mitochondrial complex II deficiency, nuclear type 1

Summary

mitochondrial complex II deficiency, nuclear type 1 (MONDO:0100294) is a disease caused by variants in SDHA, SDHAF1, and SDHD, with 4 cohort genes. The dominant Reactome pathway is Maturation of TCA enzymes and regulation of TCA cycle (4 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: SDHA (GenCC Definitive), SDHAF1 (GenCC Strong), SDHD (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 2,630
• Phenotypes (HPO): 50

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		37	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001626	Abnormality of the cardiovascular system	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001712	Left ventricular hypertrophy	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002333	Motor deterioration	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003508	Proportionate short stature	Frequent (30-79%)
HP:0003510	Severe short stature	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003756	Skeletal myopathy	Frequent (30-79%)
HP:0005162	Abnormal left ventricular function	Frequent (30-79%)
HP:0006801	Hyperactive deep tendon reflexes	Frequent (30-79%)
HP:0007083	Hyperactive patellar reflex	Frequent (30-79%)
HP:0007272	Progressive psychomotor deterioration	Frequent (30-79%)
HP:0007350	Hyperreflexia in upper limbs	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0006895	Lower limb hypertonia	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0011166	Focal myoclonic seizure	Occasional (5-29%)
HP:0011343	Moderate global developmental delay	Occasional (5-29%)
HP:0012817	Noncompaction cardiomyopathy	Occasional (5-29%)
HP:0040196	Mild microcephaly	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0002313	Spastic paraparesis	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002474	Expressive language delay	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0005150	Abnormal atrioventricular conduction	Occasional (5-29%)
HP:0006380	Knee flexion contracture	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Very rare (<1-4%)
HP:0000544	External ophthalmoplegia	Very rare (<1-4%)
HP:0000580	Pigmentary retinopathy	Very rare (<1-4%)
HP:0000618	Blindness	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0000726	Dementia	Very rare (<1-4%)
HP:0002421	Poor head control	Very rare (<1-4%)
HP:0002505	Loss of ambulation	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex II deficiency, nuclear type 1
Mondo ID	MONDO:0100294
MeSH	C565375
OMIM	252011
Orphanet	3208
DOID	DOID:0060537
SNOMED CT	124165006
UMLS	C5700310
MedGen	1814582
GARD	0005053
Is cancer (heuristic)	no

Also known as: complex 2 mitochondrial respiratory chain deficiency · isolated mitochondrial respiratory chain complex II deficiency · isolated succinate-coenzyme Q reductase deficiency · isolated succinate-CoQ reductase deficiency · isolated succinate-ubiquinone reductase deficiency · mitochondrial complex II deficiency, nuclear type 1 · mitochondrial respiratory chain complex II deficiency · succinate dehydrogenase deficiency

Data availability: 2,630 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › mitochondrial complex II deficiency, nuclear type › mitochondrial complex II deficiency, nuclear type 1

Related subtypes (3): mitochondrial complex 2 deficiency, nuclear type 2, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4

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:

276 uncertain significance, 174 likely benign, 68 benign/likely benign, 35 conflicting classifications of pathogenicity, 21 pathogenic, 12 benign, 7 pathogenic/likely pathogenic, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066704	NM_004168.4(SDHA):c.778G>C (p.Gly260Arg)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067845	NM_004168.4(SDHA):c.457-2A>G	SDHA	Pathogenic	criteria provided, single submitter
1069259	NM_004168.4(SDHA):c.1032_1033del (p.Arg345fs)	SDHA	Pathogenic	criteria provided, single submitter
1069906	NM_004168.4(SDHA):c.242_243insA (p.Ser81_Glu82insTer)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070947	NM_004168.4(SDHA):c.1012del (p.Ala338fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1071454	NM_004168.4(SDHA):c.454G>T (p.Glu152Ter)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071644	NM_004168.4(SDHA):c.554dup (p.Ala186fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072916	NM_004168.4(SDHA):c.79C>T (p.Gln27Ter)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1075636	NM_004168.4(SDHA):c.124_125dup (p.Ala43fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1354535	NM_004168.4(SDHA):c.392_396dup (p.Leu133fs)	SDHA	Pathogenic	criteria provided, single submitter
1357420	NM_004168.4(SDHA):c.1245dup (p.Asn416fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1370664	NM_004168.4(SDHA):c.467dup (p.Tyr156Ter)	SDHA	Pathogenic	criteria provided, single submitter
1389565	NM_004168.4(SDHA):c.1764dup (p.Arg589fs)	SDHA	Pathogenic	criteria provided, single submitter
1401495	NM_004168.4(SDHA):c.1035del (p.Ser346fs)	SDHA	Pathogenic	criteria provided, single submitter
1405170	NM_004168.4(SDHA):c.1755_1759del (p.Lys586fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1408872	NM_004168.4(SDHA):c.3G>T (p.Met1Ile)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
141876	NM_004168.4(SDHA):c.667del (p.Asp223fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425164	NM_004168.4(SDHA):c.1558C>T (p.Gln520Ter)	SDHA	Pathogenic	criteria provided, single submitter
1436702	NM_004168.4(SDHA):c.322_323del (p.Asn108fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442909	NM_004168.4(SDHA):c.1470_1473dup (p.Ser492fs)	SDHA	Pathogenic	criteria provided, single submitter
1451165	NM_004168.4(SDHA):c.23C>A (p.Ser8Ter)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1453363	NM_004168.4(SDHA):c.633T>G (p.Tyr211Ter)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1453517	NM_004168.4(SDHA):c.1743_1744del (p.Ala582fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1455102	NM_004168.4(SDHA):c.3G>C (p.Met1Ile)	SDHA	Pathogenic	criteria provided, single submitter
1455577	NM_004168.4(SDHA):c.298_299del (p.Thr100fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456663	NM_004168.4(SDHA):c.65G>A (p.Trp22Ter)	SDHA	Pathogenic	criteria provided, single submitter
1458523	NM_004168.4(SDHA):c.1658_1661del (p.Asp553fs)	SDHA	Pathogenic	criteria provided, single submitter
1458794	NM_004168.4(SDHA):c.447del (p.Val150fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1067316	NM_004168.4(SDHA):c.771-1G>C	SDHA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068401	NM_004168.4(SDHA):c.1664-2A>G	SDHA	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 41 · Orphanet: 20 · 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
SDHA	Definitive	Autosomal recessive	mitochondrial complex II deficiency, nuclear type 1	20
SDHAF1	Definitive	Autosomal recessive	mitochondrial complex 2 deficiency, nuclear type 2	5
SDHD	Strong	Autosomal recessive	mitochondrial complex II deficiency, nuclear type 1	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
SDHD	Orphanet:100093	Carcinoid syndrome
SDHD	Orphanet:201	Cowden syndrome
SDHD	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHD	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHD	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHD	Orphanet:97286	Carney-Stratakis syndrome
SDHAF1	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHB	Orphanet:139411	Carney triad
SDHB	Orphanet:201	Cowden syndrome
SDHB	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHB	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHB	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHB	Orphanet:44890	Gastrointestinal stromal tumor
SDHB	Orphanet:97286	Carney-Stratakis syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	gencc,clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	gencc,clinvar
SDHAF1	HGNC:33867	ENSG00000205138	A6NFY7	Succinate dehydrogenase assembly factor 1, mitochondrial	gencc,clinvar
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHD	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHAF1	Succinate dehydrogenase assembly factor 1, mitochondrial	Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transpor…
SDHB	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
SDHAF1	Other/Unknown	no		Complex1_LYR_dom, Complex1_LYR_SDHAF1_LYRM8, SDHAF1
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
heart left ventricle	2
mucosa of transverse colon	1
jejunal mucosa	1
jejunum	1
rectum	1
olfactory bulb	1
parotid gland	1
type B pancreatic cell	1
cardiac ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
SDHAF1	277	ubiquitous	marker	type B pancreatic cell, olfactory bulb, parotid gland
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
SDHB	5,471
SDHD	2,229
SDHAF1	884

Intra-cohort edges

A	B	Sources
SDHA	SDHAF1	biogrid_interaction, string_interaction
SDHA	SDHB	biogrid_interaction, intact, string_interaction
SDHA	SDHD	string_interaction
SDHAF1	SDHB	biogrid_interaction, intact, string_interaction
SDHAF1	SDHD	string_interaction
SDHB	SDHD	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SDHB	P21912	6
SDHA	P31040	5
SDHD	O14521	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SDHAF1	A6NFY7	77.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Maturation of TCA enzymes and regulation of TCA cycle	4	571.0×	3e-11	SDHA, SDHD, SDHAF1, SDHB
Citric acid cycle (TCA cycle)	4	423.0×	6e-11	SDHA, SDHD, SDHAF1, SDHB
Respiratory electron transport	3	71.4×	7e-06	SDHA, SDHD, SDHB
Aerobic respiration and respiratory electron transport	3	66.4×	7e-06	SDHA, SDHAF1, SDHB
Metabolism	3	8.7×	0.002	SDHA, SDHAF1, SDHB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial electron transport, succinate to ubiquinone	3	2527.8×	5e-10	SDHA, SDHD, SDHB
tricarboxylic acid cycle	3	383.0×	1e-07	SDHA, SDHD, SDHB
proton motive force-driven mitochondrial ATP synthesis	3	197.5×	7e-07	SDHA, SDHD, SDHB
succinate metabolic process	2	1685.2×	1e-06	SDHA, SDHB
respiratory electron transport chain	2	421.3×	2e-05	SDHA, SDHB
regulation of catecholamine secretion	1	4213.0×	4e-04	SDHD
mitochondrial respiratory chain complex II assembly	1	1053.2×	0.001	SDHAF1
aerobic respiration	1	62.0×	0.020	SDHB
cellular response to hypoxia	1	30.3×	0.036	SDHD
nervous system development	1	11.5×	0.084	SDHA

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SDHA	LINEZOLID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHA	1	4
SDHD	0	0
SDHAF1	0	0
SDHB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LINEZOLID	4	SDHA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SDHB	4	Binding:4
SDHA	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
LINEZOLID	4	SDHA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SDHA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SDHB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SDHD, SDHAF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SDHD	0	SDHA
SDHAF1	0	SDHA
SDHB	4	SDHA

Clinical trials & evidence

Clinical trials

Clinical trials: 0.