Pyruvate carboxylase deficiency disease

Summary

Pyruvate carboxylase deficiency disease (MONDO:0009949) is a disease caused by PC (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include triheptanoin.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PC (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,376
• Phenotypes (HPO): 70
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.4	Europe	Validated

Signs & symptoms

Clinical features (HPO)

70 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0032653	Elevated lactate:pyruvate ratio	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001942	Metabolic acidosis	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002161	Hyperlysinemia	Frequent (30-79%)
HP:0002490	Increased CSF lactate	Frequent (30-79%)
HP:0003348	Hyperalaninemia	Frequent (30-79%)
HP:0003542	Increased serum pyruvate	Frequent (30-79%)
HP:0003648	Lacticaciduria	Frequent (30-79%)
HP:0008358	Hyperprolinemia	Frequent (30-79%)
HP:0011966	Elevated plasma citrulline	Frequent (30-79%)
HP:0012644	Increased caudate lactate level	Frequent (30-79%)
HP:0012706	Elevated brain choline level by MRS	Frequent (30-79%)
HP:0012707	Elevated brain lactate level by MRS	Frequent (30-79%)
HP:0012708	Reduced brain N-acetyl aspartate level by MRS	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0410175	Hyperketonemia	Frequent (30-79%)
HP:0500147	Hypoglutaminemia	Frequent (30-79%)
HP:0500149	Hyperglutamatemia	Frequent (30-79%)
HP:0500181	Hypertaurinemia	Frequent (30-79%)
HP:0500198	Decreased CSF glutamine concentration	Frequent (30-79%)
HP:0500200	Increased CSF glutamate concentration	Frequent (30-79%)
HP:0500231	Abnormal CSF pyruvate family amino acid concentration	Frequent (30-79%)
HP:0500233	Increased CSF alanine concentration	Frequent (30-79%)
HP:0500246	Increased CSF citrulline concentration	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0011169	Generalized clonic seizure	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0012698	Cerebellar gliosis	Occasional (5-29%)
HP:0012762	Cerebral white matter atrophy	Occasional (5-29%)
HP:0025160	Abnormal temper tantrums	Occasional (5-29%)
HP:0025336	Delayed ability to sit	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0000817	Reduced eye contact	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate carboxylase deficiency disease
Mondo ID	MONDO:0009949
EFO	EFO:1001142
MeSH	D015324
OMIM	266150
Orphanet	3008
DOID	DOID:3651
ICD-11	2047948460
NCIT	C85040
SNOMED CT	87694001
UMLS	C0034341
MedGen	18801
GARD	0007512
Is cancer (heuristic)	no

Also known as: ataxia with lactic acidosis type 2 · ataxia with lactic acidosis type II · Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency · Leigh syndrome due to PC deficiency · Leigh syndrome due to pyruvate carboxylase deficiency · pyruvate carboxylase deficiency disease

Data availability: 1,376 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glucose metabolism disease › disorder of gluconeogenesis › pyruvate carboxylase deficiency disease

Related subtypes (6): fructose-1,6-bisphosphatase deficiency, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, glycerol kinase deficiency, infantile form, glycerol kinase deficiency, juvenile form, glycerol kinase deficiency, adult form, phosphoenolpyruvate carboxykinase deficiency

Subtypes (3): pyruvate carboxylase deficiency, infantile form, pyruvate carboxylase deficiency, severe neonatal type, pyruvate carboxylase deficiency, benign type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

407 likely benign, 68 uncertain significance, 52 likely pathogenic, 26 pathogenic, 21 conflicting classifications of pathogenicity, 13 benign, 9 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030920	NM_001040716.2(PC):c.1368+3605C>A	LRFN4	Pathogenic	criteria provided, single submitter
1457685	NC_000011.9:g.(?66618135)(66639640_?)del	LRFN4	Pathogenic	criteria provided, single submitter
1068572	NM_001040716.2(PC):c.2328_2329del (p.Ala778fs)	PC	Pathogenic	criteria provided, single submitter
1068973	NM_001040716.2(PC):c.2953del (p.Leu985fs)	PC	Pathogenic	criteria provided, single submitter
1070920	NM_001040716.2(PC):c.1663C>T (p.Arg555Ter)	PC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071460	NM_001040716.2(PC):c.2581del (p.Val861fs)	PC	Pathogenic	criteria provided, single submitter
1071602	NM_001040716.2(PC):c.3102dup (p.Thr1035fs)	PC	Pathogenic	criteria provided, single submitter
1073534	NM_001040716.2(PC):c.1042C>T (p.Gln348Ter)	PC	Pathogenic	criteria provided, single submitter
1075366	NM_001040716.2(PC):c.3288+1G>T	PC	Pathogenic	criteria provided, single submitter
1076206	NM_001040716.2(PC):c.2156_2159del (p.Ser719fs)	PC	Pathogenic	criteria provided, single submitter
1323416	NM_001040716.2(PC):c.1186-1G>T	PC	Pathogenic	criteria provided, single submitter
1359632	NM_001040716.2(PC):c.3190del (p.Ala1064fs)	PC	Pathogenic	criteria provided, single submitter
1370133	NM_001040716.2(PC):c.1702_1706del (p.Thr568fs)	PC	Pathogenic	criteria provided, single submitter
1379662	NM_001040716.2(PC):c.3164del (p.Gly1055fs)	PC	Pathogenic	criteria provided, single submitter
1413694	NM_001040716.2(PC):c.1345G>T (p.Glu449Ter)	PC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416961	NM_001040716.2(PC):c.1918C>T (p.Gln640Ter)	PC	Pathogenic	criteria provided, single submitter
1424155	NM_001040716.2(PC):c.913G>T (p.Glu305Ter)	PC	Pathogenic	criteria provided, single submitter
1425937	NM_001040716.2(PC):c.3288+2T>C	PC	Pathogenic	criteria provided, single submitter
1433419	NM_001040716.2(PC):c.1084del (p.Leu362fs)	PC	Pathogenic	criteria provided, single submitter
1454180	NM_001040716.2(PC):c.1023-1G>A	PC	Pathogenic	criteria provided, single submitter
1454797	NM_001040716.2(PC):c.366dup (p.Glu123Ter)	PC	Pathogenic	criteria provided, single submitter
1456444	NM_001040716.2(PC):c.1123C>T (p.Gln375Ter)	PC	Pathogenic	criteria provided, single submitter
1456502	NM_001040716.2(PC):c.3387del (p.Lys1130fs)	PC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457904	NM_001040716.2(PC):c.321+1G>T	PC	Pathogenic	criteria provided, single submitter
1458437	NM_001040716.2(PC):c.1067_1070delinsTCCACGTGGCTGAGGGCAGGCAG (p.Ser356fs)	PC	Pathogenic	criteria provided, single submitter
1691506	NM_001040716.2(PC):c.1513+1G>A	PC	Pathogenic	criteria provided, single submitter
1705425	NM_001040716.2(PC):c.908del (p.Gly303fs)	PC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1919134	NM_001040716.2(PC):c.1405C>T (p.Gln469Ter)	PC	Pathogenic	criteria provided, single submitter
1926728	NM_001040716.2(PC):c.2874dup (p.Phe959fs)	PC	Pathogenic	criteria provided, single submitter
2014330	NM_001040716.2(PC):c.2253del (p.Cys752fs)	PC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PC	Definitive	Autosomal recessive	pyruvate carboxylase deficiency disease	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PC	Orphanet:353308	Pyruvate carboxylase deficiency, infantile type
PC	Orphanet:353314	Pyruvate carboxylase deficiency, severe neonatal type
PC	Orphanet:353320	Pyruvate carboxylase deficiency, benign type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PC	HGNC:8636	ENSG00000173599	P11498	Pyruvate carboxylase, mitochondrial	gencc,clinvar
LRFN4	HGNC:28456	ENSG00000173621	Q6PJG9	Leucine-rich repeat and fibronectin type-III domain-containing protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PC	Pyruvate carboxylase, mitochondrial	Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second.
LRFN4	Leucine-rich repeat and fibronectin type-III domain-containing protein 4	Promotes neurite outgrowth in hippocampal neurons.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PC	Enzyme (other)	yes	6.4.1.1	Biotin_lipoyl, PYR_CT, Biotin_BS
LRFN4	Antibody/Immunoglobulin	yes		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right frontal lobe	1
right lobe of liver	1
cortical plate	1
ganglionic eminence	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PC	204	ubiquitous	marker	right lobe of liver, liver, right frontal lobe
LRFN4	214	ubiquitous	yes	ganglionic eminence, cortical plate, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PC	2,984
LRFN4	1,565

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PC	P11498	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRFN4	Q6PJG9	78.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective HLCS causes multiple carboxylase deficiency	1	815.7×	0.007	PC
Biotin transport and metabolism	1	519.1×	0.007	PC
Synaptic adhesion-like molecules	1	271.9×	0.007	LRFN4
Gluconeogenesis	1	219.6×	0.007	PC
Pyruvate metabolism	1	203.9×	0.007	PC
Protein-protein interactions at synapses	1	132.8×	0.009	LRFN4
Neuronal System	1	22.1×	0.045	LRFN4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
viral RNA genome packaging	1	4213.0×	0.003	PC
NAD+ metabolic process	1	936.2×	0.004	PC
NADP+ metabolic process	1	766.0×	0.004	PC
host-mediated activation of viral process	1	702.2×	0.004	PC
viral release from host cell	1	468.1×	0.004	PC
regulation of postsynaptic density assembly	1	443.5×	0.004	LRFN4
synaptic membrane adhesion	1	290.6×	0.005	LRFN4
regulation of presynapse assembly	1	271.8×	0.005	LRFN4
gluconeogenesis	1	162.0×	0.008	PC
lipid metabolic process	1	45.8×	0.024	PC
negative regulation of gene expression	1	34.5×	0.029	PC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PC	0	0
LRFN4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PC	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PC	6.4.1.1	pyruvate carboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PC
D	Druggable family + AlphaFold only, no drug	1	LRFN4
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PC	10	—
LRFN4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEPTANOIN	4	1