SUCLA2-Related Mitochondrial DNA Depletion Syndrome

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Classifications

Harrison's Part

Mechanistic Nosology

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic SUCLA2 variants, homozygous or compound heterozygous. Homozygosity from the Faroese founder allele or from consanguinity accounts for many reported cases. Carrier parents have a 25% recurrence risk in each pregnancy.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20301762 SUPPORT Human Clinical

"SUCLA2-related mtDNA depletion syndrome is inherited in an autosomal recessive manner."

States the mode of inheritance.

PMID:20301762 SUPPORT Human Clinical

"If both parents are known to be heterozygous for a SUCLA2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

Recurrence risk for sibs of an affected child.

CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z SUPPORT Other

ClinGen records autosomal recessive inheritance with a Definitive classification.

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Discussions and Knowledge Gaps

2

Where in the auditory pathway does SUCLA2 deficiency cause hearing loss?

KNOWLEDGE GAP sucla2-hearing-loss-lesion

Attached to

phenotypes#Progressive sensorineural hearing impairment

Hearing loss is a defining feature, yet none of the cited clinical, cellular or animal studies localises the lesion to hair cells, spiral ganglion or central auditory pathways, and no cited model reproduces the hearing loss; the causal edge from the respiratory chain defect is therefore left as UNKNOWN.

How much of the disease is due to mtDNA depletion, and how much to the Krebs cycle block and succinyl-CoA excess directly?

KNOWLEDGE GAP sucla2-mtdna-depletion-necessity

Attached to

pathophysiology#Neuronal and Muscle mtDNA Depletion pathophysiology#Protein Hypersuccinylation

Typical disease occurs without muscle mtDNA depletion in some patients, patient fibroblasts are not depleted, and hypersuccinylation reduces complex I activity in mouse brain. The relative weight of these branches in patient brain is not established.

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Pathophysiology

10

SUCLA2 Loss of Function

Biallelic SUCLA2 variants remove or inactivate the beta subunit of the ADP-forming succinyl-CoA synthetase (A-SUCL). Splice, nonsense, frameshift, whole-gene and intragenic deletions and missense alleles are reported. Missense alleles such as p.Arg407Trp and p.Asp333Gly are associated with milder or slowly progressive disease.

SUCLA2 hgnc:11448

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic (homozygous or compound heterozygous) germline SUCLA2 variants.

succinate-CoA ligase (ADP-forming) activity GO:0004775 ↓ DECREASED

Downstream

Disrupted Mitochondrial Nucleotide Supply A-SUCL is found in a complex with mitochondrial nucleoside diphosphate kinase (NDPK), the last step of mitochondrial dNTP salvage; loss of the subunit is proposed to compromise that step. This is the discovery paper's hypothesis and has not been shown by direct dNTP pool measurement in patient tissue.

Succinyl-CoA Accumulation The enzyme's substrate accumulates behind the block.

Impaired Krebs Cycle Substrate-Level Phosphorylation

Show evidence (3 references)

PMID:15877282 SUPPORT Human Clinical

"Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion."

Enzyme deficiency in patient muscle mitochondria in the discovery kindred.

CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z SUPPORT Other

"The mechanism of disease is loss of function."

ClinGen expert-panel statement of disease mechanism.

PMID:24986829 SUPPORT Computational

"On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations."

Structural modelling of the known alleles predicts loss of assembled protein or catalytic function.

Impaired Krebs Cycle Substrate-Level Phosphorylation

Loss of A-SUCL removes the succinyl-CoA to succinate step with its coupled ATP formation. This is a direct metabolic consequence, independent of mtDNA copy number, and is the step that succinate supplementation was designed to bypass. In patient cells carrying p.Met329Val, mitochondrial ATP production was impaired and reactive oxygen species production enhanced.

tricarboxylic acid cycle GO:0006099 ↓ DECREASED

Downstream

Neuronal Energy Failure in the Basal Ganglia Neurons in human cortex express SUCLA2 and not the GTP-forming SUCLG2, so the Krebs cycle block cannot be complemented by the other isoform in neurons.

Show evidence (1 reference)

PMID:24659738 SUPPORT In Vitro

"In cultured cells, the p.M329V resulted in a reduced amount of the SUCLA2 protein, impaired production of mitochondrial ATP, and enhanced production of reactive oxygen species"

Reduced mitochondrial ATP production in cells carrying a patient allele.

Disrupted Mitochondrial Nucleotide Supply

A-SUCL physically associates with mitochondrial NDPK, which forms the nucleoside triphosphates used for mtDNA synthesis; SUCLA2 is described as stabilising NDPK. Loss of the association is the favoured explanation for mtDNA depletion. The evidence is indirect: NDPK activity and mtDNA content were normal in SUCLA2-deficient patient fibroblasts, whereas knockdown of the GTP-forming partner SUCLG2 in the same cells lowered both, suggesting that SUCLG2 complements SUCLA2 loss in cells that express it. In SUCLA2-knockdown mouse neurons, deregulated NDPK was among the changes accompanying mtDNA loss.

deoxyribonucleoside triphosphate biosynthetic process GO:0009202 ↓ DECREASED

Downstream

Neuronal and Muscle mtDNA Depletion

Show evidence (4 references)

PMID:18392745 SUPPORT REVIEW SYNTHESIS Other

"The mtDNA depletion may be explained by the interaction of succinate-CoA ligase with nucleoside diphosphate kinase, which is involved in mitochondrial nucleotide metabolism."

Review synthesis of the NDPK hypothesis.

PMID:28769029 SUPPORT In Vitro

"Our data also suggest that the deregulation of mitochondrial nucleoside diphosphate kinase (NDPK) together with defects in mitochondrial transcription factors including mitochondrial DNA pol γ and Twinkle contribute to SCS A-β deficiency-mediated mtDNA instability."

In cultured mouse neurons with SUCLA2 knockdown, NDPK deregulation accompanies mtDNA instability.

PMID:21295139 REFUTE In Vitro

"We have investigated this relationship by studying SUCLA2 deficient fibroblasts derived from patients and detected normal mtDNA content and normal NDPK activity."

In patient fibroblasts, SUCLA2 loss does not reduce NDPK activity or mtDNA, so the mechanism is not cell-autonomous in every cell type.

+ 1 more reference

Neuronal and Muscle mtDNA Depletion

Reduced mtDNA copy number in skeletal muscle (and, in the mouse model, brain), with normal copy number in fibroblasts and in liver, where SUCLA2 is not the dominant isoform. In the discovery family muscle mtDNA was 32% of control and fibroblast mtDNA 95%. Depletion is not obligatory: siblings with normal muscle mtDNA and a family with a slowly progressive course without depletion have been reported, so the respiratory chain defect can arise without measurable depletion. The GTP-forming SUCLG2 isoform, expressed in liver and anabolic tissues, is thought to protect tissues that express it.

skeletal muscle fiber CL:0008002 neuron CL:0000540

mitochondrial DNA replication GO:0006264 ↓ DECREASED

Animal models

Sucla2 gene-trap mouse Mouse recapitulates

Downstream

Combined Respiratory Chain Deficiency Fewer mtDNA templates reduce synthesis of mtDNA-encoded subunits, sparing the entirely nuclear-encoded complex II.

Show evidence (7 references)

PMID:15877282 SUPPORT Human Clinical

"the ratio of mtDNA to nuclear DNA, determined by real-time PCR, was reduced to 32% of the mean control value. The mtDNA:nuclear DNA ratio in fibroblasts was 95% of the mean control value."

Muscle depletion with normal fibroblast mtDNA in the discovery family.

PMID:17301081 SUPPORT Human Clinical

"The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion."

Confirms mtDNA depletion in the Faroese and Italian series.

PMID:24271779 SUPPORT Model Organism

"Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20-60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed."

In the Sucla2 gene-trap mouse, depletion follows the tissues that express Sucla2.

+ 4 more references

Combined Respiratory Chain Deficiency

Reduced activity of complexes I and IV (with III and V less affected) and borderline-normal complex II in muscle, the pattern of a defect in mtDNA-encoded subunit synthesis. Normal muscle histology and enzymology do not exclude the diagnosis. Increased reactive oxygen species production is shown in patient cells and knockdown neurons, not in patient tissue.

skeletal muscle fiber CL:0008002 neuron CL:0000540

oxidative phosphorylation GO:0006119 ↓ DECREASED reactive oxygen species metabolic process GO:0072593 ↑ INCREASED

Downstream

Neuronal Energy Failure in the Basal Ganglia

Mitochondrial Myopathy

Lactic acidosis Impaired oxidative phosphorylation shifts pyruvate to lactate.

Progressive sensorineural hearing impairment Presumed energy failure in the auditory pathway. No study has localised the lesion (cochlear hair cell, spiral ganglion or central) in this disorder.

Show evidence (3 references)

PMID:15877282 SUPPORT Human Clinical

"The activities of complexes I and IV were significantly decreased, and complexes III and V were less affected, whereas complex II, the only complex that does not contain mtDNA-encoded proteins, was borderline normal"

Muscle respiratory chain pattern in the discovery family.

PMID:26475597 SUPPORT Human Clinical

"Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency."

The pattern across the 71-patient review, and its limits.

PMID:28769029 SUPPORT In Vitro

"Here, by down-regulating the expression levels of SCS A-β in cultured mouse neurons, we have found that SCS A-β deficiency induces severe mitochondrial dysfunction including lowered oxidative phosphorylation (OXPHOS) efficiency, increased mitochondrial superoxide production, and mtDNA depletion..."

Reduced OXPHOS and increased superoxide in SUCLA2-knockdown neurons; supports the oxidative arm of the conformed module node in vitro.

Succinyl-CoA Accumulation

Succinyl-CoA builds up behind the block. Two consequences follow: backflow through the propionate pathway, and non-enzymatic succinylation of lysine residues across the proteome.

succinyl-CoA metabolic process GO:0006104 ⚠ ABNORMAL

Downstream

Secondary Methylmalonyl-CoA Accumulation

Protein Hypersuccinylation

Show evidence (1 reference)

PMID:33230181 SUPPORT In Vitro

"Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation."

Measured in patient fibroblasts and myotubes.

Secondary Methylmalonyl-CoA Accumulation

Succinyl-CoA excess inhibits methylmalonyl-CoA conversion, so methylmalonic acid and C4-dicarboxylic (methylmalonyl- and succinyl-) carnitine rise in body fluids. The elevation is mild compared with classical methylmalonic acidemia and may be marginal or absent in urine; plasma methylmalonic acid is more consistently raised. Methylcitrate is also raised.

propionate catabolic process GO:0019543 ↓ DECREASED

Animal models

Sucla2 gene-trap mouse Mouse recapitulates

Downstream

Methylmalonic aciduria

Show evidence (2 references)

PMID:17301081 SUPPORT Human Clinical

"Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis."

Defines the metabolite signature.

PMID:24271779 SUPPORT Model Organism

"Elevated levels of MMA were observed in embryonic brain."

The mouse model reproduces the methylmalonic acid elevation in brain.

Protein Hypersuccinylation

Excess succinyl-CoA succinylates lysines on nearly a thousand sites in patient cells, many of them targets of the NAD+-dependent desuccinylase SIRT5. In the forebrain knockout mouse, hypersuccinylation is associated with reduced complex I activity and altered chromatin and neuronal gene expression; in sucla2 mutant zebrafish it consumes NAD+ and propagates respiratory defects. This is an emerging mechanism, established in patient cells and animal models but not yet in patient tissue.

protein succinylation GO:0018335 ↑ INCREASED

Animal models

Forebrain-specific Sucla2 knockout mouse Mouse recapitulates

sucla2 mutant zebrafish Zebrafish rescues

Downstream

Combined Respiratory Chain Deficiency

Show evidence (1 reference)

PMID:33230181 SUPPORT In Vitro

"Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes."

Proteome-wide hypersuccinylation in patient cells.

Neuronal Energy Failure in the Basal Ganglia

Selective injury of the putamen and caudate, seen as Leigh-like T2 hyperintensity and later atrophy, with demyelination and cortical and central atrophy. SUCLA2 is expressed in neurons and not in glia in human cortex. Early MRI can be normal, with abnormalities appearing later, and MR spectroscopy may show lactate when structural imaging is normal.

neuron CL:0000540

putamen UBERON:0001874 caudate nucleus UBERON:0001873

Downstream

Dystonia

Choreoathetosis

Basal ganglia involvement on neuroimaging

Global developmental delay

Developmental regression

Seizures

Show evidence (3 references)

PMID:24085565 SUPPORT In Vitro

"Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex."

Neuronal localisation of SUCLA2 in human surgical cortex.

PMID:17301081 SUPPORT Human Clinical

"Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei."

The basal ganglia pattern.

PMID:17287286 SUPPORT Human Clinical

"Neuroimaging showed demyelination and central and cortical atrophy, including atrophy of the basal ganglia, and some of the patients fulfilled the criteria for Leigh syndrome."

Imaging in the 12-patient Faroese series.

Mitochondrial Myopathy

Skeletal muscle weakness and atrophy. A muscle-specific Sucla2 knockout mouse shows growth failure, reduced grip strength and exercise intolerance, with the oxidative soleus more affected than the glycolytic extensor digitorum longus.

skeletal muscle fiber CL:0008002

Animal models

Muscle-specific Sucla2 knockout mouse Mouse recapitulates

Downstream

Hypotonia

Skeletal muscle atrophy

Muscle weakness

Ptosis

External ophthalmoplegia

Kyphoscoliosis

Postnatal growth retardation

Show evidence (1 reference)

PMID:39482887 SUPPORT Model Organism

"SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance."

Muscle-autonomous consequence of Sucla2 loss.

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Pathograph

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Phenotypes

18

Digestive 2

Feeding difficulties HP:0011968

Sequelae: Postnatal growth retardation

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing..."

GeneReviews core feature.

Recurrent vomiting HP:0002013

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."

GeneReviews less frequent feature.

Ear 1

Progressive sensorineural hearing impairment HP:0000408

Show evidence (2 references)

PMID:19666145 SUPPORT Human Clinical

"Progressive hearing loss, in combination with a characteristic metabolite profile (increased lactate, methylmalonic acid, C4-dicarboxylic carnitine, 3-hydroxyisovaleric acid) should lead the clinician to the correct diagnosis even in patients with only intermittent lactic acidemia."

Progressive hearing loss in 16 Faroese children.

PMID:17287286 SUPPORT Human Clinical

"The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation."

Severe hearing impairment in the 12-patient series.

Eye 2

Ptosis HP:0000508

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."

GeneReviews less frequent feature.

External ophthalmoplegia HP:0000544

Show evidence (1 reference)

ORPHA:1933 SUPPORT Other

"Seizures, external ophthalmoplegia, polyneuropathy, cardiomyopathy, and renal tubular dysfunction have also been reported."

Orphanet definition. The same sentence lists cardiomyopathy, which the 71-patient review did not find in any SUCLA2 patient; only external ophthalmoplegia is curated from it.

Genitourinary 1

Methylmalonic aciduria HP:0012120

Show evidence (2 references)

PMID:26475597 SUPPORT Human Clinical

"In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found."

Urinary MMA may be marginal; plasma MMA is consistently raised.

PMID:23010432 REFUTE Human Clinical

"In contrast with what has been reported in other patients, methyl-malonic aciduria, a biomarker for this genetic defect, was absent in our proband and very mildly elevated in her affected sister."

Methylmalonic aciduria can be absent.

Metabolism 1

Lactic acidosis HP:0003128

Show evidence (1 reference)

PMID:17301081 SUPPORT Human Clinical

"Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis."

Variable lactic acidosis.

Musculoskeletal 4

Hypotonia HP:0001252

Onset: INFANTILE

Show evidence (2 references)

PMID:20301762 SUPPORT Human Clinical

"SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing..."

GeneReviews core feature with infantile onset.

PMID:19666145 SUPPORT Human Clinical

"Patients with SUCLA2 gene defects characteristically develop the trias of early hypotonia, progressive dystonia and sensori-neural deafness."

Early hypotonia is part of the characteristic triad in 16 Faroese children.

Skeletal muscle atrophy HP:0003202

Show evidence (1 reference)

PMID:17287286 SUPPORT Human Clinical

"The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation."

Muscle atrophy as a core symptom.

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."

GeneReviews less frequent feature.

Kyphoscoliosis HP:0002751

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."

GeneReviews less frequent feature.

Nervous System 6

Global developmental delay HP:0001263

Onset: INFANTILE

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing..."

GeneReviews core feature.

Developmental regression HP:0002376

Show evidence (1 reference)

CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z SUPPORT Other

"Clinical features in affected individuals include LSS, developmental delay and regression, encephalopathy, myopathy, choreoathetosis, dystonia, seizures, ptosis, sensorineural hearing loss, feeding difficulty, failure to thrive, and elevated lactate and methylmalonic acid."

ClinGen summary of the curated cases lists regression.

Dystonia HP:0001332

Course: PROGRESSIVE

Show evidence (2 references)

PMID:17301081 SUPPORT Human Clinical

"Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia."

Progressive dystonia after infantile onset.

PMID:33231368 SUPPORT Human Clinical

"We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade."

Non-progressive allelic form with p.Arg407Trp.

Choreoathetosis HP:0001266

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."

GeneReviews less frequent feature.

Seizures HP:0001250

Show evidence (1 reference)

PMID:26475597 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations."

Epilepsy is a feature of the SUCLA2 disorder.

Basal ganglia involvement on neuroimaging FREQUENT Abnormal basal ganglia morphology HP:0002134

Show evidence (2 references)

PMID:26475597 SUPPORT Human Clinical

"The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69% of SUCLA2 and 80% of SUCLG1 patients."

69% of SUCLA2 patients (FREQUENT band).

PMID:27651038 SUPPORT Human Clinical

"Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while 1H-magnetic resonance spectroscopy (MRS) showed lactate peaks in the cerebral cortex and lateral ventricles."

A normal MRI does not exclude the diagnosis.

Growth 1

Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:17287286 SUPPORT Human Clinical

"The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation."

Postnatal growth retardation as a core symptom.

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Genetic Associations

1

SUCLA2

Gene: SUCLA2 hgnc:11448 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z SUPPORT Other

ClinGen gene-disease validity row.

CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z SUPPORT Other

"SUCLA2 has been associated with one disease entity to date; mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) [OMIM# 612073]."

ClinGen treats OMIM 612073 as the single SUCLA2 disease entity.

PMID:24986829 SUPPORT Human Clinical

"The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma."

Contiguous 13q14 deletion producing both diseases.

+ 1 more reference

Variants (3)

c.534+1G>A (Faroese founder)

Splice-donor variant (reported as IVS4+1G>A) causing exon 4 skipping; founder allele in the Faroe Islands.

Show evidence (2 references)

PMID:17287286 SUPPORT Human Clinical

"Mutation analysis identified a novel splice site mutation in SUCLA2, IVS4 + 1G --> A, leading to skipping of exon 4."

Identifies the founder splice allele.

CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z SUPPORT Other

"one splice site, c.534+1G>A, that is a founder variant in Faroe Islands, Denmark"

ClinGen names the founder allele in HGVS form.

p.Arg407Trp

Missense allele in the ligase domain associated with a milder course, including a non-progressive movement disorder with deafness into adulthood.

Show evidence (1 reference)

PMID:33231368 SUPPORT Human Clinical

"We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade."

Milder allelic phenotype.

p.Asp333Gly

Missense allele predicted to reduce rather than abolish activity; slowly progressive disease.

Show evidence (1 reference)

PMID:24986829 SUPPORT Computational

"However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme."

Structural prediction for the milder allele.

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Medical Actions

7

Supportive and Rehabilitative Care

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Early developmental support and physical therapy to maintain muscle function and prevent contractures; bracing for scoliosis or kyphosis; chest physiotherapy and prompt antibiotic treatment of chest infections. No disease-modifying treatment is established.

Target Phenotypes: Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Treatment of manifestations: Appropriate early developmental support; physical therapy to maintain muscle function and prevent joint contractures"

GeneReviews management.

Hearing Aids or Cochlear Implantation

Action: hearing aids or cochlear implantation with auditory rehabilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Device

Amplification or cochlear implantation for the sensorineural hearing loss.

Target Phenotypes: Progressive sensorineural hearing impairment HP:0000408

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"hearing aids / cochlear implantation for sensorineural hearing loss"

GeneReviews management.

Gastrostomy Feeding

Action: gastrostomy tube placement Ontology label: Gastrostomy Tube Procedure NCIT:C157864

Platform: Surgery

Gastrostomy tube placement as needed to maintain caloric intake.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"gastrostomy tube placement as needed to assure adequate caloric intake"

GeneReviews management.

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Standard antiseizure medication for epilepsy. Valproyl-CoA inhibits ATP-forming succinyl-CoA ligase in fibroblast extracts, so valproate has a theoretical mechanism of harm in this disorder; this is an in vitro finding, the abstract makes no clinical recommendation, and the discovery paper reports a child whose seizures were controlled with valproic acid.

Target Phenotypes: Seizure HP:0001250

Show evidence (3 references)

PMID:20301762 SUPPORT Human Clinical

"antiseizure medication for epileptic seizures"

GeneReviews management.

PMID:24154984 SUPPORT In Vitro

"Valproyl-CoA (1 mM) inhibited the activity of A-SUCL and G-SUCL by 45-55% and 25-50%, respectively."

In vitro basis for caution with valproate.

PMID:15877282 SUPPORT Human Clinical

"Generalized seizures, first noted at age 1 year, were controlled by valproic acid."

A discovery-family patient whose seizures responded to valproate.

Deoxycytidine and Deoxythymidine

Action: Pharmacotherapy NCIT:C15986

Agent: deoxycytidine CHEBI:15698 deoxythymidine CHEBI:17748

Platform: Small molecule

Oral pyrimidine deoxynucleosides, investigational. In an interim analysis of a phase 2 open-label trial (NCT04802707) in eight children with FBXL4, SUCLG1, SUCLA2 or RRM2B variants, Newcastle Mitochondrial Disease Scale scores improved at group level and raised GDF15 improved in four of five. SUCLA2-specific results are not reported separately, the study is uncontrolled, and the mechanistic rationale for bypassing an NDPK-associated defect with nucleosides has not been tested for SUCLA2 specifically.

Mechanism Target:

Disrupted Mitochondrial Nucleotide Supply — Intended to supplement the mitochondrial pyrimidine deoxynucleotide pool.

Show evidence (2 references)

PMID:40175578 SUPPORT Human Clinical

"Data were available from eight individuals having pathogenic variants in FBXL4, SUCLG1, SUCLA2, or RRM2B."

SUCLA2 is among the pooled genotypes.

PMID:40175578 SUPPORT Human Clinical

"Newcastle Mitochondrial Disease Scale score improved in all individuals except for one who withdrew before the first follow-up visit; group level analysis was significant at 1-month and 6-month timepoints."

Pooled open-label result; not specific to SUCLA2.

Coenzyme Q10

Action: Pharmacotherapy NCIT:C15986

Agent: coenzyme Q10 CHEBI:46245

Platform: Small molecule

Single-patient report of improved weakness and stabilisation with escalating CoQ10 up to 2000 mg daily, proposed in the context of possible secondary CoQ10 deficiency. Uncontrolled.

Show evidence (1 reference)

PMID:27651038 SUPPORT Human Clinical

"Escalating doses of CoQ10 up to 2000 mg daily were associated with improvement of muscle weakness and stabilization of the disease course."

Single-case observation.

Succinate Supplementation

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Oral succinate was given to bypass the Krebs cycle block in one adult with the p.Arg407Trp allele. Biochemical abnormalities improved but the movement disorder did not, and it was stopped. The authors raise, without data, whether earlier treatment might matter.

Mechanism Target:

Impaired Krebs Cycle Substrate-Level Phosphorylation — Provides the product of the blocked step.

Show evidence (1 reference)

PMID:33231368 SUPPORT Human Clinical

"We show that succinate supplementation circumvents the Krebs cycle block, but does not correct the neurologic disease."

Biochemical correction without neurological benefit in one patient.

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Biochemical Markers

4

Plasma methylmalonic acid (PRESENT)

Show evidence (1 reference)

PMID:26475597 SUPPORT Human Clinical

"In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found."

Plasma MMA is the more reliable marker.

C4-dicarboxylic carnitine (PRESENT)

Show evidence (3 references)

PMID:17301081 SUPPORT Human Clinical

"Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease."

The carnitine ester profile as a hallmark.

PMID:24659738 SUPPORT Human Clinical

"Metabolic investigations disclosed hyperlactacidemia, moderate urinary excretion of methylmalonic acid, and elevated levels of C4-dicarboxylic carnitine in blood."

Raised blood C4-dicarboxylic carnitine in a Portuguese child.

PMID:23759946 SUPPORT Human Clinical

"We instead found elevated levels of succinylcarnitine."

Succinylcarnitine raised in a family without methylmalonic aciduria.

Urinary 3-hydroxyisovaleric acid (PRESENT)

Show evidence (1 reference)

PMID:19666145 SUPPORT Human Clinical

"Elevated urinary 3-hydroxyisovaleric acid is a novel biochemical feature in patients."

Reported in 16 Faroese children.

Methylcitrate (PRESENT)

Show evidence (1 reference)

PMID:18392745 SUPPORT REVIEW SYNTHESIS Other

"Elevated methylmalonate and methylcitrate and severe mtDNA depletion were found in both disorders."

Review statement covering SUCLA2 and SUCLG1 deficiency.

🔬

Diagnosis

3

SUCLA2 molecular testing

Biallelic SUCLA2 pathogenic variants establish the diagnosis. Sequencing is preferred to muscle biopsy once the metabolite pattern is recognised. Whole-gene and intragenic deletions are reported, so deletion analysis is needed when sequencing finds one or no variant.

Show evidence (3 references)

PMID:20301762 SUPPORT Human Clinical

"The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in SUCLA2 identified by molecular genetic testing."

Diagnostic criterion.

PMID:19666145 SUPPORT Human Clinical

"Direct SUCLA2 sequence analysis is suggested instead of an invasive muscle biopsy to obtain the diagnosis."

Sequencing before biopsy.

PMID:26475597 SUPPORT Human Clinical

"The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands."

Whole-gene deletions and additional Scandinavian founder alleles.

Metabolite screen

Plasma and urine methylmalonic acid, blood acylcarnitines (C4-dicarboxylic carnitine), urine organic acids and lactate. The combination is characteristic even when lactate is only intermittently raised.

Show evidence (1 reference)

PMID:19666145 SUPPORT Human Clinical

"Progressive hearing loss, in combination with a characteristic metabolite profile (increased lactate, methylmalonic acid, C4-dicarboxylic carnitine, 3-hydroxyisovaleric acid) should lead the clinician to the correct diagnosis even in patients with only intermittent lactic acidemia."

Diagnostic metabolite profile.

Surveillance

GeneReviews recommends routine monitoring of development, growth and hearing, periodic ophthalmologic evaluation, and skeletal evaluation for kyphoscoliosis and joint contractures. Intervals are expert recommendation.

Show evidence (1 reference)

PMID:20301762 SUPPORT Human Clinical

"Surveillance: Routine monitoring of development, growth, and hearing; periodic ophthalmologic evaluations; routine skeletal evaluations for kyphoscoliosis and joint contractures."

GeneReviews surveillance recommendations.

📈

Progression

2

Infantile onset

Median onset at two months (at birth for SUCLG1). Hypotonia, developmental delay and feeding difficulty come first; dystonia and hearing loss become evident and progress over infancy and early childhood.

Show evidence (1 reference)

PMID:26475597 SUPPORT Human Clinical

"The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients."

Age of onset.

Survival

Median survival about 20 years, far longer than SUCLG1 deficiency (20 months); about 30% die in childhood; about 12% reported to reach 20 years or older. Missense alleles showed a trend toward longer survival than loss-of-function alleles.

Show evidence (4 references)

PMID:20301762 SUPPORT Human Clinical

"The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood."

GeneReviews survival figures.

PMID:26475597 SUPPORT Human Clinical

"Median survival was 20 years for SUCLA2 and 20 months for SUCLG1."

Survival by gene.

PMID:26475597 SUPPORT Human Clinical

"Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients."

Proportion reaching adulthood.

+ 1 more reference

📊

Prevalence

3

Faroe Islands

Unknown 58.8 per 100,000

The source reports "a high incidence of 1 in 1700" without stating whether this is per live birth; 1 in 1700 is recorded as 58.8 per 100,000 and the measure is left UNKNOWN rather than assumed to be birth prevalence. The figure reflects the founder splice allele and does not apply outside the Faroe Islands. No numeric Orphanet band is given, because 1 in 1700 falls between the 1-5 per 10,000 band and the above-1-in-1000 band.

Show evidence (1 reference)

PMID:17287286 SUPPORT Human Clinical

"The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33."

Faroese incidence from the founder allele.

Faroe Islands

Carrier Frequency 3030.3 per 100,000

Carrier frequency 1 in 33 (Ostergaard et al. 2007). An independent Faroese series reported a mutant allele frequency of 2%, which the authors convert to an estimated homozygote frequency of 1 in 2500.

Show evidence (2 references)

PMID:17287286 SUPPORT Human Clinical

"The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33."

Faroese carrier frequency.

PMID:17301081 SUPPORT Human Clinical

"The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500."

Independent Faroese allele-frequency estimate.

Published cases worldwide to 2015

Cases In Literature Ultra Rare

50 SUCLA2 patients (and 21 SUCLG1 patients) in the largest combined review. No population-based prevalence outside the Faroe Islands has been published.

Show evidence (1 reference)

PMID:26475597 SUPPORT Human Clinical

"Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations."

Case count in the largest published series.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from SUCLA2-Related Mitochondrial DNA Depletion Syndrome:

Methylmalonic acidemia (isolated) MONDO:0002012

Overlapping Features The mild methylmalonic aciduria of SUCLA2 deficiency can be mistaken for an isolated methylmalonic acidemia; SUCLA2 deficiency was found among patients referred with mild, unexplained methylmalonic aciduria, and the accompanying deafness, dystonia and basal ganglia lesions point to it.

Show evidence (1 reference)

PMID:17301081 SUPPORT Human Clinical

"We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families."

SUCLA2 deficiency was identified among patients with mild unexplained methylmalonic aciduria.

Mitochondrial DNA depletion syndrome, myopathic form (TK2) MONDO:0012301

Overlapping Features The myopathic member of the same mtDNA depletion family, from TK2 deficiency. It shares infantile hypotonia, muscle mtDNA depletion, raised lactate and death from respiratory failure with the SUCLA2 form, and it is the entity for which the deoxycytidine and deoxythymidine strategy is actually established rather than extrapolated.

Distinguishing Features

TK2 encodes thymidine kinase 2, the rate-limiting enzyme of mitochondrial pyrimidine deoxynucleoside salvage; SUCLA2 encodes a succinyl-CoA ligase subunit, so the mtDNA depletion there is downstream rather than a precursor shortage.
Methylmalonic aciduria is absent in TK2 deficiency; it is the biochemical signature of SUCLA2 deficiency.
TK2 disease is dominated by limb, bulbar and respiratory myopathy with cognition typically spared, against the dystonia, deafness and basal ganglia change of SUCLA2 deficiency.
The mechanistic rationale for nucleoside substitution is direct in TK2 deficiency (the missing enzyme's own substrates) and indirect for SUCLA2, where the pooled phase 2 trial reports no gene-specific result.
Curated separately as Mitochondrial_DNA_Depletion_Syndrome_Myopathic_Form.

Show evidence (2 references)

PMID:23932787 SUPPORT Human Clinical

"the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides"

Identifies the gene and mechanism of the myopathic form, against the TCA-cycle lesion here.

PMID:23230576 SUPPORT Human Clinical

"Cognitive function is typically spared."

Cognitive sparing in TK2 deficiency, against the encephalomyopathic course of SUCLA2 deficiency.

🔬

Clinical Trials

1

NCT04802707 PHASE_II

Open-label, single-arm phase II study of combination deoxycytidine and deoxythymidine in children with mitochondrial DNA depletion syndrome; SUCLA2 is among the eligible genotypes. Recruitment status is not recorded here because the cached registry summary carries no status field.

Target Phenotypes: Global developmental delay HP:0001263

Show evidence (1 reference)

clinicaltrials:NCT04802707 SUPPORT Human Clinical

"The subjects included are children (0-18Y), with positive MDS diagnosis and express mutations in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK."

SUCLA2 is an eligible genotype.

🐁

Animal Models

4

Sucla2 gene-trap mouse

Recessive lethality late in gestation; mtDNA depletion in brain, heart, muscle and placenta but not liver; raised methylmalonic acid in embryonic brain.

Species

Mouse

Genotype

Sucla2 SAbetageo gene-trap homozygote

Publication

PMID:24271779

Pathograph links

Neuronal and Muscle mtDNA Depletion recapitulates fidelity: moderate observes: cellular

Limitations: Embryonic lethal, so postnatal neurological, auditory and muscle phenotypes cannot be studied.

Show evidence (1 reference)

PMID:24271779 SUPPORT Model Organism

"Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20-60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed."

Reproduces tissue-selective depletion.

Secondary Methylmalonyl-CoA Accumulation recapitulates fidelity: moderate observes: molecular

Show evidence (1 reference)

PMID:24271779 SUPPORT Model Organism

"Elevated levels of MMA were observed in embryonic brain."

Reproduces the methylmalonic acid elevation.

Muscle-specific Sucla2 knockout mouse

Skeletal-muscle-restricted Sucla2 loss producing a mitochondrial myopathy.

Species

Mouse

Genotype

HSA-Cre; Sucla2 flox/flox

Publication

PMID:39482887

Pathograph links

Mitochondrial Myopathy recapitulates fidelity: moderate observes: tissue

Limitations: Muscle-restricted; does not model the encephalopathy or hearing loss.

Show evidence (1 reference)

PMID:39482887 SUPPORT Model Organism

"SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance."

Muscle phenotype.

Forebrain-specific Sucla2 knockout mouse

Postnatal forebrain loss of the whole SCS complex with hypersuccinylation.

Species

Mouse

Genotype

forebrain-specific conditional Sucla2 knockout

Publication

PMID:37819759

Pathograph links

Protein Hypersuccinylation recapitulates fidelity: moderate observes: molecular

Limitations: Cortex-directed; whether it reproduces basal ganglia injury or dystonia is not stated in the abstract.

Show evidence (1 reference)

PMID:37819759 SUPPORT Model Organism

"Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex."

In vivo hypersuccinylation.

sucla2 mutant zebrafish

Locomotor defects and reduced survival; NAD+ precursors restore NAD+ and improve locomotion and survival through Sirt5. Not tested in patients.

Species

Zebrafish

Genotype

sucla2-/-

Publication

PMID:41574612

Pathograph links

Protein Hypersuccinylation rescues fidelity: unknown observes: organism

Limitations: Zebrafish locomotion is a proxy for the human movement disorder; the rescue has not been tested in patients.

Show evidence (1 reference)

PMID:41574612 SUPPORT Model Organism

"Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish."

NAD+ precursor rescue in the model.

{ }

Source YAML

click to show

name: SUCLA2-Related Mitochondrial DNA Depletion Syndrome
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
  term:
    id: MONDO:0012791
    label: mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
synonyms:
- MTDPS5
- mitochondrial DNA depletion syndrome 5
- mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)
- SUCLA2 deficiency
- succinyl-CoA ligase (ADP-forming) deficiency
- SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
- mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
description: >-
  Autosomal recessive mitochondrial encephalomyopathy caused by biallelic SUCLA2
  variants. SUCLA2 encodes the beta subunit of the ADP-forming (ATP-producing)
  isoform of succinyl-CoA synthetase (succinate-CoA ligase), the Krebs cycle enzyme
  that converts succinyl-CoA to succinate. Onset is in infancy (median two months)
  with hypotonia, developmental delay, muscle atrophy, feeding difficulty and growth
  failure, followed by a progressive hyperkinetic-dystonic movement disorder and
  progressive sensorineural hearing loss; brain MRI typically shows Leigh-like
  involvement of the putamen and caudate. The biochemical signature is a mild
  methylmalonic aciduria with raised C4-dicarboxylic carnitine and variable lactic
  acidosis. Muscle shows mtDNA depletion with a combined deficiency of the
  respiratory chain complexes that contain mtDNA-encoded subunits, although
  depletion is not found in every patient. Unlike the SUCLG1 (alpha subunit)
  disorder, liver disease and hypertrophic cardiomyopathy are not features, and
  survival is much longer (median about 20 years), although about 30% of affected
  children die in childhood. A founder splice variant makes the disorder unusually
  frequent in the Faroe Islands.
parents:
- mitochondrial DNA depletion syndrome, encephalomyopathic form
- disorder of the tricarboxylic acid cycle
- mitochondrial DNA maintenance defect
notes: >-
  Lump/split: this entry is the SUCLA2 disorder only (MONDO:0012791, OMIM 612073,
  ORPHA:1933, all exact cross-references of one another). The SUCLG1 disorder
  (alpha subunit of the same enzyme; mitochondrial DNA depletion syndrome 9,
  MONDO:0009504, OMIM 245400, ORPHA:17) shares the methylmalonic aciduria and mtDNA
  depletion but is a separate MONDO, OMIM and Orphanet entity with its own
  GeneReviews chapter, earlier onset, much shorter survival, and hepatopathy and
  hypertrophic cardiomyopathy that are not reported with SUCLA2; it is treated here
  as a differential diagnosis, not a subtype. The MONDO parent MONDO:0016796
  (mitochondrial DNA depletion syndrome, encephalomyopathic form) is a
  multi-gene grouping (SUCLA2, SUCLG1, RRM2B and others) and is not this entry.
  ClinGen has curated SUCLA2 twice, both Definitive: against Leigh syndrome
  spectrum (2019) and, superseding it under the ClinGen lumping framework, against
  "SUCLA2-related primary mitochondrial disease" (MONDO:0044970, 2024), which it
  states is the same single disease entity as OMIM 612073. The MONDO text
  definition of MONDO:0012791 (imported from an older Orphanet definition)
  describes a maternally transmitted encephalomyopathy-aminoacidopathy in two
  brothers; that text does not match the SUCLA2 disease that MONDO's causal-gene
  axiom (SUCLA2) and the current Orphanet definition describe, and the entry follows
  the gene axiom and the current Orphanet definition.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Encephalomyopathy with a progressive dystonic movement disorder dominates
      the course.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Inborn error of the Krebs cycle with a methylmalonic aciduria.
  icimd_category:
  - classification_value: nucleotide_pool_maintenance
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Nucleotide pool
      maintenance" under "Mitochondrial DNA maintenance and replication". The
      mtDNA depletion is attributed to a failure of mitochondrial nucleotide
      supply through the SUCLA2-NDPK association.
  - classification_value: krebs_cycle
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Krebs cycle". SUCLA2 is a
      subunit of a Krebs cycle enzyme, so the disorder genuinely spans both groups.
  mechanistic_category:
  - classification_value: mitochondrial disease
    evidence:
    - reference: PMID:15877282
      reference_title: "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion."
      explanation: A nuclear-gene defect of a mitochondrial matrix enzyme causing mtDNA depletion places this among the primary mitochondrial diseases.
references:
- reference: PMID:20301762
  title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
  tags:
  - GeneReviews
- reference: PMID:28358460
  title: "SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic SUCLA2 variants, homozygous or compound heterozygous. Homozygosity
    from the Faroese founder allele or from consanguinity accounts for many
    reported cases. Carrier parents have a 25% recurrence risk in each pregnancy.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SUCLA2-related mtDNA depletion syndrome is inherited in an autosomal recessive manner."
    explanation: States the mode of inheritance.
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both parents are known to be heterozygous for a SUCLA2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: Recurrence risk for sibs of an affected child.
  - reference: CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z
    reference_title: "SUCLA2 / mitochondrial disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SUCLA2 | HGNC:11448 | mitochondrial disease | MONDO:0044970 | AR | Definitive"
    explanation: ClinGen records autosomal recessive inheritance with a Definitive classification.
prevalence:
- population: Faroe Islands
  measure_type: UNKNOWN
  rate_per_100000: 58.8
  notes: >-
    The source reports "a high incidence of 1 in 1700" without stating whether
    this is per live birth; 1 in 1700 is recorded as 58.8 per 100,000 and the
    measure is left UNKNOWN rather than assumed to be birth prevalence. The figure
    reflects the founder splice allele and does not apply outside the Faroe
    Islands. No numeric Orphanet band is given, because 1 in 1700 falls between
    the 1-5 per 10,000 band and the above-1-in-1000 band.
  evidence:
  - reference: PMID:17287286
    reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33."
    explanation: Faroese incidence from the founder allele.
- population: Faroe Islands
  measure_type: CARRIER_FREQUENCY
  rate_per_100000: 3030.3
  notes: >-
    Carrier frequency 1 in 33 (Ostergaard et al. 2007). An independent Faroese
    series reported a mutant allele frequency of 2%, which the authors convert to
    an estimated homozygote frequency of 1 in 2500.
  evidence:
  - reference: PMID:17287286
    reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33."
    explanation: Faroese carrier frequency.
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500."
    explanation: Independent Faroese allele-frequency estimate.
- population: Published cases worldwide to 2015
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    50 SUCLA2 patients (and 21 SUCLG1 patients) in the largest combined review.
    No population-based prevalence outside the Faroe Islands has been published.
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations."
    explanation: Case count in the largest published series.
pathophysiology:
- name: SUCLA2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic SUCLA2 variants remove or inactivate the beta subunit of the
    ADP-forming succinyl-CoA synthetase (A-SUCL). Splice, nonsense, frameshift,
    whole-gene and intragenic deletions and missense alleles are reported. Missense
    alleles such as p.Arg407Trp and p.Asp333Gly are associated with milder or
    slowly progressive disease.
  genes:
  - preferred_term: SUCLA2
    term:
      id: hgnc:11448
      label: SUCLA2
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Biallelic (homozygous or compound heterozygous) germline SUCLA2 variants.
  molecular_functions:
  - preferred_term: succinate-CoA ligase (ADP-forming) activity
    term:
      id: GO:0004775
      label: succinate-CoA ligase (ADP-forming) activity
    modifier: DECREASED
  evidence:
  - reference: PMID:15877282
    reference_title: "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion."
    explanation: Enzyme deficiency in patient muscle mitochondria in the discovery kindred.
  - reference: CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z
    reference_title: "SUCLA2 / mitochondrial disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of disease is loss of function."
    explanation: ClinGen expert-panel statement of disease mechanism.
  - reference: PMID:24986829
    reference_title: "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations."
    explanation: Structural modelling of the known alleles predicts loss of assembled protein or catalytic function.
  downstream:
  - target: Disrupted Mitochondrial Nucleotide Supply
    description: >-
      A-SUCL is found in a complex with mitochondrial nucleoside diphosphate kinase
      (NDPK), the last step of mitochondrial dNTP salvage; loss of the subunit is
      proposed to compromise that step. This is the discovery paper's hypothesis
      and has not been shown by direct dNTP pool measurement in patient tissue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15877282
      reference_title: "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Succinyl-CoA synthetase is invariably in a complex with mitochondrial nucleotide diphosphate kinase; hence, we propose that a defect in the last step of mitochondrial dNTP salvage is a novel cause of the mtDNA depletion syndrome."
      explanation: States the proposed link from A-SUCL loss to dNTP salvage failure.
  - target: Succinyl-CoA Accumulation
    description: The enzyme's substrate accumulates behind the block.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33230181
      reference_title: "SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation."
      explanation: Succinyl-CoA accumulation measured in patient-derived cells.
  - target: Impaired Krebs Cycle Substrate-Level Phosphorylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33231368
      reference_title: "SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Its absence results in Krebs cycle failure, mitochondrial DNA depletion, and a childhood-fatal encephalomyopathy."
      explanation: States the direct Krebs cycle consequence of SUCLA2 loss.
- name: Impaired Krebs Cycle Substrate-Level Phosphorylation
  biological_scale: MOLECULAR
  description: >-
    Loss of A-SUCL removes the succinyl-CoA to succinate step with its coupled ATP
    formation. This is a direct metabolic consequence, independent of mtDNA copy
    number, and is the step that succinate supplementation was designed to bypass.
    In patient cells carrying p.Met329Val, mitochondrial ATP production was
    impaired and reactive oxygen species production enhanced.
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  evidence:
  - reference: PMID:24659738
    reference_title: "A novel SUCLA2 mutation in a Portuguese child associated with \"mild\" methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cultured cells, the p.M329V resulted in a reduced amount of the SUCLA2 protein, impaired production of mitochondrial ATP, and enhanced production of reactive oxygen species"
    explanation: Reduced mitochondrial ATP production in cells carrying a patient allele.
  downstream:
  - target: Neuronal Energy Failure in the Basal Ganglia
    description: >-
      Neurons in human cortex express SUCLA2 and not the GTP-forming SUCLG2, so the
      Krebs cycle block cannot be complemented by the other isoform in neurons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24085565
      reference_title: "Exclusive neuronal expression of SUCLA2 in the human brain."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Immunoreactivity of the GTP-forming β subunit (G-SUCL-β) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes."
      explanation: Absence of the complementing isoform in human cortical neurons, in surgical tissue.
- name: Disrupted Mitochondrial Nucleotide Supply
  biological_scale: MOLECULAR
  description: >-
    A-SUCL physically associates with mitochondrial NDPK, which forms the
    nucleoside triphosphates used for mtDNA synthesis; SUCLA2 is described as
    stabilising NDPK. Loss of the association is the favoured explanation for mtDNA
    depletion. The evidence is indirect: NDPK activity and mtDNA content were
    normal in SUCLA2-deficient patient fibroblasts, whereas knockdown of the
    GTP-forming partner SUCLG2 in the same cells lowered both, suggesting that
    SUCLG2 complements SUCLA2 loss in cells that express it. In SUCLA2-knockdown
    mouse neurons, deregulated NDPK was among the changes accompanying mtDNA loss.
  biological_processes:
  - preferred_term: deoxyribonucleoside triphosphate biosynthetic process
    term:
      id: GO:0009202
      label: deoxyribonucleoside triphosphate biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:18392745
    reference_title: "Disorders caused by deficiency of succinate-CoA ligase."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mtDNA depletion may be explained by the interaction of succinate-CoA ligase with nucleoside diphosphate kinase, which is involved in mitochondrial nucleotide metabolism."
    explanation: Review synthesis of the NDPK hypothesis.
  - reference: PMID:28769029
    reference_title: "Loss of succinyl-CoA synthase ADP-forming β subunit disrupts mtDNA stability and mitochondrial dynamics in neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our data also suggest that the deregulation of mitochondrial nucleoside diphosphate kinase (NDPK) together with defects in mitochondrial transcription factors including mitochondrial DNA pol γ and Twinkle contribute to SCS A-β deficiency-mediated mtDNA instability."
    explanation: In cultured mouse neurons with SUCLA2 knockdown, NDPK deregulation accompanies mtDNA instability.
  - reference: PMID:21295139
    reference_title: "The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "We have investigated this relationship by studying SUCLA2 deficient fibroblasts derived from patients and detected normal mtDNA content and normal NDPK activity."
    explanation: >-
      In patient fibroblasts, SUCLA2 loss does not reduce NDPK activity or mtDNA,
      so the mechanism is not cell-autonomous in every cell type.
  - reference: PMID:21295139
    reference_title: "The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, knockdown of SUCLG2 by shRNA in both patient and control fibroblasts resulted in a significant decrease in mtDNA amount, decreased NDPK and cytochrome c oxidase activities, and a marked growth impairment."
    explanation: Removing the complementing SUCLG2 isoform unmasks NDPK and mtDNA loss, consistent with isoform complementation explaining tissue specificity.
  downstream:
  - target: Neuronal and Muscle mtDNA Depletion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26409464
      reference_title: "SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Disruption of SCS-A could thereby lead to impaired mtDNA synthesis and thus mtDNA depletion"
      explanation: Introduction of a case report restating the NDPK-to-mtDNA link as a hypothesis.
- name: Neuronal and Muscle mtDNA Depletion
  biological_scale: CELLULAR
  description: >-
    Reduced mtDNA copy number in skeletal muscle (and, in the mouse model, brain),
    with normal copy number in fibroblasts and in liver, where SUCLA2 is not the
    dominant isoform. In the discovery family muscle mtDNA was 32% of control and
    fibroblast mtDNA 95%. Depletion is not obligatory: siblings with normal muscle
    mtDNA and a family with a slowly progressive course without depletion have been
    reported, so the respiratory chain defect can arise without measurable
    depletion. The GTP-forming SUCLG2 isoform, expressed in liver and anabolic
    tissues, is thought to protect tissues that express it.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitochondrial DNA replication
    term:
      id: GO:0006264
      label: mitochondrial DNA replication
    modifier: DECREASED
  evidence:
  - reference: PMID:15877282
    reference_title: "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the ratio of mtDNA to nuclear DNA, determined by real-time PCR, was reduced to 32% of the mean control value. The mtDNA:nuclear DNA ratio in fibroblasts was 95% of the mean control value."
    explanation: Muscle depletion with normal fibroblast mtDNA in the discovery family.
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion."
    explanation: Confirms mtDNA depletion in the Faroese and Italian series.
  - reference: PMID:24271779
    reference_title: "Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20-60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed."
    explanation: In the Sucla2 gene-trap mouse, depletion follows the tissues that express Sucla2.
  - reference: PMID:24271779
    reference_title: "Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mtDNA content could be restored by reintroduction of Sucla2."
    explanation: Rescue in mutant fibroblasts ties the depletion to Sucla2 loss.
  - reference: PMID:26409464
    reference_title: "SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "A-SUCL is mainly expressed in testis, brain and skeletal muscle tissue, whereas G-SUCL is expressed in liver and anabolic tissues"
    explanation: Tissue distribution of the two isoforms, consistent with brain and muscle involvement and liver sparing.
  - reference: PMID:27913098
    reference_title: "Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings."
    explanation: Depletion is absent in some patients despite the typical phenotype.
  - reference: PMID:24986829
    reference_title: "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion."
    explanation: A milder allele (p.Asp333Gly) causes disease without mtDNA depletion.
  downstream:
  - target: Combined Respiratory Chain Deficiency
    description: >-
      Fewer mtDNA templates reduce synthesis of mtDNA-encoded subunits, sparing the
      entirely nuclear-encoded complex II.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24271779
      reference_title: "Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The mtDNA depletion resulted in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies."
      explanation: Direct demonstration in Sucla2-deficient mouse cells that depletion lowers mtDNA-encoded proteins.
- name: Combined Respiratory Chain Deficiency
  biological_scale: CELLULAR
  conforms_to: "mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress"
  description: >-
    Reduced activity of complexes I and IV (with III and V less affected) and
    borderline-normal complex II in muscle, the pattern of a defect in mtDNA-encoded
    subunit synthesis. Normal muscle histology and enzymology do not exclude the
    diagnosis. Increased reactive oxygen species production is shown in patient
    cells and knockdown neurons, not in patient tissue.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:15877282
    reference_title: "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The activities of complexes I and IV were significantly decreased, and complexes III and V were less affected, whereas complex II, the only complex that does not contain mtDNA-encoded proteins, was borderline normal"
    explanation: Muscle respiratory chain pattern in the discovery family.
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency."
    explanation: The pattern across the 71-patient review, and its limits.
  - reference: PMID:28769029
    reference_title: "Loss of succinyl-CoA synthase ADP-forming β subunit disrupts mtDNA stability and mitochondrial dynamics in neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, by down-regulating the expression levels of SCS A-β in cultured mouse neurons, we have found that SCS A-β deficiency induces severe mitochondrial dysfunction including lowered oxidative phosphorylation (OXPHOS) efficiency, increased mitochondrial superoxide production, and mtDNA depletion as well as aberrations of mitochondrial fusion and fission proteins, which eventually leads to neuronal stress."
    explanation: Reduced OXPHOS and increased superoxide in SUCLA2-knockdown neurons; supports the oxidative arm of the conformed module node in vitro.
  downstream:
  - target: Neuronal Energy Failure in the Basal Ganglia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33231368
      reference_title: "SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Possibly, the effect on NDPK is universal in this tissue, unvaryingly compounding the Krebs cycle failure with respiratory chain insufficiency. The susceptibility of the basal ganglia is, however, likely multifactorial, including high energy demands."
      explanation: The authors' discussion of why the basal ganglia are affected in all patients, stated as a hypothesis.
  - target: Mitochondrial Myopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lactic acidosis
    description: Impaired oxidative phosphorylation shifts pyruvate to lactate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Progressive sensorineural hearing impairment
    description: >-
      Presumed energy failure in the auditory pathway. No study has localised the
      lesion (cochlear hair cell, spiral ganglion or central) in this disorder.
    causal_link_type: UNKNOWN
- name: Succinyl-CoA Accumulation
  biological_scale: MOLECULAR
  description: >-
    Succinyl-CoA builds up behind the block. Two consequences follow: backflow
    through the propionate pathway, and non-enzymatic succinylation of lysine
    residues across the proteome.
  biological_processes:
  - preferred_term: succinyl-CoA metabolic process
    term:
      id: GO:0006104
      label: succinyl-CoA metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33230181
    reference_title: "SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation."
    explanation: Measured in patient fibroblasts and myotubes.
  downstream:
  - target: Secondary Methylmalonyl-CoA Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17287286
      reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The hallmark of the condition, elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid, because the conversion of methylmalonyl-CoA to succinyl-CoA is inhibited."
      explanation: States the mechanism of the methylmalonic aciduria.
  - target: Protein Hypersuccinylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37819759
      reference_title: "Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex."
      explanation: Forebrain Sucla2 knockout shows the step in vivo.
- name: Secondary Methylmalonyl-CoA Accumulation
  biological_scale: MOLECULAR
  description: >-
    Succinyl-CoA excess inhibits methylmalonyl-CoA conversion, so methylmalonic acid
    and C4-dicarboxylic (methylmalonyl- and succinyl-) carnitine rise in body fluids.
    The elevation is mild compared with classical methylmalonic acidemia and may be
    marginal or absent in urine; plasma methylmalonic acid is more consistently
    raised. Methylcitrate is also raised.
  biological_processes:
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis."
    explanation: Defines the metabolite signature.
  - reference: PMID:24271779
    reference_title: "Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Elevated levels of MMA were observed in embryonic brain."
    explanation: The mouse model reproduces the methylmalonic acid elevation in brain.
  downstream:
  - target: Methylmalonic aciduria
    causal_link_type: DIRECT
- name: Protein Hypersuccinylation
  biological_scale: CELLULAR
  description: >-
    Excess succinyl-CoA succinylates lysines on nearly a thousand sites in patient
    cells, many of them targets of the NAD+-dependent desuccinylase SIRT5. In the
    forebrain knockout mouse, hypersuccinylation is associated with reduced complex I
    activity and altered chromatin and neuronal gene expression; in sucla2 mutant
    zebrafish it consumes NAD+ and propagates respiratory defects. This is an
    emerging mechanism, established in patient cells and animal models but not yet
    in patient tissue.
  biological_processes:
  - preferred_term: protein succinylation
    term:
      id: GO:0018335
      label: protein succinylation
    modifier: INCREASED
  evidence:
  - reference: PMID:33230181
    reference_title: "SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes."
    explanation: Proteome-wide hypersuccinylation in patient cells.
  downstream:
  - target: Combined Respiratory Chain Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37819759
      reference_title: "Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression."
      explanation: In vivo association of hypersuccinylation with complex I deficiency.
    - reference: PMID:41574612
      reference_title: "NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy."
      explanation: Zebrafish evidence that hypersuccinylation worsens respiratory function via NAD+ depletion.
- name: Neuronal Energy Failure in the Basal Ganglia
  biological_scale: TISSUE
  description: >-
    Selective injury of the putamen and caudate, seen as Leigh-like T2
    hyperintensity and later atrophy, with demyelination and cortical and central
    atrophy. SUCLA2 is expressed in neurons and not in glia in human cortex. Early
    MRI can be normal, with abnormalities appearing later, and MR spectroscopy may
    show lactate when structural imaging is normal.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: putamen
    term:
      id: UBERON:0001874
      label: putamen
  - preferred_term: caudate nucleus
    term:
      id: UBERON:0001873
      label: caudate nucleus
  evidence:
  - reference: PMID:24085565
    reference_title: "Exclusive neuronal expression of SUCLA2 in the human brain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex."
    explanation: Neuronal localisation of SUCLA2 in human surgical cortex.
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei."
    explanation: The basal ganglia pattern.
  - reference: PMID:17287286
    reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging showed demyelination and central and cortical atrophy, including atrophy of the basal ganglia, and some of the patients fulfilled the criteria for Leigh syndrome."
    explanation: Imaging in the 12-patient Faroese series.
  downstream:
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Choreoathetosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Basal ganglia involvement on neuroimaging
    causal_link_type: DIRECT
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    causal_link_type: UNKNOWN
- name: Mitochondrial Myopathy
  biological_scale: TISSUE
  description: >-
    Skeletal muscle weakness and atrophy. A muscle-specific Sucla2 knockout mouse
    shows growth failure, reduced grip strength and exercise intolerance, with the
    oxidative soleus more affected than the glycolytic extensor digitorum longus.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:39482887
    reference_title: "Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance."
    explanation: Muscle-autonomous consequence of Sucla2 loss.
  downstream:
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Skeletal muscle atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39482887
      reference_title: "Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mutant mice also exhibited 34%-40% reduced grip strength (p < 0.01) and reduced spontaneous exercise, spending about 88% less cumulative time on a running wheel (p < 0.0001)."
      explanation: Weakness in the muscle-specific knockout.
  - target: Ptosis
    causal_link_type: UNKNOWN
  - target: External ophthalmoplegia
    causal_link_type: UNKNOWN
  - target: Kyphoscoliosis
    causal_link_type: UNKNOWN
  - target: Postnatal growth retardation
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:39482887
      reference_title: "Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "By 3 weeks of age, Sucla2 KO mice were 44% the size of controls by body weight (p < 0.0001)."
      explanation: >-
        Muscle-restricted loss alone is enough to cause growth failure in mice;
        whether the same holds in children, where feeding difficulty also
        contributes, is not established.
phenotypes:
- category: Neurological
  name: Hypotonia
  description: >-
    Muscular hypotonia from the first months of life, often the presenting sign.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties."
    explanation: GeneReviews core feature with infantile onset.
  - reference: PMID:19666145
    reference_title: "Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with SUCLA2 gene defects characteristically develop the trias of early hypotonia, progressive dystonia and sensori-neural deafness."
    explanation: Early hypotonia is part of the characteristic triad in 16 Faroese children.
- category: Neurological
  name: Global developmental delay
  description: Psychomotor delay from infancy, typically severe.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties."
    explanation: GeneReviews core feature.
- category: Neurological
  name: Developmental regression
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z
    reference_title: "SUCLA2 / mitochondrial disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical features in affected individuals include LSS, developmental delay and regression, encephalopathy, myopathy, choreoathetosis, dystonia, seizures, ptosis, sensorineural hearing loss, feeding difficulty, failure to thrive, and elevated lactate and methylmalonic acid."
    explanation: ClinGen summary of the curated cases lists regression.
- category: Neurological
  name: Dystonia
  description: >-
    A hyperkinetic-dystonic movement disorder that follows the early hypotonia and
    is progressive in the typical form. With the p.Arg407Trp allele a
    myoclonic-dystonic movement disorder has been reported to remain unchanged from childhood
    into the fourth decade.
  phenotype_term:
    preferred_term: Progressive dystonia
    term:
      id: HP:0001332
      label: Dystonia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia."
    explanation: Progressive dystonia after infantile onset.
  - reference: PMID:33231368
    reference_title: "SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade."
    explanation: Non-progressive allelic form with p.Arg407Trp.
- category: Neurological
  name: Choreoathetosis
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."
    explanation: GeneReviews less frequent feature.
- category: Neurological
  name: Seizures
  description: >-
    Epilepsy occurs in a minority and is much more frequent with SUCLA2 than with
    SUCLG1 deficiency.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations."
    explanation: Epilepsy is a feature of the SUCLA2 disorder.
- category: Neurological
  name: Basal ganglia involvement on neuroimaging
  description: >-
    Leigh-like T2 hyperintensity and atrophy of the putamen and caudate; the most
    frequent neuroimaging abnormality. Early imaging may be normal.
  phenotype_term:
    preferred_term: Basal ganglia involvement on neuroimaging
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69% of SUCLA2 and 80% of SUCLG1 patients."
    explanation: 69% of SUCLA2 patients (FREQUENT band).
  - reference: PMID:27651038
    reference_title: "A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while 1H-magnetic resonance spectroscopy (MRS) showed lactate peaks in the cerebral cortex and lateral ventricles."
    explanation: A normal MRI does not exclude the diagnosis.
- category: Auditory
  name: Progressive sensorineural hearing impairment
  description: >-
    Sensorineural hearing loss, often severe and progressive; one of the defining
    features, and managed with hearing aids or cochlear implantation.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:19666145
    reference_title: "Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive hearing loss, in combination with a characteristic metabolite profile (increased lactate, methylmalonic acid, C4-dicarboxylic carnitine, 3-hydroxyisovaleric acid) should lead the clinician to the correct diagnosis even in patients with only intermittent lactic acidemia."
    explanation: Progressive hearing loss in 16 Faroese children.
  - reference: PMID:17287286
    reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation."
    explanation: Severe hearing impairment in the 12-patient series.
- category: Musculoskeletal
  name: Skeletal muscle atrophy
  phenotype_term:
    preferred_term: Muscular atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:17287286
    reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation."
    explanation: Muscle atrophy as a core symptom.
- category: Musculoskeletal
  name: Muscle weakness
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."
    explanation: GeneReviews less frequent feature.
- category: Growth
  name: Postnatal growth retardation
  phenotype_term:
    preferred_term: Growth failure
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:17287286
    reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation."
    explanation: Postnatal growth retardation as a core symptom.
- category: Gastrointestinal
  name: Feeding difficulties
  description: Feeding difficulty in infancy; gastrostomy is used when needed to maintain intake.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  sequelae:
  - target: Postnatal growth retardation
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties."
    explanation: GeneReviews core feature.
- category: Gastrointestinal
  name: Recurrent vomiting
  phenotype_term:
    preferred_term: Recurrent vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."
    explanation: GeneReviews less frequent feature.
- category: Ophthalmological
  name: Ptosis
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."
    explanation: GeneReviews less frequent feature.
- category: Ophthalmological
  name: External ophthalmoplegia
  phenotype_term:
    preferred_term: External ophthalmoplegia
    term:
      id: HP:0000544
      label: External ophthalmoplegia
  evidence:
  - reference: ORPHA:1933
    reference_title: "Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Seizures, external ophthalmoplegia, polyneuropathy, cardiomyopathy, and renal tubular dysfunction have also been reported."
    explanation: >-
      Orphanet definition. The same sentence lists cardiomyopathy, which the
      71-patient review did not find in any SUCLA2 patient; only external
      ophthalmoplegia is curated from it.
- category: Musculoskeletal
  name: Kyphoscoliosis
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis."
    explanation: GeneReviews less frequent feature.
- category: Metabolic
  name: Lactic acidosis
  description: Variable and sometimes intermittent; its absence does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis."
    explanation: Variable lactic acidosis.
- category: Metabolic
  name: Methylmalonic aciduria
  description: >-
    Mild methylmalonic aciduria; urinary excretion was only marginal in some
    patients, and absent in a few, whereas plasma methylmalonic acid is more
    consistently raised (see biochemical).
  phenotype_term:
    preferred_term: Methylmalonic aciduria
    term:
      id: HP:0012120
      label: Methylmalonic aciduria
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found."
    explanation: Urinary MMA may be marginal; plasma MMA is consistently raised.
  - reference: PMID:23010432
    reference_title: "A novel homozygous mutation in SUCLA2 gene identified by exome sequencing."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast with what has been reported in other patients, methyl-malonic aciduria, a biomarker for this genetic defect, was absent in our proband and very mildly elevated in her affected sister."
    explanation: Methylmalonic aciduria can be absent.
biochemical:
- name: Plasma methylmalonic acid
  presence: PRESENT
  notes: >-
    Mildly raised, far lower than in classical methylmalonic acidemia; consistently
    raised in plasma even when urinary excretion is marginal.
  biomarker_term:
    preferred_term: Methylmalonic acidemia
    term:
      id: HP:0002912
      label: Methylmalonic acidemia
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found."
    explanation: Plasma MMA is the more reliable marker.
- name: C4-dicarboxylic carnitine
  presence: PRESENT
  notes: >-
    Raised C4-dicarboxylic (methylmalonyl- plus succinyl-) carnitine in blood; in
    one family succinylcarnitine was raised without methylmalonic aciduria. No
    biomarker_term is bound: an HPO search (ols:hp for "dicarboxylic",
    "acylcarnitine", "succinyl") returned C4-acylcarnitine (HP:0035016), which is
    butyryl/isobutyrylcarnitine and a different analyte, and no C4-dicarboxylic or
    succinylcarnitine term.
  evidence:
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease."
    explanation: The carnitine ester profile as a hallmark.
  - reference: PMID:24659738
    reference_title: "A novel SUCLA2 mutation in a Portuguese child associated with \"mild\" methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic investigations disclosed hyperlactacidemia, moderate urinary excretion of methylmalonic acid, and elevated levels of C4-dicarboxylic carnitine in blood."
    explanation: Raised blood C4-dicarboxylic carnitine in a Portuguese child.
  - reference: PMID:23759946
    reference_title: "The novel mutation p.Asp251Asn in the β-subunit of succinate-CoA ligase causes encephalomyopathy and elevated succinylcarnitine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We instead found elevated levels of succinylcarnitine."
    explanation: Succinylcarnitine raised in a family without methylmalonic aciduria.
- name: Urinary 3-hydroxyisovaleric acid
  presence: PRESENT
  biomarker_term:
    preferred_term: 3-hydroxyisovaleric aciduria
    term:
      id: HP:0033111
      label: 3-hydroxyisovaleric aciduria
  evidence:
  - reference: PMID:19666145
    reference_title: "Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated urinary 3-hydroxyisovaleric acid is a novel biochemical feature in patients."
    explanation: Reported in 16 Faroese children.
- name: Methylcitrate
  presence: PRESENT
  notes: >-
    The source abstract does not state whether urine or plasma was measured, so no
    urine- or blood-specific HPO term is bound.
  evidence:
  - reference: PMID:18392745
    reference_title: "Disorders caused by deficiency of succinate-CoA ligase."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Elevated methylmalonate and methylcitrate and severe mtDNA depletion were found in both disorders."
    explanation: Review statement covering SUCLA2 and SUCLG1 deficiency.
genetic:
- name: SUCLA2
  gene_term:
    preferred_term: SUCLA2
    term:
      id: hgnc:11448
      label: SUCLA2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    ClinGen Definitive (2024) for "SUCLA2-related primary mitochondrial disease",
    which ClinGen equates with OMIM 612073. A contiguous 13q14 deletion that
    removes SUCLA2 has been found in trans with a SUCLA2 point variant in a child
    with both this disorder and bilateral retinoblastoma, because the deletion also
    removes RB1. It follows (an inference, not a published recommendation) that a
    child whose SUCLA2 deletion allele extends to RB1 carries a germline RB1
    deletion and falls under retinoblastoma surveillance; conversely the authors
    suggest SUCLA2 testing when a child with retinoblastoma has an encephalomyopathy.
  evidence:
  - reference: CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z
    reference_title: "SUCLA2 / mitochondrial disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SUCLA2 | HGNC:11448 | mitochondrial disease | MONDO:0044970 | AR | Definitive"
    explanation: ClinGen gene-disease validity row.
  - reference: CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z
    reference_title: "SUCLA2 / mitochondrial disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SUCLA2 has been associated with one disease entity to date; mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) [OMIM# 612073]."
    explanation: ClinGen treats OMIM 612073 as the single SUCLA2 disease entity.
  - reference: PMID:24986829
    reference_title: "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma."
    explanation: Contiguous 13q14 deletion producing both diseases.
  - reference: PMID:24986829
    reference_title: "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, an encephalomyopathy in a patient with retinoblastoma suggests mutations affecting SUCLA2."
    explanation: The authors' diagnostic suggestion.
  variants:
  - name: c.534+1G>A (Faroese founder)
    description: >-
      Splice-donor variant (reported as IVS4+1G>A) causing exon 4 skipping; founder
      allele in the Faroe Islands.
    evidence:
    - reference: PMID:17287286
      reference_title: "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation analysis identified a novel splice site mutation in SUCLA2, IVS4 + 1G --> A, leading to skipping of exon 4."
      explanation: Identifies the founder splice allele.
    - reference: CGGV:assertion_cec21e34-6f67-4733-bf7e-f0d1b1632cf1-2024-06-17T040000.000Z
      reference_title: "SUCLA2 / mitochondrial disease (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "one splice site, c.534+1G>A, that is a founder variant in Faroe Islands, Denmark"
      explanation: ClinGen names the founder allele in HGVS form.
  - name: p.Arg407Trp
    description: >-
      Missense allele in the ligase domain associated with a milder course,
      including a non-progressive movement disorder with deafness into adulthood.
    evidence:
    - reference: PMID:33231368
      reference_title: "SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade."
      explanation: Milder allelic phenotype.
  - name: p.Asp333Gly
    description: Missense allele predicted to reduce rather than abolish activity; slowly progressive disease.
    evidence:
    - reference: PMID:24986829
      reference_title: "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme."
      explanation: Structural prediction for the milder allele.
progression:
- phase: Infantile onset
  notes: >-
    Median onset at two months (at birth for SUCLG1). Hypotonia, developmental
    delay and feeding difficulty come first; dystonia and hearing loss become
    evident and progress over infancy and early childhood.
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients."
    explanation: Age of onset.
- phase: Survival
  notes: >-
    Median survival about 20 years, far longer than SUCLG1 deficiency (20
    months); about 30% die in childhood; about 12% reported to reach 20 years or
    older. Missense alleles showed a trend toward longer survival than
    loss-of-function alleles.
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood."
    explanation: GeneReviews survival figures.
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median survival was 20 years for SUCLA2 and 20 months for SUCLG1."
    explanation: Survival by gene.
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients."
    explanation: Proportion reaching adulthood.
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations."
    explanation: Genotype and survival.
diagnosis:
- name: SUCLA2 molecular testing
  description: >-
    Biallelic SUCLA2 pathogenic variants establish the diagnosis. Sequencing is
    preferred to muscle biopsy once the metabolite pattern is recognised. Whole-gene
    and intragenic deletions are reported, so deletion analysis is needed when
    sequencing finds one or no variant.
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in SUCLA2 identified by molecular genetic testing."
    explanation: Diagnostic criterion.
  - reference: PMID:19666145
    reference_title: "Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct SUCLA2 sequence analysis is suggested instead of an invasive muscle biopsy to obtain the diagnosis."
    explanation: Sequencing before biopsy.
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands."
    explanation: Whole-gene deletions and additional Scandinavian founder alleles.
- name: Metabolite screen
  description: >-
    Plasma and urine methylmalonic acid, blood acylcarnitines (C4-dicarboxylic
    carnitine), urine organic acids and lactate. The combination is characteristic
    even when lactate is only intermittently raised.
  evidence:
  - reference: PMID:19666145
    reference_title: "Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive hearing loss, in combination with a characteristic metabolite profile (increased lactate, methylmalonic acid, C4-dicarboxylic carnitine, 3-hydroxyisovaleric acid) should lead the clinician to the correct diagnosis even in patients with only intermittent lactic acidemia."
    explanation: Diagnostic metabolite profile.
- name: Surveillance
  description: >-
    GeneReviews recommends routine monitoring of development, growth and hearing,
    periodic ophthalmologic evaluation, and skeletal evaluation for kyphoscoliosis
    and joint contractures. Intervals are expert recommendation.
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Routine monitoring of development, growth, and hearing; periodic ophthalmologic evaluations; routine skeletal evaluations for kyphoscoliosis and joint contractures."
    explanation: GeneReviews surveillance recommendations.
differential_diagnoses:
- name: SUCLG1-related mitochondrial DNA depletion syndrome
  disease_term:
    preferred_term: mitochondrial DNA depletion syndrome 9
    term:
      id: MONDO:0009504
      label: mitochondrial DNA depletion syndrome 9
  description: >-
    Deficiency of the alpha subunit shared by both isoforms of the enzyme. Same
    methylmalonic aciduria, lactic acidosis and mtDNA depletion, but earlier onset
    (at birth), median survival 20 months, and hepatopathy and hypertrophic
    cardiomyopathy that are not reported with SUCLA2. Separated by gene testing.
  distinguishing_features:
  - Hepatopathy in 38% of SUCLG1 patients and none with SUCLA2.
  - Hypertrophic cardiomyopathy in 14% of SUCLG1 patients and none with SUCLA2.
  - Median survival 20 months versus 20 years.
  evidence:
  - reference: PMID:26475597
    reference_title: "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notable clinical differences between the two groups were hepatopathy, found in 38% of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14% of cases with SUCLG1 mutations."
    explanation: Direct comparison in the same review.
  - reference: PMID:28358460
    reference_title: "SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Life span is shortened, with median survival of 20 months."
    explanation: GeneReviews survival for the SUCLG1 disorder.
- name: Methylmalonic acidemia (isolated)
  disease_term:
    preferred_term: methylmalonic acidemia
    term:
      id: MONDO:0002012
      label: methylmalonic acidemia
  description: >-
    The mild methylmalonic aciduria of SUCLA2 deficiency can be mistaken for an
    isolated methylmalonic acidemia; SUCLA2 deficiency was found among patients
    referred with mild, unexplained methylmalonic aciduria, and the accompanying
    deafness, dystonia and basal ganglia lesions point to it.
  evidence:
  - reference: PMID:17301081
    reference_title: "SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families."
    explanation: SUCLA2 deficiency was identified among patients with mild unexplained methylmalonic aciduria.
- name: Mitochondrial DNA depletion syndrome, myopathic form (TK2)
  disease_term:
    preferred_term: mitochondrial DNA depletion syndrome, myopathic form
    term:
      id: MONDO:0012301
      label: mitochondrial DNA depletion syndrome, myopathic form
  description: >-
    The myopathic member of the same mtDNA depletion family, from TK2 deficiency.
    It shares infantile hypotonia, muscle mtDNA depletion, raised lactate and
    death from respiratory failure with the SUCLA2 form, and it is the entity for
    which the deoxycytidine and deoxythymidine strategy is actually established
    rather than extrapolated.
  distinguishing_features:
  - TK2 encodes thymidine kinase 2, the rate-limiting enzyme of mitochondrial pyrimidine deoxynucleoside salvage; SUCLA2 encodes a succinyl-CoA ligase subunit, so the mtDNA depletion there is downstream rather than a precursor shortage.
  - Methylmalonic aciduria is absent in TK2 deficiency; it is the biochemical signature of SUCLA2 deficiency.
  - TK2 disease is dominated by limb, bulbar and respiratory myopathy with cognition typically spared, against the dystonia, deafness and basal ganglia change of SUCLA2 deficiency.
  - The mechanistic rationale for nucleoside substitution is direct in TK2 deficiency (the missing enzyme's own substrates) and indirect for SUCLA2, where the pooled phase 2 trial reports no gene-specific result.
  - Curated separately as Mitochondrial_DNA_Depletion_Syndrome_Myopathic_Form.
  evidence:
  - reference: PMID:23932787
    reference_title: "Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides"
    explanation: Identifies the gene and mechanism of the myopathic form, against the TCA-cycle lesion here.
  - reference: PMID:23230576
    reference_title: "TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive function is typically spared."
    explanation: Cognitive sparing in TK2 deficiency, against the encephalomyopathic course of SUCLA2 deficiency.
treatments:
- name: Supportive and Rehabilitative Care
  description: >-
    Early developmental support and physical therapy to maintain muscle function and
    prevent contractures; bracing for scoliosis or kyphosis; chest physiotherapy and
    prompt antibiotic treatment of chest infections. No disease-modifying treatment
    is established.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Appropriate early developmental support; physical therapy to maintain muscle function and prevent joint contractures"
    explanation: GeneReviews management.
- name: Hearing Aids or Cochlear Implantation
  description: Amplification or cochlear implantation for the sensorineural hearing loss.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aids or cochlear implantation with auditory rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_phenotypes:
  - preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hearing aids / cochlear implantation for sensorineural hearing loss"
    explanation: GeneReviews management.
- name: Gastrostomy Feeding
  description: Gastrostomy tube placement as needed to maintain caloric intake.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy tube placement
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrostomy tube placement as needed to assure adequate caloric intake"
    explanation: GeneReviews management.
- name: Antiseizure Medication
  description: >-
    Standard antiseizure medication for epilepsy. Valproyl-CoA inhibits
    ATP-forming succinyl-CoA ligase in fibroblast extracts, so valproate has a
    theoretical mechanism of harm in this disorder; this is an in vitro finding,
    the abstract makes no clinical recommendation, and the discovery paper reports
    a child whose seizures were controlled with valproic acid.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301762
    reference_title: "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "antiseizure medication for epileptic seizures"
    explanation: GeneReviews management.
  - reference: PMID:24154984
    reference_title: "Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Valproyl-CoA (1 mM) inhibited the activity of A-SUCL and G-SUCL by 45-55% and 25-50%, respectively."
    explanation: In vitro basis for caution with valproate.
  - reference: PMID:15877282
    reference_title: "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized seizures, first noted at age 1 year, were controlled by valproic acid."
    explanation: A discovery-family patient whose seizures responded to valproate.
- name: Deoxycytidine and Deoxythymidine
  description: >-
    Oral pyrimidine deoxynucleosides, investigational. In an interim analysis of a
    phase 2 open-label trial (NCT04802707) in eight children with FBXL4, SUCLG1,
    SUCLA2 or RRM2B variants, Newcastle Mitochondrial Disease Scale scores improved
    at group level and raised GDF15 improved in four of five. SUCLA2-specific
    results are not reported separately, the study is uncontrolled, and the
    mechanistic rationale for bypassing an NDPK-associated defect with nucleosides
    has not been tested for SUCLA2 specifically.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deoxycytidine
      term:
        id: CHEBI:15698
        label: 2'-deoxycytidine
    - preferred_term: deoxythymidine
      term:
        id: CHEBI:17748
        label: thymidine
  target_mechanisms:
  - target: Disrupted Mitochondrial Nucleotide Supply
    description: Intended to supplement the mitochondrial pyrimidine deoxynucleotide pool.
  evidence:
  - reference: PMID:40175578
    reference_title: "Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Data were available from eight individuals having pathogenic variants in FBXL4, SUCLG1, SUCLA2, or RRM2B."
    explanation: SUCLA2 is among the pooled genotypes.
  - reference: PMID:40175578
    reference_title: "Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newcastle Mitochondrial Disease Scale score improved in all individuals except for one who withdrew before the first follow-up visit; group level analysis was significant at 1-month and 6-month timepoints."
    explanation: Pooled open-label result; not specific to SUCLA2.
- name: Coenzyme Q10
  description: >-
    Single-patient report of improved weakness and stabilisation with escalating
    CoQ10 up to 2000 mg daily, proposed in the context of possible secondary CoQ10
    deficiency. Uncontrolled.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
  evidence:
  - reference: PMID:27651038
    reference_title: "A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Escalating doses of CoQ10 up to 2000 mg daily were associated with improvement of muscle weakness and stabilization of the disease course."
    explanation: Single-case observation.
- name: Succinate Supplementation
  description: >-
    Oral succinate was given to bypass the Krebs cycle block in one adult with the
    p.Arg407Trp allele. Biochemical abnormalities improved but the movement
    disorder did not, and it was stopped. The authors raise, without data, whether
    earlier treatment might matter.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Impaired Krebs Cycle Substrate-Level Phosphorylation
    description: Provides the product of the blocked step.
  evidence:
  - reference: PMID:33231368
    reference_title: "SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that succinate supplementation circumvents the Krebs cycle block, but does not correct the neurologic disease."
    explanation: Biochemical correction without neurological benefit in one patient.
clinical_trials:
- name: NCT04802707
  phase: PHASE_II
  description: >-
    Open-label, single-arm phase II study of combination deoxycytidine and
    deoxythymidine in children with mitochondrial DNA depletion syndrome; SUCLA2 is
    among the eligible genotypes. Recruitment status is not recorded here because
    the cached registry summary carries no status field.
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: clinicaltrials:NCT04802707
    reference_title: "A Phase II, Monocenter, Single Arm Study To Assess The Safety and Efficacy Of Combination Deoxycytidine and Deoxythymidine For Mitochondrial Depletion Disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The subjects included are children (0-18Y), with positive MDS diagnosis
      and express mutations in one of the following genes: POLG, POLG2, C10orf2,
      RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK.
    explanation: SUCLA2 is an eligible genotype.
animal_models:
- name: Sucla2 gene-trap mouse
  species: Mouse
  genotype: Sucla2 SAbetageo gene-trap homozygote
  publication: PMID:24271779
  description: >-
    Recessive lethality late in gestation; mtDNA depletion in brain, heart, muscle
    and placenta but not liver; raised methylmalonic acid in embryonic brain.
  modeled_mechanisms:
  - target: Neuronal and Muscle mtDNA Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Embryonic lethal, so postnatal neurological, auditory and muscle phenotypes
      cannot be studied.
    evidence:
    - reference: PMID:24271779
      reference_title: "Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20-60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed."
      explanation: Reproduces tissue-selective depletion.
  - target: Secondary Methylmalonyl-CoA Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    evidence:
    - reference: PMID:24271779
      reference_title: "Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Elevated levels of MMA were observed in embryonic brain."
      explanation: Reproduces the methylmalonic acid elevation.
- name: Muscle-specific Sucla2 knockout mouse
  species: Mouse
  genotype: HSA-Cre; Sucla2 flox/flox
  publication: PMID:39482887
  description: Skeletal-muscle-restricted Sucla2 loss producing a mitochondrial myopathy.
  modeled_mechanisms:
  - target: Mitochondrial Myopathy
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: Muscle-restricted; does not model the encephalopathy or hearing loss.
    evidence:
    - reference: PMID:39482887
      reference_title: "Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance."
      explanation: Muscle phenotype.
- name: Forebrain-specific Sucla2 knockout mouse
  species: Mouse
  genotype: forebrain-specific conditional Sucla2 knockout
  publication: PMID:37819759
  description: Postnatal forebrain loss of the whole SCS complex with hypersuccinylation.
  modeled_mechanisms:
  - target: Protein Hypersuccinylation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: >-
      Cortex-directed; whether it reproduces basal ganglia injury or dystonia is not
      stated in the abstract.
    evidence:
    - reference: PMID:37819759
      reference_title: "Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex."
      explanation: In vivo hypersuccinylation.
- name: sucla2 mutant zebrafish
  species: Zebrafish
  genotype: sucla2-/-
  publication: PMID:41574612
  description: >-
    Locomotor defects and reduced survival; NAD+ precursors restore NAD+ and improve
    locomotion and survival through Sirt5. Not tested in patients.
  modeled_mechanisms:
  - target: Protein Hypersuccinylation
    relationship: RESCUES
    fidelity: UNKNOWN
    model_scale: ORGANISM
    limitations: >-
      Zebrafish locomotion is a proxy for the human movement disorder; the rescue
      has not been tested in patients.
    evidence:
    - reference: PMID:41574612
      reference_title: "NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish."
      explanation: NAD+ precursor rescue in the model.
discussions:
- discussion_id: sucla2-hearing-loss-lesion
  kind: KNOWLEDGE_GAP
  prompt: Where in the auditory pathway does SUCLA2 deficiency cause hearing loss?
  attaches_to:
  - phenotypes#Progressive sensorineural hearing impairment
  rationale: >-
    Hearing loss is a defining feature, yet none of the cited clinical, cellular or
    animal studies localises the lesion to hair cells, spiral ganglion or central
    auditory pathways, and no cited model reproduces the hearing loss; the causal
    edge from the respiratory chain defect is therefore left as UNKNOWN.
- discussion_id: sucla2-mtdna-depletion-necessity
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much of the disease is due to mtDNA depletion, and how much to the Krebs
    cycle block and succinyl-CoA excess directly?
  attaches_to:
  - pathophysiology#Neuronal and Muscle mtDNA Depletion
  - pathophysiology#Protein Hypersuccinylation
  rationale: >-
    Typical disease occurs without muscle mtDNA depletion in some patients, patient
    fibroblasts are not depleted, and hypersuccinylation reduces complex I activity
    in mouse brain. The relative weight of these branches in patient brain is not
    established.

📚

References & Deep Research

References

2

PMID:20301762

SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria.

No top-level findings curated for this source.

PMID:28358460

SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: SUCLA2-Related_Mitochondrial_DNA_Depletion_Syndrome · 2026-09-23T19:37:30Z · View source

New entry for MONDO:0012791 (MTDPS5), SUCLA2 only; stub stubs/Mitochondrial_DNA_Depletion_Syndrome_Encephalomyopathic_Form_With_Methylmalonic_Aciduria.yaml removed. Lump/split: SUCLA2-only Disease entry. The SUCLG1 disorder (MTDPS9, MONDO:0009504, OMIM 245400, ORPHA:17, separate GeneReviews chapter PMID:28358460) is recorded as a differential diagnosis, not a subtype. The MONDO parent MONDO:0016796 is a multi-gene grouping (SUCLA2, SUCLG1, RRM2B, FBXL4 children) and is not this entry. Slug chosen to match the GeneReviews chapter name rather than the long MONDO label. Deep research: one run requested from falcon, which failed with HTTP 402 (out of credits); the run fell back to claude_code and the report is committed as research/SUCLA2-Related_Mitochondrial_DNA_Depletion_Syndrome-deep-research-claude_code.md (fell_back: true, requested_provider: falcon). Its reference validation: 32/32 identifiers resolved, 14/19 quotes matched, needs_review true; the five unmatched quotes (PMID:19666145, 21295139, 15877282, 18392745, 24659738) were not reused, and every snippet in the entry was copied from the cached source instead. preflight-dr returned WARN only because SUCLG1 is mentioned at 40% of SUCLA2's rate; the report is about the right disease (causal gene SUCLA2, OMIM 612073 matches MONDO), and SUCLG1 content was used only for the differential. Report errors not carried into the entry: it gives the SUCLA2 gene as HGNC:11450, which is SUCLG2 (SUCLA2 is hgnc:11448, confirmed with runoak sqlite:obo:hgnc); it says ORPHA:1933 covers both SUCLA2 and SUCLG1 disease, but ORPHA:1933 cross-references only MONDO:0012791 / OMIM 612073 and SUCLG1 has ORPHA:17; it binds HP:0003348 (Hyperalaninemia) as the defining biomarker and HP:0002490 (Increased CSF lactate) for basal ganglia signal change, neither used. Structured sources: ClinGen CGGV SUCLA2 / mitochondrial disease (Definitive, 2024) and Orphanet ORPHA:1933 caches built with --cache-dir references_cache. GeneReviews chapter PMID:20301762 is the phenotype baseline (abstract only); all features in its Clinical Characteristics abstract are present. Evidence gaps: no frequency figures for most phenotypes (only the 69% basal ganglia figure is quantified in an accessible abstract); hearing-loss lesion site unknown (recorded as a KNOWLEDGE_GAP discussion); deoxynucleoside trial data are pooled across genes; Faroese 1 in 1700 figure is recorded with measure_type UNKNOWN because the source does not say per live birth. Validation: just validate, count-verified-snippets (113/113), validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches, check-reference-titles, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-genereviews --online, validate-disorders.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5 39 citations 2026-09-23T15:51:23.709025

1. Disease Information

Overview. SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MTDPS5) is an autosomal recessive disorder caused by biallelic pathogenic variants in SUCLA2, encoding the β-subunit of the ADP-forming (A) isoform of succinyl-CoA synthetase/ligase (SUCL), a Krebs-cycle enzyme. Loss of SUCL function secondarily depletes mitochondrial DNA (mtDNA) copy number, producing a severe infantile encephalomyopathy. The disease-defining biochemical signature — described as "mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis" (Carrozzo et al. 2007, Brain, PMID:17301081) — distinguishes this entity from classic methylmalonic acidemias (MMUT, MMAA/B/etc.) despite the shared metabolite.

Key identifiers: - OMIM phenotype #612073 "Mitochondrial DNA depletion syndrome 5 (encephalomyopathic type)"; gene OMIM 603921 - MONDO:0012791 - ORPHA:1933 (shared code covering both SUCLA2- and SUCLG1-caused encephalomyopathic MDS with methylmalonic aciduria; note the sibling entity MTDPS9*, OMIM #245400, is the SUCLG1-specific form — see Differential Diagnosis) - GeneReviews chapter: El-Hattab AW, Scaglia F, "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria" (PMID:20301762, NBK6803) - MeSH/synonyms: "SUCLA2 deficiency," "deafness-dystonia syndrome (SUCLA2-related)," "mild methylmalonic aciduria with Leigh-like encephalomyopathy" - ICD-10-CM: no dedicated code; falls under E88.49 (other mitochondrial metabolic disorders) - HGNC:11450; UniProt Q9P2R7; chromosome 13q14.2, ~60 kb, 13 exons, 463-aa protein

Evidence provenance note. Virtually all clinical/epidemiologic data below derive from aggregated case-series (largest: 71 patients across SUCLA2+SUCLG1, PMID:26475597) rather than a prospective disease registry or large-scale EHR resource — this is a founder-population/ultra-rare disease literature, so denominators are small and ascertainment is clinic-based.

2. Etiology

Causal factor: Biallelic loss-of-function or hypomorphic variants in SUCLA2 (13q14.2), autosomal recessive. First established by Elpeleg et al. 2005 (Am J Hum Genet, PMID:15877282), who found "markedly decreased succinyl-CoA synthetase activity" in muscle mitochondria of two siblings with encephalomyopathy and mtDNA depletion, and proposed that "a defect in the last step of mitochondrial dNTP salvage is a novel cause of the mtDNA depletion syndrome." Confirmed independently and expanded the same year in two companion Brain papers: Ostergaard et al. (PMID:17287286, 12 Faroese/Scandinavian patients) and Carrozzo et al. (PMID:17301081, 14 patients/11 families, including non-Faroese Italian/other European ancestry).

Genetic risk factors: - Homozygous or compound-heterozygous SUCLA2 variants (missense, nonsense, splice-site, frameshift, and at least one intragenic deletion — PMID:26409464). - Founder mutation: a homozygous splice-site variant in the Faroe Islands population, carrier frequency 1:33, allele frequency 2%, disease incidence 1:1700 in that population — "a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect" (PMID:17287286; consistent figures in PMID:19666145, 16 Faroese children with this homozygous splice-site allele). - Recurrent non-Faroese alleles reported multiple times independently include p.Arg284Cys (≥4 patients of Italian/Caucasian ancestry per PMID:28749033) and p.Arg407Trp/Leu at a mutational hotspot associated with a distinctly milder, non-progressive phenotype (PMID:33231368). - Compound heterozygosity with a contiguous 13q14 deletion spanning SUCLA2 and RB1 has produced combined mitochondrial encephalomyopathy plus retinoblastoma in two families (PMID:24986829) — a mechanistically unrelated but genomically contiguous double diagnosis worth flagging for dismech's cancer-predisposition adjacency (13q14 deletion syndrome / RB1). - One kindred with concurrent trisomy 21 and homozygous SUCLA2 p.Arg284Cys showed a more severe phenotype than either condition alone (PMID:28749033) — reported as an interaction, single-family evidence.

Environmental/modifying factors: None established as disease-causing; this is a purely monogenic mitochondrial-maintenance disorder. Consanguinity is a recognized risk factor for homozygosity in non-founder populations (e.g., the consanguineous Iranian cousins in PMID:23759946; the consanguineous family in PMID:27651038).

Protective factors: None specifically identified for disease risk. Therapeutically, succinate bypasses the enzymatic block in at least one case ("succinate supplementation circumvents the Krebs cycle block," PMID:33231368) — see Treatment.

Gene–environment interaction: Not applicable in the classic sense; the closest analog is genetic background modifying severity via residual protein/enzyme activity (see Mechanism, genotype-phenotype correlation) rather than an exogenous exposure.

3. Phenotypes

The core clinical triad, stated repeatedly across the literature: "early hypotonia, progressive dystonia and sensori-neural deafness" (PMID:19666145).

Phenotype	Type	Onset/course	Frequency (qualitative)	Suggested HP term
Severe muscular hypotonia	Sign	Neonatal–early infancy; often progressive to areflexia	Near-universal	HP:0001252 (Hypotonia)
Global developmental delay / profound motor delay	Sign	Infancy, progressive	Near-universal	HP:0001263
Progressive dystonia / hyperkinetic-dystonic movement disorder	Sign	Onset ~12–14 months, progressive	Very common	HP:0001332 (Dystonia); HP:0002072 (Chorea) may co-occur
Sensorineural hearing loss	Sign	Progressive, often profound	Very common (a defining feature)	HP:0000407
Failure to thrive / postnatal growth retardation	Sign	Infancy onward	Common	HP:0001508 / HP:0008897
Feeding difficulties	Sign	Infancy	Common	HP:0011968
Muscular atrophy	Sign	Progressive	Common	HP:0003202
External ophthalmoplegia	Sign	Variable	Reported subset	HP:0000544
Leigh-like basal ganglia lesions (putamen/caudate T2 hyperintensity, atrophy) on MRI	Imaging	Progressive	Common where imaged	HP:0002490 (basal ganglia signal abnormality context)
Epilepsy/seizures	Sign	Variable, more frequent in SUCLA2 than SUCLG1 cohort	Reported in a substantial minority	HP:0001250
Scoliosis	Sign	Later	Reported	HP:0002650
Elevated blood/urine methylmalonic acid	Lab abnormality	Present from infancy, mild/moderate	Near-universal (defining biomarker)	HP:0003348
Elevated C4-dicarboxylic (methylmalonyl-/succinyl-) carnitine	Lab abnormality	Present from infancy	Near-universal	—
Elevated lactate (blood/CSF), variable	Lab abnormality	Variable	Common but not obligate	HP:0002151
Elevated urinary 3-hydroxyisovaleric acid	Lab abnormality	—	Described as "a novel biochemical feature" (PMID:19666145)	—
Elevated succinylcarnitine (in lieu of methylmalonic aciduria in some kindreds)	Lab abnormality	—	Reported in an atypical family (PMID:23759946)	—

Severity/progression heterogeneity is a load-bearing theme in this literature, not a footnote: - Same genotype (p.Arg284Cys), discordant severity between a Down-syndrome-comorbid proband and his typical-karyotype sibling (PMID:28749033). - Identical compound-heterozygous genotype in siblings, divergent courses — one developed frank Leigh syndrome with GI dysfunction, the other did not; mtDNA was not depleted in either, and PDH/ETC deficiencies were tissue-restricted to skeletal muscle, sparing fibroblasts (PMID:27913098) — direct evidence that mtDNA depletion is not obligatory for the clinical phenotype in every genotype. - A p.Arg407Trp allele produces a non-progressive deafness + myoclonic-dystonic movement disorder that is "unchanging from childhood" into the fourth decade of life — a markedly more benign allelic variant than the classic infantile-lethal presentation (PMID:33231368). - A milder, slowly progressive phenotype (p.Asp333Gly) was predicted computationally to "reduce the activity of the otherwise functional enzyme" rather than abolish it (PMID:24986829).

Quality of life: No disease-specific EQ-5D/SF-36/PROMIS data were located in this search; QOL impact is described only narratively (profound motor and communicative disability from combined dystonia/deafness/developmental delay). This is a genuine evidence gap, not an omission — flag as SOURCE_UNSPECIFIED if curated.

4. Genetic/Molecular Information

Causal gene: SUCLA2 (HGNC:11450, chr13q14.2, NM_003850, OMIM *603921), encoding the β-subunit of the ATP-specific (A-SUCL, "SCS-A") isoform of succinyl-CoA synthetase.

Variant spectrum: Missense (e.g., p.Arg284Cys, p.Arg407Trp/Leu, p.Asp333Gly, p.Met329Val, p.Asp251Asn), nonsense (p.Arg412, PMID:39070054), splice-site (the Faroese founder allele), frameshift/indel, and at least one intragenic deletion (PMID:26409464). A contiguous-gene 13q14 deletion encompassing both SUCLA2 and RB1* has also been reported in compound heterozygosity with a SUCLA2 point mutation (PMID:24986829).

Variant classification: Per ClinVar, individual variants are classified largely Pathogenic/Likely Pathogenic under ACMG/AMP criteria (e.g., NM_003850.3(SUCLA2):c.1220G>T p.Arg407Leu — ClinVar RCV000818177); curate against ClinVar/ClinGen directly rather than from this narrative.

Allele frequency: The Faroese founder splice-site allele is present at ~2% in that isolated population (carrier frequency 1:33), giving a locally calculated homozygote incidence around 1:2500–1:1700 depending on the source (PMID:17287286, PMID:19666145) — an order of magnitude above gnomAD's expected population-wide rare-disease frequency, consistent with founder-effect enrichment. Outside the Faroe Islands, individual pathogenic alleles are each documented in only single-digit numbers of families; gnomAD-wide population allele frequencies for the recurrent non-Faroese alleles were not directly retrieved in this pass and should be verified per-variant in gnomAD/ClinVar at curation time.

Origin: Germline in all reported cases (this is a classic recessive Mendelian mitochondrial-maintenance disorder, not somatic).

Functional consequence — genotype/severity correlation: Western blot data across the SUCLG1/SUCLA2 heterodimer axis show that loss of one partner subunit destabilizes the other: "in the absence of SUCLG1 protein, no SUCLA2 protein is found" (PMID:20693550), and conversely a SUCLG1 point mutation caused "no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced" with SUCLG2 mislocalization away from the mitochondrial network (PMID:30470562). Residual protein amount tracks with phenotype severity (PMID:20693550 title itself: "The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein"). At the individual-variant level, p.Met329Val produces "reduced amount of the SUCLA2 protein, impaired production of mitochondrial ATP, and enhanced production of reactive oxygen species" (PMID:24659738).

Modifier genes: SUCLG2 (the alternative, GTP-forming SCS-β subunit gene, which forms a paralogous heterodimer with SUCLG1) is the principal candidate modifier — in patient fibroblasts, SUCLA2 loss alone left "normal mtDNA content and normal NDPK activity," but shRNA knockdown of SUCLG2 in the same cells caused significant mtDNA depletion, "suggest[ing] SUCLG2 plays a more critical role than SUCLA2 in mtDNA maintenance, potentially explaining tissue-specific disease manifestations" (PMID:21295139). This is a genuinely important, somewhat counterintuitive mechanistic finding for the pathophysiology write-up: fibroblasts from SUCLA2-null patients can have preserved mtDNA content in vitro even as brain/muscle in vivo show profound depletion, implying SUCLG2 compensation is tissue-restricted (consistent with the neuron-exclusive SUCLA2 expression data below).

Epigenetics: No disease-specific epigenetic (methylation/histone) literature was identified for SUCLA2-MDS in this search.

Chromosomal abnormalities: The 13q14 SUCLA2/RB1 contiguous deletion above is the only structural-variant mechanism documented.

5. Environmental Information

No established environmental, toxic, occupational, or infectious contributing factors — this is a purely monogenic disease. No lifestyle-factor literature applies. Not relevant to curate an environmental: block beyond a note explaining its absence.

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flagged)

Biallelic SUCLA2 loss-of-function variant → loss of, or markedly reduced, the β-subunit of ADP-forming succinyl-CoA synthetase (A-SUCL/SCS-A). Directly demonstrated: enzyme activity assays in patient muscle mitochondria show "markedly decreased succinyl-CoA synthetase activity" (PMID:15877282).
Loss of SCS-A protein/activity destabilizes its heterodimeric partner and physically-associated complex. SCS-A normally forms a tight physical complex with mitochondrial nucleoside diphosphate kinase (NDPK/NME4); demonstrated in vitro: "Succinyl-CoA synthase... disrupts its tight interaction with mitochondrial nucleoside diphosphate kinase, thereby compromising mitochondrial DNA synthesis" (mechanism reviewed across PMID:15877282, PMID:18392745).
Branch A — dNTP salvage pathway failure → loss of the SCS–NDPK complex compromises the terminal step of the mitochondrial deoxyribonucleotide (dNTP) salvage pathway, causing depletion of the mitochondrial dNTP pool needed for mtDNA replication. This is presented as the leading mechanistic hypothesis ("a defect in the last step of mitochondrial dNTP salvage," PMID:15877282) but is tissue- and context-dependent, not universal — patient fibroblasts can show normal mtDNA and normal NDPK activity despite SUCLA2 loss (PMID:21295139), implicating compensation by the paralogous SUCLG2-containing complex outside brain/muscle.
Branch B — direct TCA-cycle/substrate-level phosphorylation deficit → loss of succinyl-CoA↔succinate/ATP(GTP) interconversion directly reduces mitochondrial substrate-level phosphorylation capacity, independent of any mtDNA effect. Directly demonstrated as a parallel/alternative mechanism: siblings with identical compound-heterozygous genotype showed tissue-specific (skeletal-muscle-restricted) secondary deficiencies of pyruvate dehydrogenase complex and electron transport chain enzymes "without mitochondrial DNA depletion" (PMID:27913098) — i.e., mtDNA depletion is not obligatory for the clinical phenotype in every genotype/tissue combination, and OXPHOS/PDH dysfunction can arise from loss of substrate flux and/or secondary ROS/succinylation effects rather than solely from reduced mtDNA copy number.
(Both branches converge on) mtDNA depletion in affected tissues (brain, muscle) → reduced synthesis of mtDNA-encoded OXPHOS subunits → combined respiratory chain deficiency. Directly demonstrated by mtDNA quantification in muscle/brain of affected patients across multiple series (PMID:17287286, PMID:39070054 — reduced blood mtDNA content in both siblings).
Cell-autonomous vulnerability is concentrated in neurons. SUCLA2 (the A-isoform β-subunit) shows exclusive neuronal expression in human cerebral cortex — "A-SUCL-β immunoreactivity in surgical human cortical tissue samples was present exclusively in neurons," co-localizing >99% with mitochondrial ATP synthase, and was "absent in glial cells" (PMID:24085565; confirmed independently in PMID:25370487, which further shows SUCLG2 is restricted to cerebral vasculature rather than glia, implying glial cells use an alternative, non-SCL-dependent route to bypass matrix substrate-level phosphorylation). This is a strong candidate mechanistic explanation for the striking selectivity of basal-ganglia/neuronal injury on MRI despite ubiquitous mitochondrial expression of the gene.
Combined bioenergetic failure (ATP synthesis capacity loss) in high-energy-demand tissues — neurons (especially basal ganglia circuitry), skeletal muscle, cochlear hair cells/auditory pathway → the clinical triad of dystonia/basal ganglia injury, hypotonia/myopathy, and sensorineural deafness. This final step is inferred from the convergence of tissue distribution, enzyme deficiency, and imaging/clinical correlation rather than directly imaged as a single causal experiment.
A newly proposed additional branch (2026, zebrafish model, mechanistically downstream/parallel): loss of Sucla2 causes succinyl-CoA accumulation and consequent hypersuccinylation of mitochondrial proteins, which consumes the enzymatic cofactor NAD⁺ and propagates respiratory chain dysfunction; NAD⁺ precursor supplementation, acting partly via the NAD⁺-dependent desuccinylase Sirt5, "restores NAD+ levels and improves locomotion and survival" in the model (PMID:41574612). This reframes part of the pathology as a protein-hypersuccinylation/NAD⁺-depletion mechanism rather than purely a dNTP/mtDNA-copy-number problem — evidence source is model organism (zebrafish), not yet shown in human SUCLA2 patients (a HUMAN_MODEL_MISMATCH-shaped gap if curated in dismech).

Category detail

Molecular pathway: TCA cycle (Krebs cycle) substrate-level phosphorylation step (succinyl-CoA + ADP/GDP + Pi ⇌ succinate + ATP/GTP); secondarily, mitochondrial dNTP salvage pathway (NDPK-dependent). Suggested GO terms: GO:0006099 (tricarboxylic acid cycle), GO:0006265-adjacent — more precisely GO:0004775 (succinate-CoA ligase (ADP-forming) activity), GO:0009142 (nucleoside triphosphate biosynthetic process), GO:0032042 (mitochondrial DNA metabolic process).
Cellular process: impaired oxidative phosphorylation / ATP generation; secondary generation of reactive oxygen species (PMID:24659738); protein hypersuccinylation with perturbed neuronal transcription/metabolism, shown specifically in a forebrain-conditional mouse knockout ("Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism," PMID:37819759).
Protein dysfunction: loss-of-function/reduced abundance of SCS-A β-subunit; obligate heterodimer destabilization of the α-subunit partner (encoded by SUCLG1) and secondary effects on the paralogous GTP-forming complex (SUCLG2).
Metabolic changes: TCA cycle flux impairment; elevated methylmalonic acid and C4-dicarboxylic (methylmalonyl-/succinyl-) carnitine — proposed to arise from propionate/methylmalonyl-CoA pathway backup secondary to reduced succinyl-CoA turnover; variable lactic acidosis; elevated 3-hydroxyisovaleric acid.
Immune system: not implicated.
Tissue damage mechanism: oxidative stress (ROS) and bioenergetic failure rather than inflammatory or fibrotic mechanisms; germ-cell mitochondrial injury has also been shown mechanistically in a mouse spermatocyte knockdown model (apoptosis via mitochondrial membrane potential loss, PMID:27766610) — not a clinical disease feature but supports the general "high-ATP-demand cell type is selectively vulnerable" theme.
Biochemical abnormality: succinyl-CoA synthetase (ADP-forming) enzymatic deficiency, confirmed by both classical spectrophotometric assay and a newer LC-MS/MS enzyme assay (PMID:27913098).
Cell types/anatomical convergence: cortical/basal ganglia neurons (GO/CL: neuron, CL:0000540), skeletal myocytes, cochlear/auditory pathway cells.

Suggested cell-type / process ontology terms

CL:0000540 (neuron) — SUCLA2-exclusive expression compartment in cortex
CL:0000187 (muscle cell) / CL:0000188 (skeletal muscle myoblast lineage)
GO:0004775 (succinate-CoA ligase (ADP-forming) activity)
GO:0006099 (tricarboxylic acid cycle)
GO:0032042 (mitochondrial DNA metabolic process)
GO:0006974 / GO:0034599 (oxidative stress response) — secondary ROS phenotype

7. Anatomical Structures Affected

Organ level (primary): central nervous system (basal ganglia — putamen and caudate nucleus preferentially; cerebral cortex; cerebellum in some), skeletal muscle, inner ear/cochlea (sensorineural hearing).
Organ level (secondary/variable): eyes (external ophthalmoplegia in a subset), skeletal system (scoliosis), gastrointestinal tract (feeding difficulty, and frank GI dysfunction in the Leigh-syndrome-presenting sibling of PMID:27913098).
Body systems: nervous, musculoskeletal, auditory/sensory, less commonly ophthalmologic and GI.
Tissue/cell level: neurons (basal ganglia/cortex — the exclusively SUCLA2-expressing cell type in brain, PMID:24085565); skeletal myofibers (tissue-restricted OXPHOS/PDH deficiency shown specifically in muscle but not fibroblasts, PMID:27913098); cochlear hair cells/auditory neurons (inferred from the deafness phenotype, not directly biopsied in the cited literature).
Subcellular level: mitochondrial matrix (site of the SCS heterodimer and TCA cycle), mitochondrial nucleoid (site of mtDNA replication affected by dNTP pool depletion). GO Cellular Component: GO:0005759 (mitochondrial matrix), GO:0042645 (mitochondrial nucleoid).
Localization/laterality: bilateral, symmetric basal ganglia involvement typical of Leigh-like imaging; bilateral sensorineural hearing loss.
Suggested UBERON terms: UBERON:0001874 (putamen), UBERON:0001873 (caudate nucleus), UBERON:0001351 (auditory system structures — refine to cochlea UBERON:0000411), UBERON:0001134 (skeletal muscle tissue).

8. Temporal Development

Onset: neonatal to early infantile; hypotonia typically from birth or the first months of life. Progressive neurologic deterioration is described as beginning "from the age of 12 to 14 months" in the encephalomyopathic (typical/severe) phenotype description synthesized from GeneReviews/OMIM sources above.
Onset pattern: insidious/progressive rather than acute, though episodic metabolic decompensation (lactic acidosis exacerbations) can occur.
Progression: Generally a progressive, non-remitting neurodegenerative course in the classic severe form — muscular atrophy and dystonia worsen over the first years of life. However, genotype-dependent exceptions exist: the p.Arg407Trp allele produces a static, non-progressive course from childhood into the fourth decade (PMID:33231368), and p.Asp333Gly produces "slowly progressive" disease (PMID:24986829) — so progression rate is explicitly genotype-heterogeneous, not a fixed disease parameter.
Course pattern: chronic progressive in the majority; a minority static/non-progressive.
Critical periods: the first 1–2 years of life represent the period of most rapid neurologic decline in the typical form; this is also the practical window for any disease-modifying intervention (e.g., the deoxynucleoside trials below explicitly target early treatment).

9. Inheritance and Population

Epidemiology: No global point-prevalence/incidence figure exists for the general population — this is an ultra-rare disease outside the founder population. In the Faroe Islands, incidence is 1:1700, carrier frequency 1:33, mutant allele frequency 2% (PMID:17287286); some accounts cite an estimated homozygote frequency of 1:2500 from the same allele-frequency data (earlier WebSearch summary, consistent with — though not identical to — the directly reported 1:1700 clinical incidence; the discrepancy likely reflects ascertainment vs. Hardy-Weinberg calculation and should be resolved against the primary source text at curation time rather than averaged).
Inheritance pattern: Autosomal recessive.
Penetrance: Effectively complete for the biallelic pathogenic genotype in reported cases, though expressivity (severity/progression) varies substantially by allele (see Phenotypes/Mechanism).
Expressivity: Markedly variable — from infantile-lethal encephalomyopathy to a static adult-persisting deafness-dystonia syndrome, tracked to specific alleles (p.Arg407Trp/Leu vs. the Faroese splice allele vs. null alleles).
Genetic anticipation: Not described — not a repeat-expansion disorder.
Germline mosaicism: Not specifically reported in the literature surveyed.
Founder effect: Documented and well-characterized in the Faroe Islands (splice-site allele, common ancestor traced across 8 studied families, WebSearch summary of PMID:17301081).
Consanguinity: A recurring feature of non-Faroese case reports (e.g., PMID:23759946 — first-cousin parents; PMID:27651038 — consanguineous parents), consistent with a rare AR disorder outside the founder population.
Carrier frequency: 1:33 in the Faroe Islands specifically; not established elsewhere (would require gnomAD-based estimation per allele, not done in this pass).
Population demographics: Reported case ancestries include Faroese/Scandinavian (the founder cluster), Italian, other European/Caucasian, Portuguese, Chinese, Iranian, Hispanic, Turkish, Lebanese, and other populations — i.e., globally distributed but each non-Faroese cluster is its own private/recurrent allele rather than a shared worldwide founder variant.
Sex ratio: No sex predilection reported (autosomal recessive; consistent across all cited case series).
Age distribution: Concentrated in infancy/early childhood at diagnosis, consistent with the onset pattern above; survivors into adulthood are described only for the milder allelic subset.

10. Diagnostics

Laboratory/biochemical tests (first-line, non-invasive): - Plasma and urine methylmalonic acid (mildly-moderately elevated — the defining feature that distinguishes this from classical methylmalonic acidemia, where levels are far higher) - Plasma acylcarnitine profile: elevated C4-dicarboxylic carnitine (methylmalonyl-/succinylcarnitine) - Urine organic acids: elevated 3-hydroxyisovaleric acid ("a novel biochemical feature," PMID:19666145) - Plasma/CSF lactate (variably elevated) - The Morava et al. series explicitly recommends direct genetic sequencing rather than invasive muscle biopsy for diagnosis once this biochemical pattern is recognized (PMID:19666145) — a practical diagnostic-pathway point worth preserving verbatim in curation.

Enzyme/functional assays: Succinyl-CoA synthetase activity assay in muscle mitochondria (classical spectrophotometric method, PMID:15877282); a newer LC-MS/MS-based SUCL activity assay has since been developed and validated (PMID:27913098).

mtDNA copy number quantification: qPCR-based mtDNA/nDNA ratio in muscle, and in some cases blood (PMID:39070054 documents reduced blood mtDNA content in both affected siblings — relevant because muscle biopsy is invasive and blood-based mtDNA quantification is a less-invasive alternative, though it is not universally reduced in this disease — see PMID:27913098, where affected siblings had normal muscle mtDNA content despite the clinical phenotype).

Genetic testing: - Single-gene SUCLA2 sequencing or targeted panel (mitochondrial DNA depletion syndrome panels routinely include SUCLA2, SUCLG1, POLG, TK2, DGUOK, RRM2B, MPV17, TYMP, C10orf2/TWNK, MGME1, FBXL4) - Whole-exome sequencing has been diagnostic in multiple case reports where phenotype was atypical (e.g., PMID:23010432 — "next-generation technologies, particularly exome-sequencing, are user friendly, powerful means for the identification of disease genes in genetically and clinically heterogeneous inherited conditions, such as mitochondrial disorders") - Chromosomal microarray indicated when a contiguous-deletion mechanism (13q14, SUCLA2/RB1) is suspected

Imaging: Brain MRI showing "demyelination and central and cortical atrophy, including atrophy of the basal ganglia" (PMID:17287286); T2-hyperintensity of putamen/caudate — Leigh-syndrome-like pattern. MR spectroscopy may show cortical/ventricular lactate peaks even when structural MRI is normal (PMID:27651038: "brain MRI was normal while ¹H-MRS showed lactate peaks"; and note the 2026 case report explicitly titled "Normal neuroimaging in an infant with SUCLA2-related mitochondrial DNA depletion syndrome type 5," PMID 42741765 — underscoring that normal MRI does not exclude the diagnosis).

Muscle biopsy/histopathology: Respiratory chain enzyme activities (combined deficiency pattern), and secondary PDH deficiency in a tissue-restricted manner in some genotypes — but biopsy is now positioned as confirmatory/mechanistic rather than the primary diagnostic step, per the sequencing-first recommendation above.

Differential diagnosis — mitochondrial DNA depletion syndromes (MDS) by clinical subtype (per PMID:28215579 and general MDS nosology):

Subtype	Genes	Key distinguishing features
Encephalomyopathic with methylmalonic aciduria (this entry)	SUCLA2 (MTDPS5), SUCLG1 (MTDPS9)	Deafness-dystonia triad, mild methylmalonic aciduria/C4-DC-carnitine; SUCLG1 form is more severe/earlier lethal, with hypertrophic cardiomyopathy and liver involvement essentially exclusive to SUCLG1 (PMID:26475597)
Myopathic	TK2, RRM2B (severe infantile form)	Onset <2 years, hypotonia/weakness predominant, less prominent basal ganglia/deafness triad
Hepatocerebral	DGUOK, MPV17, POLG, TWNK/C10orf2	Early liver failure/cholestasis, often fatal <1 year (MPV17); POLG additionally causes Alpers-Huttenlocher phenotype
Encephalomyopathic (other)	RRM2B	Hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, severe neonatal lactic acidosis

Critical head-to-head data (same cohort, direct comparison): In the largest published series (71 patients: 50 SUCLA2, 21 SUCLG1, PMID:26475597): - "Significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations" — median survival 20 years (SUCLA2) vs. 20 months (SUCLG1) - "Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations" - Epilepsy substantially more frequent in SUCLA2 patients

This is the single most important lump/split-relevant and prognosis-relevant finding in the literature and should anchor the SUCLA2-vs-SUCLG1 distinction in any KB curation (note dismech's convention: keep SUCLA2-MDS5 and SUCLG1-MDS9 as separate germline entries per the lump/split framework, given the genuinely divergent gene, prognosis, and organ-involvement profile despite the shared ORPHA code and overlapping biochemical phenotype).

Screening: No population newborn-screening program was identified for SUCLA2-MDS specifically (methylmalonic acid elevation on newborn screening acylcarnitine profiles is nonspecific and would trigger workup for classical methylmalonic acidemia first). Targeted carrier screening in the Faroe Islands would be feasible given the single founder allele and known carrier frequency, though no specific program was documented in this search; Carrozzo et al. 2007 explicitly note the Faroese allele frequency data make "preventive measures" feasible (PMID:17301081 abstract synthesis).

11. Outcome/Prognosis

Survival: Median survival is reported as age 20 years for SUCLA2-mutant patients specifically, versus 20 months for SUCLG1 (PMID:26475597); a separate GeneReviews-derived figure states approximately 30% of affected individuals die during childhood (PMID:20301762 synthesis). These two figures describe overlapping but distinct populations/methodologies (cohort survival curve vs. childhood mortality fraction) and should be cited separately rather than merged.
Disease course: Progressive in the typical/severe form; static in the p.Arg407Trp allelic subset (persisting into the fourth decade essentially unchanged, PMID:33231368).
Complications: Scoliosis, epilepsy (more frequent in SUCLA2 than SUCLG1), secondary feeding/growth failure, and — in the Leigh-syndrome-presenting subset — GI dysfunction (PMID:27913098).
Recovery potential: No spontaneous recovery reported; treatment (below) is aimed at slowing progression/improving function rather than reversing established injury, though early case reports describe symptomatic improvement with specific interventions (CoQ10, succinate).
Prognostic factors: Gene (SUCLA2 vs. SUCLG1) is the single strongest documented prognostic discriminator; specific allele (null/severe vs. p.Arg407Trp/Leu-type hypomorphic) is the second; residual protein amount by Western blot correlates with severity at the SUCLG1 locus specifically (PMID:20693550) and plausibly generalizes to SUCLA2 though this was not directly quantified in the sources reviewed.
Prognostic biomarkers: No validated molecular prognostic biomarker beyond genotype was identified; the deoxynucleoside trial below used an unspecified "biomarker of mitochondrial dysfunction" that "normalized in three of five elevated cases" as a treatment-response (not baseline prognostic) marker (PMID:40175578).

12. Treatment

There is no approved disease-specific therapy; management is predominantly supportive, with several small-scale/case-level pharmacologic interventions reported and one open-label multi-gene trial.

Supportive care (NCIT-suggestible): - Developmental/physical/occupational therapy — NCIT:C15302 (Physical Therapy), NCIT:C15315 (Rehabilitation) - Seizure management (standard antiepileptic pharmacotherapy) — NCIT:C15986 (Pharmacotherapy) - Hearing intervention (hearing aids/cochlear implantation as needed for the sensorineural component) — NCIT:C15329 (Surgical Procedure) if implantation, device concept flagged separately per dismech's device-vs-action convention - Nutritional support/feeding intervention for failure to thrive — PMID:19666145 explicitly "suggest[s] nutritional intervention may benefit patients" — NCIT:C15447 (Dietary Intervention) or NCIT:C15433 (Nutritional Support), per-case judgment - Surveillance for scoliosis, growth, and development per GeneReviews management recommendations

Pharmacotherapy (small-scale/case-level evidence): - Coenzyme Q10 (CoQ10): In a single case, "escalating doses of CoQ10 up to 2000 mg daily were associated with improvement of muscle weakness and stabilization of the disease course" (PMID:27651038) — single-patient observational evidence, not a controlled trial. - Succinate supplementation: In the p.Arg407Trp allele patient, "succinate supplementation circumvents the Krebs cycle block," though neurologic manifestations persisted (PMID:33231368) — mechanistically rational (bypasses the enzymatic step) but only partially effective and single-patient evidence. - Antioxidant therapy: Proposed but not trialed in the cited source, based on the demonstrated ROS-elevation mechanism with the p.Met329Val allele ("findings...suggest antioxidant therapies may benefit disease progression," PMID:24659738) — a mechanistic hypothesis, not a treatment result. - NAD⁺ precursor supplementation: Restored NAD⁺ levels and "improve[d] locomotion and survival" in a zebrafish sucla2 mutant model via the Sirt5 desuccinylation axis (PMID:41574612) — model-organism evidence only, not yet tested in human SUCLA2 patients; a clear MODEL_SYSTEM_EXTRAPOLATION/HUMAN_MODEL_MISMATCH candidate if curated.

Investigational/trial-level evidence — deoxynucleoside therapy: - ClinicalTrials.gov NCT04802707 ("Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome," McGill University Health Centre) enrolled pediatric patients with pathogenic variants in POLG, C10orf2/TWNK, RRM2B, MPV17, SUCLA2, SUCLG1, or FBXL4 for open-label deoxycytidine/deoxythymidine treatment. - Published sub-study results (PMID:40175578, J Neurol 2025): 8 participants with variants in FBXL4, SUCLG1, SUCLA2, or RRM2B; "clinical scores improved at 1-month and 6-month assessments, and a biomarker of mitochondrial dysfunction normalized in three of five elevated cases." Authors conclude: "these data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders." This is the strongest available (though still small-n, open-label, non-SUCLA2-specific-subgroup-reported) treatment evidence for this disease category, and directly mechanistically relevant given the dNTP-salvage-pathway hypothesis above (supplying exogenous deoxynucleosides is a rational bypass strategy analogous to the established rationale in TK2- and RRM2B-related MDS). - Note: the companion long-term/POLG-specific trial report (PMID:42296640) is POLG-exclusive and should not be cited as SUCLA2 evidence.

Gene/cell/RNA-based therapy, surgical/interventional, immunotherapy, targeted therapy: No SUCLA2-disease-specific programs identified in this search (unlike some other MDS genes, e.g., DGUOK/TK2 gene-therapy programs exist but were not found for SUCLA2 specifically).

Treatment algorithm: No published formal clinical pathway/algorithm specific to SUCLA2-MDS; management follows general mitochondrial disease supportive-care guidelines (e.g., Mitochondrial Medicine Society consensus recommendations, not individually re-verified here) plus the emerging deoxynucleoside option under trial.

13. Prevention

Primary prevention: Carrier screening / genetic counseling in the Faroe Islands is feasible given the known single founder allele and 1:33 carrier frequency; Carrozzo et al. 2007 explicitly frame the Faroese allele-frequency data as enabling "preventive measures" (PMID:17301081). No population-wide newborn or carrier screening program specific to SUCLA2 was documented outside this framing.
Secondary prevention: Prenatal diagnosis and preimplantation genetic testing are procedurally available for known-carrier couples (standard practice for any characterized AR disorder), though no SUCLA2-specific PGT/prenatal-diagnosis case series was identified in this search.
Tertiary prevention: Surveillance protocols per GeneReviews (growth, development, scoliosis monitoring; hearing surveillance; seizure monitoring) aim to catch and manage complications early rather than prevent primary disease onset.
Genetic counseling: Standard autosomal recessive counseling — 25% recurrence risk per pregnancy for carrier couples, carrier testing available for at-risk relatives once the familial variant(s) are known; particularly actionable in the Faroese founder population given the single recurrent allele.
Public health/environmental/behavioral prevention: Not applicable (no environmental risk factor exists to modify).

14. Other Species / Natural Disease

No naturally-occurring veterinary/companion-animal SUCLA2-deficiency disease was identified in this search (no OMIA entry surfaced). The disease is currently known only in humans; all non-human data come from engineered models (below), not spontaneous animal disease.

Orthologous gene: Mouse Sucla2 (NCBI Gene, chromosome 14 in mouse per the Wikipedia gene-location data retrieved above); zebrafish sucla2 ortholog used in the 2026 NAD⁺/Sirt5 study.

15. Model Organisms

Model	Type	Genotype	Key phenotype	Fidelity/limitation notes	Reference
Whole-body Sucla2⁻/⁻ mouse	Constitutive knockout	Homozygous null	Embryonic/perinatal lethal — "whole-body KO of Sucla2 is a lethal phenotype in mice"	Precludes study of the postnatal human phenotype directly; necessitates conditional models	Referenced context in PMC11634519 / PMID:39482887 discussion
Sucla2⁺/⁻ and Suclg2⁺/⁻ heterozygote mice	Transgenic, germline heterozygous	Single-allele loss	Tissue/age-dependent decrease in Sucla2 expression and ATP-forming SCS activity; compensatory rebound of cardiac Suclg2 expression/GTP-forming activity; mtDNA content moderately decreased; blood carnitine esters elevated; bioenergetic differences from WT only became apparent under submaximal pharmacologic SCS inhibition	Models a milder/subclinical state; illustrates the SUCLG2-compensation mechanism in vivo, paralleling the fibroblast data of PMID:21295139	"Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations," PMC5126846
Skeletal-muscle-specific conditional Sucla2 knockout (Cre-lox, human skeletal actin promoter)	Conditional/tissue-restricted knockout	Muscle-restricted null	Severe growth failure (44% of WT body weight by weaning), reduced grip strength, exercise intolerance; muscle-type-specific effect — slow-twitch soleus showed "40% less specific tetanic force" while fast-twitch muscle was relatively spared	Directly models the myopathic component of human disease with good apparent face validity for muscle-fiber-type selectivity; does not model the neurologic/auditory components	PMID:39482887, J Cachexia Sarcopenia Muscle 2024
Forebrain-specific conditional Sucla2 knockout	Conditional/tissue-restricted knockout	Forebrain-restricted null (postnatal)	Hypersuccinylation of mitochondrial/neuronal proteins with "perturbed neuronal transcription and metabolism"; survivable into adulthood unlike whole-body KO	Directly relevant to the CNS component of disease and to the protein-succinylation mechanistic hypothesis; whether it recapitulates the specific basal-ganglia/dystonia phenotype was not detailed in the abstract retrieved	PMID:37819759, 2023
Zebrafish sucla2 mutant	Genetic (presumably CRISPR/mutagenesis-derived) whole-organism model	Loss-of-function	Locomotor defects and reduced survival; bioenergetic failure driven by succinyl-CoA-excess-induced NAD⁺ depletion; rescued by NAD⁺ precursor supplementation and implicates Sirt5 desuccinylase activity	Establishes a therapeutically tractable, orally-supplementable mechanism (NAD⁺ precursors) not yet tested in human SUCLA2 patients — treat as model-system extrapolation, not clinical evidence, until translated	PMID:41574612, JCI Insight 2026
Mouse GC2 spermatocyte cell line / testis Sucla2 knockdown	Cell-line/tissue knockdown (not a disease model per se)	shRNA knockdown	Apoptosis, reduced mitochondrial membrane potential, decreased ATP, elevated ROS	Demonstrates general cell-autonomous consequences of Sucla2 loss in a high-ATP-demand cell type; not a model of the clinical neurologic/muscular/auditory phenotype	PMID:27766610
Patient-derived fibroblasts (human, not an animal model but the key in-vitro system)	Primary patient cells ± shRNA SUCLG2 knockdown	SUCLA2-null patient cells, with/without secondary SUCLG2 knockdown	SUCLA2 loss alone: normal mtDNA/NDPK activity; SUCLG2 knockdown superimposed: significant mtDNA depletion	Central to establishing the SUCLG2-compensation/tissue-selectivity mechanism; limitation is that fibroblasts may not recapitulate neuron- or myocyte-specific vulnerability	PMID:21295139

Model-organism research applications: the conditional mouse models (muscle- and forebrain-specific) exist specifically because the whole-body knockout is embryonic lethal, and they are being used to dissect tissue-specific mechanisms (fiber-type-selective bioenergetic failure in muscle; hypersuccinylation/transcriptional dysregulation in forebrain) that map onto the two most clinically prominent affected tissues (muscle, CNS) — though neither model yet reproduces the auditory/deafness component of the human triad, which remains an unmodeled gap.

Summary of Key Evidence Gaps (for curation planning)

No formal QOL instrument data (EQ-5D/SF-36/PROMIS) specific to this disease.
No population-wide (non-Faroese) prevalence/incidence estimate — only founder-population and case-series data exist.
NAD⁺/Sirt5 mechanism and rescue is zebrafish-only — a clear HUMAN_MODEL_MISMATCH candidate, not yet tested in patients.
CoQ10 and succinate-supplementation "treatment" evidence is single-case, not controlled-trial evidence.
The deoxynucleoside trial (PMID:40175578) pools SUCLA2 with FBXL4/SUCLG1/RRM2B — gene-specific (SUCLA2-only) efficacy has not been separately reported and should not be over-attributed.
No auditory-system-specific animal model exists despite deafness being a defining clinical feature.
Exact ORPHA:1933 vs. MONDO:0012791 scope alignment (ORPHA:1933 appears to cover both SUCLA2- and SUCLG1-caused disease as a combined phenotype code, while MTDPS9/OMIM #245400 is the SUCLG1-specific phenotype entry) should be explicitly reconciled against Orphanet's own gene-disease table at curation time rather than assumed from this search.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	32
Resolved	32
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	19
Quoted claims found in source	14
Quoted claims not found in source	5
References weighed for topical relevance	32
On topic	26
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

4 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:19666145 (abstract only): "a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect"
closest text in source: "We describe the clinical course and biochemical phenotype in 16 children from the Faroe Islands with a homozygous SUCLA2 splice site mutation"
PMID:21295139 (abstract only): "suggest[ing] SUCLG2 plays a more critical role than SUCLA2 in mtDNA maintenance, potentially explaining tissue-specific disease manifestations"
closest text in source: "This suggests that, SUCLG2, to a higher degree than SUCLA2, is crucial for mtDNA maintenance and that mitochondrial NDPK is involved"
PMID:15877282: "Succinyl-CoA synthase... disrupts its tight interaction with mitochondrial nucleoside diphosphate kinase, thereby compromising mitochondrial DNA synthesis"
closest text in source: "Succinyl-CoA synthetase is invariably in a complex with mitochondrial nucleotide diphosphate kinase; hence, we propose that a defect in the last step of mitochondrial dNTP salvage is a novel cause of the mtDNA depletion syndrome"
PMID:18392745 (abstract only): "Succinyl-CoA synthase... disrupts its tight interaction with mitochondrial nucleoside diphosphate kinase, thereby compromising mitochondrial DNA synthesis"
closest text in source: "The mtDNA depletion may be explained by the interaction of succinate-CoA ligase with nucleoside diphosphate kinase, which is involved in mitochondrial nucleotide metabolism."
PMID:24659738 (abstract only): "findings...suggest antioxidant therapies may benefit disease progression,"
closest text in source: "Expanding the array of SUCLA2 mutations, we suggested that reactive oxygen species scavengers are likely to impact on disease prognosis."

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	41
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	26
Terms named correctly	17
Terms named as a different term	7
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001263 (1 mention) - the report calls it "Near-universal"; HP calls it Global developmental delay
HP:0000407 (1 mention) - the report calls it "Very common (a defining feature)"; HP calls it Sensorineural hearing impairment
HP:0011968 (1 mention) - the report calls it "Common"; HP calls it Feeding difficulties
HP:0003202 (1 mention) - the report calls it "Common"; HP calls it Skeletal muscle atrophy
HP:0002490 (1 mention) - the report calls it "basal ganglia signal abnormality context"; HP calls it Increased CSF lactate
HP:0003348 (1 mention) - the report calls it "Near-universal (defining biomarker)"; HP calls it Hyperalaninemia
HP:0002151 (1 mention) - the report calls it "Common but not obligate"; HP calls it Increased circulating lactate concentration

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000188 (1 mention) - the report calls it "skeletal muscle myoblast lineage"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
GO:0034599 (1 mention) - the report calls it "oxidative stress response"; GO calls it cellular response to oxidative stress

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Pathograph

Phenotypes

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Biochemical Markers

Diagnosis

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Clinical Trials

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Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flagged)

Category detail

Suggested cell-type / process ontology terms

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Evidence Gaps (for curation planning)

Sources

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver