mitochondrial DNA depletion syndrome 9
diseaseOn this page
Also known as lactic acidosis congenital infantilelactic acidosis, fatal infantilemitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)mitochondrial DNA depletion syndrome caused by mutation in SUCLG1mitochondrial DNA depletion syndrome type 9MTDPS9succinate-CoA ligase deficiencySUCLG1 mitochondrial DNA depletion syndrome
Summary
mitochondrial DNA depletion syndrome 9 (MONDO:0009504) is a disease caused by SUCLG1 (GenCC Definitive), with 2 cohort genes.
At a glance
- Prevalence: Unknown (Worldwide)
- Causal gene: SUCLG1 (GenCC Definitive)
- Cohort genes: 2
- ClinVar variants: 288
- Phenotypes (HPO): 64
Clinical features
Signs & symptoms
Clinical features (HPO)
64 HPO clinical features (Orphanet curated; top 50 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0002912 | Methylmalonic acidemia | Obligate (100%) |
| HP:0012120 | Methylmalonic aciduria | Obligate (100%) |
| HP:0001263 | Global developmental delay | Very frequent (80-99%) |
| HP:0003535 | 3-Methylglutaconic aciduria | Very frequent (80-99%) |
| HP:0008947 | Floppy infant | Very frequent (80-99%) |
| HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (80-99%) |
| HP:0012751 | Abnormal basal ganglia MRI signal intensity | Very frequent (80-99%) |
| HP:0001249 | Intellectual disability | Frequent (30-79%) |
| HP:0001298 | Encephalopathy | Frequent (30-79%) |
| HP:0001397 | Hepatic steatosis | Frequent (30-79%) |
| HP:0001508 | Failure to thrive | Frequent (30-79%) |
| HP:0001510 | Growth delay | Frequent (30-79%) |
| HP:0002059 | Cerebral atrophy | Frequent (30-79%) |
| HP:0002151 | Increased circulating lactate concentration | Frequent (30-79%) |
| HP:0002240 | Hepatomegaly | Frequent (30-79%) |
| HP:0002490 | Increased CSF lactate | Frequent (30-79%) |
| HP:0002910 | Elevated circulating hepatic transaminase concentration | Frequent (30-79%) |
| HP:0003128 | Lactic acidosis | Frequent (30-79%) |
| HP:0003202 | Skeletal muscle atrophy | Frequent (30-79%) |
| HP:0008347 | Decreased activity of mitochondrial complex IV | Frequent (30-79%) |
| HP:0011923 | Decreased activity of mitochondrial complex I | Frequent (30-79%) |
| HP:0011924 | Decreased activity of mitochondrial complex III | Frequent (30-79%) |
| HP:0011968 | Feeding difficulties | Frequent (30-79%) |
| HP:0000252 | Microcephaly | Occasional (5-29%) |
| HP:0000407 | Sensorineural hearing impairment | Occasional (5-29%) |
| HP:0000486 | Strabismus | Occasional (5-29%) |
| HP:0000508 | Ptosis | Occasional (5-29%) |
| HP:0000718 | Aggressive behavior | Occasional (5-29%) |
| HP:0000736 | Short attention span | Occasional (5-29%) |
| HP:0000975 | Hyperhidrosis | Occasional (5-29%) |
| HP:0001250 | Seizure | Occasional (5-29%) |
| HP:0001266 | Choreoathetosis | Occasional (5-29%) |
| HP:0001276 | Hypertonia | Occasional (5-29%) |
| HP:0001332 | Dystonia | Occasional (5-29%) |
| HP:0001336 | Myoclonus | Occasional (5-29%) |
| HP:0001371 | Flexion contracture | Occasional (5-29%) |
| HP:0001639 | Hypertrophic cardiomyopathy | Occasional (5-29%) |
| HP:0001943 | Hypoglycemia | Occasional (5-29%) |
| HP:0002013 | Vomiting | Occasional (5-29%) |
| HP:0002020 | Gastroesophageal reflux | Occasional (5-29%) |
| HP:0002045 | Hypothermia | Occasional (5-29%) |
| HP:0002098 | Respiratory distress | Occasional (5-29%) |
| HP:0002104 | Apnea | Occasional (5-29%) |
| HP:0002205 | Recurrent respiratory infections | Occasional (5-29%) |
| HP:0002317 | Unsteady gait | Occasional (5-29%) |
| HP:0002352 | Leukoencephalopathy | Occasional (5-29%) |
| HP:0002360 | Sleep abnormality | Occasional (5-29%) |
| HP:0002487 | Hyperkinetic movements | Occasional (5-29%) |
| HP:0003200 | Ragged-red muscle fibers | Occasional (5-29%) |
| HP:0003201 | Rhabdomyolysis | Occasional (5-29%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | mitochondrial DNA depletion syndrome 9 |
| Mondo ID | MONDO:0009504 |
| MeSH | C538134, C566885 |
| OMIM | 245400 |
| Orphanet | 17 |
| DOID | DOID:0080128 |
| SNOMED CT | 715338007 |
| UMLS | C3151476 |
| MedGen | 462826 |
| GARD | 0003163 |
| Is cancer (heuristic) | no |
Also known as: lactic acidosis congenital infantile · lactic acidosis, fatal infantile · mitochondrial DNA depletion syndrome 9 · mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) · mitochondrial DNA depletion syndrome caused by mutation in SUCLG1 · mitochondrial DNA depletion syndrome type 9 · MTDPS9 · succinate-CoA ligase deficiency · SUCLG1 mitochondrial DNA depletion syndrome
Data availability: 288 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.
Disease family
Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lactic acidosis › mitochondrial DNA depletion syndrome 9
Related subtypes (2): cardiomyopathy-hypotonia-lactic acidosis syndrome, acquired lactic acidosis
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
288 retrieved; paginated sample, class counts are floors:
125 likely benign, 99 uncertain significance, 24 pathogenic, 19 conflicting classifications of pathogenicity, 8 likely pathogenic, 7 benign/likely benign, 6 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 998016 | NM_003849.4(SUCLG1):c.[460C>T;987dup] | Pathogenic | no assertion criteria provided | |
| 1012244 | NM_003849.4(SUCLG1):c.460C>T (p.Arg154Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 1071175 | NC_000002.11:g.(?84650850)(84686413_?)del | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 1185061 | NM_003849.4(SUCLG1):c.724del (p.Ile242fs) | SUCLG1 | Pathogenic | no assertion criteria provided |
| 1325153 | NM_003849.4(SUCLG1):c.814C>T (p.Gln272Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 1375896 | NM_003849.4(SUCLG1):c.169_170del (p.Lys57fs) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 1686238 | NM_003849.4(SUCLG1):c.643C>T (p.Gln215Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 1686239 | NM_003849.4(SUCLG1):c.458T>A (p.Val153Glu) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 18409 | NM_003849.4(SUCLG1):c.254G>C (p.Gly85Ala) | SUCLG1 | Pathogenic | no assertion criteria provided |
| 18410 | NM_003849.4(SUCLG1):c.509C>G (p.Pro170Arg) | SUCLG1 | Pathogenic | no assertion criteria provided |
| 18411 | NM_003849.4(SUCLG1):c.97+3G>C | SUCLG1 | Pathogenic | no assertion criteria provided |
| 18412 | NM_003849.4(SUCLG1):c.448C>T (p.Gln150Ter) | SUCLG1 | Pathogenic | no assertion criteria provided |
| 212328 | NM_003849.4(SUCLG1):c.507del (p.Asn171fs) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 2982185 | NM_003849.4(SUCLG1):c.445C>T (p.Gln149Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 3005619 | NM_003849.4(SUCLG1):c.835del (p.Ser279fs) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 3651171 | NM_003849.4(SUCLG1):c.583_586del (p.Arg195fs) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 3724793 | NM_003849.4(SUCLG1):c.199C>T (p.Gln67Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 4688454 | NM_003849.4(SUCLG1):c.937G>T (p.Glu313Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 4712015 | NM_003849.4(SUCLG1):c.390_393del (p.Asn130fs) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 4721624 | NM_003849.4(SUCLG1):c.220C>T (p.Gln74Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 632365 | NM_003849.4(SUCLG1):c.152_153del (p.Tyr51fs) | SUCLG1 | Pathogenic | no assertion criteria provided |
| 801730 | NM_003849.4(SUCLG1):c.201+1G>T | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 818207 | NM_003849.4(SUCLG1):c.457_458delinsTA (p.Val153Ter) | SUCLG1 | Pathogenic | criteria provided, single submitter |
| 992828 | NM_003849.4(SUCLG1):c.626C>A (p.Ala209Glu) | SUCLG1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 2130397 | NM_003849.4(SUCLG1):c.826-1G>A | SUCLG1 | Likely pathogenic | criteria provided, single submitter |
| 2434026 | NM_003849.4(SUCLG1):c.790G>T (p.Glu264Ter) | SUCLG1 | Likely pathogenic | criteria provided, single submitter |
| 2734239 | NM_003849.4(SUCLG1):c.319-1G>A | SUCLG1 | Likely pathogenic | criteria provided, single submitter |
| 2850714 | NM_003849.4(SUCLG1):c.673+1G>C | SUCLG1 | Likely pathogenic | criteria provided, single submitter |
| 3247379 | NC_000002.11:g.(?84650870)(84652747_?)del | SUCLG1 | Likely pathogenic | criteria provided, single submitter |
| 3780681 | NM_003849.4(SUCLG1):c.787G>A (p.Glu263Lys) | SUCLG1 | Likely pathogenic | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 5 · Orphanet: 1 · 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 |
|---|---|---|---|---|
| SUCLG1 | Definitive | Autosomal recessive | mitochondrial DNA depletion syndrome 9 | 5 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| SUCLG1 | Orphanet:17 | Fatal infantile lactic acidosis with methylmalonic aciduria |
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 |
|---|---|---|---|---|---|
| SUCLG1 | HGNC:11449 | ENSG00000163541 | P53597 | Succinate–CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial | gencc,clinvar |
| SUCLG2 | HGNC:11450 | ENSG00000172340 | Q96I99 | Succinate–CoA ligase [GDP-forming] subunit beta, mitochondrial | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| SUCLG1 | Succinate–CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial | Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. |
| SUCLG2 | Succinate–CoA ligase [GDP-forming] subunit beta, mitochondrial | GTP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of GTP and thus represents the only step of substrate-level phosphorylation in the TCA. |
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 |
|---|---|---|---|
| Enzyme (other) | 2 | 12.0× | 0.007 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| SUCLG1 | Enzyme (other) | yes | 6.2.1.4 | CoA-bd, CoA_lig_alpha, SUCC_ACL_C |
| SUCLG2 | Enzyme (other) | yes | 6.2.1.4 | Succ_CoA_ligase-like_bsu, SUCC_ACL_C, ATP-grasp_succ-CoA_synth-type |
Expression context
Cohort genes with no expression data: 0.
2 cohort genes 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 |
|---|---|
| metanephric glomerulus | 1 |
| nephron tubule | 1 |
| renal glomerulus | 1 |
| colonic mucosa | 1 |
| mucosa of sigmoid colon | 1 |
| rectum | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| SUCLG1 | 288 | ubiquitous | marker | nephron tubule, renal glomerulus, metanephric glomerulus |
| SUCLG2 | 286 | ubiquitous | marker | colonic mucosa, mucosa of sigmoid colon, rectum |
Protein interactions among cohort
Intra-cohort edges: 1.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| SUCLG2 | 6,231 |
| SUCLG1 | 3,794 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| SUCLG1 | SUCLG2 | biogrid_interaction, intact, string_interaction |
Structural data
PDB: 2 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| SUCLG1 | P53597 | 8 |
| SUCLG2 | Q96I99 | 6 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 5. 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 |
|---|---|---|---|---|
| Citric acid cycle (TCA cycle) | 2 | 423.0× | 3e-05 | SUCLG1, SUCLG2 |
| Aerobic respiration and respiratory electron transport | 2 | 88.5× | 3e-04 | SUCLG1, SUCLG2 |
| Metabolism | 2 | 11.6× | 0.012 | SUCLG1, SUCLG2 |
| Mitochondrial protein degradation | 1 | 57.1× | 0.022 | SUCLG2 |
| Metabolism of proteins | 1 | 6.2× | 0.155 | SUCLG2 |
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 |
|---|---|---|---|---|
| succinyl-CoA catabolic process | 2 | 2407.4× | 6e-07 | SUCLG1, SUCLG2 |
| tricarboxylic acid cycle | 2 | 510.7× | 7e-06 | SUCLG1, SUCLG2 |
| succinyl-CoA metabolic process | 1 | 1685.2× | 6e-04 | SUCLG2 |
| succinate metabolic process | 1 | 1685.2× | 6e-04 | SUCLG2 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2
Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| SUCLG1 | 0 | 0 |
| SUCLG2 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 2.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| SUCLG1 | 1 | Binding:1 |
| SUCLG2 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| SUCLG1 | 6.2.1.4, 6.2.1.5 | succinate-CoA ligase (GDP-forming), succinate-CoA ligase (ADP-forming) |
| SUCLG2 | 6.2.1.4 | succinate-CoA ligase (GDP-forming) |
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 | 2 | SUCLG1, SUCLG2 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| 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) |
|---|---|---|
| SUCLG1 | 1 | — |
| SUCLG2 | 1 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.