Table 4. [Disorders in the Differential Diagnosis of Pyruvate Carboxylase Deficiency]. - GeneReviews®

Gene(s)	Disorder	MOI	Selected Features / Comments
>350 genes ¹	Primary mitochondrial disorders	AD AR Mat XL	Lactate & pyruvate concentrations are ↑; lactate-to-pyruvate ratio is ↑, often >20
BTD	Biotinidase deficiency	AR	Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, seizures w/metabolic acidosis, hearing loss, alopecia, & perioral/facial dermatitis Laboratory findings incl metabolic ketolactic acidosis, organic aciduria, & hyperammonemia If diagnosed through newborn screening, usually asymptomatic w/lifelong treatment of oral biotin
CA5A	Carbonic anhydrase VA deficiency	AR	Neonatal, infantile, or early-childhood metabolic hyperammonemic encephalopathy combined w/lactic acidosis
>30 genes	Organic acidemias (incl propionic acidemia, isolated methylmalonic acidemia, disorders of intracellular cobalamin metabolism, & other organic acidemias)	AR XL	Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, encephalopathy, seizure, & metabolic acidosis &/or metabolic stroke Lactic acidemia, hypoglycemia, hyperammonemia, ketosis Multiorgan system involvement
DLAT DLD PDHA1 PDHB PDHX PDK3 PDP1	Primary pyruvate dehydrogenase complex deficiency (PDCD)	AR XL	Lactic acidemia w/progressive or intermittent neurologic features (poor acquisition or loss of motor milestones, hypotonia, epilepsy, ataxia), nystagmus, & dystonia ↑ blood & CSF lactate concentrations & ↑ blood & CSF concentrations of pyruvate & alanine Blood ketone bodies usually not detectable & normal lactate-to-pyruvate ratio in plasma, unlike PC deficiency
Disorders assoc w/secondary PDCD that are phenotypically similar to primary PDCD
OLA3 IBA57 ISCA1 ISCA2 NFU1 PMPCB	Multiple mitochondrial dysfunction syndromes (MMDS) (See ISCA1-MMDS & ISCA2-MMDS.)	AR	Neonatal lactic acidosis ↑ glycine concentration Electron transport chain enzyme activity deficiencies
ECHS1	Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency	AR	Lactic acidosis ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal) May be assoc w/abnormal acylcarnitine profile &/or ↑ urine organic acid w/marked 2-methyl-2,3-dihydroxybutyric acid
HIBCH	3-hydroxyisobutyryl-CoA hydrolase deficiency (OMIM 250620)	AR	Lactic acidosis ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal) May be assoc w/abnormal acylcarnitine profile &/or urine organic acids
LIAS	Lipoic acid synthetase deficiency (OMIM 614462)	AR	Lactic acidosis & seizures ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal or elevated) ↑ glycine concentration Electron transport chain enzyme activity deficiencies
LIPT1	Lipoyltransferase 1 deficiency (OMIM 616299)
LIPT2	Lipoyltransferase 2 deficiency (OMIM 617668)
SLC25A1	Mitochondrial citrate carrier deficiency (combined D-2- & L-2-hydroxyglutaric aciduria) (OMIM 615182)	AR	Neonatal lactic acidosis ↑ 2-hydroxyglutaric acid concentration
TPK1	Thiamine pyrophosphokinase deficiency (thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type) (OMIM 614458)	AR	↑ lactate & pyruvate concentrations (normal lactate-to-pyruvate ratio) Treatable w/high-dose thiamine ²
Gluconeogenic disorders
FBP1	Fructose-1,6-bisphosphatase deficiency	AR	↑ blood lactate, pyruvate, & alanine concentrations w/clinical symptoms Hypoglycemia ↑ ketone bodies
G6PC3	G6PC3 deficiency (ubiquitous glucose-6-phosphatase deficiency)
PCK1	Phosphoenolpyruvate carboxykinase deficiency, cytosolic (OMIM 261680)
Tricarboxylic acid cycle (TCA) disorders
FH	Fumarate hydratase deficiency	AR	↑ lactate & pyruvate concentrations ↑ lactate-to-pyruvate ratio ↑ fumaric acid or other TCA cycle intermediates
OGDH	Oxoglutarate dehydrogenase deficiency (OMIM 203740)
SDHA SDHAF1 SDHB SDHD	Mitochondrial complex II deficiency, nuclear type (OMIM PS252011)
SUCLA2	SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria
Defects of ketone body utilization or transport
OXCT1	Succinyl-CoA:3-oxoacid CoA transferase (SCOT) (OMIM 245050)	AR	Severe ketoacidosis, metabolic acidosis, tachypnea (due to acidosis), vomiting May have seizures May be hypo- or hyperglycemic or have mild hyperammonemia
ACAT1	Mitochondrial acetoacetyl-CoA thiolase (T2) (OMIM 203750)
SLC16A1	Moncarboxylate transporter (MCT1) deficiencies (OMIM 616095)

Gene(s)

Disorder

MOI

Selected Features / Comments

>350 genes ¹

Primary mitochondrial disorders

AD
AR
Mat
XL

Lactate & pyruvate concentrations are ↑; lactate-to-pyruvate ratio is ↑, often >20

BTD

Biotinidase deficiency

Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, seizures w/metabolic acidosis, hearing loss, alopecia, & perioral/facial dermatitis
Laboratory findings incl metabolic ketolactic acidosis, organic aciduria, & hyperammonemia
If diagnosed through newborn screening, usually asymptomatic w/lifelong treatment of oral biotin

CA5A

Carbonic anhydrase VA deficiency

Neonatal, infantile, or early-childhood metabolic hyperammonemic encephalopathy combined w/lactic acidosis

>30 genes

Organic acidemias (incl propionic acidemia, isolated methylmalonic acidemia, disorders of intracellular cobalamin metabolism, & other organic acidemias)

AR
XL

Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, encephalopathy, seizure, & metabolic acidosis &/or metabolic stroke
Lactic acidemia, hypoglycemia, hyperammonemia, ketosis
Multiorgan system involvement

DLAT
DLD
PDHA1
PDHB
PDHX
PDK3
PDP1

Primary pyruvate dehydrogenase complex deficiency (PDCD)

AR
XL

Lactic acidemia w/progressive or intermittent neurologic features (poor acquisition or loss of motor milestones, hypotonia, epilepsy, ataxia), nystagmus, & dystonia
↑ blood & CSF lactate concentrations & ↑ blood & CSF concentrations of pyruvate & alanine
Blood ketone bodies usually not detectable & normal lactate-to-pyruvate ratio in plasma, unlike PC deficiency

Disorders assoc w/secondary PDCD that are phenotypically similar to primary PDCD

OLA3
IBA57
ISCA1
ISCA2
NFU1
PMPCB

Multiple mitochondrial dysfunction syndromes (MMDS) (See ISCA1-MMDS & ISCA2-MMDS.)

Neonatal lactic acidosis
↑ glycine concentration
Electron transport chain enzyme activity deficiencies

ECHS1

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency

Lactic acidosis
↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal)
May be assoc w/abnormal acylcarnitine profile &/or ↑ urine organic acid w/marked 2-methyl-2,3-dihydroxybutyric acid

HIBCH

3-hydroxyisobutyryl-CoA hydrolase deficiency (OMIM 250620)

Lactic acidosis
↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal)
May be assoc w/abnormal acylcarnitine profile &/or urine organic acids

LIAS

Lipoic acid synthetase deficiency (OMIM 614462)

Lactic acidosis & seizures
↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal or elevated)
↑ glycine concentration
Electron transport chain enzyme activity deficiencies

LIPT1

Lipoyltransferase 1 deficiency (OMIM 616299)

LIPT2

Lipoyltransferase 2 deficiency (OMIM 617668)

SLC25A1

Mitochondrial citrate carrier deficiency (combined D-2- & L-2-hydroxyglutaric aciduria) (OMIM 615182)

Neonatal lactic acidosis
↑ 2-hydroxyglutaric acid concentration

TPK1

Thiamine pyrophosphokinase deficiency (thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type) (OMIM 614458)

↑ lactate & pyruvate concentrations (normal lactate-to-pyruvate ratio)
Treatable w/high-dose thiamine ²

Gluconeogenic disorders

FBP1

Fructose-1,6-bisphosphatase deficiency

↑ blood lactate, pyruvate, & alanine concentrations w/clinical symptoms
Hypoglycemia
↑ ketone bodies

G6PC3

G6PC3 deficiency (ubiquitous glucose-6-phosphatase deficiency)

PCK1

Phosphoenolpyruvate carboxykinase deficiency, cytosolic (OMIM 261680)

Tricarboxylic acid cycle (TCA) disorders

Fumarate hydratase deficiency

↑ lactate & pyruvate concentrations
↑ lactate-to-pyruvate ratio
↑ fumaric acid or other TCA cycle intermediates

OGDH

Oxoglutarate dehydrogenase deficiency (OMIM 203740)

SDHA
SDHAF1
SDHB
SDHD

Mitochondrial complex II deficiency, nuclear type (OMIM PS252011)

SUCLA2

Defects of ketone body utilization or transport

OXCT1

Succinyl-CoA:3-oxoacid CoA transferase (SCOT) (OMIM 245050)

Severe ketoacidosis, metabolic acidosis, tachypnea (due to acidosis), vomiting
May have seizures
May be hypo- or hyperglycemic or have mild hyperammonemia

ACAT1

Mitochondrial acetoacetyl-CoA thiolase (T2) (OMIM 203750)

SLC16A1

Moncarboxylate transporter (MCT1) deficiencies (OMIM 616095)

From: Pyruvate Carboxylase Deficiency

GeneReviews^® [Internet].

Adam MP, Feldman J, Mirzaa GM, et al., editors.

Seattle (WA): University of Washington, Seattle; 1993-2024.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.