that includes PDHA1 and other pyruvate dehydrogenase complex deficiency-associated genes of interest (such as the panel noted in legend of Table 2) may be more likely to identify the genetic cause of the condition while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. However, comprehensive exome or genome testing does not require the clinician to determine which gene is likely involved. Therefore, exome or genome sequencing can be used. Although most pathogenic variants in pyruvate dehydrogenase complex deficiency-associated genes to date are within the coding regions and are likely to be identified on exome sequencing, pathogenic splicing variants outside the canonical splice junction, deep intronic variants, as well as structural variants resulting in pyruvate dehydrogenase complex deficiency, could be identified by genome sequencing. Ordering expedited exome or genome sequencing is necessary in cases of critically ill newborns or infants.

Classes of pathogenic variants. Although truncating or nonsense variants in pyruvate dehydrogenase complex deficiency-associated genes are more often associated with severe pyruvate dehydrogenase complex deficiency phenotype, the clinical phenotype of individuals with missense, splice site, or deep intronic variants in those same genes may vary from mild to severe presentations. Individuals with thiamine-responsive PDHA1 variants tend to more often have a mild to moderate phenotype, likely depending on disease onset and start and choices of management interventions after diagnosis is established.

Management

	• Ketogenic diet is the main therapeutic intervention for primary-specific pyruvate dehydrogenase complex deficiency due to PDHA1, PDHB, DLAT, PDP1, and PDHX.
	• The efficacy of ketogenic diet intervention depends on the pyruvate dehydrogenase complex deficiency disease phenotype and the attainment and maintenance of ketosis.
	• Ketogenic diet can be difficult to tolerate long-term. Tolerance of the ketogenic diet varies between individuals; thus, treatment must be individualized. Ketogenic diet can still leave patients with significant systemic disease and developmental disability.
	• Ketogenic diet can be ineffective in patients with severe brain damage in utero or at birth and may be harmful (or even lethal) in cases other than primary-specific pyruvate dehydrogenase complex deficiency where pyruvate dehydrogenase complex deficiency is associated with more general impairment of formation or oxidation of acetyl-CoA.
	• Certain PDHA1 (and likely PDHB) variants are responsive to thiamine supplementation, but in addition to thiamine supplementation certain patients may still require concurrent use of ketogenic diet for optional metabolic balance.
	• Dichloroacetate can be effective for certain cases of primary-specific pyruvate dehydrogenase complex deficiency and those with specific gene variants.

There is no cure for pyruvate dehydrogenase complex deficiency. In most cases, polytherapy is the management approach for individuals with pyruvate dehydrogenase complex deficiency. However, the specific approach depends on the patient and their specific disease. Molecular genetic confirmation of the pyruvate dehydrogenase complex deficiency diagnosis is necessary for best management choices and outcomes.

Ketogenic diet. Life-long use of ketogenic diet (and avoidance of high carbohydrate diets) is the main therapeutic intervention for primary-specific pyruvate dehydrogenase complex deficiency, with positive outcomes noted in the areas of epilepsy, ataxia, sleep disturbance, speech and language development, social functioning, and frequency of hospitalizations (89; 17; 68; 73; 16). Although ketogenic diet therapy has never been evaluated in a clinical trial (and probably will not be in the future), its use has the basis of rationale in the oxidation of beta-hydroxybutyrate and acetoacetate (ketone bodies), which cross the brain barrier and do not depend on pyruvate dehydrogenase complex for oxidation. Oxidation of the ketone bodies provides the brain with an alternative fuel source to generate acetyl-CoA used for maintaining the mitochondrial pools of tricarboxylic acid cycle intermediates and production of reducing equivalents for subsequent ATP production through the mitochondrial respiratory chain, thus restoring the energy deficit characteristic of pyruvate dehydrogenase complex deficiency. Diffusion of ketone bodies across the blood-brain barrier is facilitated by the monocarboxylic transporters.

The proportions of fat, carbohydrate, and protein in ketogenic diet vary considerably in actual practice (eg, 4:1 or 2:1 fat-to-carbohydrate and protein ratio), with recommendations for minimal (less than 10%) energy from carbohydrates (89). The recommended ketogenic diet ratio varies from as low as a ketogenic diet 1:1 fat-to-carbohydrate and protein ratio ("modified" ketogenic diet or equivalent to a modified Atkins diet) to as high as a ketogenic diet 4:1 ratio or slightly more. No studies have definitively demonstrated the superiority of any particular ketogenic diet ratio. Tolerance of ketogenic diet varies between individuals; thus, treatment must be individualized. The recommended amount of dietary fat can vary widely, from approximately 55% to 80%, with variable proportions of unsaturated and saturated fats. The best outcomes are associated with maintaining plasma or serum beta-hydroxybutyrate concentration at 3.0 to 3.5 mEq/L (73). Ketosis is infrequently monitored by measurement of blood beta-hydroxybutyrate or beta-hydroxybutyrate/acetoacetate ratio, but these are helpful measures for maintaining ketosis. Additionally, long-term ketogenic diet use can be detrimental to lipid metabolism with regard to cholesterol or lipid profiles (23). Poor cholesterol/lipid profiles in patients on the ketogenic diet presumably can lead to a higher risk of cardiovascular disease. A less restrictive partial ketogenic diet has been used on a select cohort of patients with DLD-E3 deficiency (categorized as primary-generalized pyruvate dehydrogenase complex deficiency) due to a homozygous DLD p.D479V variant; the less restrictive diet showed improved survival but no significant improvement in quality of life (81). Certain ketogenic diet regimens can be deficient in vitamins and calcium; therefore, they should be supplemented with carbohydrate-free preparations as needed.

Because of the delayed diagnosis of individuals with pyruvate dehydrogenase complex deficiency (17; 73; 87), the efficacy of early perinatal intervention with ketogenic diet has not been systematically investigated. In utero brain anomalies in fetuses later assessed to have primary-specific pyruvate dehydrogenase complex deficiency due to PDHA1, PDHX, and DLAT are well documented (74; 50; 60; 66), but the use of ketogenic diet in a pregnant mother with an affected fetus with known pyruvate dehydrogenase complex deficiency has not been reported. Although the use of beta-hydroxybutyrate in infants has been found to be safe and effective for multiple acyl-CoA dehydrogenase deficiency (85; 86), the utility of beta-hydroxybutyrate (whether as a dietary supplement during inpatient management) for rapid induction of ketosis in newborns or infants with pyruvate dehydrogenase complex deficiency has not been tried.

Thiamine (vitamin B)*. Supplementation with high-dose thiamine (500 to 2000 mg/day) is most commonly used. Several reports of thiamine-responsive PDHA1 variants are known (Table 3) (49; 70; 17; 13; 15; 84; 19). Certain pathogenic PDHA1 variants impacting E1α regions that are either not directly participating in thiamine pyrophosphate binding or have low affinity for thiamine pyrophosphate are considered thiamine-responsive (Table 3) (49; 70; 32; 17; 13; 15; 84; 54; 55; 19). In contrast, the PDHA1 precursor p.R119W variant, where mature R90 directly binds thiamine pyrophosphate and is catalytically crucial, is not responsive to thiamine, at least in vitro in cultured fibroblasts (32). Thiamine use has not been reported to have adverse side effects; consequently, it is commonly administered to patients with pyruvate dehydrogenase complex deficiency, irrespective of responsiveness or efficacy.

Table 3. Thiamine-Responsive Pathogenic Variants of E1α *

Amino acid change	Mature residue	Exon #	Reference
p.H44R	His15	3	(19)
p.V71A	Val42	3	(84; 19)
p.I87M	Ile58	3	(13; 19)
p.R88S, p.R88C	Arg59	3	(13; 19)
p.G89S	Gly60	3	(13; 19)
p.C101F	Cys72	4	(84; 19)
p.Y161C	Tyr132	5	(84; 19)
p.F205L	Phe176	7	(13; 19)
p.M210V	Met181	7	(13)
p.W214R	Trp185	7	(19)
p.L216F, p.L216S	Leu187	7	(13; 15; 19)
p.Y243S	Tyr214	7	(84)
p.R253G	Arg224	8	(55)
p.R263G	Arg234	8	(84; 19)
p.S390KextX32	Ser361	C-tail extension	(49; 84)
p.X391FextX33		C-tail extension	This review
* High-dose thiamine supplementation does not fully restore maximum in vitro enzyme activity in cultured fibroblasts. Therefore, affected individuals with thiamine-responsiveness pathogenic PDHA1 variants may still require additional therapeutic interventions such as ketogenic diet or dichloroacetate for maximal favorable biochemical, neurologic, and developmental outcomes.

Dichloroacetate. Dichloroacetate is a structural analogue of pyruvate and an activator of pyruvate dehydrogenase complex that has been recognized to have potential clinical benefit and has been used in clinical trials. The mechanism of dichloroacetate activation of pyruvate dehydrogenase complex and, thus, lowering of blood lactate was shown to be inhibition of pyruvate dehydrogenase kinases, with different binding sites (78). As an inhibitor of the E1 kinase, dichloroacetate maintains any residual E1 activity of mutant pyruvate dehydrogenase complex in its maximal active (dephosphorylated) form. Two prior clinical trials of dichloroacetate, one controlled, the other open-label, in children with congenital lactic acidosis and adults with various mitochondrial disorders, including pyruvate dehydrogenase complex deficiency, showed a reduction in CSF or blood lactate but did not show significant overall clinical benefit (04; 77). Dichloroacetate has been associated with toxic neuropathy in subjects with other mitochondrial disorders, such as MELAS (35). A difference between children and adults and an individual association with genetic variations have been shown to affect the rate of catabolism of dichloroacetate (and the risk of peripheral neuropathy) (35), which has been proposed as a basis for pharmacokinetic monitoring and management of safe clinical use of dichloroacetate (78). Stimulation of pyruvate dehydrogenase complex with dichloroacetate enhances tricarboxylic acid cycle anabolic bioenergetics in monocytes (90). Furthermore, dichloroacetate metabolism correlates with the expression of the GSTZ1 protein (40). The lower expression of GSTZ1 in Whites, Hispanics, and Asians who possess a specific lysine (K) carrier haplotype of GSTZ1 results in lower enzymatic activity and slower metabolism of dichloroacetate compared with those who possess the non-K carrier haplotype (40). There are three nonsynonymous functional single nucleotide polymorphisms in human GSTZ1 [rs7975 G > A (E32K), rs7972 G > A (G42R), and rs1046428 C > T (T82 M)] that give rise to five major haplotypes in order of population frequency haplotypes, EGT (GSTZ1C, wild type 50%); KGT (GSTZ1B, 28%); EGM (GSTZ1D, 15%); KRT (GSTZ1A, 7%); and KGM (GSTZ1F, 0.4%) (39). Patients with at least one EGT haplotype (EGT carrier) metabolized dichloroacetate faster than EGT noncarriers. The most common dosage of dichloroacetate used is about 25 mg/kg/day divided in two doses for patients with the GSTZ1 EGT carrier haplotype (“fast metabolizer”) and about half this dosage for those GSTZ1 EGT noncarriers (“slow metabolizer”) (39). A controlled Phase III trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency (ClinicalTrials.gov ID#: NCT02616484), using a validated parental observation of child behavior scale as the primary outcome measure is undergoing result analysis and FDA review.

Lipoic acid. Studies have suggested that exogenous lipoic acid, although beneficial as an antioxidant with very low toxicity, is not utilized for mitochondrial lipoylation (45). Thus, the utility of lipoic acid supplementation in pyruvate dehydrogenase complex deficiency is unclear.

L-carnitine (if on the ketogenic diet). Supplementation with L-carnitine (carbohydrate or sugar-free) is utilized to protect against secondary carnitine deficiency, which is associated with long-term use of the ketogenic diet.

Bicarbonate or buffering agents for metabolic acidosis (due to elevated lactate or ketosis) at 0.5 to 2.5 mEq/kg/day is necessary for individuals with pyruvate dehydrogenase complex deficiency, particularly those on ketogenic diet. Examples of buffering agents include Bicitra (sodium citrate/citric acid) where 1 mL = 1 mEq bicarbonate, Cytra-K (potassium citrate/citric acid) where one packet = 30 mEq bicarbonate with 0.063 g CHO/packet, or a mix of both for sodium or potassium balance.

Any standard antiseizure therapy or other medications or supplements (such as riboflavin) should be carbohydrate- or sugar-free if the patient is on the ketogenic diet. Sleep disturbances, including difficulty falling asleep, are common in pyruvate dehydrogenase complex deficiency, and melatonin (sugar-free) has proven useful.

Emergency room protocol to provide to patient and family:
	• Contact (your metabolic team) at (phone) and ask them to page the metabolic geneticist on-call.
	• Obtain labs preferably before starting intravenous fluids:
		- STAT arterial blood gas or venous blood gas, STAT blood lactate and pyruvate concentrations
		- STAT Comprehensive metabolic panel (which should include glucose, electrolytes with bicarbonate, blood urea nitrogen and creatinine, liver function tests, protein, and albumin) and beta-hydroxybutyrate.
		- CBC with differential (add blood cultures if febrile)
		- Free and total carnitine as well as serum CK and plasma or serum amino acids.
		- Urine analysis and urine ketones (add urine cultures if febrile).
	• Intravenous treatment:
		- Start an intravenous line immediately (even if not clinically dehydrated) with a bolus of normal saline at 20 cc/kg and then 0.5 (or 1.0) normal saline with 25 mg thiamine per 1 liter and 30 mEq/L potassium acetate at maintenance. Lactate Ringer’s solution is contraindicated in pyruvate dehydrogenase complex deficiency. Do NOT use lactate Ringer’s solution.
		- Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH less than 7.10 or bicarbonate less than 10 mEq/L).
		- Lipids should be started for calories if the patient is not tolerating oral feeds. Intravenous intralipids may be started at 2 gm/kg/day over 24 hours and increased by 0.5 mg/kg/d every day to a maximum of 3 gm/kg/day. Follow triglyceride concentrations as needed.
		- If the patient remains on intravenous fluids for an extended period (more than 2 days), the minimum daily requirement of amino acids must be added to the carbohydrate-free intravenous fluids (keeping in mind that gluconeogenic amino acids may be converted to pyruvate, which is the reason for giving them at the minimum requirement).
		- Start intravenous carnitine 100 mg/kg/day divided every 6 hours. If not available in intravenous form, start oral (or via nasogastric tube) carnitine (carbohydrate- or sugar-free) 100 mg/kg/day divided every 6 hours.
		- As with all mitochondrial disorders, propofol should be used with caution or avoided and should not be used for an extended period, such as for prolonged sedation. Similarly, known mitochondrial toxins, such as valproic acid (divalproex sodium) and derivatives, should be avoided.

Medical therapy for the underlying intercurrent illness should be instituted concurrent to treatment for the inborn error of metabolism.

Outcomes

The efficacy of ketogenic diet intervention depends on the pyruvate dehydrogenase complex deficiency disease phenotype and the attainment and maintenance of ketosis (73). The most favorable developmental outcomes are associated with early implementation of the ketogenic diet (89) and are most pronounced in individuals with relatively mild presentations of pyruvate dehydrogenase complex deficiency, such as childhood-onset ataxia (73). Ketogenic diet is most beneficial in individuals with a milder pre-treatment disease course, disease onset after the neonatal period, higher baseline developmental functioning, and absence of structural brain anomalies (73). However, ketogenic diet can be ineffective in patients with severe brain damage in utero or at birth and may be harmful (or even lethal) in cases where pyruvate dehydrogenase complex deficiency is associated with more general impairment of formation of acetyl-CoA (eg, fatty acid beta-oxidation, branched-chain amino acids metabolism defects or E3 deficiency) or oxidation of acetyl-CoA (eg, tricarboxylic acid cycle defects, such as SUCLA2 deficiency or other mitochondrial dysfunction) (20; 05; 31). Ketogenic diet can be difficult to tolerate long-term, and nausea is reported with ketogenic diet use, which has been suggested as a manifestation of excess ketosis (88). Ketogenic diet still leaves patients, particularly those with severe disease and brain anomalies, with significant systemic disease and developmental disability.

Individuals on ketogenic diet should be provided bicarbonate or buffering agents for metabolic acidosis secondary to ketosis and should have scheduled thyroid function, iron, total iron binding capacity and ferritin, vitamins (including vitamin D 25-hydroxy battery), zinc, selenium, and free and total plasma carnitine concentrations evaluated and supplemented as needed for best outcomes. Carnitine deficiency can be seen during the course of ketogenic diet treatment, but it is rarely symptomatic. Selenium deficiency was found in 20% of patients on a ketogenic diet, and this deficiency may not be evident for several months (09). Furthermore, because selenium deficiency can alter normal cardiac function (02), obtaining an initial echocardiogram, electrocardiography, and selenium concentration are advised before initiation of ketogenic diet.

Among more than 130 known nonduplicate PDHA1 pathogenic variants, less than 20 (Table 3) are thiamine-responsive. The efficacy of high-dose thiamine supplementation (usually administered in a sugar-free form) is variable and depends on the individual’s thiamine-responsive PDHA1 pathogenic variant (49; 70; 32; 17; 13; 15; 84; 54; 55). Despite the use of nonphysiologic high-dose thiamine (500 to 2000 mg/day), only up to two thirds maximal in vitro enzymatic efficacy is usually achieved. Consequently, a low-strength ketogenic diet (modified Atkins diet to ketogenic diet 2.5:1) is usually administrated in conjunction with high-dose thiamine for better metabolic balance and more efficacious clinical outcomes and quality of life.

Special considerations

Pregnancy

Once the primary pyruvate dehydrogenase complex deficiency-causing pathogenic variants are identified in an affected family member, molecular genetic prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. There could be differences in perspective among medical professionals and within families regarding the use of prenatal testing, so discussion of these issues may be helpful. Prenatal fetal brain anomalies have been observed, such as cerebellar hypoplasia and ventriculomegaly and ventricular asymmetry, periventricular cystic lesions, corpus callosum anomalies (thin or absent), absent septum pellucidum, basal ganglia and midbrain anomalies and cystic cavitations, mega cisterna magna, hypoplastic cerebellum, cerebellum vermian anomalies or absence, optic nerve hypoplasia at different stages of gestational age (50; 57; 83; 22; author personal experience).

Anesthesia

As with all mitochondrial disorders, propofol should be used with caution or avoided and should not be used for an extended period, such as for prolonged sedation. Similarly, known mitochondrial toxins, such as valproic acid (divalproex sodium) and derivatives, should be avoided. Fentanyl or remifentanil have minimal mitochondrial effects (30). Remifentanil, an opioid with a fast offset because it is rapidly metabolized by serum cholinesterases, has proven useful. The sedative benzodiazepines, as well as the CNS alpha-adrenergic agonist dexmedetomidine, have also proven useful for mitochondrial diseases, although their clearance may be slowed and effects prolonged (61; 30). Analgesic doses of ketamine generally are well tolerated (61; 30).

For pyruvate dehydrogenase complex deficiency patients with malignant hyperthermia, a nontriggering anesthetic consisting of bolus of low-dose propofol for induction, ketamine boluses, benzodiazepine-like midazolam boluses, dexmedetomidine hydrochloride, and remifentanil infusions, +/- muscle relaxation as needed have proven useful as well.

References

01: Ah Mew N, Loewenstein JB, Kadom N, et al. MRI features of 4 female patients with pyruvate dehydrogenase E1 alpha deficiency. Pediatr Neurol 2011;45(1):57-9. PMID 21723463
02: Bank IM, Shemie SD, Rosenblatt B, Bernard C, Mackie AS. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol 2008;39(6):429-31. PMID 19027591
03: Barnerias C, Saudubray JM, Touati G, et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol 2010;52(2):e1-9. PMID 20002125
04: Barshop BA, Naviaux RK, McGowan KA, et al. Chronic treatment of mitochondrial disease patients with dichloroacetate. Mol Genet Metab 2004;83(1-2):138-49. PMID 15464428
05: Bedoyan JK, Yang SP, Ferdinandusse S, et al. Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 2017;120(4):342-9. PMID 28202214
06: Bedoyan JK, Hecht L, Zhang S, et al. A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep 2019;48(1):26-35. PMID 31392110
07: Bedoyan JK, Hage R, Shin HK, et al. Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects. JIMD Rep 2020;56(1):70-81.** PMID 33204598
08: Behal RH, Buxton DB, Robertson JG, Olson MS. Regulation of the pyruvate dehydrogenase multienzyme complex. Annu Rev Nutr 1993;13:497-520. PMID 8369156
09: Bergqvist AG, Chee CM, Lutchka L, Rychik J, Stallings VA. Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia 2003;44(4):618-20. PMID 12681013
10: Blass JP, Avigan J, Uhlendorf BW. A defect in pyruvate decarboxylase in a child with an intermittent movement disorder. J Clin Invest 1970;49(3):423-32. PMID 4313434
11: Brivet M, Moutard ML, Zater M, et al. First characterization of a large deletion of the PDHA 1 gene. Mol Genet Metab 2005;86(4):456-61. PMID 16256390
12: Brown RM, Head RA, Morris AA, et al. Pyruvate dehydrogenase E3 binding protein (protein X) deficiency. Dev Med Child Neurol 2006;48(9):756-60. PMID 16904023
13: Brown G. Defects of thiamine transport and metabolism. J Inherit Metab Dis 2014;37(4):577-85.** PMID 24789339
14: Cameron JM, Maj M, Levandovskiy V, et al. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. Hum Genet 2009;125(3):319-26. PMID 19184109
15: Castiglioni C, Verrigni D, Okuma C, et al. Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review. Eur J Paediatr Neurol 2015;19(5):497-503. PMID 26008863
16: Chida R, Shimura M, Nishimata S, Kashiwagi Y, Kawashima H. Efficacy of ketogenic diet for pyruvate dehydrogenase complex deficiency. Pediatr Int 2018;60(11):1041-2.** PMID 30407699
17: DeBrosse SD, Okajima K, Zhang S, et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab 2012;107(3):394-402.** PMID 23021068
18: Deeb KK, Bedoyan JK, Wang R, et al. Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency. Mol Genet Metab Rep 2014;1:362-67. PMID 27896109
19: Ducich NH, Mears JA, Bedoyan JK. Solvent accessibility of E1α and E1β residues with known missense mutations causing pyruvate dehydrogenase complex (PDC) deficiency: Impact on PDC-E1 structure and function. J Inherit Metab Dis 2022;45(3):557-570.** PMID 35038180
20: Ferdinandusse S, Friederich MW, Burlina A, et al. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis 2015;10:79. PMID 26081110
21: Fisher-Wellman KH, Gilliam LA, Lin CT, Cathey BL, Lark DS, Darrell Neufer P. Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. Free Radic Biol Med 2013;65:1201-8. PMID 24056031
22: Fortin O, Christoffel K, Shoaib A, et al. Characteristic fetal brain MRI abnormalities in pyruvate dehydrogenase complex deficiency. medRxiv [Preprint] 2024:2024.04.08.24303574. PMID 38645225
23: Fuehrlein BS, Rutenberg MS, Silver JN, et al. Differential metabolic effects of saturated versus polyunsaturated fats in ketogenic diets. J Clin Endocrinol Metab 2004;89(4):1641-5. PMID 15070924
24: Gokcan H, Bedoyan JK, Isayev O. Simulations of pathogenic E1α variants: allostery and impact on pyruvate dehydrogenase complex-E1 structure and function. J Chem Inf Model 2022;62(14):3463-75.** PMID 35797142
25: Hard ML, Raha S, Spino M, Robinson BH, Koren G. Impairment of pyruvate dehydrogenase activity by acetaldehyde. Alcohol 2001;25(1):1-8. PMID 11668012
26: Han Z, Zhong L, Srivastava A, Stacpoole PW. Pyruvate dehydrogenase complex deficiency caused by ubiquitination and proteasome-mediated degradation of the E1 subunit. J Biol Chem 2008;283(1):237-43. PMID 17923481
27: Harris RA, Bowker-Kinley MM, Huang B, Wu P. Regulation of the activity of the pyruvate dehydrogenase complex. Adv Enzyme Regul 2002;42:249-59. PMID 12123719
28: Head RA, Brown RM, Zolkipli Z, et al. Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann Neurol 2005;58(2):234-41. PMID 16049940
29: Hezaveh S, Zeng AP, Jandt U. Full enzyme complex simulation: interactions in human pyruvate dehydrogenase complex. J Chem Inf Model 2018;58(2):362-9. PMID 29298056
30: Hsieh VC, Krane EJ, Morgan PG. Mitochondrial disease and anesthesia. J Inborn Errors Metab Screen 2017;5.
31: Huang X, Bedoyan JK, Demirbas D, et al. Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab 2017;120(3):213-22. PMID 27913098
32: Imbard A, Boutron A, Vequaud C, et al. Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. Mol Genet Metab 2011;104(4):507-16. PMID 21914562
33: Ivanov IS, Azmanov DN, Ivanova MB, et al. Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children. Mol Genet Metab 2014;113(1-2):76-83. PMID 25087164
34: Jones DE, Klacking E, Ryan RO. Inborn errors of metabolism associated with 3-methylglutaconic aciduria. Clin Chim Acta 2021;522:96-104. PMID 25087164
35: Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006;66(3):324-30. PMID 16476929
36: Kennerson ML, Yiu EM, Chuang DT, et al. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet 2013;22(7):1404-16. PMID 23297365
37: Korotchkina LG, Ciszak EM, Patel MS. Function of several critical amino acids in human pyruvate dehydrogenase revealed by its structure. Arch Biochem Biophys 2004;429(2):171-9. PMID 15313220
38: Kowaloff EM, Phang JM, Granger AS, Downing SJ. Regulation of proline oxidase activity by lactate. Proc Natl Acad Sci U S A 1977;74(12):5368-71. PMID 271958
39: Langaee T, Wagner R, Horne LP, et al. Personalized dosing of dichloroacetate using GSTZ1 clinical genotyping assay. Genet Test Mol Biomarkers 2018;22(4):266-69. PMID 29641284
40: Langaee TY, Zhong G, Li W, et al. The influence of human GSTZ1 gene haplotype variations on GSTZ1 expression. Pharmacogenet Genomics 2015;25(5):239-45. PMID 25738370
41: Li Y, Lou W, Raja V, et al. Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function. J Biol Chem 2019;294(30):11568-78. PMID 31186346
42: Lissens W, De Meirleir L, Seneca S, et al. Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 2000;15(3):209-19. PMID 10679936
43: Maj MC, MacKay N, Levandovskiy V, et al. Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. J Clin Endocrinol Metab 2005;90(7):4101-7. PMID 15855260
44: Mathias RA, Greco TM, Oberstein A, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159(7):1615-25. PMID 25525879
45: Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W. Lipoic acid biosynthesis defects. J Inherit Metab Dis 2014;37(4):553-63.** PMID 24777537
46: Mine M, Brivet M, Schiff M, de Baulny HO, Chuzhanova N, Marsac C. A novel gross deletion caused by non-homologous recombination of the PDHX gene in a patient with pyruvate dehydrogenase deficiency. Mol Genet Metab 2006;89(1-2):106-10. PMID 16843025
47: McWilliam CA, Ridout CK, Brown RM, McWilliam RC, Tolmie J, Brown GK. Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia. Eur J Paediatr Neurol 2010;14(4):349-53. PMID 20022530
48: Murali CN, Ganetzky R. Persistent lactic acidosis in an 18-month-old girl status post bone marrow transplant. Pediatr Rev 2020;41(Suppl 1):S20-2. PMID 33004573
49: Narisawa K, Endo H, Miyabayashi S, Tada K. Thiamine responsive pyruvate dehydrogenase deficiency. J Nutr Sci Vitaminol (Tokyo) 1992;Spec No:585-8. PMID 1297818
50: Natarajan N, Tully HM, Chapman T. Prenatal presentation of pyruvate dehydrogenase complex deficiency. Pediatr Radiol 2016;46(9):1354-7. PMID 27026023
51: O'Brien M, Chalker J, Slade L, Gardiner D, Mailloux RJ. Protein S-glutathionylation alters superoxide/hydrogen peroxide emission from pyruvate dehydrogenase complex. Free Radic Biol Med 2017;106:302-14. PMID 28242228
52: Okajima K, Korotchkina LG, Prasad C, et al. Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency. Mol Genet Metab 2008;93(4):371-80. PMID 18164639
53: Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012;106(3):385-94.** PMID 22896851
54: Pavlu-Pereira H, Silva MJ, Florindo C, et al. Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients. Orphanet J Rare Dis 2020;15(1):298. PMID 33092611
55: Pavlu-Pereira H, Lousa D, Tomé CS, et al. Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency. Biochimie 2021;183:78-88. PMID 33588022
56: Perez-Siles G, Ly C, Grant A, et al. Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation. Neurobiol Dis 2016;94:237-44. PMID 27388934
57: Pirot N, Crahes M, Adle-Biassette H, et al. Phenotypic and neuropathological characterization of fetal pyruvate dehydrogenase deficiency. J Neuropathol Exp Neurol 2016;75(3):227-38. PMID 26865159
58: Plokhikh KS, Nesterov SV, Chesnokov YM, et al. Association of 2-oxoacid dehydrogenase complexes with respirasomes in mitochondria. FEBS J 2024;291(1):132-41. PMID 37789611
59: Quintana E, Gort L, Busquets C, et al. Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clin Genet 2010;77(5):474-82. PMID 20002461
60: Rahesh J, Anand R, Mendiola V, Jacob R. Pyruvate dehydrogenase complex deficiency mimicking congenital cytomegalovirus infection on imaging. Proc (Bayl Univ Med Cent) 2021;35(2):232-3. PMID 35261462
61: Rafique MB, Cameron SD, Khan Q, Biliciler S, Zubair S. Anesthesia for children with mitochondrial disorders: a national survey and review. J Anesth 2013;27(2):186-91. PMID 23007905
62: Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-24. PMID 25741868
63: Ridout CK, Keighley P, Krywawych S, Brown RM, Brown GK. A putative exonic splicing enhancer in exon 7 of the PDHA1 gene affects splicing of adjacent exons. Hum Mutat 2008;29(3):451. PMID 18273899
64: Robinson BH, MacMillan H, Petrova-Benedict R, Sherwood WG. Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J Pediatr 1987;111(4):525-33. PMID 3116190
65: Robinson BH, MacKay N, Chun K, Ling M. Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex. J Inherit Metab Dis 1996;19(4):452-62. PMID 8884569
66: Savvidou A, Ivarsson L, Naess K, et al. Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency: results from a nationwide population-based study. J Inherit Metab Dis 2022;45(2):248-63.** PMID 34873726
67: Savvidou A, Sofou K, Eklund EA, Aronsson J, Darin N. Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers. Eur J Neurol 2024;31(7):e16283. PMID 38497591
68: Scholl-Burgi S, Höller A, Pichler K, Michel M, Haberlandt E, Karall D. Ketogenic diets in patients with inherited metabolic disorders. J Inherit Metab Dis 2015;38(4):765-73. PMID 26109259
69: Schwab MA, Sauer SW, Okun JG, et al. Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 2006;398(1):107-12. PMID 16686602
70: Sedel F, Challe G, Mayer JM, et al. Thiamine responsive pyruvate dehydrogenase deficiency in an adult with peripheral neuropathy and optic neuropathy. J Neurol Neurosurg Psychiatry 2008;79(7):846-7. PMID 18559466
71: Sen K, Grahame G, Bedoyan JK, Gropman AL. Novel presentations associated with a PDHA1 variant: alternating hemiplegia in Hemizygote proband and Guillain Barre Syndrome in Heterozygote mother. Eur J Paediatr Neurol 2021;31:27-30. PMID 33592356
72: Shin HK, Grahame G, McCandless SE, Kerr DS, Bedoyan JK. Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 2017;122(3):61-6.** PMID 28918066
73: Sofou K, Dahlin M, Hallböök T, Lindefeldt M, Viggedal G, Darin N. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis 2017;40(2):237-45.** PMID 28101805
74: Soares-Fernandes JP, Teixeira-Gomes R, Cruz R, et al. Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings. Pediatr Radiol 2008;38(5):559-62. PMID 18197404
75: Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation. J Biol Chem 2018;293(20):7522-30. PMID 29191830
76: Sperl W, Fleuren L, Freisinger P, et al. The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. J Inherit Metab Dis 2015;38(3):391-403.** PMID 25526709
77: Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 2006;117(5):1519-31.** PMID 16651305
78: Stacpoole PW. The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. Aging Cell 2012;11(3):371-7. PMID 22321732
79: Stacpoole PW. Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. J Natl Cancer Inst 2017;109(11). PMID 29059435
80: Stacpoole PW, Dirain CO. The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation. Mol Genet Metab 2024. [Epub ahead of print].**
81: Staretz-Chacham O, Pode-Shakked B, Kristal E, et al. The effects of a ketogenic diet on patients with dihydrolipoamide dehydrogenase deficiency. Nutrients 2021;13(10):3523. PMID 34684524
82: Sutendra G, Kinnaird A, Dromparis P, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 2014;158(1):84-97. PMID 24995980
83: Tanner LM, Tynninen O, Piippo K, Puhakka AM. X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus. Prenat Diagn 2023;43(6):730-3. PMID 37160702
84: van Dongen S, Brown RM, Brown GK, Thorburn DR, Boneh A. Thiamine-responsive and non-responsive patients with PDHC-E1 deficiency: a retrospective assessment. JIMD Rep 2015;15:13-27. PMID 24718837
85: van Rijt WJ, Jager EA, Allersma DP, et al. Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency. Genet Med 2020;22(5):908-16. PMID 31904027
86: van Rijt WJ, Van Hove JL, Vaz FM, et al. Enantiomer-specific pharmacokinetics of D,L-3-hydroxybutyrate: implications for the treatment of multiple acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2021;44(4):926-38. PMID 33543789
87: Verma A, Lehman AN, Gokcan H, et al. Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism. Mol Genet Genomic Med 2024;12(1):e2283.** PMID 37688338
88: Vining EP, Freeman JM, Ballaban-Gil K, et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;55(11):1433-7. PMID 9823827
89: Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 1997;49(6):1655-61.** PMID 9409363
90: Zhu X, Long D, Zabalawi M, et al. Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes. J Leukoc Biol 2020;107(3):467-84. PMID 31894617
91: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Jirair Bedoyan MD PhD FACMG

Dr. Bedoyan of University of Pittsburgh School of Medicine and UPMC Children’s Hospital of Pittsburgh has no relevant financial relationships to disclose.
See Profile

Editor

Barry Wolf MD PhD

Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.
See Profile

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female
Heredity: heredity may be a factor
Population groups selectively affected: Bulgaria, Romania, Slovakia, and Hungary (founder PDHX p.R446* variant)

ICD & OMIM codes

ICD-10: Pyruvate dehydrogenase complex deficiency: E74.4
ICD-11: Pyruvate dehydrogenase complex deficiency: 5C53.02
OMIM: Pyruvate dehydrogenase E1-alpha deficiency, PDHAD: 312170

Pyruvate dehydrogenase alpha-1, PDHA1: 300502

Pyruvate dehydrogenase E1-beta deficiency, PDHBD: 614111

Pyruvate dehydrogenase, beta polypeptide, PDHB: 179060

Pyruvate dehydrogenase E2 deficiency, PDHDD: 245348

Dihydrolipoamide A-acetyltransferase, DLAT: 608770

Dihydrolipoamide dehydrogenase deficiency, DLDD: 246900

Dihydrolipoamide dehydrogenase, DLD: 238331

Pyruvate dehydrogenase Complex, component X, PDHX: 608769

Pyruvate dehydrogenase E3-binding protein deficiency, PDHXD: 245349

Pyruvate dehydrogenase phosphatase deficiency, PDHPD: 608782

Pyruvate dehydrogenase phosphatase catalytic subunit 1, PDP1: 605993

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Pyruvate dehydrogenase complex deficiency

Associated Disorders

Disorder of pyruvate oxidation
Mitochondrial disorder
Mitochondrial disorders of pyruvate metabolism associated with primary lactic acidosis

Also Relevant

2-Hydroxyglutaric acidurias
Alpha-ketoglutarate dehydrogenase deficiency
Barth syndrome
Leigh syndrome
Maple syrup urine disease
- Mitochondrial disorders
- Pyruvate carboxylase deficiency

Clinical Categories

Neurogenetic Disorders

Pyruvate dehydrogenase complex deficiency

Introduction

Overview

Key points

Historical note and terminology

Key points

Clinical manifestations

Presentation and course

Table 1. Newborn and Infant Pyruvate Dehydrogenase Complex Deficiency Presentation Vignettes: Diagnostic Approaches and Intervention Impacts

Prognosis and complications

Neuroimaging findings

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Table 2. Subclassification of Pyruvate Dehydrogenase Complex Deficiency and Other Pyruvate Metabolism-Related Disorders (currently known, possible, and potential molecular etiologies of impaired pyruvate oxidation)

Acquired disorders

Diagnostic workup

Key tests and procedures

Management

Table 3. Thiamine-Responsive Pathogenic Variants of E1α *

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hypermethioninemia

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Nonketotic hyperglycinemia

Leukodystrophies

Mucopolysaccharidoses

Alexander disease

This is an article preview.
Start a Free Account
to access the full version.