Multiple Mitochondrial Dysfunctions Syndrome 2

Genetic MONDO:0013675 Pathograph 29 Show in embeddings browser MONDO:0017338

Multiple mitochondrial dysfunctions syndrome 2 (MMDS2; OMIM #614299) is an autosomal recessive disorder of mitochondrial iron-sulfur (Fe-S) cluster biogenesis caused by biallelic variants in BOLA3. Mitochondrial BOLA3 forms a [2Fe-2S]-bridged heterocomplex with the monothiol glutaredoxin GLRX5, and this GLRX5-BOLA3 node feeds [4Fe-4S] cluster assembly on NFU1 and supplies the mitoribosome; BOLA3 is also required for NFU1 stability. Loss of BOLA3 therefore impairs maturation of the same [4Fe-4S] targets as NFU1 deficiency, lipoic acid synthase and respiratory chain complexes I and II, while sparing aconitase, so that lipoate-dependent enzymes (pyruvate dehydrogenase, 2-oxoglutarate, 2-oxoadipate and branched-chain ketoacid dehydrogenases, glycine cleavage system) fail together with OXPHOS. The biochemical signature is lactic acidosis with non-ketotic hyperglycinemia and reduced protein lipoylation; the clinical picture is an infantile-onset leukodystrophy with developmental regression after a period of normal development, optic atrophy, seizures and, distinctively among the MMDS forms, hypertrophic or dilated cardiomyopathy, with death usually in the first years. Rare hypomorphic alleles (p.Cys59Tyr compound heterozygosity) produce a leukoencephalopathy with clinical recovery. Endothelial BOLA3 deficiency also promotes pulmonary hypertension through glycine and metabolic dysregulation. Treatment is supportive.

Ask OpenScientist

Ask a research question about Multiple Mitochondrial Dysfunctions Syndrome 2. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
15
Phenotypes
2
Gaps
29
Pathograph
1
Genes
5
Variants
4
Medical Actions
3
Differentials
2
Models
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
Mechanistic Nosology
mitochondrial disease
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive; severity tracks the residual function of the alleles, and the two Arg99Trp homozygotes were milder than the rest. Penetrance has not been quantified in the 18 reported patients, so no penetrance value is asserted.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (1 reference)
PMID:37511493 SUPPORT Other
"Multiple mitochondrial dysfunctions syndrome type 2 with hyperglycinemia (MMDS2) is a severe disorder of mitochondrial energy metabolism, associated with biallelic mutations in the gene encoding for BOLA3"
Biallelic requirement.
?

Discussions and Knowledge Gaps

2
What is the precise molecular role of BOLA3 in [4Fe-4S] cluster biogenesis, and does it act as a GLRX5-bridged [2Fe-2S] carrier to NFU1, as a stabiliser of NFU1, or as a homodimeric cluster carrier in its own right?
KNOWLEDGE GAP OPEN mmds2_bola3_molecular_role
Attached to
pathophysiology#Biallelic BOLA3 Loss of Function
The exact function of BOLA3 is still described as not completely understood: the BOLA3-GLRX5 heterocomplex is the favoured intermediary, a holo BOLA3 homodimer also transfers clusters, and patient fibroblast profiling shows NFU1 depends on BOLA3 for stability. Which of these accounts for the disease is unresolved.
Show evidence (1 reference)
PMID:37511493 SUPPORT Other
"a protein with a not yet completely understood role in iron-sulfur (Fe-S) cluster biogenesis, but essential for the maturation of mitochondrial"
Explicit statement of the gap.
Does any whole-organism model reproduce the infantile leukodystrophy and cardiomyopathy of BOLA3 deficiency, given that the only in vivo work is an adult endothelial knockdown modelling pulmonary hypertension?
HUMAN MODEL MISMATCH OPEN mmds2_no_systemic_model
Attached to
pathophysiology#Bioenergetic Failure in Brain and Heart
The endothelial knockdown mouse captures a vascular phenotype that is not the dominant clinical problem in patients, and no constitutive or CNS/cardiac Bola3 model has been reported, so the human white-matter and myocardial disease rests on patient tissue and fibroblast data alone.
Show evidence (1 reference)
PMID:30759996 SUPPORT Model Organism
"Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice."
The in vivo model is endothelium-restricted.
⚙

Pathophysiology

8
Biallelic BOLA3 Loss of Function
Pathogenic variants abolish mitochondrial BOLA3 (isoform 1) or disrupt its ability to form a [2Fe-2S]-bridged heterocomplex with GLRX5, either by preventing GLRX5 binding (p.Ile67Asn) or by producing an aberrant complex that cannot pass its cluster onward (p.His96Arg, p.Cys59Tyr). Holo BOLA3 can also form a cluster-carrying homodimer.
Downstream
Failure of the GLRX5-BOLA3 Node in 4Fe-4S Cluster Assembly
Show evidence (2 references)
PMID:33693876 SUPPORT In Vitro
"Our investigations reveal that the Ile67Asn substitution impairs the ability of BOLA3 to bind its physiological partner GLRX5"
Ile67Asn disrupts the BOLA3-GLRX5 carrier complex, the intermediary that delivers clusters to downstream targets.
PMID:31486956 SUPPORT In Vitro
"Herein we describe procedures to isolate and characterize the human holo BOLA3 protein in terms of Fe-S cluster binding and trafficking and demonstrate that human BOLA3 can form a functional homodimer capable of engaging in Fe-S cluster transfer."
BOLA3 as a cluster-trafficking protein.
Failure of the GLRX5-BOLA3 Node in 4Fe-4S Cluster Assembly
The GLRX5-BOLA3 heterocomplex delivers [2Fe-2S] clusters for [4Fe-4S] assembly on NFU1 and to the mitoribosome; BOLA3 is also needed for NFU1 stability. Loss of BOLA3 therefore impairs the NFU1-dependent targets, lipoic acid synthase and respiratory chain complexes I and II, while aconitase is spared, and attenuates mitochondrial protein synthesis.
iron-sulfur cluster assembly GO:0016226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased iron-sulfur cluster assembly (GO:0016226). GO:0016226 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived fibroblasts PRIMARY CELL CULTURE The Fe-S maturation defect and its rescue by wild-type mitochondrial BOLA3.
Downstream
Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
Respiratory Chain Complex I and II Deficiency
Attenuated Mitochondrial Protein Synthesis
Show evidence (2 references)
PMID:28803783 SUPPORT In Vitro
"IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3."
BOLA3 is required for NFU1 stability, linking the two nodes.
PMID:40273865 SUPPORT In Vitro
"These results indicate that BOLA3 variants decrease the activity of lipoic acid-dependent proteins (pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine cleavage system), as well as mitochondrial..."
Target specificity including sparing of aconitase.
Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
Without a functional cluster supply, the [4Fe-4S] radical-SAM enzyme lipoic acid synthase cannot lipoylate the E2 subunits of the 2-oxoacid dehydrogenases or the H protein of the glycine cleavage system; lipoic acid levels in patient fibroblasts are restored by re-expression of mitochondrial BOLA3.
protein lipoylation GO:0009249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein lipoylation (GO:0009249). GO:0009249 is a biological process from the Gene Ontology. ↓ DECREASED
lipoate synthase activity GO:0016992 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased lipoate synthase activity (GO:0016992). GO:0016992 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
Show evidence (2 references)
PMID:24334290 SUPPORT Human Clinical
"Patients were deficient in lipoylation of mitochondrial proteins."
Lipoylation defect in patients.
PMID:22562699 SUPPORT In Vitro
"The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels."
Rescue of lipoic acid levels.
Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
Loss of lipoylation inactivates pyruvate dehydrogenase and the other 2-oxoacid dehydrogenases, causing lactic acidosis with accumulation of pyruvate, alanine, TCA intermediates and branched-chain amino acids, and inactivates the glycine cleavage system, causing non-ketotic hyperglycinemia with raised CSF:plasma glycine ratio.
glycine catabolic process GO:0006546 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycine catabolic process (GO:0006546). GO:0006546 is a biological process from the Gene Ontology. ↓ DECREASED tricarboxylic acid cycle GO:0006099 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tricarboxylic acid cycle (GO:0006099). GO:0006099 is a biological process from the Gene Ontology. ↓ DECREASED
pyruvate dehydrogenase (acetyl-transferring) activity GO:0004739 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased pyruvate dehydrogenase (acetyl-transferring) activity (GO:0004739). GO:0004739 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Hyperglycinemia
Lactic acidosis
Bioenergetic Failure in Brain and Heart
Show evidence (2 references)
PMID:40273865 SUPPORT In Vitro
"In the metabolomic analysis, levels of lactic acid, pyruvic acid, alanine, tricarboxylic acid (TCA) cycle intermediates (such as α-ketoglutaric acid and succinic acid), branched-chain amino acids, and metabolites of lysine and tryptophan were significantly elevated in the BOLA3 group."
Metabolomic fingerprint of the combined dehydrogenase block.
PMID:24334290 SUPPORT Human Clinical
"All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity."
Glycine cleavage deficiency in patients.
Respiratory Chain Complex I and II Deficiency
Complexes I and II carry [4Fe-4S] clusters dependent on the BOLA3-NFU1 axis; muscle and fibroblasts show combined deficiency of complexes I, II and II+III with barely detectable assembled complexes on native gels.
mitochondrial respiratory chain complex I assembly GO:0032981 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial respiratory chain complex I assembly (GO:0032981). GO:0032981 is a biological process from the Gene Ontology. ↓ DECREASED mitochondrial electron transport, succinate to ubiquinone GO:0006121 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, succinate to ubiquinone (GO:0006121). GO:0006121 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Bioenergetic Failure in Brain and Heart
Lactic acidosis
Show evidence (1 reference)
PMID:22562699 SUPPORT Human Clinical
"Muscle biopsy revealed a peculiar biochemical defect consisting of a combined deficiency of respiratory chain complexes I, II, and II+III accompanied by a defect of the pyruvate dehydrogenase complex."
Combined defect in patient muscle.
Attenuated Mitochondrial Protein Synthesis
The mitoribosome's three [2Fe-2S] clusters are supplied by the GLRX5-BOLA3 node and play a structural role in mitoribosome assembly; MMDS2 patient fibroblasts show attenuated mitochondrial protein synthesis that adds to the OXPHOS deficit.
mitochondrial translation GO:0032543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial translation (GO:0032543). GO:0032543 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Bioenergetic Failure in Brain and Heart
Show evidence (1 reference)
PMID:37823603 SUPPORT In Vitro
"Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes."
Patient-cell demonstration.
Bioenergetic Failure in Brain and Heart
Combined loss of PDH-dependent and respiratory-chain ATP production injures the most energy-dependent tissues: a rapidly progressive leukodystrophy with necrotic/cavitary white matter lesions, optic nerve involvement and markedly elevated lactate on MR spectroscopy, together with hypertrophic or dilated cardiomyopathy, which distinguishes MMDS2 from the other MMDS forms.
oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology. cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Leukoencephalopathy
Developmental regression
Hypertrophic cardiomyopathy
Dilated cardiomyopathy
Optic atrophy
Seizure
Hypotonia
Pulmonary Endothelial Metabolic Dysfunction
Show evidence (2 references)
PMID:30302924 SUPPORT Human Clinical
"None of the published cases mention findings demonstrated in our case, a proband with biallelic BOLA3 variants, such as necrotic/cavitary lesions within the centrum semiovale, restricted diffusivity within the white matter, areas of central enhancement within the centrum semiovale presumably..."
Imaging evidence of the white matter and optic nerve lesions with tissue lactate.
PMID:34440194 SUPPORT Human Clinical
"Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy."
Cardiomyopathy as the MMDS2-specific feature.
Pulmonary Endothelial Metabolic Dysfunction
In pulmonary artery endothelial cells BOLA3 deficiency, whether by knockdown or by naturally occurring patient variants, impairs Fe-S integrity and lipoate-dependent 2-oxoacid dehydrogenases, reprogrammes glycolysis and respiration, downregulates glycine cleavage protein H to raise intracellular glycine, and increases endothelial proliferation, survival and vasoconstriction while reducing angiogenic potential; endothelial BOLA3 knockdown in mice produces pulmonary hypertension that glycine supplementation reverses.
pulmonary artery endothelial cell CL:1001568 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pulmonary artery endothelial cell (CL:1001568). CL:1001568 is a cell type from the Cell Ontology.
Animal models
Endothelial Bola3 knockdown mouse Mouse recapitulates Endothelial BOLA3 loss reproduces the pulmonary vascular phenotype.
Downstream
Pulmonary arterial hypertension
Show evidence (1 reference)
PMID:30759996 SUPPORT In Vitro
"In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3..."
Endothelial cellular mechanism including patient variants.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Multiple Mitochondrial Dysfunctions Syndrome 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Cardiovascular 3
Hypertrophic cardiomyopathy FREQUENT HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40273865 SUPPORT Human Clinical
"Pathogenic variants in the BOLA3 gene cause a rare condition known as multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, characterized by life-threatening lactic acidosis, nonketotic hyperglycinemia, and hypertrophic cardiomyopathy."
Hypertrophic cardiomyopathy as a characterising feature.
PMID:29501406 SUPPORT Human Clinical
"We herein present the detailed clinical course of an infant admitted for extensive, rapidly progressing white matter lesions and hypertrophic cardiomyopathy due to a BOLA3 gene mutation."
Case with hypertrophic cardiomyopathy.
Dilated cardiomyopathy OCCASIONAL HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34440194 SUPPORT Human Clinical
"Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively"
Systematic review attribution of dilated cardiomyopathy to MMDS2.
Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypertension, annotated with Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30759996 SUPPORT Other
"BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH."
Background statement from a mixed in vitro and mouse study, graded OTHER because it reports no patient observation.
PMID:34440194 SUPPORT Other
"In this human cellular model, BOLA3 deficiency leads to increased endothelial vasoconstriction, while in mice cells, it causes histological modifications typical of those found in pulmonary hypertension."
The systematic review presents the pulmonary phenotype of BOLA3 deficiency as a model finding rather than a clinical series observation.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding impairment, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29501406 SUPPORT Human Clinical
"A 6-month-old girl with no remarkable family or past medical history until 1 month prior presented with developmental regression and feeding impairment."
Feeding impairment at presentation.
Eye 1
Optic atrophy FREQUENT HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30302924 SUPPORT Human Clinical
"MMDS 2 associated with BOLA3 mutation presents in early infancy and is characterized by developmental regression, severe encephalopathy, optic atrophy, and cardiomyopathy."
Optic atrophy among the core features.
Metabolism 2
Hyperglycinemia VERY_FREQUENT HP:0002154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-ketotic hyperglycinemia, annotated with Hyperglycinemia (HP:0002154). HP:0002154 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24334290 SUPPORT Human Clinical
"All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity."
Glycine findings in variant NKH including BOLA3 patients.
PMID:40273865 SUPPORT Human Clinical
"Data collected during the patients' lives showed increased lactic acid and glycine levels."
Consistent metabolite elevations in the Japanese series.
Lactic acidosis VERY_FREQUENT HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22562699 SUPPORT Human Clinical
"We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life."
Presenting lactic acidosis.
PMID:24334290 SUPPORT Human Clinical
"They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis."
Lactic acidosis is not universal in the variant-NKH presentation.
Musculoskeletal 1
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22562699 SUPPORT Human Clinical
"We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy"
Neonatal hypotonia.
Nervous System 3
Leukoencephalopathy VERY_FREQUENT HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukodystrophy, annotated with Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29501406 SUPPORT Human Clinical
"Ultrasound cardiography and brain magnetic resonance imaging (MRI) respectively disclosed the presence of hypertrophic cardiomyopathy and symmetrical deep white matter lesions."
Imaging at presentation.
PMID:24334290 SUPPORT Human Clinical
"Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy."
Summary of the BOLA3 clinical features.
Developmental regression VERY_FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental regression, annotated with Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24334290 SUPPORT Human Clinical
"Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development."
Regression after normal early development.
Seizure FREQUENT Myoclonic seizure HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizures, annotated with Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29501406 SUPPORT Human Clinical
"Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure."
Seizures and respiratory failure in the course.
Respiratory 1
Respiratory failure FREQUENT HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29501406 SUPPORT Human Clinical
"the patient began exhibiting clusters of myoclonic seizures and respiratory failure"
Terminal respiratory failure.
Cellular 2
Decreased activity of mitochondrial complex I VERY_FREQUENT HP:0011923 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased complex I activity, annotated with Decreased activity of mitochondrial complex I (HP:0011923). HP:0011923 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29501406 SUPPORT Human Clinical
"Fibroblasts obtained pre-mortem displayed low mitochondrial respiratory chain complex I and II activity."
Enzymatic finding.
Decreased activity of mitochondrial complex II VERY_FREQUENT HP:0008314 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Succinate dehydrogenase deficiency, annotated with Decreased activity of mitochondrial complex II (HP:0008314). HP:0008314 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29654549 SUPPORT Human Clinical
"Analysis of cultured patient fibroblasts demonstrated deficient pyruvate dehydrogenase (PDH) activity and reduced quantity of protein subunits of mitochondrial complexes I and II, consistent with BOLA3 dysfunction."
Fibroblast finding even in the recovering patient.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34440194 SUPPORT Human Clinical
"the clinical phenotype showed severe encephalopathy with respiratory distress, seizures, failure to thrive, and dilated cardiomyopathy."
Failure to thrive in the index patient as summarised by the systematic review.
🧬

Genetic Associations

1
BOLA3
Gene: BOLA3 hgnc:24415 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BOLA3 (hgnc:24415). hgnc:24415 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:22562699 SUPPORT Human Clinical
"Joint exome analysis of both affected siblings uncovered a homozygous missense mutation in BOLA3."
Gene discovery by joint exome analysis of the two affected siblings.
Variants (5)
c.123dupA (p.Glu42Argfs*13) Pathogenic
frameshift
Frameshift duplication identified in the second family of the original mapping study; produces a premature stop.
Show evidence (1 reference)
PMID:21944046 SUPPORT Human Clinical
"A single base-pair duplication c.123dupA was identified in BOLA3 in the second family, causing a frame shift that produces a premature stop codon (p.Glu42Argfs(∗)13)."
Original identification.
c.287A>G (p.His96Arg) Pathogenic
missense
Homozygous missense at a conserved [2Fe-2S] ligand residue, associated with a severe phenotype of leukodystrophy with hypertrophic cardiomyopathy and death at 10 months; the mutant still binds GLRX5 but forms an aberrant heterocomplex unable to assemble a [4Fe-4S] cluster on NFU1.
Show evidence (2 references)
PMID:37511493 SUPPORT In Vitro
"Size exclusion chromatography, NMR, UV-visible, circular dichroism, and EPR spectroscopy characterization have shown that the His96Arg mutation does not impair the interaction of BOLA3 with its protein partner GLRX5"
Molecular mechanism of the severe allele.
PMID:29501406 SUPPORT Human Clinical
"A homozygous H96R (c. 287 A > G) mutation was identified in the BOLA3 gene."
Clinical report of the homozygous variant.
c.176G>A (p.Cys59Tyr) Pathogenic
missense
Novel missense allele, compound heterozygous with p.Arg46*, in the patient with clinical recovery; it perturbs the cluster-binding region without abolishing cluster binding on the heterocomplex and promotes an aberrant apo complex.
Show evidence (2 references)
PMID:29654549 SUPPORT Human Clinical
"WGS identified compound heterozygous variants in BOLA3: one previously reported (c.136C>T, p.Arg46*) and one novel variant (c.176G>A, p.Cys59Tyr)."
Identification of the allele.
PMID:34063696 SUPPORT In Vitro
"tyrosine 59 did not replace cysteine 59 as iron-sulfur cluster ligand; and (3) the mutation promoted the formation of an aberrant apo C59Y BOLA3-GLRX5 complex."
Molecular basis of the milder allele.
p.Ile67Asn Pathogenic
missense
Missense allele that impairs binding of BOLA3 to GLRX5 and prevents formation of the bridged heterocomplex without gross structural change.
Show evidence (1 reference)
PMID:33693876 SUPPORT In Vitro
"Our investigations reveal that the Ile67Asn substitution impairs the ability of BOLA3 to bind its physiological partner GLRX5"
Mechanism of the allele.
p.Arg99Trp Pathogenic
missense
Homozygous missense variant; both reported carriers had a milder phenotype than the other patients, and one of the two was the only patient alive at 12 years of age with no cardiomyopathy recorded. The informative outlier for variable expressivity.
Show evidence (1 reference)
PMID:34440194 SUPPORT Human Clinical
"It is noteworthy that both patients carrying the homozygous variant Arg99Trp presented a milder phenotype than the others"
Milder phenotype of the Arg99Trp homozygotes.
💊

Medical Actions

4
Supportive and multidisciplinary care
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No therapy corrects the Fe-S defect; vitamin cocktails and ketogenic diet did not alter the course in a homozygous H96R infant. Management is supportive: nutrition, antiseizure medication, cardiac care and respiratory support, with treatment of intercurrent illness.
Show evidence (1 reference)
PMID:29501406 SUPPORT Human Clinical
"Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure."
Documents lack of response to metabolic cocktails and ketogenic diet.
Cardiomyopathy management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Standard heart-failure care for the hypertrophic or dilated cardiomyopathy; cardiomyopathy was intractable in the original siblings.
Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22562699 SUPPORT Human Clinical
"We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life."
Cardiomyopathy refractory to treatment.
Glycine supplementation (preclinical, pulmonary hypertension)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: glycine CHEBI:15428 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses glycine (CHEBI:15428). CHEBI:15428 is a therapeutic agent from Chemical Entities of Biological Interest.
In mice, the therapeutic effect of restoring endothelial BOLA3 on pulmonary hypertension was reversed by exogenous glycine, identifying glycine homeostasis as a druggable axis; glycine reduction is untested in patients and would run against the hyperglycinemia of the systemic disease.
Mechanism Target:
Pulmonary Endothelial Metabolic Dysfunction — Glycine level modulates the endothelial phenotype downstream of BOLA3 deficiency.
Show evidence (1 reference)
PMID:30759996 SUPPORT Model Organism
"Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation."
Glycine as the effector of the endothelial phenotype in mice.
Genetic counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive counselling with 25% recurrence risk; carrier and prenatal testing once the familial variants are known.
🔬

Biochemical Markers

1
Elevated plasma glycine and lactate with reduced protein lipoylation (present)
Pathograph Readouts
Readout Of Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency Positive Diagnostic
Glycine and lactate accumulate when the lipoate-dependent enzymes fail.
Show evidence (1 reference)
PMID:34440194 SUPPORT Human Clinical
"Diagnosis could be suggested by high lactate, pyruvate, and glycine levels in body fluids."
Diagnostic biomarker guidance.
🔬

Diagnosis

4
Molecular genetic testing for biallelic BOLA3 variants
Exome or genome sequencing, or a mitochondrial/leukodystrophy panel, confirms the diagnosis; trio genome sequencing identified the recovering case.
Show evidence (2 references)
PMID:29654549 SUPPORT Human Clinical
"We performed trio whole genome sequencing (WGS) to determine the genetic basis of the disorder."
Sequencing strategy.
PMID:22562699 SUPPORT Human Clinical
"We conclude that broad sequencing approaches combined with appropriate prioritization filters and experimental validation enable efficient molecular diagnosis and have the potential to discover new disease loci."
Exome-based diagnosis.
Metabolic screening and glycine cleavage enzyme assay
Elevated plasma and CSF glycine with raised CSF:plasma ratio, lactate and pyruvate; variant NKH with normal GLDC/AMT/GCSH should prompt lipoylation and Fe-S gene testing.
Show evidence (1 reference)
PMID:24334290 SUPPORT Human Clinical
"We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and iron-sulphur cluster biogenesis."
Diagnostic reasoning from variant NKH to Fe-S genes.
Brain and spinal MRI with spectroscopy
Symmetrical deep white matter lesions with cavitation, restricted diffusion, optic nerve enhancement and a lactate peak.
Show evidence (1 reference)
PMID:30302924 SUPPORT Human Clinical
"Neuroimaging phenotype associated with MMDS 2 has never been described in its entirety in literature, with few reported cases till date."
Imaging phenotype description.
Fibroblast enzyme and native-gel analysis
Deficient PDH activity with barely detectable assembled complexes I and II on BN-PAGE, and metabolomic accumulation of TCA intermediates and branched-chain amino acids.
Show evidence (1 reference)
PMID:40273865 SUPPORT In Vitro
"In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases."
Fibroblast diagnostic pattern.
📈

Progression

2
Infantile onset with regression and early death
After a period of normal development, infants present at a few months of age with developmental regression, feeding impairment, hypotonia, seizures and cardiomyopathy; rapidly progressive white matter disease follows and no homozygous truncating case has survived beyond the first year.
Show evidence (2 references)
PMID:29501406 SUPPORT Human Clinical
"A 6-month-old girl with no remarkable family or past medical history until 1 month prior presented with developmental regression and feeding impairment."
Typical onset.
PMID:29501406 SUPPORT Human Clinical
"No reported case of a homozygous BOLA3 gene mutation has survived past 1 year of life."
Survival in the severe form.
Milder course with clinical recovery (hypomorphic alleles)
A compound heterozygote for p.Arg46* and p.Cys59Tyr presented at 18 months with acute hemiplegia and regression, then recovered clinically over four years with partial resolution of MRI abnormalities and normal respiratory chain activities in tissues.
Show evidence (1 reference)
PMID:29654549 SUPPORT Human Clinical
"The patient presented at 18 months with acute hemiplegia and cognitive regression without obvious trigger. This was followed by clinical recovery over 4 years."
Documents the recovering phenotype.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare. Eighteen patients from 14 families had been reported worldwide by 2021, carrying six missense and six nonsense disease-causing BOLA3 variants; a 2025 Japanese series added eight patients.
Show evidence (3 references)
PMID:34440194 SUPPORT Human Clinical
"Among the 18 reported patients from 14 families worldwide, only 8 variants were identified (Figure 3)."
Patient and family count as of the 2021 systematic review.
PMID:34063696 SUPPORT Other
"Six missense and six non-sense disease-causing variants in BOLA3 have been identified to date in patients affected by MMDS2"
Variant count as of 2021.
PMID:40273865 SUPPORT Human Clinical
"The characteristics, clinical course, and biochemical data of eight Japanese patients with BOLA3 pathogenic variants were collected."
Recent national series.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Multiple Mitochondrial Dysfunctions Syndrome 2:

Multiple mitochondrial dysfunctions syndrome 1 MONDO:0011582
Overlapping Features NFU1 deficiency shares the lipoylation and complex I/II defects; pulmonary hypertension favours MMDS1 and cardiomyopathy MMDS2, but sequencing is required.
Distinguishing Features
  • Pulmonary arterial hypertension prominent in MMDS1
  • Cardiomyopathy prominent in MMDS2
Show evidence (1 reference)
PMID:34440194 SUPPORT Human Clinical
"Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively"
Distinguishing clinical elements.
Classic non-ketotic hyperglycinemia
Overlapping Features GLDC/AMT/GCSH deficiency causes hyperglycinemia without the combined PDH and respiratory chain defect.
Distinguishing Features
  • Low PDH activity and complex I/II deficiency in MMDS2
  • Reduced protein lipoylation
Show evidence (1 reference)
PMID:24334290 SUPPORT Human Clinical
"Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call 'variant nonketotic hyperglycinemia'."
Defines the variant-NKH group in which BOLA3 sits.
🧫

Experimental Models

1
Patient-derived fibroblasts PRIMARY_CELL_CULTURE
Fibroblasts from BOLA3 patients show combined PDH and complex I/II deficiency, reduced lipoylation, attenuated mitochondrial protein synthesis and a metabolomic signature of 2-oxoacid dehydrogenase block; lentiviral expression of mitochondrial BOLA3 restores enzyme activities and lipoic acid.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:22562699
Pathograph links
Failure of the GLRX5-BOLA3 Node in 4Fe-4S Cluster Assembly recapitulates fidelity: high observes: cellular The Fe-S maturation defect and its rescue by wild-type mitochondrial BOLA3.
Limitations: Fibroblasts do not reproduce the tissue-specific vulnerability of white matter or myocardium.
Show evidence (1 reference)
PMID:22562699 SUPPORT In Vitro
"The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels."
Rescue experiment in patient cells.
🐁

Animal Models

1
Endothelial Bola3 knockdown mouse
Pharmacological knockdown of endothelial BOLA3 in mice produced histological and haemodynamic pulmonary hypertension, and targeted BOLA3 overexpression protected in rodent PH models, with the protection reversed by glycine.
Species
Mouse
Genotype
Lung endothelium-specific Bola3 siRNA knockdown (7C1 nanoparticle); AAV pulmonary vascular Bola3 overexpression in PH models
Publication
PMID:30759996
Pathograph links
Pulmonary Endothelial Metabolic Dysfunction recapitulates fidelity: moderate observes: tissue Endothelial BOLA3 loss reproduces the pulmonary vascular phenotype.
Limitations: A tissue-restricted knockdown of BOLA3 in adult mice models the pulmonary vascular component only, not the systemic infantile disorder or its CNS and cardiac disease.
Readouts
Pulmonary haemodynamics and vascular histology
Direction: INCREASED
Interpretation: Pulmonary hypertension after endothelial BOLA3 knockdown.
Show evidence (1 reference)
PMID:30759996 SUPPORT Model Organism
"In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH."
Reports the in vivo readout.
{ }

Source YAML

click to show 
name: Multiple Mitochondrial Dysfunctions Syndrome 2
category: Genetic
creation_date: "2026-09-05T16:30:00Z"
synonyms:
- MMDS2
- Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia
- BOLA3 deficiency
- BOLA3-related multiple mitochondrial dysfunctions syndrome
- BOLA3-associated variant non-ketotic hyperglycinemia
description: >
  Multiple mitochondrial dysfunctions syndrome 2 (MMDS2; OMIM #614299) is an autosomal
  recessive disorder of mitochondrial iron-sulfur (Fe-S) cluster biogenesis caused by
  biallelic variants in BOLA3. Mitochondrial BOLA3 forms a [2Fe-2S]-bridged heterocomplex
  with the monothiol glutaredoxin GLRX5, and this GLRX5-BOLA3 node feeds [4Fe-4S] cluster
  assembly on NFU1 and supplies the mitoribosome; BOLA3 is also required for NFU1 stability.
  Loss of BOLA3 therefore impairs maturation of the same [4Fe-4S] targets as NFU1 deficiency,
  lipoic acid synthase and respiratory chain complexes I and II, while sparing aconitase, so
  that lipoate-dependent enzymes (pyruvate dehydrogenase, 2-oxoglutarate, 2-oxoadipate and
  branched-chain ketoacid dehydrogenases, glycine cleavage system) fail together with
  OXPHOS. The biochemical signature is lactic acidosis with non-ketotic hyperglycinemia and
  reduced protein lipoylation; the clinical picture is an infantile-onset leukodystrophy with
  developmental regression after a period of normal development, optic atrophy, seizures and,
  distinctively among the MMDS forms, hypertrophic or dilated cardiomyopathy, with death
  usually in the first years. Rare hypomorphic alleles (p.Cys59Tyr compound heterozygosity)
  produce a leukoencephalopathy with clinical recovery. Endothelial BOLA3 deficiency also
  promotes pulmonary hypertension through glycine and metabolic dysregulation. Treatment is
  supportive.
disease_term:
  preferred_term: Multiple mitochondrial dysfunctions syndrome 2
  term:
    id: MONDO:0013675
    label: multiple mitochondrial dysfunctions syndrome 2
parents:
- MONDO:0017338
classifications:
  mechanistic_category:
  - classification_value: mitochondrial disease
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare. Eighteen patients from 14 families had been reported worldwide by 2021,
    carrying six missense and six nonsense disease-causing BOLA3 variants; a 2025 Japanese
    series added eight patients.
  evidence:
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 18 reported patients from 14 families worldwide, only 8 variants were identified (Figure 3)."
    explanation: Patient and family count as of the 2021 systematic review.
  - reference: PMID:34063696
    reference_title: "Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Six missense and six non-sense disease-causing variants in BOLA3 have been identified to date in patients affected by MMDS2"
    explanation: Variant count as of 2021.
  - reference: PMID:40273865
    reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristics, clinical course, and biochemical data of eight Japanese patients with BOLA3 pathogenic variants were collected."
    explanation: Recent national series.
progression:
- phase: Infantile onset with regression and early death
  notes: >-
    After a period of normal development, infants present at a few months of age with
    developmental regression, feeding impairment, hypotonia, seizures and cardiomyopathy;
    rapidly progressive white matter disease follows and no homozygous truncating case has
    survived beyond the first year.
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 6-month-old girl with no remarkable family or past medical history until 1 month prior presented with developmental regression and feeding impairment."
    explanation: Typical onset.
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No reported case of a homozygous BOLA3 gene mutation has survived past 1 year of life."
    explanation: Survival in the severe form.
- phase: Milder course with clinical recovery (hypomorphic alleles)
  notes: >-
    A compound heterozygote for p.Arg46* and p.Cys59Tyr presented at 18 months with acute
    hemiplegia and regression, then recovered clinically over four years with partial
    resolution of MRI abnormalities and normal respiratory chain activities in tissues.
  evidence:
  - reference: PMID:29654549
    reference_title: "Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented at 18 months with acute hemiplegia and cognitive regression without obvious trigger. This was followed by clinical recovery over 4 years."
    explanation: Documents the recovering phenotype.
genetic:
- name: BOLA3
  gene_term:
    preferred_term: BOLA3
    term:
      id: hgnc:24415
      label: BOLA3
  relationship_type: CAUSATIVE
  notes: >
    Biallelic BOLA3 (2p13.1) variants cause MMDS2; the disease is caused by loss of the
    mitochondrial isoform 1, which alone rescues patient fibroblasts. Truncating alleles
    (c.123dupA p.Glu42Argfs*13, p.Arg46*) and missense alleles at cluster-ligand or
    partner-binding residues (p.His96Arg, p.Ile67Asn, p.Cys59Tyr) are reported; structural
    studies show that His96Arg and Ile67Asn abolish a functional BOLA3-[2Fe-2S]-GLRX5
    heterocomplex, whereas Cys59Tyr perturbs but does not abolish cluster binding, matching
    its milder phenotype.
  variants:
  - name: c.123dupA (p.Glu42Argfs*13)
    description: Frameshift duplication identified in the second family of the original mapping study; produces a premature stop.
    type: frameshift
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:21944046
      reference_title: "Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A single base-pair duplication c.123dupA was identified in BOLA3 in the second family, causing a frame shift that produces a premature stop codon (p.Glu42Argfs(∗)13)."
      explanation: Original identification.
  - name: c.287A>G (p.His96Arg)
    description: >
      Homozygous missense at a conserved [2Fe-2S] ligand residue, associated with a severe
      phenotype of leukodystrophy with hypertrophic cardiomyopathy and death at 10 months;
      the mutant still binds GLRX5 but forms an aberrant heterocomplex unable to assemble a
      [4Fe-4S] cluster on NFU1.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:37511493
      reference_title: "Understanding the Molecular Basis of the Multiple Mitochondrial Dysfunctions Syndrome 2: The Disease-Causing His96Arg Mutation of BOLA3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Size exclusion chromatography, NMR, UV-visible, circular dichroism, and EPR spectroscopy characterization have shown that the His96Arg mutation does not impair the interaction of BOLA3 with its protein partner GLRX5"
      explanation: Molecular mechanism of the severe allele.
    - reference: PMID:29501406
      reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A homozygous H96R (c. 287 A > G) mutation was identified in the BOLA3 gene."
      explanation: Clinical report of the homozygous variant.
  - name: c.176G>A (p.Cys59Tyr)
    description: >
      Novel missense allele, compound heterozygous with p.Arg46*, in the patient with
      clinical recovery; it perturbs the cluster-binding region without abolishing cluster
      binding on the heterocomplex and promotes an aberrant apo complex.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:29654549
      reference_title: "Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "WGS identified compound heterozygous variants in BOLA3: one previously reported (c.136C>T, p.Arg46*) and one novel variant (c.176G>A, p.Cys59Tyr)."
      explanation: Identification of the allele.
    - reference: PMID:34063696
      reference_title: "Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "tyrosine 59 did not replace cysteine 59 as iron-sulfur cluster ligand; and (3) the mutation promoted the formation of an aberrant apo C59Y BOLA3-GLRX5 complex."
      explanation: Molecular basis of the milder allele.
  - name: p.Ile67Asn
    description: Missense allele that impairs binding of BOLA3 to GLRX5 and prevents formation of the bridged heterocomplex without gross structural change.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:33693876
      reference_title: "Biochemical impact of a disease-causing Ile67Asn substitution on BOLA3 protein."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our investigations reveal that the Ile67Asn substitution impairs the ability of BOLA3 to bind its physiological partner GLRX5"
      explanation: Mechanism of the allele.
  - name: p.Arg99Trp
    description: >
      Homozygous missense variant; both reported carriers had a milder phenotype than the
      other patients, and one of the two was the only patient alive at 12 years of age with
      no cardiomyopathy recorded. The informative outlier for variable expressivity.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:34440194
      reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is noteworthy that both patients carrying the homozygous variant Arg99Trp presented a milder phenotype than the others"
      explanation: Milder phenotype of the Arg99Trp homozygotes.
  evidence:
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Joint exome analysis of both affected siblings uncovered a homozygous missense mutation in BOLA3."
    explanation: Gene discovery by joint exome analysis of the two affected siblings.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    Autosomal recessive; severity tracks the residual function of the alleles, and the two
    Arg99Trp homozygotes were milder than the rest. Penetrance has not been quantified in the
    18 reported patients, so no penetrance value is asserted.
  evidence:
  - reference: PMID:37511493
    reference_title: "Understanding the Molecular Basis of the Multiple Mitochondrial Dysfunctions Syndrome 2: The Disease-Causing His96Arg Mutation of BOLA3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multiple mitochondrial dysfunctions syndrome type 2 with hyperglycinemia (MMDS2) is a severe disorder of mitochondrial energy metabolism, associated with biallelic mutations in the gene encoding for BOLA3"
    explanation: Biallelic requirement.
pathophysiology:
- name: Biallelic BOLA3 Loss of Function
  description: >
    Pathogenic variants abolish mitochondrial BOLA3 (isoform 1) or disrupt its ability to
    form a [2Fe-2S]-bridged heterocomplex with GLRX5, either by preventing GLRX5 binding
    (p.Ile67Asn) or by producing an aberrant complex that cannot pass its cluster onward
    (p.His96Arg, p.Cys59Tyr). Holo BOLA3 can also form a cluster-carrying homodimer.
  biological_scale: MOLECULAR
  downstream:
  - target: Failure of the GLRX5-BOLA3 Node in 4Fe-4S Cluster Assembly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37511493
      reference_title: "Understanding the Molecular Basis of the Multiple Mitochondrial Dysfunctions Syndrome 2: The Disease-Causing His96Arg Mutation of BOLA3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Size exclusion chromatography, NMR, UV-visible, circular dichroism, and EPR spectroscopy characterization have shown that the His96Arg mutation does not impair the interaction of BOLA3 with its protein partner GLRX5"
      explanation: The His96Arg mutant still binds GLRX5 but forms an aberrant heterocomplex that no longer assembles a cluster on NFU1; the rest of the sentence carries bracketed cluster notation that the snippet matcher cannot match.
  evidence:
  - reference: PMID:33693876
    reference_title: "Biochemical impact of a disease-causing Ile67Asn substitution on BOLA3 protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our investigations reveal that the Ile67Asn substitution impairs the ability of BOLA3 to bind its physiological partner GLRX5"
    explanation: Ile67Asn disrupts the BOLA3-GLRX5 carrier complex, the intermediary that delivers clusters to downstream targets.
  - reference: PMID:31486956
    reference_title: "Reconstitution, characterization, and [2Fe-2S] cluster exchange reactivity of a holo human BOLA3 homodimer."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Herein we describe procedures to isolate and characterize the human holo BOLA3 protein in terms of Fe-S cluster binding and trafficking and demonstrate that human BOLA3 can form a functional homodimer capable of engaging in Fe-S cluster transfer."
    explanation: BOLA3 as a cluster-trafficking protein.
- name: Failure of the GLRX5-BOLA3 Node in 4Fe-4S Cluster Assembly
  description: >
    The GLRX5-BOLA3 heterocomplex delivers [2Fe-2S] clusters for [4Fe-4S] assembly on NFU1
    and to the mitoribosome; BOLA3 is also needed for NFU1 stability. Loss of BOLA3 therefore
    impairs the NFU1-dependent targets, lipoic acid synthase and respiratory chain complexes
    I and II, while aconitase is spared, and attenuates mitochondrial protein synthesis.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: iron-sulfur cluster assembly
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    modifier: DECREASED
  downstream:
  - target: Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22562699
      reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our results suggest that BOLA3 plays a crucial role in the biogenesis of iron-sulfur clusters necessary for proper function of respiratory chain and 2-oxoacid dehydrogenase complexes."
      explanation: BOLA3 loss impairs both lipoate-dependent and respiratory-chain targets.
  - target: Respiratory Chain Complex I and II Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40273865
      reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases."
      explanation: Complex I and II loss in all patients' fibroblasts.
  - target: Attenuated Mitochondrial Protein Synthesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37823603
      reference_title: "BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The GLRX5-BOLA3 and ISCA1-NFU1 Fe–S cluster delivery pathways are required for mitoribosome biogenesis."
      explanation: The GLRX5-BOLA3 pathway supplies the mitoribosome with its clusters.
  evidence:
  - reference: PMID:28803783
    reference_title: "Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3."
    explanation: BOLA3 is required for NFU1 stability, linking the two nodes.
  - reference: PMID:40273865
    reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results indicate that BOLA3 variants decrease the activity of lipoic acid-dependent proteins (pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine cleavage system), as well as mitochondrial respiratory chain complexes I and II, but do not affect aconitase."
    explanation: Target specificity including sparing of aconitase.
- name: Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
  description: >
    Without a functional cluster supply, the [4Fe-4S] radical-SAM enzyme lipoic acid synthase
    cannot lipoylate the E2 subunits of the 2-oxoacid dehydrogenases or the H protein of the
    glycine cleavage system; lipoic acid levels in patient fibroblasts are restored by
    re-expression of mitochondrial BOLA3.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: lipoate synthase activity
    term:
      id: GO:0016992
      label: lipoate synthase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein lipoylation
    term:
      id: GO:0009249
      label: protein lipoylation
    modifier: DECREASED
  downstream:
  - target: Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients were deficient in lipoylation of mitochondrial proteins."
    explanation: Lipoylation defect in patients.
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels."
    explanation: Rescue of lipoic acid levels.
- name: Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
  description: >
    Loss of lipoylation inactivates pyruvate dehydrogenase and the other 2-oxoacid
    dehydrogenases, causing lactic acidosis with accumulation of pyruvate, alanine, TCA
    intermediates and branched-chain amino acids, and inactivates the glycine cleavage
    system, causing non-ketotic hyperglycinemia with raised CSF:plasma glycine ratio.
  biological_scale: CELLULAR
  molecular_functions:
  - preferred_term: pyruvate dehydrogenase (acetyl-transferring) activity
    term:
      id: GO:0004739
      label: pyruvate dehydrogenase (acetyl-transferring) activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: glycine catabolic process
    term:
      id: GO:0006546
      label: glycine catabolic process
    modifier: DECREASED
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  downstream:
  - target: Hyperglycinemia
    causal_link_type: DIRECT
  - target: Lactic acidosis
    causal_link_type: DIRECT
  - target: Bioenergetic Failure in Brain and Heart
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40273865
    reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the metabolomic analysis, levels of lactic acid, pyruvic acid, alanine, tricarboxylic acid (TCA) cycle intermediates (such as α-ketoglutaric acid and succinic acid), branched-chain amino acids, and metabolites of lysine and tryptophan were significantly elevated in the BOLA3 group."
    explanation: Metabolomic fingerprint of the combined dehydrogenase block.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity."
    explanation: Glycine cleavage deficiency in patients.
- name: Respiratory Chain Complex I and II Deficiency
  description: >
    Complexes I and II carry [4Fe-4S] clusters dependent on the BOLA3-NFU1 axis; muscle and
    fibroblasts show combined deficiency of complexes I, II and II+III with barely detectable
    assembled complexes on native gels.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex I assembly
    term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    modifier: DECREASED
  - preferred_term: mitochondrial electron transport, succinate to ubiquinone
    term:
      id: GO:0006121
      label: mitochondrial electron transport, succinate to ubiquinone
    modifier: DECREASED
  downstream:
  - target: Bioenergetic Failure in Brain and Heart
    causal_link_type: DIRECT
  - target: Lactic acidosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy revealed a peculiar biochemical defect consisting of a combined deficiency of respiratory chain complexes I, II, and II+III accompanied by a defect of the pyruvate dehydrogenase complex."
    explanation: Combined defect in patient muscle.
- name: Attenuated Mitochondrial Protein Synthesis
  description: >
    The mitoribosome's three [2Fe-2S] clusters are supplied by the GLRX5-BOLA3 node and play
    a structural role in mitoribosome assembly; MMDS2 patient fibroblasts show attenuated
    mitochondrial protein synthesis that adds to the OXPHOS deficit.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  downstream:
  - target: Bioenergetic Failure in Brain and Heart
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37823603
    reference_title: "BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes."
    explanation: Patient-cell demonstration.
- name: Bioenergetic Failure in Brain and Heart
  description: >
    Combined loss of PDH-dependent and respiratory-chain ATP production injures the most
    energy-dependent tissues: a rapidly progressive leukodystrophy with necrotic/cavitary
    white matter lesions, optic nerve involvement and markedly elevated lactate on MR
    spectroscopy, together with hypertrophic or dilated cardiomyopathy, which distinguishes
    MMDS2 from the other MMDS forms.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Leukoencephalopathy
    causal_link_type: DIRECT
  - target: Developmental regression
    causal_link_type: DIRECT
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Optic atrophy
    causal_link_type: DIRECT
  - target: Seizure
    causal_link_type: DIRECT
  - target: Hypotonia
    causal_link_type: DIRECT
  - target: Pulmonary Endothelial Metabolic Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:30302924
    reference_title: "Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the published cases mention findings demonstrated in our case, a proband with biallelic BOLA3 variants, such as necrotic/cavitary lesions within the centrum semiovale, restricted diffusivity within the white matter, areas of central enhancement within the centrum semiovale presumably related to leakage of contrast within the necrotic center, enhancement of bilateral optic nerves, and markedly elevated lactate on magnetic resonance spectroscopy."
    explanation: Imaging evidence of the white matter and optic nerve lesions with tissue lactate.
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy."
    explanation: Cardiomyopathy as the MMDS2-specific feature.
- name: Pulmonary Endothelial Metabolic Dysfunction
  description: >
    In pulmonary artery endothelial cells BOLA3 deficiency, whether by knockdown or by
    naturally occurring patient variants, impairs Fe-S integrity and lipoate-dependent
    2-oxoacid dehydrogenases, reprogrammes glycolysis and respiration, downregulates glycine
    cleavage protein H to raise intracellular glycine, and increases endothelial
    proliferation, survival and vasoconstriction while reducing angiogenic potential;
    endothelial BOLA3 knockdown in mice produces pulmonary hypertension that glycine
    supplementation reverses.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: pulmonary artery endothelial cell
    term:
      id: CL:1001568
      label: pulmonary artery endothelial cell
  downstream:
  - target: Pulmonary arterial hypertension
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30759996
      reference_title: "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH."
      explanation: Endothelial BOLA3 loss is sufficient for pulmonary hypertension in mice.
  evidence:
  - reference: PMID:30759996
    reference_title: "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential."
    explanation: Endothelial cellular mechanism including patient variants.
phenotypes:
- name: Hyperglycinemia
  category: Metabolic
  frequency: VERY_FREQUENT
  description: Non-ketotic hyperglycinemia with high serum and borderline elevated CSF glycine; the eponymous feature "with hyperglycinemia".
  phenotype_term:
    preferred_term: Non-ketotic hyperglycinemia
    term:
      id: HP:0002154
      label: Hyperglycinemia
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity."
    explanation: Glycine findings in variant NKH including BOLA3 patients.
  - reference: PMID:40273865
    reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Data collected during the patients' lives showed increased lactic acid and glycine levels."
    explanation: Consistent metabolite elevations in the Japanese series.
- name: Lactic acidosis
  category: Metabolic
  frequency: VERY_FREQUENT
  description: Severe neonatal or infantile lactic acidosis, with elevated CSF lactate and a lactate peak on MR spectroscopy; some variant-NKH patients lack acidosis despite low PDH activity.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life."
    explanation: Presenting lactic acidosis.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis."
    explanation: Lactic acidosis is not universal in the variant-NKH presentation.
- name: Leukoencephalopathy
  category: Neurological
  frequency: VERY_FREQUENT
  description: Rapidly progressive symmetrical deep white matter and spinal cord lesions, with necrotic/cavitary centrum semiovale lesions and restricted diffusion.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrasound cardiography and brain magnetic resonance imaging (MRI) respectively disclosed the presence of hypertrophic cardiomyopathy and symmetrical deep white matter lesions."
    explanation: Imaging at presentation.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy."
    explanation: Summary of the BOLA3 clinical features.
- name: Developmental regression
  category: Neurological
  frequency: VERY_FREQUENT
  description: Severe neurodegeneration after a period of normal development.
  phenotype_term:
    preferred_term: Neurodevelopmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development."
    explanation: Regression after normal early development.
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  frequency: FREQUENT
  description: Hypertrophic cardiomyopathy is reported in the Japanese series and the H96R case; cardiomyopathy is the feature that distinguishes MMDS2 within the series.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:40273865
    reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the BOLA3 gene cause a rare condition known as multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, characterized by life-threatening lactic acidosis, nonketotic hyperglycinemia, and hypertrophic cardiomyopathy."
    explanation: Hypertrophic cardiomyopathy as a characterising feature.
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We herein present the detailed clinical course of an infant admitted for extensive, rapidly progressing white matter lesions and hypertrophic cardiomyopathy due to a BOLA3 gene mutation."
    explanation: Case with hypertrophic cardiomyopathy.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  frequency: OCCASIONAL
  description: Dilated cardiomyopathy is recorded as the MMDS2-specific element in the systematic review; the original siblings had intractable cardiomyopathy.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively"
    explanation: Systematic review attribution of dilated cardiomyopathy to MMDS2.
- name: Optic atrophy
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:30302924
    reference_title: "Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MMDS 2 associated with BOLA3 mutation presents in early infancy and is characterized by developmental regression, severe encephalopathy, optic atrophy, and cardiomyopathy."
    explanation: Optic atrophy among the core features.
- name: Seizure
  category: Neurological
  frequency: FREQUENT
  description: Clusters of myoclonic seizures in the terminal phase.
  phenotype_term:
    preferred_term: Myoclonic seizures
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure."
    explanation: Seizures and respiratory failure in the course.
- name: Hypotonia
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy"
    explanation: Neonatal hypotonia.
- name: Respiratory failure
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient began exhibiting clusters of myoclonic seizures and respiratory failure"
    explanation: Terminal respiratory failure.
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  description: >-
    Pulmonary hypertension is the feature that distinguishes MMDS1, not MMDS2, in the clinical
    series; in BOLA3 deficiency it is mechanistically implicated through the endothelial
    metabolic defect and is reproduced by endothelial BOLA3 knockdown in mice, but it is not
    an established patient-level finding, so no frequency is asserted.
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:30759996
    reference_title: "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH."
    explanation: Background statement from a mixed in vitro and mouse study, graded OTHER because it reports no patient observation.
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In this human cellular model, BOLA3 deficiency leads to increased endothelial vasoconstriction, while in mice cells, it causes histological modifications typical of those found in pulmonary hypertension."
    explanation: The systematic review presents the pulmonary phenotype of BOLA3 deficiency as a model finding rather than a clinical series observation.
- name: Decreased activity of mitochondrial complex I
  category: Laboratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased complex I activity
    term:
      id: HP:0011923
      label: Decreased activity of mitochondrial complex I
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibroblasts obtained pre-mortem displayed low mitochondrial respiratory chain complex I and II activity."
    explanation: Enzymatic finding.
- name: Decreased activity of mitochondrial complex II
  category: Laboratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Succinate dehydrogenase deficiency
    term:
      id: HP:0008314
      label: Decreased activity of mitochondrial complex II
  evidence:
  - reference: PMID:29654549
    reference_title: "Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of cultured patient fibroblasts demonstrated deficient pyruvate dehydrogenase (PDH) activity and reduced quantity of protein subunits of mitochondrial complexes I and II, consistent with BOLA3 dysfunction."
    explanation: Fibroblast finding even in the recovering patient.
- name: Feeding difficulties
  category: Gastrointestinal
  description: Feeding impairment accompanies the regression at onset.
  phenotype_term:
    preferred_term: Feeding impairment
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 6-month-old girl with no remarkable family or past medical history until 1 month prior presented with developmental regression and feeding impairment."
    explanation: Feeding impairment at presentation.
- name: Failure to thrive
  category: Growth
  description: Failure to thrive was part of the phenotype of the first reported patient.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical phenotype showed severe encephalopathy with respiratory distress, seizures, failure to thrive, and dilated cardiomyopathy."
    explanation: Failure to thrive in the index patient as summarised by the systematic review.
biochemical:
- name: Elevated plasma glycine and lactate with reduced protein lipoylation
  presence: present
  notes: Screening biomarkers shared across the MMDS series; lipoylation of PDH-E2 and other targets is reduced in patient cells and restored by BOLA3 re-expression.
  readouts:
  - target: Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Glycine and lactate accumulate when the lipoate-dependent enzymes fail.
  evidence:
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis could be suggested by high lactate, pyruvate, and glycine levels in body fluids."
    explanation: Diagnostic biomarker guidance.
treatments:
- name: Supportive and multidisciplinary care
  description: >
    No therapy corrects the Fe-S defect; vitamin cocktails and ketogenic diet did not alter
    the course in a homozygous H96R infant. Management is supportive: nutrition, antiseizure
    medication, cardiac care and respiratory support, with treatment of intercurrent illness.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29501406
    reference_title: "An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure."
    explanation: Documents lack of response to metabolic cocktails and ketogenic diet.
- name: Cardiomyopathy management
  description: Standard heart-failure care for the hypertrophic or dilated cardiomyopathy; cardiomyopathy was intractable in the original siblings.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life."
    explanation: Cardiomyopathy refractory to treatment.
- name: Glycine supplementation (preclinical, pulmonary hypertension)
  description: >
    In mice, the therapeutic effect of restoring endothelial BOLA3 on pulmonary hypertension
    was reversed by exogenous glycine, identifying glycine homeostasis as a druggable axis;
    glycine reduction is untested in patients and would run against the hyperglycinemia of
    the systemic disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glycine
      term:
        id: CHEBI:15428
        label: glycine
  target_mechanisms:
  - target: Pulmonary Endothelial Metabolic Dysfunction
    description: Glycine level modulates the endothelial phenotype downstream of BOLA3 deficiency.
  evidence:
  - reference: PMID:30759996
    reference_title: "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation."
    explanation: Glycine as the effector of the endothelial phenotype in mice.
- name: Genetic counseling
  description: Autosomal recessive counselling with 25% recurrence risk; carrier and prenatal testing once the familial variants are known.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
diagnosis:
- name: Molecular genetic testing for biallelic BOLA3 variants
  description: Exome or genome sequencing, or a mitochondrial/leukodystrophy panel, confirms the diagnosis; trio genome sequencing identified the recovering case.
  evidence:
  - reference: PMID:29654549
    reference_title: "Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed trio whole genome sequencing (WGS) to determine the genetic basis of the disorder."
    explanation: Sequencing strategy.
  - reference: PMID:22562699
    reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that broad sequencing approaches combined with appropriate prioritization filters and experimental validation enable efficient molecular diagnosis and have the potential to discover new disease loci."
    explanation: Exome-based diagnosis.
- name: Metabolic screening and glycine cleavage enzyme assay
  description: Elevated plasma and CSF glycine with raised CSF:plasma ratio, lactate and pyruvate; variant NKH with normal GLDC/AMT/GCSH should prompt lipoylation and Fe-S gene testing.
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and iron-sulphur cluster biogenesis."
    explanation: Diagnostic reasoning from variant NKH to Fe-S genes.
- name: Brain and spinal MRI with spectroscopy
  description: Symmetrical deep white matter lesions with cavitation, restricted diffusion, optic nerve enhancement and a lactate peak.
  evidence:
  - reference: PMID:30302924
    reference_title: "Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging phenotype associated with MMDS 2 has never been described in its entirety in literature, with few reported cases till date."
    explanation: Imaging phenotype description.
- name: Fibroblast enzyme and native-gel analysis
  description: Deficient PDH activity with barely detectable assembled complexes I and II on BN-PAGE, and metabolomic accumulation of TCA intermediates and branched-chain amino acids.
  evidence:
  - reference: PMID:40273865
    reference_title: "Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases."
    explanation: Fibroblast diagnostic pattern.
differential_diagnoses:
- name: Multiple mitochondrial dysfunctions syndrome 1
  description: NFU1 deficiency shares the lipoylation and complex I/II defects; pulmonary hypertension favours MMDS1 and cardiomyopathy MMDS2, but sequencing is required.
  disease_term:
    preferred_term: multiple mitochondrial dysfunctions syndrome 1
    term:
      id: MONDO:0011582
      label: multiple mitochondrial dysfunctions syndrome 1
  distinguishing_features:
  - Pulmonary arterial hypertension prominent in MMDS1
  - Cardiomyopathy prominent in MMDS2
  evidence:
  - reference: PMID:34440194
    reference_title: "A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively"
    explanation: Distinguishing clinical elements.
- name: Lipoic acid synthetase deficiency and GLRX5-related variant NKH
  description: LIAS and GLRX5 defects also cause variant non-ketotic hyperglycinemia with lipoylation deficiency; GLRX5 patients have childhood-onset spastic paraplegia with spinal lesions and optic atrophy rather than infantile neurodegeneration.
  disease_term:
    preferred_term: lipoic acid synthetase deficiency
    term:
      id: MONDO:0013762
      label: lipoic acid synthetase deficiency
  distinguishing_features:
  - Normal development with childhood-onset spastic paraplegia in GLRX5 deficiency
  - Static encephalopathy to Leigh-like disease in LIAS deficiency
  - Cardiomyopathy and infantile regression in BOLA3 deficiency
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with GLRX5-associated variant nonketotic hyperglycinemia had normal development with childhood-onset spastic paraplegia, spinal lesion, and optic atrophy."
    explanation: Contrasting GLRX5 phenotype.
- name: Classic non-ketotic hyperglycinemia
  description: GLDC/AMT/GCSH deficiency causes hyperglycinemia without the combined PDH and respiratory chain defect.
  distinguishing_features:
  - Low PDH activity and complex I/II deficiency in MMDS2
  - Reduced protein lipoylation
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call 'variant nonketotic hyperglycinemia'."
    explanation: Defines the variant-NKH group in which BOLA3 sits.
animal_models:
- name: Endothelial Bola3 knockdown mouse
  species: Mouse
  genotype: Lung endothelium-specific Bola3 siRNA knockdown (7C1 nanoparticle); AAV pulmonary vascular Bola3 overexpression in PH models
  publication: PMID:30759996
  description: >
    Pharmacological knockdown of endothelial BOLA3 in mice produced histological and
    haemodynamic pulmonary hypertension, and targeted BOLA3 overexpression protected in
    rodent PH models, with the protection reversed by glycine.
  modeled_mechanisms:
  - target: Pulmonary Endothelial Metabolic Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Endothelial BOLA3 loss reproduces the pulmonary vascular phenotype.
    limitations: >-
      A tissue-restricted knockdown of BOLA3 in adult mice models the pulmonary vascular
      component only, not the systemic infantile disorder or its CNS and cardiac disease.
    readouts:
    - name: Pulmonary haemodynamics and vascular histology
      target: Pulmonary Endothelial Metabolic Dysfunction
      direction: INCREASED
      interpretation: Pulmonary hypertension after endothelial BOLA3 knockdown.
      evidence:
      - reference: PMID:30759996
        reference_title: "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH."
        explanation: Reports the in vivo readout.
experimental_models:
- name: Patient-derived fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Fibroblasts from BOLA3 patients show combined PDH and complex I/II deficiency, reduced
    lipoylation, attenuated mitochondrial protein synthesis and a metabolomic signature of
    2-oxoacid dehydrogenase block; lentiviral expression of mitochondrial BOLA3 restores
    enzyme activities and lipoic acid.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:22562699
  modeled_mechanisms:
  - target: Failure of the GLRX5-BOLA3 Node in 4Fe-4S Cluster Assembly
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The Fe-S maturation defect and its rescue by wild-type mitochondrial BOLA3.
    limitations: >-
      Fibroblasts do not reproduce the tissue-specific vulnerability of white matter or
      myocardium.
    evidence:
    - reference: PMID:22562699
      reference_title: "Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels."
      explanation: Rescue experiment in patient cells.
discussions:
- discussion_id: mmds2_bola3_molecular_role
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic BOLA3 Loss of Function
  prompt: >
    What is the precise molecular role of BOLA3 in [4Fe-4S] cluster biogenesis, and does it
    act as a GLRX5-bridged [2Fe-2S] carrier to NFU1, as a stabiliser of NFU1, or as a
    homodimeric cluster carrier in its own right?
  rationale: >
    The exact function of BOLA3 is still described as not completely understood: the
    BOLA3-GLRX5 heterocomplex is the favoured intermediary, a holo BOLA3 homodimer also
    transfers clusters, and patient fibroblast profiling shows NFU1 depends on BOLA3 for
    stability. Which of these accounts for the disease is unresolved.
  evidence:
  - reference: PMID:37511493
    reference_title: "Understanding the Molecular Basis of the Multiple Mitochondrial Dysfunctions Syndrome 2: The Disease-Causing His96Arg Mutation of BOLA3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a protein with a not yet completely understood role in iron-sulfur (Fe-S) cluster biogenesis, but essential for the maturation of mitochondrial"
    explanation: Explicit statement of the gap.
- discussion_id: mmds2_no_systemic_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Bioenergetic Failure in Brain and Heart
  prompt: >
    Does any whole-organism model reproduce the infantile leukodystrophy and cardiomyopathy
    of BOLA3 deficiency, given that the only in vivo work is an adult endothelial knockdown
    modelling pulmonary hypertension?
  rationale: >
    The endothelial knockdown mouse captures a vascular phenotype that is not the dominant
    clinical problem in patients, and no constitutive or CNS/cardiac Bola3 model has been
    reported, so the human white-matter and myocardial disease rests on patient tissue and
    fibroblast data alone.
  evidence:
  - reference: PMID:30759996
    reference_title: "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice."
    explanation: The in vivo model is endothelium-restricted.
notes: >
  Curated as a per-gene Disease entry (stub entry_type decision: DISEASE) alongside MMDS1
  (NFU1) and MMDS5 (ISCA1); the shared lipoate-deficiency chain is duplicated in each entry
  rather than merged, consistent with MMDS9B and the open MMDS4/MMDS6 PRs. Sources: the
  discovery and early clinical papers (PMID:21944046, PMID:22562699, PMID:24334290), case
  reports and series (PMID:29501406, PMID:29654549, PMID:30302924, PMID:40273865),
  structural/biochemical studies (PMID:34063696, PMID:37511493, PMID:33693876, PMID:31486956,
  PMID:37823603, PMID:28803783), the endothelial pulmonary hypertension study (PMID:30759996)
  and the systematic review (PMID:34440194). Several snippets end at a propositional main
  clause because the rest of the sentence carries bracketed Fe-S notation, which the snippet
  matcher strips from the quote but not from the cache. The pulmonary endothelial node does
  not declare module conformance: the BOLA3 endothelial mechanism is metabolic (lipoate
  and glycine) rather than the BMP and nitric-oxide axis that the
  pulmonary_vascular_remodeling entry node is defined by. The Edison/falcon
  deep-research report completed after the first draft and passed preflight; every reference
  in its list was already cited, so it added no new sources. No GeneReviews chapter
  exists for BOLA3-related MMDS.
📚

References & Deep Research

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 (3)

Record notes

Curated as a per-gene Disease entry (stub entry_type decision: DISEASE) alongside MMDS1 (NFU1) and MMDS5 (ISCA1); the shared lipoate-deficiency chain is duplicated in each entry rather than merged, consistent with MMDS9B and the open MMDS4/MMDS6 PRs. Sources: the discovery and early clinical papers (PMID:21944046, PMID:22562699, PMID:24334290), case reports and series (PMID:29501406, PMID:29654549, PMID:30302924, PMID:40273865), structural/biochemical studies (PMID:34063696, PMID:37511493, PMID:33693876, PMID:31486956, PMID:37823603, PMID:28803783), the endothelial pulmonary hypertension study (PMID:30759996) and the systematic review (PMID:34440194). Several snippets end at a propositional main clause because the rest of the sentence carries bracketed Fe-S notation, which the snippet matcher strips from the quote but not from the cache. The pulmonary endothelial node does not declare module conformance: the BOLA3 endothelial mechanism is metabolic (lipoate and glycine) rather than the BMP and nitric-oxide axis that the pulmonary_vascular_remodeling entry node is defined by. The Edison/falcon deep-research report completed after the first draft and passed preflight; every reference in its list was already cited, so it added no new sources. No GeneReviews chapter exists for BOLA3-related MMDS.

Edit: record the completed deep-research report · 2026-09-06T03:15:41Z · View source

The relaunched Edison/falcon deep-research run completed after the entry was first committed and passed just preflight-dr (BOLA3 55 mentions, OMIM 614299). Every reference in its list was already cited by the entry, so no content changed; the notes sentence that described the run as incomplete was replaced, and the report, its citations sidecar and artifacts are committed alongside the entry. Validation: just validate pass, count-verified-snippets 64/64.

Create: Multiple_Mitochondrial_Dysfunctions_Syndrome_2 (BOLA3, MONDO:0013675) · 2026-09-06T02:52:00Z · View source

Created MMDS2 as a per-gene Disease entry (stub entry_type decision: DISEASE), sibling to MMDS1 and MMDS5 in the same tranche; the stub's suggestion of merging MMDS1/MMDS2 into one entry with subtypes was declined for series uniformity, and the shared lipoate-deficiency chain is duplicated. Chain: biallelic BOLA3 loss, failure of the GLRX5-BOLA3 node, LIAS deficiency, combined 2-oxoacid dehydrogenase/GCS deficiency, complex I/II deficiency, attenuated mitochondrial translation, bioenergetic failure in brain and heart (cardiomyopathy as the distinguishing feature), and a pulmonary endothelial node conforming to pulmonary_vascular_remodeling grounded in the BOLA3 endothelial knockdown study. Sources: PMID:21944046, PMID:22562699, PMID:24334290, PMID:29501406, PMID:29654549, PMID:30302924, PMID:40273865, PMID:34063696, PMID:37511493, PMID:33693876, PMID:31486956, PMID:37823603, PMID:28803783, PMID:30759996, PMID:34440194. Snippets containing bracketed Fe-S notation were trimmed because bracketed spans are stripped before matching. The Edison/falcon deep-research run had not completed when the entry was written (provider retries; runs relaunched with fallback). Validation: just validate pass, just validate-terms pass, count-verified-snippets 64/64, check-causal-targets and check-entity-refs clean. No GeneReviews chapter exists for BOLA3-related MMDS.

Falcon ▸
Multiple Mitochondrial Dysfunctions Syndrome 2 (MMDS2): Research Report
Edison Scientific Literature 29 citations 2026-09-06T02:56:36.318456

Multiple Mitochondrial Dysfunctions Syndrome 2 (MMDS2): Research Report

Executive summary

Multiple mitochondrial dysfunctions syndrome 2 (MMDS2) is an ultrarare, autosomal-recessive mitochondrial disorder caused by biallelic BOLA3 variants. BOLA3 participates in mitochondrial iron–sulfur (Fe–S) cluster delivery. Its deficiency compromises oxidative phosphorylation, lipoate-dependent 2-oxoacid dehydrogenases, glycine cleavage, and—as demonstrated in 2023—mitochondrial ribosome assembly and translation. Classical MMDS2 presents in infancy with rapidly progressive encephalopathy, leukodystrophy, hypotonia or weakness, lactic acidosis, hyperglycinemia, cardiomyopathy, respiratory failure, and early death. Nevertheless, residual-function alleles can produce substantially attenuated disease, including documented neurological recovery. Evidence remains limited to fewer than a few dozen published patients, retrospective reports, patient fibroblasts, and experimental models; there is no established disease-modifying treatment or disease-specific clinical trial.

The following compact table summarizes the principal knowledge-base fields; the narrative afterward supplies interpretation and ontology annotations.

Knowledge-base field MMDS2 summary Evidence
Identity and identifiers Multiple mitochondrial dysfunctions syndrome 2 (MMDS2); multiple mitochondrial dysfunctions syndrome type 2 with hyperglycinemia; BOLA3-related multiple mitochondrial dysfunction syndrome. MONDO: MONDO:0013675; OMIM: 614299. Specific ICD-10, ICD-11, MeSH, and Orphanet identifiers were not established from the retrieved evidence. Open Targets independently maps MONDO:0013675 to BOLA3; systematic clinical literature identifies OMIM 614299 (OpenTargets Search: multiple mitochondrial dysfunctions syndrome 2-BOLA3, stutterd2019severeleukoencephalopathywith pages 1-2, lebigot2021areviewof pages 7-9).
Gene and inheritance Caused by biallelic germline variants in BOLA3 (bolA family member 3; Ensembl ENSG00000163170). Inheritance is autosomal recessive; obligate heterozygous parents are generally unaffected. Penetrance has not been quantified but appears high for damaging biallelic genotypes. Human genetic association and recessive pedigrees (OpenTargets Search: multiple mitochondrial dysfunctions syndrome 2-BOLA3, stutterd2019severeleukoencephalopathywith pages 1-2, stutterd2019severeleukoencephalopathywith pages 2-4).
Reported population A 2021 systematic review identified 18 patients from 14 families worldwide and eight BOLA3 variants. Disease-specific prevalence, incidence, carrier frequency, sex ratio, and population-based survival statistics are unavailable. Aggregated systematic-review evidence; very small, ascertainment-biased case series (lebigot2021areviewof pages 11-13).
Onset and core neurologic phenotypes Usually neonatal or infantile onset, commonly within the first year; prior cases in one comparison began from birth to 8 months. Motor delay or regression occurred in 12/12, seizures in 5/10, and independent walking in 1/5 evaluable previously reported patients. An attenuated case began acutely at 18 months with hemiparesis, ataxia, and speech/cognitive regression. Patient-level and aggregated human evidence (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 1-2, stutterd2019severeleukoencephalopathywith pages 2-4).
Multisystem manifestations Severe cases may include hypotonia or weakness, feeding difficulty/failure to thrive, respiratory failure, optic atrophy or nystagmus, renal or hepatic failure, and cardiomyopathy. Cardiomyopathy occurred in 7/9 in one historical comparison and in approximately half of the 18-patient review cohort; hypertrophic and dilated forms were reported. Aggregated human clinical evidence (stutterd2019severeleukoencephalopathywith pages 4-6, lebigot2021areviewof pages 7-9, lebigot2021areviewof pages 11-13).
Biochemical markers Typical abnormalities include elevated plasma/urine glycine, lactate, pyruvate, and metabolic acidosis; historical denominators were elevated lactate 11/12, glycine 8/8, reduced respiratory-chain complex I/II activity 10/12, and reduced pyruvate-dehydrogenase activity 6/7. Normal lactate or tissue respiratory-chain assays do not exclude MMDS2: the recovery case had elevated plasma/urine glycine, normal CSF glycine and lactate, but fibroblast PDH activity was 20% of control with reduced complex I/II subunits. Human biochemical evidence (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 2-4).
Neuroimaging Characteristic MRI findings include bilateral diffuse or multifocal periventricular/deep-white-matter T2 hyperintensity, dysmyelination or cavitating/cystic leukodystrophy, restricted diffusion, corpus-callosum, brainstem, cerebellar, spinal-cord, or basal-ganglia involvement, and cerebral/cerebellar atrophy. MR spectroscopy may show a lactate peak and reduced N-acetylaspartate. Human neuroradiologic evidence (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 2-4, lebigot2021areviewof pages 9-11).
Key variants Reported variants include c.123dupA (p.Glu42Argfs13), c.136C>T (p.Arg46), c.159dupT (p.Asp54), c.176G>A (p.Cys59Tyr), c.200T>A (p.Ile67Asn), c.220_222del (p.Glu74del), c.225_229del (p.Lys75Asnfs9), c.287A>G (p.His96Arg), and c.295C>T (p.Arg99Trp) across retrieved reports/reviews. The 2021 review counted eight variants; the larger list reflects subsequent/independently tabulated reports and should be reconciled against current ClinVar and transcript versions before database import. Population allele frequencies and current ACMG/ClinVar classifications were not retrieved. Aggregated variant tables and case report (lebigot2021areviewof pages 7-9, stutterd2019severeleukoencephalopathywith pages 2-4, lebigot2021areviewof pages 9-11).
Variant-specific functional effects p.Cys59Tyr: retains partial Fe–S transfer; NFU1 became [4Fe–4S]-bound at 25% versus 65% with wild type, consistent with an attenuated Arg46/Cys59Tyr phenotype. p.Ile67Asn: preserves global fold but disrupts GLRX5 binding and BOLA3–GLRX5 heterocomplex formation. p.His96Arg: permits partner interaction but forms an aberrant complex unable to assemble an NFU1 [4Fe–4S] cluster. p.Arg46*:* predicted/truncating loss of function; direct functional quantification was not retrieved. Recombinant-protein/in-vitro studies and human genotype–phenotype correlation; DOI 10.3390/ijms22094848, 10.1093/mtomcs/mfab010, and 10.3390/ijms241411734 (sen2021biochemicalimpactof pages 1-2, bargagna2023understandingthemolecular pages 1-2, saudino2021molecularbasisof pages 1-2, saudino2021molecularbasisof pages 11-12, sen2021biochemicalimpactof pages 7-8).
Core mechanism BOLA3 and GLRX5 form a bridged [2Fe–2S] carrier complex that transfers clusters to NFU1, where reductive coupling generates [4Fe–4S] clusters. BOLA3 deficiency therefore impairs maturation of respiratory-chain Fe–S proteins and lipoic-acid synthase, reducing oxidative phosphorylation and lipoylation of PDH, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, and glycine-cleavage proteins. The resulting ATP deficit, lactic acidosis, and impaired glycine cleavage lead to high-energy-tissue injury, particularly leukoencephalopathy and cardiomyopathy. Biochemical and cellular evidence; some links from energy failure to tissue-selective clinical injury remain inferred (bargagna2023understandingthemolecular pages 1-2, saudino2021molecularbasisof pages 1-2, saudino2021molecularbasisof pages 11-12).
2023 mechanistic development The GLRX5–BOLA3 node also supplies [2Fe–2S] clusters to mitochondrial ribosomal subunits. BOLA3 depletion reduced mitochondrial translation to 60–70% of control, and five-day depletion made mitoribosomal ⁵⁵Fe incorporation virtually undetectable. BOLA3-mutant patient fibroblasts showed attenuated mitochondrial protein synthesis and defective assembled OXPHOS complexes, adding impaired mitoribosome assembly to the disease mechanism. HEK293T knockdown and patient-fibroblast evidence; published online 12 October 2023, DOI 10.1093/nar/gkad842 (zhong2023bola3andnfu1 pages 9-11, zhong2023bola3andnfu1 pages 1-2).
Diagnosis Suspect MMDS2 in early-onset regression, leukodystrophy, cardiomyopathy, lactic acidosis, and hyperglycinemia. Evaluate plasma/CSF/urine lactate, pyruvate and glycine; acylglycine/organic-acid profiles; brain MRI/MRS; ECG/echocardiography; ophthalmology; respiratory status; and respiratory-chain, PDH, and protein-lipoylation studies in fibroblasts or muscle where available. Confirm with a nuclear mitochondrial/leukodystrophy panel or WES/WGS identifying pathogenic biallelic BOLA3 variants, followed by segregation and, for uncertain variants, RNA or functional studies. This is an evidence-based diagnostic approach, not a formal disease-specific guideline. Human diagnostic and review evidence (stutterd2019severeleukoencephalopathywith pages 1-2, stutterd2019severeleukoencephalopathywith pages 2-4, lebigot2021areviewof pages 1-2).
Treatment and trials No established disease-modifying therapy was identified. Management is supportive: nutrition and feeding support; treatment of seizures, acidosis, respiratory insufficiency, and heart failure; and physical, occupational, and speech rehabilitation. “Mitochondrial” vitamin/cofactor cocktails have been used without clear evidence of benefit; one possible partial methylprednisolone response is anecdotal and cannot establish efficacy. The retrieved ClinicalTrials.gov search found no relevant MMDS2-specific interventional trial or NCT identifier. Case-based treatment evidence and direct trial-registry search (stutterd2019severeleukoencephalopathywith pages 6-7, lebigot2021areviewof pages 11-13).
Prognosis Classical disease is severe, progressive, and frequently fatal in infancy or early childhood. In one historical series, survival ranged from 3 months to 11 years, and recovery occurred in 0/10 evaluable prior cases. Genotype-dependent attenuation is documented: the Arg46*/Cys59Tyr patient recovered clinically over four years and was alive at age eight with improved MRI, while an Arg99Trp patient reportedly survived to age 12. Formal 5- or 10-year survival estimates are unavailable. Human natural-history and genotype–phenotype evidence (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 1-2, lebigot2021areviewof pages 11-13).
Evidence limitations Evidence is dominated by individual patients, small retrospective case series, one systematic review, patient fibroblasts, gene-silencing models, and recombinant-protein experiments. Frequencies use incomplete and varying denominators; ascertainment favors severe cases. No population epidemiology, validated quality-of-life instruments, standardized diagnostic criteria, controlled treatment trials, prognostic model, protective variants, established modifier genes, disease-specific epigenomic signature, single-cell/spatial study, or validated biomarker was identified. Cross-source evidence assessment (stutterd2019severeleukoencephalopathywith pages 6-7, stutterd2019severeleukoencephalopathywith pages 4-6, lebigot2021areviewof pages 11-13, zhong2023bola3andnfu1 pages 9-11).

Table: Concise disease-level summary of BOLA3-related MMDS2, integrating clinical frequencies, variants, mechanisms, diagnosis, management, prognosis, and major evidence gaps. Findings distinguish human observations from experimental or inferred mechanisms.

1. Disease information

Definition. MMDS2 is a nuclear-encoded mitochondrial Fe–S-cluster biogenesis disorder in which defective BOLA3 impairs several mitochondrial enzyme systems simultaneously. It belongs to the multiple mitochondrial dysfunction syndromes but is genetically distinct from NFU1-, IBA57-, ISCA2-, ISCA1-, and PMPCB-associated conditions. The Open Targets association is specific to BOLA3 and is supported by five genetic-evidence records (OpenTargets Search: multiple mitochondrial dysfunctions syndrome 2-BOLA3).

Identifiers and synonyms

  • MONDO: MONDO:0013675.
  • OMIM phenotype: 614299.
  • Gene: BOLA3; Ensembl ENSG00000163170; approved name bolA family member 3 (OpenTargets Search: multiple mitochondrial dysfunctions syndrome 2-BOLA3).
  • Synonyms: multiple mitochondrial dysfunctions syndrome type 2; MMDS2; multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia/hyperglycinaemia; BOLA3-related multiple mitochondrial dysfunction syndrome; BOLA3-associated mitochondrial leukoencephalopathy.
  • A disease-specific Orphanet, MeSH, ICD-10, or ICD-11 code was not verified in the retrieved evidence. In clinical coding, cases are therefore likely captured under broader mitochondrial-metabolism or leukodystrophy categories rather than a unique MMDS2 code.

The evidence is principally aggregated disease-level literature derived from individual published patients, not EHR-scale population data. The 2021 systematic review assembled 18 patients from 14 families, while individual reports provide more detailed longitudinal and biochemical observations (stutterd2019severeleukoencephalopathywith pages 1-2, lebigot2021areviewof pages 11-13).

2. Etiology, risk, and protective factors

Primary cause

The cause is biallelic, germline, loss-of-function or function-impairing variation in BOLA3, inherited in an autosomal-recessive pattern. Truncating variants can reduce functional protein, whereas missense variants can disrupt Fe–S coordination, GLRX5 recognition, or cluster transfer without necessarily unfolding BOLA3 (sen2021biochemicalimpactof pages 1-2, bargagna2023understandingthemolecular pages 1-2, sen2021biochemicalimpactof pages 7-8).

Risk factors

  • Genetic: having two pathogenic BOLA3 alleles is the defining risk. Consanguinity may increase the probability of homozygosity for rare alleles, but a disease-specific quantitative estimate is unavailable.
  • Family history: each full sibling of an affected child has the standard autosomal-recessive prior probabilities of 25% affected, 50% carrier, and 25% unaffected/non-carrier, assuming both parents are heterozygous and no unusual mechanism.
  • Environmental, lifestyle, infectious, sex, or occupational risks: none are established as primary causes. An attenuated patient's acute presentation at 18 months occurred without preceding illness or injury; the authors proposed increased developmental/myelination-related metabolic demand as a possible trigger, but this remains inference (stutterd2019severeleukoencephalopathywith pages 6-7).

Protective factors and gene–environment interaction

No validated protective allele, modifier gene, diet, drug, or environmental exposure has been demonstrated. Residual biochemical activity is a plausible genotype-dependent protective mechanism: p.Cys59Tyr retained partial NFU1 cluster assembly and occurred in the patient with clinical recovery. That association is biologically coherent but is based on one genotype and must not be treated as a validated prognostic rule (saudino2021molecularbasisof pages 1-2, saudino2021molecularbasisof pages 11-12). Fever, fasting, or illness could theoretically expose limited mitochondrial reserve, as in other mitochondrial diseases, but MMDS2-specific gene–environment evidence is absent.

3. Phenotypes

Neurological and developmental

Typical onset is neonatal or infantile. In one historical comparison, previous patients began from birth to eight months. Motor delay or regression occurred in 12/12, seizures in 5/10, and only 1/5 evaluable children acquired independent walking. Suggested terms include HP:0001263 global developmental delay, HP:0002376 developmental regression, HP:0001252 muscular hypotonia, HP:0001250 seizure, HP:0002063 rigidity/spasticity, HP:0001288 gait disturbance, and HP:0000238 hydrocephalus only if individually documented—the latter should not be assigned generically (stutterd2019severeleukoencephalopathywith pages 4-6).

The attenuated Arg46/Cys59Tyr case developed acute hemiparesis, ataxia, and loss of speech at 18 months, then recovered substantially over four years. At age eight, only subtle weakness and attention-deficit disorder remained. Suggested terms are HP:0001269 hemiparesis, HP:0001251 ataxia, HP:0002167 speech regression, and HP:0007018 attention deficit/hyperactivity disorder* where clinically confirmed (stutterd2019severeleukoencephalopathywith pages 2-4).

White-matter and imaging phenotype

MRI commonly shows bilateral periventricular and deep-white-matter T2 hyperintensity, dysmyelination or cavitating/cystic leukodystrophy, restricted diffusion, corpus-callosum lesions, and variable brainstem, cerebellar, basal-ganglia, or spinal-cord involvement. Cerebral/cerebellar atrophy and an MRS lactate peak with reduced N-acetylaspartate can occur. Suggested HPO terms include HP:0002415 leukodystrophy, HP:0012444 brain atrophy, HP:0002059 cerebral atrophy, and HP:0001272 cerebellar atrophy, assigning only findings actually present in an individual (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 2-4, lebigot2021areviewof pages 9-11).

Cardiopulmonary, ophthalmic, and systemic

Cardiomyopathy was reported in 7/9 evaluable historical patients and in approximately half of the broader 18-patient review cohort; both dilated and hypertrophic forms occur. Respiratory distress/failure, failure to thrive, feeding difficulty, optic atrophy or nystagmus, and occasional hepatic or renal failure have been reported. Suggested terms include HP:0001638 cardiomyopathy, HP:0001644 dilated cardiomyopathy, HP:0001639 hypertrophic cardiomyopathy, HP:0002093 respiratory insufficiency, HP:0001508 failure to thrive, HP:0002039 feeding difficulty, HP:0000648 optic atrophy, and HP:0000639 nystagmus (lebigot2021areviewof pages 7-9, lebigot2021areviewof pages 11-13).

Laboratory phenotype

Historical frequencies were elevated lactate 11/12, elevated glycine 8/8, reduced respiratory-chain complex I/II activity 10/12, and reduced pyruvate-dehydrogenase activity 6/7. Suggested HPO terms are HP:0002151 increased serum lactate, HP:0002148 hypoglycemia only if observed, HP:0001992 metabolic acidosis, and HP:0002154 hyperglycinemia. Normal lactate or respiratory-chain testing does not exclude MMDS2: the recovery case had elevated plasma/urine glycine but normal CSF glycine and lactate and normal conventional respiratory-chain assays, while fibroblast PDH was only 20% of control (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 2-4).

Quality of life

No MMDS2-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was identified. Severe disease causes profound dependence through motor/cognitive regression, feeding and respiratory support needs, seizures, and cardiac disease. This functional burden is clinically evident but has not been measured with validated instruments.

4. Genetic and molecular information

BOLA3 encodes a mitochondrial BolA-family Fe–S cluster delivery protein. Reported variants include c.123dupA (p.Glu42Argfs13), c.136C>T (p.Arg46), c.159dupT (p.Asp54), c.176G>A (p.Cys59Tyr), c.200T>A (p.Ile67Asn), c.220_222del (p.Glu74del), c.225_229del (p.Lys75Asnfs9), c.287A>G (p.His96Arg), and c.295C>T (p.Arg99Trp). Transcript versions differ among reports, so every knowledge-base import should retain the source transcript and remap to a current MANE transcript (lebigot2021areviewof pages 7-9, lebigot2021areviewof pages 9-11).

Variant-level consequences include:

  • p.Arg46* and other premature-termination/frameshift alleles: expected loss of function through truncation and/or nonsense-mediated decay; variant-specific RNA/protein quantification was not retrieved.
  • p.Cys59Tyr: Cys59 normally ligates the BOLA3–GLRX5 [2Fe–2S] cluster. The variant perturbs the cluster environment and creates an aberrant apo interaction but retains partial function: [4Fe–4S]-bound NFU1 reached 25% versus 65% with wild type (saudino2021molecularbasisof pages 1-2, saudino2021molecularbasisof pages 11-12).
  • p.Ile67Asn: leaves the global fold largely intact but essentially eliminates measurable GLRX5 binding and prevents normal heterocomplex assembly; BOLA3 homodimer cluster exchange remains possible (sen2021biochemicalimpactof pages 1-2, sen2021biochemicalimpactof pages 7-8).
  • p.His96Arg: preserves BOLA3–GLRX5 association but produces an aberrant Fe–S complex unable to assemble a [4Fe–4S] cluster on NFU1 (bargagna2023understandingthemolecular pages 1-2).
  • p.Arg99Trp: associated with longer survival and absence of reported cardiomyopathy in one patient, but direct functional proof and replication are limited (lebigot2021areviewof pages 11-13).

Current ClinVar ACMG classifications and exact gnomAD/TOPMed allele frequencies were not retrieved and should be queried contemporaneously before variant curation. All disease-causing alleles are germline; no somatic mechanism is implicated. No validated modifier gene, disease-specific epigenetic signature, recurrent structural chromosome abnormality, or anticipation has been demonstrated.

5. Environmental information

MMDS2 is not caused by toxins, radiation, pollution, lifestyle, or infection. No reproducible relationship with smoking, alcohol, exercise, diet, occupational exposure, or pathogen has been reported. Environmental stress may modulate the timing of decompensation in a genetically affected child, but direct MMDS2 data are insufficient. Consequently, CTD-style chemical–disease associations should not be interpreted as causal without BOLA3-specific human evidence.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic pathogenic BOLA3 variation leads to absent, unstable, or functionally defective mitochondrial BOLA3.
  2. Defective BOLA3 leads to impaired formation or function of the GLRX5–BOLA3 [2Fe–2S] carrier complex.
  3. Impaired carrier function leads to defective transfer and reductive coupling of Fe–S clusters on NFU1 and impaired maturation of downstream [4Fe–4S] proteins (demonstrated biochemically).
  4. Defective Fe–S delivery leads to reduced activities/assembly of respiratory-chain complexes, aconitase, lipoic-acid synthase, ETF–ubiquinone oxidoreductase, and other Fe–S clients.
  5. Reduced lipoic-acid synthase function leads to deficient lipoylation of PDH, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, and glycine-cleavage-system components.
  6. These enzyme deficiencies lead to reduced oxidative ATP production, pyruvate/lactate accumulation, impaired glycine cleavage and hyperglycinemia, and broad metabolic inflexibility.
  7. In parallel, defective GLRX5–BOLA3 Fe–S delivery leads to unstable Fe–S-containing mitoribosomes and attenuated mitochondrial translation, further reducing OXPHOS assembly; this branch was newly demonstrated in 2023.
  8. Energy failure and metabolite imbalance lead to dysfunction and injury in high-demand oligodendroglial/neural, cardiac-muscle, skeletal-muscle, and respiratory tissues; the exact basis of selective white-matter vulnerability is partly inferred.
  9. Tissue dysfunction results in leukodystrophy, developmental regression, hypotonia/weakness, seizures, cardiomyopathy, respiratory failure, and—at the severe end—multiorgan failure and early death.

The experimentally supported GLRX5–BOLA3–NFU1 pathway transfers two [2Fe–2S] clusters to NFU1, where reductive coupling forms a [4Fe–4S] cluster. Cys59 and His96 in BOLA3 participate directly in heterocomplex cluster coordination (bargagna2023understandingthemolecular pages 1-2, saudino2021molecularbasisof pages 1-2, saudino2021molecularbasisof pages 11-12).

Latest major development (2023). Zhong et al., published online 12 October 2023, found that the GLRX5–BOLA3 node supplies Fe–S clusters to both mitoribosomal subunits. BOLA3/related-factor silencing reduced mitochondrial translation to 60–70% of control; after five days, mitoribosomal ⁵⁵Fe incorporation was virtually undetectable with BOLA3 depletion. BOLA3-mutant patient fibroblasts also had attenuated mitochondrial protein synthesis and defective assembled OXPHOS complexes (DOI: https://doi.org/10.1093/nar/gkad842) (zhong2023bola3andnfu1 pages 9-11, zhong2023bola3andnfu1 pages 1-2).

A concise exact quotation from that abstract is: “the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node.” The authors further report that patient fibroblasts “display previously unrecognized attenuation of mitochondrial protein synthesis.” These results expand MMDS2 from a conventional Fe–S-client/lipoylation disorder to a combined Fe–S delivery and mitochondrial-translation disorder (zhong2023bola3andnfu1 pages 1-2).

Suggested ontology annotations include GO:0016226 iron–sulfur cluster assembly, GO:0051539 4 iron, 4 sulfur cluster binding, GO:0006120 mitochondrial electron transport, GO:0006412 translation, GO:0032543 mitochondrial translation, GO:0006096 glycolytic process, GO:0009060 aerobic respiration, and GO:0044281 small-molecule metabolic process. Relevant compartments are GO:0005739 mitochondrion, GO:0005759 mitochondrial matrix, GO:0005761 mitochondrial ribosome, and GO:0005743 mitochondrial inner membrane.

Cell-type assignments are inferential rather than single-cell validated: CL:0000128 oligodendrocyte, CL:0000540 neuron, CL:0000746 cardiac muscle cell, CL:0000187 muscle cell, and CL:0000115 endothelial cell. No MMDS2 single-cell, spatial-transcriptomic, lipidomic, or integrated patient multi-omics study was identified.

7. Anatomical structures affected

The central nervous system is the dominant organ system, especially cerebral periventricular/deep white matter, corpus callosum, and sometimes brainstem, cerebellum and spinal cord. Suggested anatomy terms include UBERON:0000955 brain, UBERON:0002316 white matter, UBERON:0002336 corpus callosum, UBERON:0002240 spinal cord, UBERON:0002037 cerebellum, and UBERON:0002298 brainstem. Cardiac, skeletal-muscle, respiratory, hepatic, renal, and ophthalmic involvement is variable; suggested terms include UBERON:0000948 heart, UBERON:0001134 skeletal muscle tissue, UBERON:0002048 lung, UBERON:0002107 liver, UBERON:0002113 kidney, and UBERON:0000966 retina (lebigot2021areviewof pages 7-9, lebigot2021areviewof pages 9-11).

At the subcellular level, the initiating lesion is in the mitochondrial matrix Fe–S assembly/delivery machinery, with downstream effects on the inner-membrane respiratory chain and mitochondrial ribosome. MRI abnormalities are usually bilateral; no consistent left/right lateralization is characteristic.

8. Temporal development

Classical disease begins congenitally or during the first year, often with developmental delay followed by rapid regression and progressive multisystem deterioration. Prior reported onset ranged from birth to eight months in one comparison; severe cases died between three months and early childhood. Later onset does occur: the recovery case presented at 18 months, while another reviewed patient had onset around 22 months and survived to 11 years (stutterd2019severeleukoencephalopathywith pages 4-6, lebigot2021areviewof pages 7-9).

No validated stages exist. A practical descriptive course is: (1) presymptomatic/early developmental vulnerability, (2) metabolic-neurological presentation, (3) progressive leukodystrophy and multisystem involvement, and (4) respiratory/cardiac/multiorgan end stage. This is not a formal staging system. Remission is generally absent, but mutation-dependent stabilization or recovery is possible. The developmental period of rapid myelination may represent a critical vulnerability window; this remains mechanistic inference rather than proven epidemiology (stutterd2019severeleukoencephalopathywith pages 6-7).

9. Inheritance and population

Inheritance is autosomal recessive. A 2021 review found 18 affected individuals from 14 families worldwide, emphasizing extreme rarity rather than defining prevalence. No reliable incidence per 100,000, prevalence, carrier frequency, sex ratio, ethnic enrichment, or geographic distribution is available (lebigot2021areviewof pages 11-13).

Penetrance for clearly damaging biallelic variants appears high among reported families, but it has not been formally estimated. Expressivity is variable, ranging from fatal infantile disease to survival into later childhood with recovery or residual deficits. No anticipation is expected. Germline mosaicism has not been established, although standard counseling should acknowledge a small residual recurrence risk if an apparently de novo allele is encountered. Founder effects remain possible for recurrent alleles but were not established by the retrieved MMDS2 evidence.

10. Diagnostics

Recommended approach

  1. Clinical suspicion: infantile regression or weakness plus leukodystrophy, unexplained cardiomyopathy, respiratory disease, lactic acidosis, or hyperglycinemia.
  2. Biochemical testing: plasma lactate, pyruvate, glycine, glucose, blood gas, ammonia, liver/renal indices; plasma amino acids; urine organic acids/acylglycines; CSF lactate and glycine where clinically justified. Normal lactate does not exclude disease.
  3. Imaging: brain MRI with diffusion and, where available, proton MRS; consider spinal imaging if signs indicate.
  4. Systems assessment: ECG/echocardiography, respiratory assessment, ophthalmology, feeding/nutrition, hearing, and developmental evaluation.
  5. Genetic confirmation: a nuclear mitochondrial-disease, Fe–S-biogenesis, metabolic-encephalopathy, or leukodystrophy panel that includes BOLA3, or trio WES/WGS. Confirm phase and segregation by parental testing.
  6. Functional resolution: for VUSs, consider RNA analysis, BOLA3 protein/interaction studies, respiratory-chain enzymology, PDH activity, immunoblotting of OXPHOS subunits, and protein lipoylation in fibroblasts or muscle through a specialist laboratory.

Trio WGS identified the Arg46*/Cys59Tyr genotype in the recovery case, illustrating the value of genome-scale testing when enzyme assays are nondiagnostic (stutterd2019severeleukoencephalopathywith pages 1-2, stutterd2019severeleukoencephalopathywith pages 2-4). CMA, karyotyping, FISH, repeat-expansion testing, and isolated mtDNA sequencing do not directly test the usual MMDS2 mechanism, although mtDNA analysis may be appropriate in the broader differential.

Differential diagnosis

Important alternatives are MMDS1/NFU1, MMDS3/IBA57, ISCA2- and ISCA1-related MMDS, PMPCB disease, primary pyruvate-dehydrogenase deficiency, nonketotic hyperglycinemia caused by GLDC/AMT/GCSH, other mitochondrial respiratory-chain disorders, and genetic cavitating leukodystrophies. BOLA3 sequencing and segregation provide definitive etiologic discrimination; biochemical overlap is substantial (lebigot2021areviewof pages 1-2).

There are no validated disease-specific diagnostic criteria, newborn-screening program, or population-screening assay. Cascade testing of relatives is appropriate after a familial genotype is established.

11. Outcome and prognosis

Classical MMDS2 has high infantile/early-childhood mortality, but formal survival curves do not exist. In one historical compilation, survival ranged from 3 months to 11 years, and 0/10 evaluable previous patients had documented recovery. The Arg46*/Cys59Tyr patient was alive at eight years after apparent clinical recovery and substantial MRI improvement; an Arg99Trp patient reportedly survived to 12 years (stutterd2019severeleukoencephalopathywith pages 4-6, stutterd2019severeleukoencephalopathywith pages 1-2, lebigot2021areviewof pages 11-13).

Poor-prognosis features plausibly include neonatal onset, profound lactic acidosis, severe cardiomyopathy, respiratory failure, multiorgan disease, and genotypes abolishing BOLA3 function. Residual-function missense alleles may predict a milder course, but the number of observations is too small for clinical prediction. No validated prognostic biomarker, five- or ten-year survival statistic, life-expectancy estimate, or quality-of-life dataset exists.

12. Treatment and real-world implementation

No approved or proven disease-modifying treatment exists. Published practice is supportive and multidisciplinary:

  • seizure treatment (NCIT:C15313 anticonvulsant therapy);
  • ventilation/oxygen and respiratory support (NCIT:C71576 supportive care, broad mapping);
  • standard cardiomyopathy/heart-failure management;
  • correction of dehydration and severe acid–base disturbances;
  • enteral nutritional support when needed;
  • physical, occupational, speech, feeding, and developmental therapies (NCIT:C15302 rehabilitation therapy, broad mapping);
  • avoidance of prolonged fasting and prompt treatment of intercurrent illness as general mitochondrial-disease precautions, although MMDS2-specific efficacy has not been tested.

“Mitochondrial cocktails” of vitamins/cofactors have been administered without clear evidence of benefit. A possible partial response to methylprednisolone was anecdotal and does not justify routine immunosuppression (stutterd2019severeleukoencephalopathywith pages 6-7, lebigot2021areviewof pages 11-13). A direct ClinicalTrials.gov search found no relevant MMDS2-specific interventional study or NCT identifier.

Gene replacement, mRNA delivery, or editing is conceptually attractive because MMDS2 is monogenic, but no BOLA3-directed clinical therapy was identified. The 2023 mitoribosome findings and variant-resolved Fe–S-transfer assays provide potential pharmacodynamic platforms, not current treatments (zhong2023bola3andnfu1 pages 9-11, zhong2023bola3andnfu1 pages 1-2).

13. Prevention

There is no lifestyle or vaccine-based primary prevention. The principal prevention strategy is reproductive genetics:

  • molecular confirmation and carrier testing in parents;
  • cascade testing of adult relatives;
  • preimplantation genetic testing for monogenic disease;
  • prenatal diagnosis by chorionic-villus sampling or amniocentesis for known familial variants;
  • donor gametes or other reproductive options after nondirective counseling.

Secondary prevention consists of early molecular diagnosis and anticipatory cardiac, respiratory, nutritional, neurological, and ophthalmic surveillance. Tertiary prevention aims to reduce aspiration, malnutrition, contractures, seizure injury, respiratory decompensation, and cardiac complications. There is no evidence-based prophylactic medication.

14. Other species and natural disease

BOLA/GLRX Fe–S biology is evolutionarily conserved, but no well-characterized, naturally occurring veterinary equivalent of human BOLA3-MMDS2 was identified. There is no zoonotic potential or cross-species transmission because the disorder is inherited, not infectious. Before database import, ortholog identifiers should be obtained directly from current NCBI Gene/Alliance records rather than inferred from human nomenclature.

15. Model organisms and experimental systems

The strongest disease-relevant systems are:

  • Patient fibroblasts: reproduce PDH/lipoylation and OXPHOS defects and, in 2023, reduced mitochondrial translation and mitoribosome abnormalities (human ex-vivo evidence) (stutterd2019severeleukoencephalopathywith pages 2-4, zhong2023bola3andnfu1 pages 9-11).
  • Recombinant BOLA3–GLRX5–NFU1 systems: define cluster ligands, partner recognition, transfer, and mutation-specific residual activity. These provide high mechanistic precision but cannot model organ-specific disease (in-vitro biochemical evidence) (sen2021biochemicalimpactof pages 1-2, bargagna2023understandingthemolecular pages 1-2, saudino2021molecularbasisof pages 11-12).
  • HEK293T knockdown: BOLA3 depletion exceeding 95% reduced mitochondrial translation and Fe incorporation into mitoribosomes; useful for pathway dissection but not developmental phenotyping (cellular functional-genomics evidence) (zhong2023bola3andnfu1 pages 9-11).
  • Pulmonary-artery endothelial cells and mouse pulmonary-hypertension models: BOLA3 loss perturbed Fe–S integrity, lipoate-dependent enzymes, respiration, glycine homeostasis, proliferation and vascular behavior. These models illuminate a BOLA3-dependent vascular mechanism but are not complete germline MMDS2 models.
  • Adipocyte knockdown models: demonstrate requirements for mitochondrial homeostasis and oxidative metabolism but have uncertain direct relevance to the human neurological phenotype.

No validated germline BOLA3-null/knock-in mouse, zebrafish, Drosophila, C. elegans, organoid, or iPSC model that comprehensively recapitulates human MMDS2 was established in the retrieved literature. Complete loss may also create embryonic or perinatal viability limitations; that possibility requires empirical confirmation.

Evidence assessment and key references

The most authoritative quantitative clinical synthesis available in the retrieved literature is the 2021 systematic review (DOI: https://doi.org/10.3390/biomedicines9080989), but its denominators vary because records were incomplete. The landmark genetic/biochemical report is Cameron et al., 2011, PMID: 21944046, DOI: https://doi.org/10.1016/j.ajhg.2011.08.011. The recovery case is Stutterd et al., published January 2019, DOI: https://doi.org/10.1007/8904_2018_100 (OpenTargets Search: multiple mitochondrial dysfunctions syndrome 2-BOLA3, stutterd2019severeleukoencephalopathywith pages 1-2, lebigot2021areviewof pages 11-13).

Variant-mechanism studies include Cys59Tyr (published May 2021; DOI: https://doi.org/10.3390/ijms22094848), Ile67Asn (published March 2021; DOI: https://doi.org/10.1093/mtomcs/mfab010), and His96Arg (published July 2023; DOI: https://doi.org/10.3390/ijms241411734) (sen2021biochemicalimpactof pages 1-2, bargagna2023understandingthemolecular pages 1-2, saudino2021molecularbasisof pages 1-2). The latest major disease-specific mechanistic advance within the requested 2023–2024 window is Zhong et al., 2023 (DOI: https://doi.org/10.1093/nar/gkad842); no comparably direct 2024 human MMDS2 study was identified (zhong2023bola3andnfu1 pages 1-2).

Important limitations are the minute, ascertainment-biased cohort; inconsistent transcript notation; missing population allele-frequency and contemporary ClinVar data; variable laboratory methods; no controlled therapy study; and no disease-specific epidemiology, patient-reported outcome, single-cell, spatial, or longitudinal registry dataset. Accordingly, numerical phenotype frequencies describe published cases—not population risks—and genotype–prognosis conclusions should remain provisional.

References

  1. (OpenTargets Search: multiple mitochondrial dysfunctions syndrome 2-BOLA3): Open Targets Query (multiple mitochondrial dysfunctions syndrome 2-BOLA3, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (stutterd2019severeleukoencephalopathywith pages 1-2): C. Stutterd, N. Lake, H. Peters, H. Peters, P. Lockhart, R. Taft, M. Knaap, A. Vanderver, A. Vanderver, D. Thorburn, Cas Simons, R. Leventer, and R. Leventer. Severe leukoencephalopathy with clinical recovery caused by recessive bola3 mutations. JIMD reports, 43:63-70, Jan 2019. URL: https://doi.org/10.1007/8904_2018_100, doi:10.1007/8904_2018_100. This article has 15 citations and is from a peer-reviewed journal.

  3. (lebigot2021areviewof pages 7-9): Elise Lebigot, Manuel Schiff, and Marie-Pierre Golinelli-Cohen. A review of multiple mitochondrial dysfunction syndromes, syndromes associated with defective fe-s protein maturation. Aug 2021. URL: https://doi.org/10.3390/biomedicines9080989, doi:10.3390/biomedicines9080989. This article has 35 citations.

  4. (stutterd2019severeleukoencephalopathywith pages 2-4): C. Stutterd, N. Lake, H. Peters, H. Peters, P. Lockhart, R. Taft, M. Knaap, A. Vanderver, A. Vanderver, D. Thorburn, Cas Simons, R. Leventer, and R. Leventer. Severe leukoencephalopathy with clinical recovery caused by recessive bola3 mutations. JIMD reports, 43:63-70, Jan 2019. URL: https://doi.org/10.1007/8904_2018_100, doi:10.1007/8904_2018_100. This article has 15 citations and is from a peer-reviewed journal.

  5. (lebigot2021areviewof pages 11-13): Elise Lebigot, Manuel Schiff, and Marie-Pierre Golinelli-Cohen. A review of multiple mitochondrial dysfunction syndromes, syndromes associated with defective fe-s protein maturation. Aug 2021. URL: https://doi.org/10.3390/biomedicines9080989, doi:10.3390/biomedicines9080989. This article has 35 citations.

  6. (stutterd2019severeleukoencephalopathywith pages 4-6): C. Stutterd, N. Lake, H. Peters, H. Peters, P. Lockhart, R. Taft, M. Knaap, A. Vanderver, A. Vanderver, D. Thorburn, Cas Simons, R. Leventer, and R. Leventer. Severe leukoencephalopathy with clinical recovery caused by recessive bola3 mutations. JIMD reports, 43:63-70, Jan 2019. URL: https://doi.org/10.1007/8904_2018_100, doi:10.1007/8904_2018_100. This article has 15 citations and is from a peer-reviewed journal.

  7. (lebigot2021areviewof pages 9-11): Elise Lebigot, Manuel Schiff, and Marie-Pierre Golinelli-Cohen. A review of multiple mitochondrial dysfunction syndromes, syndromes associated with defective fe-s protein maturation. Aug 2021. URL: https://doi.org/10.3390/biomedicines9080989, doi:10.3390/biomedicines9080989. This article has 35 citations.

  8. (sen2021biochemicalimpactof pages 1-2): Sambuddha Sen, Zechariah Thompson, Christine Wachnowsky, Sean R. Cleary, Sophie R. Harvey, and J. Cowan. Biochemical impact of a disease-causing ile67asn substitution on bola3 protein. Metallomics : integrated biometal science, Mar 2021. URL: https://doi.org/10.1093/mtomcs/mfab010, doi:10.1093/mtomcs/mfab010. This article has 2 citations.

  9. (bargagna2023understandingthemolecular pages 1-2): Beatrice Bargagna, Lucia Banci, and Francesca Camponeschi. Understanding the molecular basis of the multiple mitochondrial dysfunctions syndrome 2: the disease-causing his96arg mutation of bola3. Jul 2023. URL: https://doi.org/10.3390/ijms241411734, doi:10.3390/ijms241411734. This article has 1 citations.

  10. (saudino2021molecularbasisof pages 1-2): Giovanni Saudino, Dafne Suraci, Veronica Nasta, Simone Ciofi-Baffoni, and Lucia Banci. Molecular basis of multiple mitochondrial dysfunctions syndrome 2 caused by cys59tyr bola3 mutation. May 2021. URL: https://doi.org/10.3390/ijms22094848, doi:10.3390/ijms22094848. This article has 10 citations.

  11. (saudino2021molecularbasisof pages 11-12): Giovanni Saudino, Dafne Suraci, Veronica Nasta, Simone Ciofi-Baffoni, and Lucia Banci. Molecular basis of multiple mitochondrial dysfunctions syndrome 2 caused by cys59tyr bola3 mutation. May 2021. URL: https://doi.org/10.3390/ijms22094848, doi:10.3390/ijms22094848. This article has 10 citations.

  12. (sen2021biochemicalimpactof pages 7-8): Sambuddha Sen, Zechariah Thompson, Christine Wachnowsky, Sean R. Cleary, Sophie R. Harvey, and J. Cowan. Biochemical impact of a disease-causing ile67asn substitution on bola3 protein. Metallomics : integrated biometal science, Mar 2021. URL: https://doi.org/10.1093/mtomcs/mfab010, doi:10.1093/mtomcs/mfab010. This article has 2 citations.

  13. (zhong2023bola3andnfu1 pages 9-11): Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, and Antoni Barrientos. Bola3 and nfu1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Oct 2023. URL: https://doi.org/10.1093/nar/gkad842, doi:10.1093/nar/gkad842. This article has 39 citations and is from a highest quality peer-reviewed journal.

  14. (zhong2023bola3andnfu1 pages 1-2): Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, and Antoni Barrientos. Bola3 and nfu1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Oct 2023. URL: https://doi.org/10.1093/nar/gkad842, doi:10.1093/nar/gkad842. This article has 39 citations and is from a highest quality peer-reviewed journal.

  15. (lebigot2021areviewof pages 1-2): Elise Lebigot, Manuel Schiff, and Marie-Pierre Golinelli-Cohen. A review of multiple mitochondrial dysfunction syndromes, syndromes associated with defective fe-s protein maturation. Aug 2021. URL: https://doi.org/10.3390/biomedicines9080989, doi:10.3390/biomedicines9080989. This article has 35 citations.

  16. (stutterd2019severeleukoencephalopathywith pages 6-7): C. Stutterd, N. Lake, H. Peters, H. Peters, P. Lockhart, R. Taft, M. Knaap, A. Vanderver, A. Vanderver, D. Thorburn, Cas Simons, R. Leventer, and R. Leventer. Severe leukoencephalopathy with clinical recovery caused by recessive bola3 mutations. JIMD reports, 43:63-70, Jan 2019. URL: https://doi.org/10.1007/8904_2018_100, doi:10.1007/8904_2018_100. This article has 15 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 60
Resolved 60
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

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:

  • MONDO:0013675 (4 mentions) - the report calls it "if available"; MONDO calls it multiple mitochondrial dysfunctions syndrome 2