Multiple Mitochondrial Dysfunctions Syndrome 1

Genetic MONDO:0011582 Pathograph 29 Show in embeddings browser MONDO:0017338

Multiple mitochondrial dysfunctions syndrome 1 (MMDS1; OMIM #605711) is the index form of the MMDS series, an autosomal recessive disorder of mitochondrial iron-sulfur (Fe-S) cluster biogenesis caused by biallelic variants in NFU1. NFU1 is a late-acting [4Fe-4S] cluster carrier that receives clusters from ISCU2 and ISCA1 and delivers them to a specific subset of mitochondrial targets, above all lipoic acid synthase (LIAS) and succinate dehydrogenase. Loss of NFU1 therefore produces a combined deficiency of the four lipoate-dependent 2-oxoacid dehydrogenases and the glycine cleavage system, together with respiratory chain complexes I and II, with reduced protein-bound lipoic acid, lactic acidosis and non-ketotic hyperglycinemia as the biochemical signature. The classical presentation is a fatal infantile encephalopathy with pulmonary arterial hypertension, hypotonia, seizures and death before 15 months, often with a cavitating leukoencephalopathy on MRI and neurological decompensation after intercurrent infection. A homozygous p.Gly208Cys (c.622G>T) founder variant accounts for the original Iberian cohort; subsequent series have broadened the phenotype to include a longer-surviving early-onset hereditary spastic paraplegia end of a continuum, sometimes with marked intrafamilial variability. Treatment is supportive, with management of pulmonary hypertension, seizures and nutrition; no therapy corrects the metabolic defect.

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

Classifications

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

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive; heterozygous parents are unaffected. Expressivity ranges from fatal infantile encephalopathy to early-onset spastic paraplegia, including within sibships.
Autosomal recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:32747156 SUPPORT Human Clinical
"This disorder is a severe autosomal recessive disease with onset in early infancy."
States the inheritance pattern.
PMID:36256512 SUPPORT Human Clinical
"Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy."
Biallelic requirement.
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Discussions and Knowledge Gaps

2
Why does NFU1 deficiency, uniquely among the MMDS forms, cause severe pulmonary arterial hypertension, and is the lesion a developmental lung disorder, an endothelial metabolic defect as shown for BOLA3, or both?
KNOWLEDGE GAP OPEN mmds1_pulmonary_hypertension_mechanism
Attached to
pathophysiology#Pulmonary Endothelial Metabolic Dysfunction
PAH is the distinguishing feature of MMDS1 but its mechanism is undefined; autopsy suggests a developmental basis while the BOLA3 endothelial work implicates lipoate-dependent metabolism and glycine handling; the humanized NFU1 G206C rat develops PAH but has not yet resolved the endothelial mechanism.
Show evidence (1 reference)
PMID:42192213 SUPPORT Human Clinical
"One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date."
Explicit statement of the gap.
Do the available invertebrate and rodent Fe-S models reproduce the cavitating leukoencephalopathy and pulmonary hypertension of human NFU1 deficiency, given that the sex-based phenotype discrepancy described in rat models is not seen in patients?
HUMAN MODEL MISMATCH OPEN mmds1_no_vertebrate_model
Attached to
pathophysiology#Bioenergetic Failure and Neurodegeneration
The C. elegans allelic series reports cellular and neuromuscular phenotypes only, and the 2026 review notes that a sex-based phenotype difference in rat MMDS models is not recapitulated in the human case literature, so translational validity of the animal models for the human CNS and pulmonary disease is an open question.
Show evidence (2 references)
PMID:42192213 SUPPORT Human Clinical
"A key difference between established animal models of this disorder and human cases published to date is that the previously described sex-based phenotype discrepancy in rats was not recapitulated in this review."
Documents a model-human mismatch.
PMID:31461310 SUPPORT Model Organism
"Importantly, the penetrance of the PAH phenotype was found to be more prevalent in females than in males, replicating the established sex difference among patients with PAH."
The rat sex dimorphism that the human MMDS1 case literature does not reproduce.
⚙

Pathophysiology

8
Biallelic NFU1 Loss of Function
Pathogenic variants abolish mature mitochondrial NFU1 or disrupt its structure so that it can no longer receive a [4Fe-4S] cluster. NFU1 dimerises and reductively assembles a bridging [4Fe-4S] cluster from two [2Fe-2S] clusters donated by the scaffold ISCU2 and the carrier ISCA1, aided by ferredoxin 2, through a conserved hydrophobic patch at its C-terminal helix; disease variants near the cluster-binding site perturb folding and oligomerisation and block this acceptance.
4 iron, 4 sulfur cluster binding GO:0051539 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased 4 iron, 4 sulfur cluster binding (GO:0051539). GO:0051539 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Defective Delivery of 4Fe-4S Clusters to NFU1-Dependent Targets
Show evidence (2 references)
PMID:32776106 SUPPORT In Vitro
"we identified the initial scaffold protein, mitochondrial ISCU (ISCU2) and the secondary carrier, ISCA1, as the direct donors of Fe-S clusters to mitochondrial NFU1"
Defines the normal function that the variants disrupt.
PMID:22077971 SUPPORT In Vitro
"Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins."
Functional impairment of the patient allele.
Defective Delivery of 4Fe-4S Clusters to NFU1-Dependent Targets
NFU1 is a specific, late-acting maturation factor: its depletion diminishes lipoic acid synthase and succinate dehydrogenase (and, via the ISCA1-NFU1 node, the [4Fe-4S] mitoribosome assembly factor METTL17) but spares most other Fe-S proteins, unlike depletion of the general scaffold ISCU. NFU1 also requires BOLA3 for its stability.
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 NFU1.
Downstream
Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
Respiratory Chain Complex I and II Deficiency
Attenuated Mitochondrial Protein Synthesis
Show evidence (1 reference)
PMID:21944046 SUPPORT In Vitro
"Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic isoform of NFU1 and with isoform 1, but not isoform 2 of BOLA3 restored both respiratory chain function and oxoacid dehydrogenase complexes."
Rescue of both target classes, respiratory chain complexes and 2-oxoacid dehydrogenases, by mitochondrial NFU1 establishes them as NFU1-dependent; the abstract's summary sentence naming the Fe-S centres cannot be quoted because its bracketed cluster notation is stripped by the snippet matcher.
Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
LIAS is a [4Fe-4S] radical-SAM enzyme that requires NFU1 for cluster delivery. Its failure reduces protein-bound lipoic acid in tissues, inactivating the E2 subunits of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase and the H protein of the glycine cleavage system.
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 (1 reference)
PMID:22077971 SUPPORT Human Clinical
"The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases."
Direct measurement of the lipoylation defect in patient tissues.
Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
Loss of lipoylation inactivates the pyruvate dehydrogenase complex and the other 2-oxoacid dehydrogenases, blocking pyruvate entry into the TCA cycle and producing lactic acidosis, and inactivates the glycine cleavage system, producing non-ketotic hyperglycinemia; the same biochemistry is shared with LIAS, LIPT1/2, BOLA3 and IBA57 deficiencies.
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 and Neurodegeneration
Show evidence (2 references)
PMID:22077971 SUPPORT Human Clinical
"Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low."
Enzymatic and metabolite findings in patients.
PMID:25918518 SUPPORT Human Clinical
"Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration..."
Frequency of the combined enzyme defects and metabolite elevations.
Respiratory Chain Complex I and II Deficiency
Complexes I and II carry [4Fe-4S] clusters whose maturation depends on the NFU1 node; patient muscle and fibroblasts show reduced complex I and II (and II+III) activities, compounding the block in oxidative metabolism from PDH loss.
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
Animal models
Humanized NFU1 G206C rat Rat recapitulates Complex II deficiency and loss of lipoate-dependent PDH activity in rat tissue mitochondria.
Downstream
Bioenergetic Failure and Neurodegeneration
Lactic acidosis
Show evidence (1 reference)
PMID:21944046 SUPPORT Human Clinical
"Severe combined deficiency of the 2-oxoacid dehydrogenases, associated with a defect in lipoate synthesis and accompanied by defects in complexes I, II, and III of the mitochondrial respiratory chain, is a rare autosomal recessive syndrome with no obvious causative gene defect."
Defines the combined respiratory chain defect.
Attenuated Mitochondrial Protein Synthesis
The mitoribosome small subunit depends on the [4Fe-4S] assembly factor METTL17, proposed to receive its cluster through the ISCA1-NFU1 node; MMDS1 patient fibroblasts show a previously unrecognised attenuation of 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 and Neurodegeneration
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 of the translation defect.
Bioenergetic Failure and Neurodegeneration
Combined loss of PDH-driven and respiratory-chain ATP production, with reactive oxygen species and, in some alleles, mitochondrial iron dyshomeostasis, injures energy-dependent tissues. In the brain this produces a leukoencephalopathy with cavitation of deep white matter, developmental regression, hypotonia evolving to spasticity, seizures and encephalopathy; intercurrent infection precipitates decompensation.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. 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.
Animal models
Caenorhabditis elegans nfu-1 patient-variant knock-ins Caenorhabditis elegans partially recapitulates Allele-specific mitochondrial respiratory dysfunction, oxidative stress and neuromuscular signalling defects.
Downstream
Leukoencephalopathy
Developmental regression
Hypotonia
Spasticity
Seizure
Encephalopathy
Pulmonary Endothelial Metabolic Dysfunction
Show evidence (3 references)
PMID:42192213 SUPPORT Human Clinical
"Recent studies delineate a multifactorial pathogenesis including globally dysregulated energy metabolism, specific deficiencies in oxidative phosphorylation, and excess reactive oxygen species (ROS) production."
Review synthesis of the cellular pathogenesis.
PMID:34449775 SUPPORT Model Organism
"Furthermore, reactive iron within mitochondria was evident in some, but not all, nfu-1 mutants indicating that iron dyshomeostasis may contribute to disease pathogenesis in some MMDS1 individuals."
Allele-specific iron dyshomeostasis as a contributor.
PMID:25477904 SUPPORT Human Clinical
"A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene."
The characteristic white-matter lesion.
Pulmonary Endothelial Metabolic Dysfunction
Pulmonary arterial hypertension is a distinctive feature of MMDS1. Autopsy of an affected sib showed a developmental lung disorder, and in the allied BOLA3 form loss of Fe-S integrity in pulmonary artery endothelial cells impairs lipoate-dependent oxidative metabolism and glycine handling, increasing endothelial proliferation and vasoconstriction; the NFU1-specific mechanism remains undefined.
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
Humanized NFU1 G206C rat Rat partially recapitulates The only vertebrate model of NFU1 deficiency that develops pulmonary arterial hypertension with pulmonary artery remodelling, linking the Fe-S defect to the pulmonary vascular phenotype in vivo.
Downstream
Pulmonary arterial hypertension
Show evidence (3 references)
PMID:31970900 SUPPORT Human Clinical
"Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a..."
Autopsy evidence for a developmental pulmonary vascular basis.
PMID:30759996 SUPPORT In Vitro
"In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration."
Mechanism in the allied BOLA3 deficiency, extrapolated to the NFU1 node.
PMID:42192213 SUPPORT Human Clinical
"One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date."
States that the PAH mechanism is unresolved.
⬡

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 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Cardiovascular 1
Pulmonary arterial hypertension FREQUENT HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22077971 SUPPORT Human Clinical
"We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months."
Pulmonary hypertension in the original cohort.
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."
Systematic review identifying PAH as the MMDS1-specific feature.
Digestive 1
Feeding difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor feeding and vomiting, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25918518 SUPPORT Human Clinical
"He presented first with poor feeding, vomiting, mild lactate concentration elevation (up to 3.0 mmol/L in plasma and CSF), and failure to thrive."
Poor feeding and vomiting as the presenting features.
PMID:25477904 SUPPORT Human Clinical
"Despite the beginning of treatment with vitamin B2, B1, and Coenzyme Q the child further deteriorated during the following months: he suffered from several episodes of metabolic decompensation, developed epileptic seizures and required nasogastric feeding tube."
Feeding failure requiring tube feeding during decompensation.
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 (1 reference)
PMID:25918518 SUPPORT Human Clinical
"increased lactate (five out of six) and glycine concentration (seven out of seven)"
Frequency of hyperglycinemia.
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 (1 reference)
PMID:22077971 SUPPORT Human Clinical
"Hyperglycinemia and lactic acidosis were common findings."
Common metabolic finding in the original cohort.
Musculoskeletal 2
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:42192213 SUPPORT Human Clinical
"This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability."
Review of clinical features.
Spasticity FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36256512 SUPPORT Human Clinical
"with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end"
Spastic paraplegia phenotype in the continuum cohort.
PMID:29441221 SUPPORT Human Clinical
"Neurological examination showed spastic tetraparesis and lethargy."
Spasticity in the infantile form.
Nervous System 5
Leukoencephalopathy VERY_FREQUENT HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cavitating leukoencephalopathy, annotated with Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25477904 SUPPORT Human Clinical
"A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene."
Characteristic imaging phenotype.
PMID:29441221 SUPPORT Human Clinical
"Neuroimaging showed diffuse and symmetric cavitating cystic leukoencephalopathy. Whole-exome sequencing revealed compound heterozygous mutations in the NFU1 gene, providing definite genetic diagnosis of multiple mitochondrial dysfunction syndrome type 1."
Independent case confirming the cavitating pattern.
Developmental regression VERY_FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurological regression, annotated with Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25477904 SUPPORT Human Clinical
"We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity."
Regression after infection.
PMID:29441221 SUPPORT Human Clinical
"We describe a 6-month-old Brazilian boy with a 2-month history of severe and rapidly progressive developmental and psychomotor regression and seizures."
Rapid regression in infancy.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42192213 SUPPORT Human Clinical
"Here, we report a case of infantile-onset lactic acidosis, refractory epilepsy with encephalopathy, hyperglycinemia, and severe PAH in a patient who underwent rapid genome sequencing (GS) which identified compound heterozygous variants in NFU1 consistent with a diagnosis of MMDS1."
Refractory epilepsy in a molecularly confirmed case.
Encephalopathy VERY_FREQUENT HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile encephalopathy, annotated with Encephalopathy (HP:0001298). HP:0001298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25918518 SUPPORT Human Clinical
"Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients."
Encephalopathy as the characteristic feature.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25918518 SUPPORT Human Clinical
"He also showed developmental delay, muscular hypotonia, and apnea."
Developmental delay reported in an early-onset patient.
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:42192213 SUPPORT Human Clinical
"This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability."
Review listing 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 Combined complex I and II deficiency in muscle and fibroblasts, 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:25918518 SUPPORT Human Clinical
"Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts"
Enzymatic findings.
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:25477904 SUPPORT Human Clinical
"reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity"
Complex II deficiency with PDH deficiency.
Growth 1
Failure to thrive FREQUENT 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 (2 references)
PMID:25918518 SUPPORT Human Clinical
"Key phenotypic features included failure to thrive, pulmonary hypertension, infantile encephalopathy, and neurological regression."
Failure to thrive as a key feature of the seven-patient series.
PMID:25477904 SUPPORT Human Clinical
"They presented with failure to thrive, pulmonary hypertension, and neurological regression."
Independent report of failure to thrive at presentation.
🧬

Genetic Associations

1
NFU1
Gene: NFU1 hgnc:16287 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NFU1 (hgnc:16287). hgnc:16287 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:34449775 SUPPORT Model Organism
"To date, 20 NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over half of MMDS1 individuals are compound heterozygous for different NFU1 variants, it is valuable to investigate individual variants in an isogenic background."
Variant count and compound heterozygosity rate.
PMID:28470589 SUPPORT Human Clinical
"NGS found that the probands had homozygous mutation of c.545 + 5G > A and compound heterozygous variants of exon 4 deletion and c.721G > T in NFU1, respectively."
Additional allele classes including an exon deletion.
Variants (3)
c.622G>T (p.Gly208Cys) Pathogenic
missense
Founder missense variant, homozygous in nine of the ten original Spanish patients; near the cluster-binding site, it increases dimerisation, perturbs secondary structure and severely reduces the ability of NFU1 to accept an Fe-S cluster.
Show evidence (2 references)
PMID:22077971 SUPPORT Human Clinical
"Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G > T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine..."
Original identification and founder frequency.
PMID:28161430 SUPPORT In Vitro
"Analysis of protein stability and oligomeric state demonstrates that the mutant increases the propensity to dimerize and perturbs the secondary structure composition. These changes appear to underlie the severely decreased ability of mutant NFU1 to accept an Fe/S cluster from physiologically..."
Biochemical mechanism of the founder allele.
c.545G>A (p.Arg182Gln) Pathogenic
missense
Missense variant near the exon 6 splice donor found in the first Canadian family; it causes abnormal splicing of exon 6 and no mature protein is detectable in fibroblast mitochondria.
Show evidence (1 reference)
PMID:21944046 SUPPORT Human Clinical
"A homozygous missense mutation, c.545G>A, near the splice donor of exon 6 in NFU1 predicting a p.Arg182Gln substitution was found in one of the families. The mutation results in abnormal mRNA splicing of exon 6, and no mature protein could be detected in fibroblast mitochondria."
Splicing consequence of the variant.
c.565G>A (p.Gly189Arg) Pathogenic
missense
Recurrent missense variant, reported compound heterozygous with p.Cys210Phe in an Italian cavitating-leukoencephalopathy case and homozygous in a Turkish family with marked intrafamilial variability; in vitro it increases flexibility, decreases stability and shifts NFU1 toward monomer, impairing cluster acceptance.
Show evidence (2 references)
PMID:28906594 SUPPORT In Vitro
"In vitro investigation into the structure-function relationship of the Gly189Arg derivative, along with two other variants, reveals that substitution at position 189 triggers structural changes that increase flexibility, decrease stability, and alter the monomer-dimer equilibrium toward monomer,..."
Structural consequence of the variant.
PMID:32747156 SUPPORT Human Clinical
"Homozygous NM_001002755.4:c.565G>A (p.Gly189Arg) mutation was identified in the NFU1 gene; this had not previously been reported as homozygous."
Homozygous occurrence with variable phenotype.
💊

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 treatment corrects the Fe-S defect; management is supportive, including nutritional support with tube feeding, antiseizure therapy, management of spasticity and respiratory support, with prompt treatment of intercurrent infections that precipitate decompensation.
Show evidence (1 reference)
PMID:36256512 SUPPORT Human Clinical
"Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort"
Basis for aggressive management of intercurrent illness.
Pulmonary hypertension 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
Agent: sildenafil CHEBI:9139 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sildenafil (CHEBI:9139). CHEBI:9139 is a therapeutic agent from Chemical Entities of Biological Interest.
Pulmonary hypertension in MMDS1 is treated with standard pulmonary vasodilator and supportive strategies; a single-centre report describes novel management strategies for pHTN and MMDS1-associated complications.
Target Phenotypes: Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31970900 SUPPORT Human Clinical
"Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population."
Reports management of pulmonary hypertension in MMDS1.
Antiseizure pharmacotherapy
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
Platform: Small molecule
Standard antiseizure medication for the epileptic encephalopathy, which can be refractory.
Target Phenotypes: Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
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 are possible once the familial variants are known.
🌍

Environmental Factors

1
Febrile illness
febrile infectious illness Relation: this environmental factor is this exposure This environmental factor is febrile infectious illness.
ECTO was searched through the repository label cache for a fever or febrile-illness exposure term and none is cached; the exposure is left unbound rather than bound to an unrelated infection term.
Intercurrent febrile illness is the usual trigger of acute neurological decompensation, which may be reversible or irreversible, and precipitated death in six children of the largest cohort; the added metabolic demand of fever is presumed to unmask the bioenergetic deficit.
Show evidence (1 reference)
PMID:36256512 SUPPORT Human Clinical
"Six affected individuals succumbed to their rapidly progressive disease course triggered by a febrile illness between the ages of 6–36 months."
Fatal decompensations triggered by febrile illness.
Mechanism Target:
EXACERBATES Bioenergetic Failure and Neurodegeneration — Fever precipitates reversible or irreversible neurological deterioration and, in some children, a rapidly fatal course.
Show evidence (1 reference)
PMID:36256512 SUPPORT Human Clinical
"Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging."
Febrile illness as the trigger of neurological decompensation.
🔬

Biochemical Markers

2
Reduced protein-bound lipoic acid (present)
Pathograph Readouts
Readout Of Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation Negative Diagnostic
Loss of lipoylated E2 subunits reports the LIAS maturation failure.
Show evidence (1 reference)
PMID:22077971 SUPPORT Human Clinical
"Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases."
Tissue lipoic acid measurement.
Elevated plasma glycine and lactate (present)
Pathograph Readouts
Readout Of Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency Positive Diagnostic
Glycine and lactate accumulate when the glycine cleavage system and PDH lose lipoate.
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 NFU1 variants
Diagnosis is confirmed by identifying biallelic NFU1 variants on a large gene panel or exome/genome sequencing; rapid genome sequencing has established the diagnosis in an acutely ill infant.
Show evidence (1 reference)
PMID:34440194 SUPPORT Human Clinical
"Genetic analysis including large gene panels (Next Generation Sequencing) or whole exome sequencing is needed to confirm diagnosis."
Confirmatory testing.
Metabolic screening for lactate and glycine
The combination of lactic acidosis, hyperglycinemia and pulmonary hypertension should raise suspicion of a Fe-S cluster defect.
Show evidence (1 reference)
PMID:42192213 SUPPORT Human Clinical
"Identification of the clinical combination of lactic acidosis, PAH, and hyperglycinemia during diagnostic evaluation should raise suspicion for a defect of the ISC pathway"
Clinical-biochemical diagnostic triad.
Brain MRI
Diffuse symmetric leukoencephalopathy with deep white matter cavitation is characteristic and should prompt NFU1 testing.
Show evidence (1 reference)
PMID:32747156 SUPPORT Human Clinical
"Hyperglycinemia and cavitating leukodystrophy are suggestive of an NFU1 mutation diagnosis."
Imaging and biochemical clue to the diagnosis.
Enzyme assays in muscle or fibroblasts
Combined PDH and respiratory chain complex I and II (II+III) deficiency in muscle or cultured fibroblasts supports the diagnosis and distinguishes it from isolated PDH deficiency.
Show evidence (1 reference)
PMID:25918518 SUPPORT Human Clinical
"Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts"
Enzymatic diagnostic pattern.
📈

Progression

2
Fatal infantile encephalopathy with pulmonary hypertension
In the classical form, infants present in the first months with hypotonia, feeding difficulty, seizures and pulmonary arterial hypertension, with rapid neurological regression and death before 15 months, frequently within 6 months.
Show evidence (2 references)
PMID:22077971 SUPPORT Human Clinical
"We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months."
Original cohort course.
PMID:25918518 SUPPORT Human Clinical
"Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients."
Confirms early lethality in an independent cohort.
Early-onset spastic paraplegia continuum
Missense alleles with residual function produce early-onset pure or complex hereditary spastic paraplegia with longer survival, invariable white matter abnormalities and reversible or irreversible decompensation after febrile illness; the same homozygous genotype can produce a fatal infantile course in one sib and relapsing-remitting spastic paraparesis in another.
Show evidence (2 references)
PMID:36256512 SUPPORT Human Clinical
"Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum."
Defines the milder end of the continuum.
PMID:32747156 SUPPORT Human Clinical
"This report documents the case of a 27-month-old girl, who showed clinical signs and symptoms of spastic paraparesis with a relapsing-remitting course. The patient had a sister with a severe phenotype who died at the age of 16 months."
Intrafamilial variability across the continuum.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare: 38 cases and 20 NFU1 variants had been reported by 2023, with a further 19 individuals from 10 families described in the 2022 phenotypic-continuum series. The original Iberian cohort shares the p.Gly208Cys founder allele.
Show evidence (2 references)
PMID:36645076 SUPPORT Other
"Complicating our understanding of MMDS1 pathogenesis are the small number of cases (38 reported to date) and the diverse genetic variations of NFU1 that are potentially pathogenic."
Reported-case count as of 2023.
PMID:36256512 SUPPORT Human Clinical
"We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with..."
Largest single series, expanding the phenotype.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Multiple Mitochondrial Dysfunctions Syndrome 1:

Lipoic acid synthetase deficiency MONDO:0013762
Overlapping Features Primary LIAS deficiency produces the same lipoylation defect with hyperglycinemia and PDH deficiency but without the [4Fe-4S]-dependent respiratory chain complex I/II defect.
Distinguishing Features
  • Isolated lipoylation defect with preserved complex I and II
  • Biallelic LIAS rather than NFU1 variants
Show evidence (1 reference)
PMID:25477904 SUPPORT Human Clinical
"Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc)."
The combined respiratory-chain plus PDH pattern that separates MMDS from isolated LIAS deficiency.
Other multiple mitochondrial dysfunctions syndromes (BOLA3, IBA57, ISCA2, ISCA1)
Overlapping Features MMDS2-5 share the lipoylation and complex I/II defects and early leukoencephalopathy; pulmonary hypertension favours MMDS1 and dilated cardiomyopathy favours MMDS2, but genetic testing is required to distinguish them.
Distinguishing Features
  • Pulmonary arterial hypertension in MMDS1
  • Dilated cardiomyopathy in MMDS2 (BOLA3)
  • Gene identified by sequencing
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, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy."
Distinguishing features across the series.
Non-ketotic hyperglycinemia and pyruvate dehydrogenase deficiency
Overlapping Features Classic NKH (GLDC/AMT) and primary PDH deficiency each explain one arm of the biochemistry; their co-occurrence points to a lipoylation or Fe-S defect.
Distinguishing Features
  • Combined glycine cleavage and PDH deficiency with respiratory chain involvement
  • Reduced protein-bound lipoic acid
Show evidence (1 reference)
PMID:22077971 SUPPORT Human Clinical
"Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low."
Both enzyme systems affected together.
🧫

Experimental Models

1
Patient-derived fibroblasts PRIMARY_CELL_CULTURE
Fibroblasts from MMDS1 patients show combined PDH and complex I/II deficiency, reduced lipoylation and attenuated mitochondrial protein synthesis; retroviral expression of the mitochondrial NFU1 isoform restores respiratory chain and oxoacid dehydrogenase function.
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:21944046
Pathograph links
Defective Delivery of 4Fe-4S Clusters to NFU1-Dependent Targets recapitulates fidelity: high observes: cellular The Fe-S maturation defect and its rescue by wild-type mitochondrial NFU1.
Limitations: Fibroblasts do not model the tissue-specific vulnerability of white matter or the pulmonary vasculature.
Show evidence (2 references)
PMID:21944046 SUPPORT In Vitro
"Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic isoform of NFU1 and with isoform 1, but not isoform 2 of BOLA3 restored both respiratory chain function and oxoacid dehydrogenase complexes."
Rescue experiment establishing causality in patient cells.
+ 1 more reference
🐁

Animal Models

2
Caenorhabditis elegans nfu-1 patient-variant knock-ins
Exact patient variants recreated in the worm orthologue form an allelic series of respiratory dysfunction and oxidative stress, with mitochondrial reactive iron in some alleles; Gly147Arg and Gly166Cys alter acetylcholine signalling at neuromuscular junctions with opposite effects on motility, and knockdown of acetylcholine release rescues the Gly147Arg phenotypes.
Species
Caenorhabditis elegans
Genotype
nfu-1 (formerly lpd-8) CRISPR knock-ins of patient NFU1 variants (five alleles including Gly147Arg and Gly166Cys)
Publication
PMID:34449775
Pathograph links
Bioenergetic Failure and Neurodegeneration partially recapitulates fidelity: low observes: cellular Allele-specific mitochondrial respiratory dysfunction, oxidative stress and neuromuscular signalling defects.
Limitations: Invertebrate model without myelinated white matter, pulmonary vasculature or an equivalent of the human leukoencephalopathy; phenotypes are cellular and neuromuscular rather than neurodegenerative.
Readouts
Mitochondrial respiration and oxidative stress
Direction: ALTERED
Interpretation: Variable, allele-dependent respiratory dysfunction and oxidative stress.
Show evidence (1 reference)
PMID:34449775 SUPPORT Model Organism
"Phenotypes were variable between the mutant nfu-1 alleles and generally presented as an allelic series indicating that not all variants have lost complete function."
Reports the allelic-series readout.
Show evidence (1 reference)
PMID:36645076 SUPPORT Model Organism
"Each of these mutants, Gly147Arg and Gly166Cys, have altered acetylcholine signaling at neuromuscular junctions, but opposite effects on activity and motility."
Neuromuscular phenotypes of the patient-variant models.
Humanized NFU1 G206C rat
Rats carrying the common human NFU1 Gly208Cys allele at the orthologous position develop pulmonary arterial hypertension with raised right ventricular pressure, right ventricular hypertrophy and angio-obliterative pulmonary artery remodelling, together with decreased complex II expression and activity, markedly reduced pyruvate dehydrogenase activity and lipoate binding; penetrance of the PAH phenotype is higher in females, and males preserve oligomeric NFU1 and upregulate ISCU.
Species
Rat
Genotype
Nfu1 p.Gly206Cys (human p.Gly208Cys) homozygous CRISPR/Cas9 knock-in
Publication
PMID:31461310
Pathograph links
Pulmonary Endothelial Metabolic Dysfunction partially recapitulates fidelity: moderate observes: organism The only vertebrate model of NFU1 deficiency that develops pulmonary arterial hypertension with pulmonary artery remodelling, linking the Fe-S defect to the pulmonary vascular phenotype in vivo.
Limitations: The rat phenotype is a haemodynamic and histological PAH readout rather than a defined endothelial mechanism; the model shows a female-predominant penetrance that the human case literature does not recapitulate, and the developmental lung disorder seen at human autopsy has not been described in the rat.
Readouts
Right ventricular pressure and pulmonary artery remodelling
Direction: INCREASED
Interpretation: Haemodynamic and histological evidence of pulmonary arterial hypertension in the humanized rat.
Show evidence (1 reference)
PMID:31461310 SUPPORT Model Organism
"NFU1G206C rats showed increased right ventricular pressure, right ventricular hypertrophy, and high levels of pulmonary artery remodeling."
Reports the PAH readouts in the knock-in rat.
Show evidence (1 reference)
PMID:31461310 SUPPORT Model Organism
"Our work describes a novel, humanized rat model of NFU1 deficiency that showed mitochondrial dysfunction similar to that observed in patients and developed PAH with the same sex dimorphism."
Establishes the rat as an in vivo model of the NFU1-associated pulmonary phenotype.
Respiratory Chain Complex I and II Deficiency recapitulates fidelity: high observes: molecular Complex II deficiency and loss of lipoate-dependent PDH activity in rat tissue mitochondria.
Limitations: Complex I activity is not reported in the abstract, so only the complex II arm of the node is documented in the rat.
Readouts
Mitochondrial complex II expression and activity
Direction: DECREASED
Interpretation: Reproduces the complex II deficiency of patients.
Show evidence (1 reference)
PMID:31461310 SUPPORT Model Organism
"Male and female homozygote rats exhibited decreased expression and activity of mitochondrial Complex II, and markedly decreased pyruvate dehydrogenase activity and lipoate binding."
Reports the complex II and PDH readouts.
Show evidence (1 reference)
PMID:31461310 SUPPORT Model Organism
"Male and female homozygote rats exhibited decreased expression and activity of mitochondrial Complex II, and markedly decreased pyruvate dehydrogenase activity and lipoate binding."
The biochemical phenotype matches the patient enzymology.
{ }

Source YAML

click to show 
name: Multiple Mitochondrial Dysfunctions Syndrome 1
category: Genetic
creation_date: "2026-09-05T16:30:00Z"
synonyms:
- MMDS1
- NFU1 deficiency
- NFU1-related multiple mitochondrial dysfunctions syndrome
- Fatal infantile encephalopathy with pulmonary hypertension due to NFU1 deficiency
description: >
  Multiple mitochondrial dysfunctions syndrome 1 (MMDS1; OMIM #605711) is the index form of
  the MMDS series, an autosomal recessive disorder of mitochondrial iron-sulfur (Fe-S)
  cluster biogenesis caused by biallelic variants in NFU1. NFU1 is a late-acting [4Fe-4S]
  cluster carrier that receives clusters from ISCU2 and ISCA1 and delivers them to a
  specific subset of mitochondrial targets, above all lipoic acid synthase (LIAS) and
  succinate dehydrogenase. Loss of NFU1 therefore produces a combined deficiency of the four
  lipoate-dependent 2-oxoacid dehydrogenases and the glycine cleavage system, together with
  respiratory chain complexes I and II, with reduced protein-bound lipoic acid, lactic
  acidosis and non-ketotic hyperglycinemia as the biochemical signature. The classical
  presentation is a fatal infantile encephalopathy with pulmonary arterial hypertension,
  hypotonia, seizures and death before 15 months, often with a cavitating
  leukoencephalopathy on MRI and neurological decompensation after intercurrent infection.
  A homozygous p.Gly208Cys (c.622G>T) founder variant accounts for the original Iberian
  cohort; subsequent series have broadened the phenotype to include a longer-surviving
  early-onset hereditary spastic paraplegia end of a continuum, sometimes with marked
  intrafamilial variability. Treatment is supportive, with management of pulmonary
  hypertension, seizures and nutrition; no therapy corrects the metabolic defect.
disease_term:
  preferred_term: Multiple mitochondrial dysfunctions syndrome 1
  term:
    id: MONDO:0011582
    label: multiple mitochondrial dysfunctions syndrome 1
parents:
- MONDO:0017338
classifications:
  mechanistic_category:
  - classification_value: mitochondrial disease
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare: 38 cases and 20 NFU1 variants had been reported by 2023, with a further 19
    individuals from 10 families described in the 2022 phenotypic-continuum series. The
    original Iberian cohort shares the p.Gly208Cys founder allele.
  evidence:
  - reference: PMID:36645076
    reference_title: "Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complicating our understanding of MMDS1 pathogenesis are the small number of cases (38 reported to date) and the diverse genetic variations of NFU1 that are potentially pathogenic."
    explanation: Reported-case count as of 2023.
  - reference: PMID:36256512
    reference_title: "Phenotypic continuum of NFU1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other."
    explanation: Largest single series, expanding the phenotype.
progression:
- phase: Fatal infantile encephalopathy with pulmonary hypertension
  notes: >-
    In the classical form, infants present in the first months with hypotonia, feeding
    difficulty, seizures and pulmonary arterial hypertension, with rapid neurological
    regression and death before 15 months, frequently within 6 months.
  evidence:
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months."
    explanation: Original cohort course.
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients."
    explanation: Confirms early lethality in an independent cohort.
- phase: Early-onset spastic paraplegia continuum
  notes: >-
    Missense alleles with residual function produce early-onset pure or complex hereditary
    spastic paraplegia with longer survival, invariable white matter abnormalities and
    reversible or irreversible decompensation after febrile illness; the same homozygous
    genotype can produce a fatal infantile course in one sib and relapsing-remitting spastic
    paraparesis in another.
  evidence:
  - reference: PMID:36256512
    reference_title: "Phenotypic continuum of NFU1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum."
    explanation: Defines the milder end of the continuum.
  - reference: PMID:32747156
    reference_title: "A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report documents the case of a 27-month-old girl, who showed clinical signs and symptoms of spastic paraparesis with a relapsing-remitting course. The patient had a sister with a severe phenotype who died at the age of 16 months."
    explanation: Intrafamilial variability across the continuum.
genetic:
- name: NFU1
  gene_term:
    preferred_term: NFU1
    term:
      id: hgnc:16287
      label: NFU1
  relationship_type: CAUSATIVE
  notes: >
    Biallelic NFU1 (2p13.3) variants cause MMDS1; about 20 variants (missense, splice,
    frameshift, exon deletion) are reported and over half of patients are compound
    heterozygous. The Iberian founder p.Gly208Cys (c.622G>T) and the splice-region
    c.545+5G>A / p.Arg182Gln alleles are recurrent; structural work shows that Gly208Cys and
    Gly189Arg perturb NFU1 folding and oligomerisation and abolish cluster acceptance from
    physiological donors. Variants form an allelic series with residual function tracking
    phenotype severity.
  variants:
  - name: c.622G>T (p.Gly208Cys)
    description: >
      Founder missense variant, homozygous in nine of the ten original Spanish patients;
      near the cluster-binding site, it increases dimerisation, perturbs secondary structure
      and severely reduces the ability of NFU1 to accept an Fe-S cluster.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22077971
      reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G > T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545 + 5G > A) mutation."
      explanation: Original identification and founder frequency.
    - reference: PMID:28161430
      reference_title: "Understanding the Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1)-Impact of a Disease-Causing Gly208Cys Substitution on Structure and Activity of NFU1 in the Fe/S Cluster Biosynthetic Pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Analysis of protein stability and oligomeric state demonstrates that the mutant increases the propensity to dimerize and perturbs the secondary structure composition. These changes appear to underlie the severely decreased ability of mutant NFU1 to accept an Fe/S cluster from physiologically relevant sources."
      explanation: Biochemical mechanism of the founder allele.
  - name: c.545G>A (p.Arg182Gln)
    description: >
      Missense variant near the exon 6 splice donor found in the first Canadian family; it
      causes abnormal splicing of exon 6 and no mature protein is detectable in fibroblast
      mitochondria.
    type: missense
    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 homozygous missense mutation, c.545G>A, near the splice donor of exon 6 in NFU1 predicting a p.Arg182Gln substitution was found in one of the families. The mutation results in abnormal mRNA splicing of exon 6, and no mature protein could be detected in fibroblast mitochondria."
      explanation: Splicing consequence of the variant.
  - name: c.565G>A (p.Gly189Arg)
    description: >
      Recurrent missense variant, reported compound heterozygous with p.Cys210Phe in an
      Italian cavitating-leukoencephalopathy case and homozygous in a Turkish family with
      marked intrafamilial variability; in vitro it increases flexibility, decreases stability
      and shifts NFU1 toward monomer, impairing cluster acceptance.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28906594
      reference_title: "Understanding the molecular basis for multiple mitochondrial dysfunctions syndrome 1 (MMDS1): impact of a disease-causing Gly189Arg substitution on NFU1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro investigation into the structure-function relationship of the Gly189Arg derivative, along with two other variants, reveals that substitution at position 189 triggers structural changes that increase flexibility, decrease stability, and alter the monomer-dimer equilibrium toward monomer, thereby impairing the ability of the Gly189X derivatives to receive an Fe/S cluster from physiologically relevant sources."
      explanation: Structural consequence of the variant.
    - reference: PMID:32747156
      reference_title: "A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Homozygous NM_001002755.4:c.565G>A (p.Gly189Arg) mutation was identified in the NFU1 gene; this had not previously been reported as homozygous."
      explanation: Homozygous occurrence with variable phenotype.
  evidence:
  - reference: PMID:34449775
    reference_title: "Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To date, 20 NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over half of MMDS1 individuals are compound heterozygous for different NFU1 variants, it is valuable to investigate individual variants in an isogenic background."
    explanation: Variant count and compound heterozygosity rate.
  - reference: PMID:28470589
    reference_title: "Novel NFU1 Variants Induced MMDS Behaved as Special Leukodystrophy in Chinese Sufferers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NGS found that the probands had homozygous mutation of c.545 + 5G > A and compound heterozygous variants of exon 4 deletion and c.721G > T in NFU1, respectively."
    explanation: Additional allele classes including an exon deletion.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >
    Autosomal recessive; heterozygous parents are unaffected. Expressivity ranges from fatal
    infantile encephalopathy to early-onset spastic paraplegia, including within sibships.
  evidence:
  - reference: PMID:32747156
    reference_title: "A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder is a severe autosomal recessive disease with onset in early infancy."
    explanation: States the inheritance pattern.
  - reference: PMID:36256512
    reference_title: "Phenotypic continuum of NFU1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy."
    explanation: Biallelic requirement.
pathophysiology:
- name: Biallelic NFU1 Loss of Function
  description: >
    Pathogenic variants abolish mature mitochondrial NFU1 or disrupt its structure so that it
    can no longer receive a [4Fe-4S] cluster. NFU1 dimerises and reductively assembles a
    bridging [4Fe-4S] cluster from two [2Fe-2S] clusters donated by the scaffold ISCU2 and the
    carrier ISCA1, aided by ferredoxin 2, through a conserved hydrophobic patch at its
    C-terminal helix; disease variants near the cluster-binding site perturb folding and
    oligomerisation and block this acceptance.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: 4 iron, 4 sulfur cluster binding
    term:
      id: GO:0051539
      label: 4 iron, 4 sulfur cluster binding
    modifier: DECREASED
  downstream:
  - target: Defective Delivery of 4Fe-4S Clusters to NFU1-Dependent Targets
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32776106
      reference_title: "Assembly of the [4Fe-4S] cluster of NFU1 requires the coordinated donation of two [2Fe-2S] clusters from the scaffold proteins, ISCU2 and ISCA1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, we showed that NFU1 lost its ability to acquire its Fe-S cluster when mutagenized at the identified site of interaction with ISCU2 and ISCA1, which thereby adversely affected biochemical functions of proteins that are thought to acquire their Fe-S clusters directly from NFU1, such as lipoic acid synthase, which supports the Fe-S-dependent process of lipoylation of components of multiple key enzyme complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and the glycine cleavage complex."
      explanation: Loss of cluster acquisition by NFU1 directly impairs its downstream targets.
  evidence:
  - reference: PMID:32776106
    reference_title: "Assembly of the [4Fe-4S] cluster of NFU1 requires the coordinated donation of two [2Fe-2S] clusters from the scaffold proteins, ISCU2 and ISCA1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identified the initial scaffold protein, mitochondrial ISCU (ISCU2) and the secondary carrier, ISCA1, as the direct donors of Fe-S clusters to mitochondrial NFU1"
    explanation: Defines the normal function that the variants disrupt.
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins."
    explanation: Functional impairment of the patient allele.
- name: Defective Delivery of 4Fe-4S Clusters to NFU1-Dependent Targets
  description: >
    NFU1 is a specific, late-acting maturation factor: its depletion diminishes lipoic acid
    synthase and succinate dehydrogenase (and, via the ISCA1-NFU1 node, the [4Fe-4S]
    mitoribosome assembly factor METTL17) but spares most other Fe-S proteins, unlike
    depletion of the general scaffold ISCU. NFU1 also requires BOLA3 for its stability.
  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:22077971
      reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished."
      explanation: NFU1 depletion directly reduces lipoic acid synthase and then PDH activity.
  - target: Respiratory Chain Complex I and II Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22077971
      reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation."
      explanation: Target specificity including succinate dehydrogenase.
  - 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: Places NFU1 in the Fe-S delivery pathway that mitoribosome biogenesis requires.
    - 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-fibroblast demonstration that NFU1 loss attenuates mitochondrial protein synthesis.
  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: IN_VITRO
    snippet: "Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic isoform of NFU1 and with isoform 1, but not isoform 2 of BOLA3 restored both respiratory chain function and oxoacid dehydrogenase complexes."
    explanation: Rescue of both target classes, respiratory chain complexes and 2-oxoacid dehydrogenases, by mitochondrial NFU1 establishes them as NFU1-dependent; the abstract's summary sentence naming the Fe-S centres cannot be quoted because its bracketed cluster notation is stripped by the snippet matcher.
- name: Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
  description: >
    LIAS is a [4Fe-4S] radical-SAM enzyme that requires NFU1 for cluster delivery. Its
    failure reduces protein-bound lipoic acid in tissues, inactivating the E2 subunits of
    pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain ketoacid
    dehydrogenase and the H protein of the glycine cleavage system.
  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:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases."
    explanation: Direct measurement of the lipoylation defect in patient tissues.
- name: Combined 2-Oxoacid Dehydrogenase and Glycine Cleavage System Deficiency
  description: >
    Loss of lipoylation inactivates the pyruvate dehydrogenase complex and the other
    2-oxoacid dehydrogenases, blocking pyruvate entry into the TCA cycle and producing
    lactic acidosis, and inactivates the glycine cleavage system, producing non-ketotic
    hyperglycinemia; the same biochemistry is shared with LIAS, LIPT1/2, BOLA3 and IBA57
    deficiencies.
  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 and Neurodegeneration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low."
    explanation: Enzymatic and metabolite findings in patients.
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven)."
    explanation: Frequency of the combined enzyme defects and metabolite elevations.
- name: Respiratory Chain Complex I and II Deficiency
  description: >
    Complexes I and II carry [4Fe-4S] clusters whose maturation depends on the NFU1 node;
    patient muscle and fibroblasts show reduced complex I and II (and II+III) activities,
    compounding the block in oxidative metabolism from PDH loss.
  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 and Neurodegeneration
    causal_link_type: DIRECT
  - target: Lactic acidosis
    causal_link_type: DIRECT
  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: "Severe combined deficiency of the 2-oxoacid dehydrogenases, associated with a defect in lipoate synthesis and accompanied by defects in complexes I, II, and III of the mitochondrial respiratory chain, is a rare autosomal recessive syndrome with no obvious causative gene defect."
    explanation: Defines the combined respiratory chain defect.
- name: Attenuated Mitochondrial Protein Synthesis
  description: >
    The mitoribosome small subunit depends on the [4Fe-4S] assembly factor METTL17, proposed
    to receive its cluster through the ISCA1-NFU1 node; MMDS1 patient fibroblasts show a
    previously unrecognised attenuation of 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 and Neurodegeneration
    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 of the translation defect.
- name: Bioenergetic Failure and Neurodegeneration
  description: >
    Combined loss of PDH-driven and respiratory-chain ATP production, with reactive oxygen
    species and, in some alleles, mitochondrial iron dyshomeostasis, injures energy-dependent
    tissues. In the brain this produces a leukoencephalopathy with cavitation of deep white
    matter, developmental regression, hypotonia evolving to spasticity, seizures and
    encephalopathy; intercurrent infection precipitates decompensation.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  downstream:
  - target: Leukoencephalopathy
    causal_link_type: DIRECT
  - target: Developmental regression
    causal_link_type: DIRECT
  - target: Hypotonia
    causal_link_type: DIRECT
  - target: Spasticity
    causal_link_type: DIRECT
  - target: Seizure
    causal_link_type: DIRECT
  - target: Encephalopathy
    causal_link_type: DIRECT
  - target: Pulmonary Endothelial Metabolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies delineate a multifactorial pathogenesis including globally dysregulated energy metabolism, specific deficiencies in oxidative phosphorylation, and excess reactive oxygen species (ROS) production."
    explanation: Review synthesis of the cellular pathogenesis.
  - reference: PMID:34449775
    reference_title: "Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, reactive iron within mitochondria was evident in some, but not all, nfu-1 mutants indicating that iron dyshomeostasis may contribute to disease pathogenesis in some MMDS1 individuals."
    explanation: Allele-specific iron dyshomeostasis as a contributor.
  - reference: PMID:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene."
    explanation: The characteristic white-matter lesion.
- name: Pulmonary Endothelial Metabolic Dysfunction
  description: >
    Pulmonary arterial hypertension is a distinctive feature of MMDS1. Autopsy of an affected
    sib showed a developmental lung disorder, and in the allied BOLA3 form loss of Fe-S
    integrity in pulmonary artery endothelial cells impairs lipoate-dependent oxidative
    metabolism and glycine handling, increasing endothelial proliferation and
    vasoconstriction; the NFU1-specific mechanism remains undefined.
  biological_scale: CELLULAR
  conforms_to: "pulmonary_vascular_remodeling#Pulmonary Endothelial Dysfunction and Impaired BMP Signaling"
  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: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31970900
    reference_title: "Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease."
    explanation: Autopsy evidence for a developmental pulmonary vascular basis.
  - 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 vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration."
    explanation: Mechanism in the allied BOLA3 deficiency, extrapolated to the NFU1 node.
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date."
    explanation: States that the PAH mechanism is unresolved.
phenotypes:
- name: Hyperglycinemia
  category: Metabolic
  frequency: VERY_FREQUENT
  description: Non-ketotic hyperglycinemia from glycine cleavage system inactivation; present in all seven patients of one series.
  phenotype_term:
    preferred_term: Non-ketotic hyperglycinemia
    term:
      id: HP:0002154
      label: Hyperglycinemia
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased lactate (five out of six) and glycine concentration (seven out of seven)"
    explanation: Frequency of hyperglycinemia.
- name: Lactic acidosis
  category: Metabolic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperglycinemia and lactic acidosis were common findings."
    explanation: Common metabolic finding in the original cohort.
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  frequency: FREQUENT
  description: Severe, often presenting pulmonary hypertension distinguishes MMDS1 from the other MMDS forms.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months."
    explanation: Pulmonary hypertension in the original cohort.
  - 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: Systematic review identifying PAH as the MMDS1-specific feature.
- name: Leukoencephalopathy
  category: Neurological
  frequency: VERY_FREQUENT
  description: Early-onset leukoencephalopathy, characteristically with cavitation of the deep white matter; white matter abnormalities were invariable in the spastic-paraplegia cohort.
  phenotype_term:
    preferred_term: Cavitating leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene."
    explanation: Characteristic imaging phenotype.
  - reference: PMID:29441221
    reference_title: "NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging showed diffuse and symmetric cavitating cystic leukoencephalopathy. Whole-exome sequencing revealed compound heterozygous mutations in the NFU1 gene, providing definite genetic diagnosis of multiple mitochondrial dysfunction syndrome type 1."
    explanation: Independent case confirming the cavitating pattern.
- name: Developmental regression
  category: Neurological
  frequency: VERY_FREQUENT
  description: Rapid psychomotor regression, often precipitated by infection, is the presenting neurological course.
  phenotype_term:
    preferred_term: Neurological regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity."
    explanation: Regression after infection.
  - reference: PMID:29441221
    reference_title: "NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a 6-month-old Brazilian boy with a 2-month history of severe and rapidly progressive developmental and psychomotor regression and seizures."
    explanation: Rapid regression in infancy.
- name: Hypotonia
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability."
    explanation: Review of clinical features.
- name: Seizure
  category: Neurological
  frequency: FREQUENT
  description: Epileptic encephalopathy, which may be refractory.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a case of infantile-onset lactic acidosis, refractory epilepsy with encephalopathy, hyperglycinemia, and severe PAH in a patient who underwent rapid genome sequencing (GS) which identified compound heterozygous variants in NFU1 consistent with a diagnosis of MMDS1."
    explanation: Refractory epilepsy in a molecularly confirmed case.
- name: Encephalopathy
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Infantile encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients."
    explanation: Encephalopathy as the characteristic feature.
- name: Spasticity
  category: Neurological
  frequency: FREQUENT
  description: Spastic tetraparesis in the infantile form and pure or complex spastic paraplegia at the milder end of the continuum.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:36256512
    reference_title: "Phenotypic continuum of NFU1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end"
    explanation: Spastic paraplegia phenotype in the continuum cohort.
  - reference: PMID:29441221
    reference_title: "NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination showed spastic tetraparesis and lethargy."
    explanation: Spasticity in the infantile form.
- name: Respiratory failure
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability."
    explanation: Review listing respiratory failure.
- name: Decreased activity of mitochondrial complex I
  category: Laboratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Combined complex I and II deficiency in muscle and fibroblasts
    term:
      id: HP:0011923
      label: Decreased activity of mitochondrial complex I
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts"
    explanation: Enzymatic findings.
- 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:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity"
    explanation: Complex II deficiency with PDH deficiency.
- name: Failure to thrive
  category: Growth
  frequency: FREQUENT
  description: >
    Failure to thrive is a key early feature, usually from the first weeks of life, alongside
    poor feeding and vomiting.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key phenotypic features included failure to thrive, pulmonary hypertension, infantile encephalopathy, and neurological regression."
    explanation: Failure to thrive as a key feature of the seven-patient series.
  - reference: PMID:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented with failure to thrive, pulmonary hypertension, and neurological regression."
    explanation: Independent report of failure to thrive at presentation.
- name: Feeding difficulties
  category: Gastrointestinal
  frequency: FREQUENT
  description: >
    Poor feeding and vomiting are among the earliest manifestations and recur with
    metabolic decompensation; nasogastric feeding is often needed.
  phenotype_term:
    preferred_term: Poor feeding and vomiting
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented first with poor feeding, vomiting, mild lactate concentration elevation (up to 3.0 mmol/L in plasma and CSF), and failure to thrive."
    explanation: Poor feeding and vomiting as the presenting features.
  - reference: PMID:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the beginning of treatment with vitamin B2, B1, and Coenzyme Q the child further deteriorated during the following months: he suffered from several episodes of metabolic decompensation, developed epileptic seizures and required nasogastric feeding tube."
    explanation: Feeding failure requiring tube feeding during decompensation.
- name: Global developmental delay
  category: Neurological
  description: >
    Developmental delay precedes or accompanies regression in patients with early onset;
    it is a distinct claim from the loss of acquired milestones curated separately.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also showed developmental delay, muscular hypotonia, and apnea."
    explanation: Developmental delay reported in an early-onset patient.
biochemical:
- name: Reduced protein-bound lipoic acid
  presence: present
  notes: Direct measurement of protein-bound lipoic acid in patient tissues shows marked decreases, the proximate biochemical signature of the NFU1 defect.
  readouts:
  - target: Lipoic Acid Synthase Deficiency and Loss of Protein Lipoylation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Loss of lipoylated E2 subunits reports the LIAS maturation failure.
  evidence:
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases."
    explanation: Tissue lipoic acid measurement.
- name: Elevated plasma glycine and lactate
  presence: present
  notes: Screening biomarkers; high lactate, pyruvate and glycine in body fluids suggest the diagnosis across MMDS types.
  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 glycine cleavage system and PDH lose lipoate.
  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.
environmental:
- name: Febrile illness
  description: >
    Intercurrent febrile illness is the usual trigger of acute neurological decompensation,
    which may be reversible or irreversible, and precipitated death in six children of the
    largest cohort; the added metabolic demand of fever is presumed to unmask the bioenergetic
    deficit.
  exposure_term:
    preferred_term: febrile infectious illness
  influences_mechanisms:
  - target: Bioenergetic Failure and Neurodegeneration
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Fever precipitates reversible or irreversible neurological deterioration and, in some
      children, a rapidly fatal course.
    evidence:
    - reference: PMID:36256512
      reference_title: "Phenotypic continuum of NFU1-related disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging."
      explanation: Febrile illness as the trigger of neurological decompensation.
  evidence:
  - reference: PMID:36256512
    reference_title: "Phenotypic continuum of NFU1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six affected individuals succumbed to their rapidly progressive disease course triggered by a febrile illness between the ages of 6–36 months."
    explanation: Fatal decompensations triggered by febrile illness.
  notes: >-
    ECTO was searched through the repository label cache for a fever or febrile-illness
    exposure term and none is cached; the exposure is left unbound rather than bound to an
    unrelated infection term.
treatments:
- name: Supportive and multidisciplinary care
  description: >
    No treatment corrects the Fe-S defect; management is supportive, including nutritional
    support with tube feeding, antiseizure therapy, management of spasticity and respiratory
    support, with prompt treatment of intercurrent infections that precipitate
    decompensation.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36256512
    reference_title: "Phenotypic continuum of NFU1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort"
    explanation: Basis for aggressive management of intercurrent illness.
- name: Pulmonary hypertension management
  description: >
    Pulmonary hypertension in MMDS1 is treated with standard pulmonary vasodilator and
    supportive strategies; a single-centre report describes novel management strategies for
    pHTN and MMDS1-associated complications.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sildenafil
      term:
        id: CHEBI:9139
        label: sildenafil
  target_phenotypes:
  - preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:31970900
    reference_title: "Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population."
    explanation: Reports management of pulmonary hypertension in MMDS1.
  notes: >-
    Sildenafil is bound as the representative pulmonary vasodilator used in paediatric PAH;
    the cited report does not name a specific agent in its abstract.
- name: Antiseizure pharmacotherapy
  description: Standard antiseizure medication for the epileptic encephalopathy, which can be refractory.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- name: Genetic counseling
  description: Autosomal recessive counselling with 25% recurrence risk; carrier and prenatal testing are possible 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 NFU1 variants
  description: >
    Diagnosis is confirmed by identifying biallelic NFU1 variants on a large gene panel or
    exome/genome sequencing; rapid genome sequencing has established the diagnosis in an
    acutely ill infant.
  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: "Genetic analysis including large gene panels (Next Generation Sequencing) or whole exome sequencing is needed to confirm diagnosis."
    explanation: Confirmatory testing.
- name: Metabolic screening for lactate and glycine
  description: The combination of lactic acidosis, hyperglycinemia and pulmonary hypertension should raise suspicion of a Fe-S cluster defect.
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of the clinical combination of lactic acidosis, PAH, and hyperglycinemia during diagnostic evaluation should raise suspicion for a defect of the ISC pathway"
    explanation: Clinical-biochemical diagnostic triad.
- name: Brain MRI
  description: Diffuse symmetric leukoencephalopathy with deep white matter cavitation is characteristic and should prompt NFU1 testing.
  evidence:
  - reference: PMID:32747156
    reference_title: "A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperglycinemia and cavitating leukodystrophy are suggestive of an NFU1 mutation diagnosis."
    explanation: Imaging and biochemical clue to the diagnosis.
- name: Enzyme assays in muscle or fibroblasts
  description: Combined PDH and respiratory chain complex I and II (II+III) deficiency in muscle or cultured fibroblasts supports the diagnosis and distinguishes it from isolated PDH deficiency.
  evidence:
  - reference: PMID:25918518
    reference_title: "Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts"
    explanation: Enzymatic diagnostic pattern.
differential_diagnoses:
- name: Lipoic acid synthetase deficiency
  description: >
    Primary LIAS deficiency produces the same lipoylation defect with hyperglycinemia and
    PDH deficiency but without the [4Fe-4S]-dependent respiratory chain complex I/II defect.
  disease_term:
    preferred_term: lipoic acid synthetase deficiency
    term:
      id: MONDO:0013762
      label: lipoic acid synthetase deficiency
  distinguishing_features:
  - Isolated lipoylation defect with preserved complex I and II
  - Biallelic LIAS rather than NFU1 variants
  evidence:
  - reference: PMID:25477904
    reference_title: "Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc)."
    explanation: The combined respiratory-chain plus PDH pattern that separates MMDS from isolated LIAS deficiency.
- name: Other multiple mitochondrial dysfunctions syndromes (BOLA3, IBA57, ISCA2, ISCA1)
  description: >
    MMDS2-5 share the lipoylation and complex I/II defects and early leukoencephalopathy;
    pulmonary hypertension favours MMDS1 and dilated cardiomyopathy favours MMDS2, but
    genetic testing is required to distinguish them.
  distinguishing_features:
  - Pulmonary arterial hypertension in MMDS1
  - Dilated cardiomyopathy in MMDS2 (BOLA3)
  - Gene identified by sequencing
  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, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy."
    explanation: Distinguishing features across the series.
- name: Non-ketotic hyperglycinemia and pyruvate dehydrogenase deficiency
  description: Classic NKH (GLDC/AMT) and primary PDH deficiency each explain one arm of the biochemistry; their co-occurrence points to a lipoylation or Fe-S defect.
  distinguishing_features:
  - Combined glycine cleavage and PDH deficiency with respiratory chain involvement
  - Reduced protein-bound lipoic acid
  evidence:
  - reference: PMID:22077971
    reference_title: "A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low."
    explanation: Both enzyme systems affected together.
animal_models:
- name: Caenorhabditis elegans nfu-1 patient-variant knock-ins
  species: Caenorhabditis elegans
  genotype: nfu-1 (formerly lpd-8) CRISPR knock-ins of patient NFU1 variants (five alleles including Gly147Arg and Gly166Cys)
  publication: PMID:34449775
  description: >
    Exact patient variants recreated in the worm orthologue form an allelic series of
    respiratory dysfunction and oxidative stress, with mitochondrial reactive iron in some
    alleles; Gly147Arg and Gly166Cys alter acetylcholine signalling at neuromuscular junctions
    with opposite effects on motility, and knockdown of acetylcholine release rescues the
    Gly147Arg phenotypes.
  modeled_mechanisms:
  - target: Bioenergetic Failure and Neurodegeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Allele-specific mitochondrial respiratory dysfunction, oxidative stress and neuromuscular signalling defects.
    limitations: >-
      Invertebrate model without myelinated white matter, pulmonary vasculature or an
      equivalent of the human leukoencephalopathy; phenotypes are cellular and
      neuromuscular rather than neurodegenerative.
    readouts:
    - name: Mitochondrial respiration and oxidative stress
      target: Bioenergetic Failure and Neurodegeneration
      direction: ALTERED
      interpretation: Variable, allele-dependent respiratory dysfunction and oxidative stress.
      evidence:
      - reference: PMID:34449775
        reference_title: "Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Phenotypes were variable between the mutant nfu-1 alleles and generally presented as an allelic series indicating that not all variants have lost complete function."
        explanation: Reports the allelic-series readout.
    evidence:
    - reference: PMID:36645076
      reference_title: "Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Each of these mutants, Gly147Arg and Gly166Cys, have altered acetylcholine signaling at neuromuscular junctions, but opposite effects on activity and motility."
      explanation: Neuromuscular phenotypes of the patient-variant models.
- name: Humanized NFU1 G206C rat
  species: Rat
  genotype: Nfu1 p.Gly206Cys (human p.Gly208Cys) homozygous CRISPR/Cas9 knock-in
  publication: PMID:31461310
  description: >
    Rats carrying the common human NFU1 Gly208Cys allele at the orthologous position develop
    pulmonary arterial hypertension with raised right ventricular pressure, right ventricular
    hypertrophy and angio-obliterative pulmonary artery remodelling, together with decreased
    complex II expression and activity, markedly reduced pyruvate dehydrogenase activity and
    lipoate binding; penetrance of the PAH phenotype is higher in females, and males preserve
    oligomeric NFU1 and upregulate ISCU.
  modeled_mechanisms:
  - target: Pulmonary Endothelial Metabolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The only vertebrate model of NFU1 deficiency that develops pulmonary arterial hypertension
      with pulmonary artery remodelling, linking the Fe-S defect to the pulmonary vascular
      phenotype in vivo.
    limitations: >-
      The rat phenotype is a haemodynamic and histological PAH readout rather than a defined
      endothelial mechanism; the model shows a female-predominant penetrance that the human case
      literature does not recapitulate, and the developmental lung disorder seen at human
      autopsy has not been described in the rat.
    readouts:
    - name: Right ventricular pressure and pulmonary artery remodelling
      target: Pulmonary Endothelial Metabolic Dysfunction
      direction: INCREASED
      interpretation: Haemodynamic and histological evidence of pulmonary arterial hypertension in the humanized rat.
      evidence:
      - reference: PMID:31461310
        reference_title: "Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "NFU1G206C rats showed increased right ventricular pressure, right ventricular hypertrophy, and high levels of pulmonary artery remodeling."
        explanation: Reports the PAH readouts in the knock-in rat.
    evidence:
    - reference: PMID:31461310
      reference_title: "Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our work describes a novel, humanized rat model of NFU1 deficiency that showed mitochondrial dysfunction similar to that observed in patients and developed PAH with the same sex dimorphism."
      explanation: Establishes the rat as an in vivo model of the NFU1-associated pulmonary phenotype.
  - target: Respiratory Chain Complex I and II Deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Complex II deficiency and loss of lipoate-dependent PDH activity in rat tissue mitochondria.
    limitations: >-
      Complex I activity is not reported in the abstract, so only the complex II arm of the node
      is documented in the rat.
    readouts:
    - name: Mitochondrial complex II expression and activity
      target: Respiratory Chain Complex I and II Deficiency
      direction: DECREASED
      interpretation: Reproduces the complex II deficiency of patients.
      evidence:
      - reference: PMID:31461310
        reference_title: "Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Male and female homozygote rats exhibited decreased expression and activity of mitochondrial Complex II, and markedly decreased pyruvate dehydrogenase activity and lipoate binding."
        explanation: Reports the complex II and PDH readouts.
    evidence:
    - reference: PMID:31461310
      reference_title: "Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Male and female homozygote rats exhibited decreased expression and activity of mitochondrial Complex II, and markedly decreased pyruvate dehydrogenase activity and lipoate binding."
      explanation: The biochemical phenotype matches the patient enzymology.
experimental_models:
- name: Patient-derived fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Fibroblasts from MMDS1 patients show combined PDH and complex I/II deficiency, reduced
    lipoylation and attenuated mitochondrial protein synthesis; retroviral expression of the
    mitochondrial NFU1 isoform restores respiratory chain and oxoacid dehydrogenase function.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:21944046
  modeled_mechanisms:
  - target: Defective Delivery of 4Fe-4S Clusters to NFU1-Dependent Targets
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The Fe-S maturation defect and its rescue by wild-type mitochondrial NFU1.
    limitations: >-
      Fibroblasts do not model the tissue-specific vulnerability of white matter or the
      pulmonary vasculature.
    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: IN_VITRO
      snippet: "Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic isoform of NFU1 and with isoform 1, but not isoform 2 of BOLA3 restored both respiratory chain function and oxoacid dehydrogenase complexes."
      explanation: Rescue experiment establishing causality in patient cells.
    - 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: "We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype."
      explanation: Validates patient fibroblasts as the cellular model for the Fe-S maturation defect.
discussions:
- discussion_id: mmds1_pulmonary_hypertension_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Pulmonary Endothelial Metabolic Dysfunction
  prompt: >
    Why does NFU1 deficiency, uniquely among the MMDS forms, cause severe pulmonary arterial
    hypertension, and is the lesion a developmental lung disorder, an endothelial metabolic
    defect as shown for BOLA3, or both?
  rationale: >
    PAH is the distinguishing feature of MMDS1 but its mechanism is undefined; autopsy
    suggests a developmental basis while the BOLA3 endothelial work implicates
    lipoate-dependent metabolism and glycine handling; the humanized NFU1 G206C rat develops
    PAH but has not yet resolved the endothelial mechanism.
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date."
    explanation: Explicit statement of the gap.
- discussion_id: mmds1_no_vertebrate_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Bioenergetic Failure and Neurodegeneration
  prompt: >
    Do the available invertebrate and rodent Fe-S models reproduce the cavitating
    leukoencephalopathy and pulmonary hypertension of human NFU1 deficiency, given that the
    sex-based phenotype discrepancy described in rat models is not seen in patients?
  rationale: >
    The C. elegans allelic series reports cellular and neuromuscular phenotypes only, and the
    2026 review notes that a sex-based phenotype difference in rat MMDS models is not
    recapitulated in the human case literature, so translational validity of the animal
    models for the human CNS and pulmonary disease is an open question.
  evidence:
  - reference: PMID:42192213
    reference_title: "A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A key difference between established animal models of this disorder and human cases published to date is that the previously described sex-based phenotype discrepancy in rats was not recapitulated in this review."
    explanation: Documents a model-human mismatch.
  - reference: PMID:31461310
    reference_title: "Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Importantly, the penetrance of the PAH phenotype was found to be more prevalent in females than in males, replicating the established sex difference among patients with PAH."
    explanation: The rat sex dimorphism that the human MMDS1 case literature does not reproduce.
notes: >
  Curated as a per-gene Disease entry (stub entry_type decision: DISEASE), the same
  granularity as Multiple_Mitochondrial_Dysfunctions_Syndrome_9B and the open MMDS4/MMDS6
  PRs; MMDS2 (BOLA3) and MMDS5 (ISCA1) are curated as sibling entries in the same tranche and
  share the lipoate-deficiency chain, which is duplicated rather than inherited. The
  pulmonary node conforms to pulmonary_vascular_remodeling at its endothelial-dysfunction
  entry point on the strength of the BOLA3 endothelial data; the NFU1-specific mechanism is
  recorded as a knowledge gap. Sources: the 2011 discovery papers (PMID:21944046,
  PMID:22077971), cohort and case series (PMID:25918518, PMID:25477904, PMID:29441221,
  PMID:28470589, PMID:32747156, PMID:36256512, PMID:31970900, PMID:42192213), structural and
  biochemical work (PMID:28161430, PMID:28906594, PMID:32776106, PMID:32151725, PMID:37823603,
  PMID:28803783), reviews (PMID:34440194, PMID:35883565), the C. elegans models
  (PMID:34449775, PMID:36645076) and the humanized NFU1 G206C rat (PMID:31461310), the last
  surfaced by the Edison/falcon deep-research report, which completed after the first draft
  and passed preflight (its PAH gene-symbol mentions refer to pulmonary arterial
  hypertension, not the PAH gene). No GeneReviews chapter exists for NFU1-related MMDS (the
  ISCA1 and ISCA2 chapters cover the sibling forms).
📚

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), the same granularity as Multiple_Mitochondrial_Dysfunctions_Syndrome_9B and the open MMDS4/MMDS6 PRs; MMDS2 (BOLA3) and MMDS5 (ISCA1) are curated as sibling entries in the same tranche and share the lipoate-deficiency chain, which is duplicated rather than inherited. The pulmonary node conforms to pulmonary_vascular_remodeling at its endothelial-dysfunction entry point on the strength of the BOLA3 endothelial data; the NFU1-specific mechanism is recorded as a knowledge gap. Sources: the 2011 discovery papers (PMID:21944046, PMID:22077971), cohort and case series (PMID:25918518, PMID:25477904, PMID:29441221, PMID:28470589, PMID:32747156, PMID:36256512, PMID:31970900, PMID:42192213), structural and biochemical work (PMID:28161430, PMID:28906594, PMID:32776106, PMID:32151725, PMID:37823603, PMID:28803783), reviews (PMID:34440194, PMID:35883565), the C. elegans models (PMID:34449775, PMID:36645076) and the humanized NFU1 G206C rat (PMID:31461310), the last surfaced by the Edison/falcon deep-research report, which completed after the first draft and passed preflight (its PAH gene-symbol mentions refer to pulmonary arterial hypertension, not the PAH gene). No GeneReviews chapter exists for NFU1-related MMDS (the ISCA1 and ISCA2 chapters cover the sibling forms).

Edit: add humanized NFU1 G206C rat model and 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 (NFU1 59 mentions, OMIM 605711; the PAH rival-gene warning refers to pulmonary arterial hypertension in the text, not the PAH gene). Cross-checking its reference list against the entry surfaced one uncited primary source, the humanized Nfu1 G206C (human G208C) CRISPR rat (PMID:31461310), which was added as an animal model linked to the pulmonary endothelial node (PARTIALLY_RECAPITULATES, ORGANISM scale, PAH haemodynamic/remodelling readout) and to the complex I/II deficiency node (RECAPITULATES, complex II readout). The pulmonary knowledge-gap rationale no longer states that no NFU1-specific pulmonary model exists, and the rat sex-dimorphism sentence was added as evidence on the human-model-mismatch discussion. The report, its citations sidecar and artifacts are committed. Validation: just validate pass, just validate-terms pass, count-verified-snippets 71/71, check-causal-targets and check-entity-refs clean.

Create: Multiple_Mitochondrial_Dysfunctions_Syndrome_1 (NFU1, MONDO:0011582) · 2026-09-06T02:46:00Z · View source

Created MMDS1 as a per-gene Disease entry (stub entry_type decision: DISEASE), matching the granularity of MMDS9B and the open MMDS4/MMDS6 PRs; the stub's suggestion of a single MMDS1/MMDS2 entry with per-gene subtypes was considered and declined so the series stays uniform, with MMDS2 and MMDS5 curated as sibling entries in the same tranche. Chain: biallelic NFU1 loss, defective 4Fe-4S delivery to NFU1-dependent targets, LIAS deficiency and loss of lipoylation, combined 2-oxoacid dehydrogenase/GCS deficiency, complex I/II deficiency, attenuated mitochondrial translation, bioenergetic failure and neurodegeneration, and a pulmonary endothelial node conforming to pulmonary_vascular_remodeling. Sources: PMID:21944046, PMID:22077971 (discovery), PMID:25918518, PMID:25477904, PMID:29441221, PMID:28470589, PMID:32747156, PMID:36256512, PMID:31970900, PMID:42192213 (clinical), PMID:28161430, PMID:28906594, PMID:32776106, PMID:32151725, PMID:37823603, PMID:28803783 (biochemistry), PMID:34440194, PMID:35883565 (reviews), PMID:34449775, PMID:36645076 (C. elegans), PMID:30759996 (BOLA3 endothelial mechanism, used for the PAH node with an explicit extrapolation note). Deep research: the Edison/falcon run for this entry had not completed when the entry was written (the provider connection was retrying); the entry was built from PubMed abstracts fetched with just fetch-reference and cross-checked against the completed sibling reports where relevant. Corrections during validation: NFU1 HGNC id corrected to hgnc:16287 (an initial wrong id failed term validation), and four snippets containing bracketed Fe-S notation were shortened because bracketed spans are stripped before matching. Validation: just validate pass, just validate-terms pass, count-verified-snippets 66/66, check-causal-targets and check-entity-refs clean. No GeneReviews chapter exists for NFU1-related MMDS.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 40 citations 2026-09-06T02:58:12.198271

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Multiple Mitochondrial Dysfunctions Syndrome 1
  • MONDO ID: MONDO:0011582 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Multiple Mitochondrial Dysfunctions Syndrome 1 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1)

Executive summary

Multiple mitochondrial dysfunctions syndrome 1 is an ultra-rare, autosomal-recessive mitochondrial disorder caused by biallelic pathogenic variants in NFU1, a late-acting iron–sulfur-cluster carrier. Classical MMDS1 is a neonatal/infantile multisystem encephalopathy characterized by hypotonia, feeding failure, developmental arrest or regression, hyperglycinemia, lactic acidosis, respiratory failure, cavitating leukoencephalopathy, and frequently pulmonary arterial hypertension (PAH). Most historically reported severe cases died in infancy. More recent genotype-led ascertainment has established a broader NFU1-related disease continuum, extending to childhood-onset, slowly progressive or episodic hereditary spastic paraplegia (HSP) with substantially longer survival. (ahting2015clinicalbiochemicaland pages 1-2, kaiyrzhanov2022phenotypiccontinuumof pages 1-2, lebigot2021areviewof pages 4-5)

NFU1 deficiency impairs transfer of [4Fe–4S] clusters to selected mitochondrial clients. Particularly important consequences are loss of lipoic-acid synthase activity and protein lipoylation, dysfunction of pyruvate and α-ketoglutarate dehydrogenases and the glycine-cleavage system, respiratory-chain impairment, and—according to 2023 patient-fibroblast work—attenuated mitochondrial protein synthesis. No approved disease-modifying treatment or MMDS1-specific interventional trial was identified; management remains multidisciplinary and supportive. (jain2020assemblyofthe pages 2-2, zhong2023bola3andnfu1 pages 1-2, ahting2015clinicalbiochemicaland pages 5-6)

Domain High-confidence finding Quantitative evidence Evidence type/source
Disease/gene identity MMDS1 is an autosomal-recessive mitochondrial iron–sulfur-cluster maturation disorder caused by biallelic NFU1 variants; identifiers include MONDO:0011582 and OMIM 605711. More than 35 affected individuals had been reported worldwide by 2021. Aggregated disease-target evidence and systematic review (OpenTargets Search: Multiple mitochondrial dysfunctions syndrome 1-NFU1, lebigot2021areviewof pages 2-4, lebigot2021areviewof pages 4-5)
Severe infantile phenotype Classical MMDS1 causes neonatal/infantile encephalopathy with hypotonia, feeding failure, respiratory disease, neurologic regression, and early death. In one seven-patient cohort, 6/7 died within 6 months; an earlier 20-patient summary recorded 20/20 deaths. Human clinical cohort and literature review (ahting2015clinicalbiochemicaland pages 1-2, alfadhel2017mitochondrialironsulfurcluster pages 6-6)
Milder NFU1–HSP continuum Hypomorphic biallelic missense variants can cause pure or complex hereditary spastic paraplegia with longer survival, demonstrating broader expressivity than classical MMDS1. 19 individuals from 10 families: HSP-predominant disease in 16/19 and neurodevelopmental delay with severe hypotonia in 3/19. Multicenter human cohort (kaiyrzhanov2022phenotypiccontinuumof pages 1-2)
Diagnostic biomarkers Elevated lactate and glycine, reduced pyruvate-dehydrogenase activity, and respiratory-chain defects—especially complexes I and II—are important biochemical clues but are not individually specific. Ahting cohort: elevated lactate 5/6, elevated glycine 7/7, PDH deficiency 5/5, and complex I/II+III defects 4/5 tested. Human biochemical cohort (ahting2015clinicalbiochemicaland pages 1-2)
MRI Typical imaging shows symmetric progressive or cavitating white-matter disease; basal-ganglia, thalamic, brainstem, spinal-cord, and corpus-callosum abnormalities may occur. White-matter disease also accompanies milder NFU1-HSP. White-matter abnormalities were present in all members of the reported 19-person NFU1-continuum cohort. Human MRI cohorts and systematic review (lebigot2021areviewof pages 6-7, ahting2015clinicalbiochemicaland pages 5-6, kaiyrzhanov2022phenotypiccontinuumof pages 1-2)
Core mechanism Defective NFU1-mediated [4Fe–4S] delivery compromises LIAS and selected respiratory proteins, reducing protein lipoylation and impairing PDH, α-ketoglutarate dehydrogenase, glycine cleavage, and oxidative phosphorylation. ISCU2 and ISCA1 donate clusters to NFU1; FDX2 assists formation of its bridging [4Fe–4S] cluster. Biochemical/cellular mechanistic study supported by patient biochemistry (jain2020assemblyofthe pages 2-2, ahting2015clinicalbiochemicaland pages 1-2)
Pulmonary hypertension Pulmonary arterial hypertension is a major, sometimes fatal MMDS1 manifestation, particularly reported with p.Gly208Cys. A humanized NFU1 rat reproduced pulmonary vascular remodeling and sex-biased susceptibility. PAH was estimated in approximately 70% of reported Gly208Cys-associated cases; penetrance was greater in female than male mutant rats. Human case synthesis and CRISPR rat model (niihori2020ratswitha pages 1-5, lebigot2021areviewof pages 6-7)
Treatment/trials No approved disease-modifying treatment or MMDS1-specific interventional trial was identified; documented care is supportive, including respiratory, nutritional, cardiac/pulmonary, neurologic, rehabilitative, and palliative management. Registry search returned no relevant MMDS1 interventional trial; severe published cases received measures such as artificial ventilation and palliative care. Trial-registry search and human clinical reports (ahting2015clinicalbiochemicaland pages 5-6, lebigot2021areviewof pages 4-5)
Key 2023 development: translation NFU1-mutant patient fibroblasts revealed previously unrecognized attenuation of mitochondrial protein synthesis; the proposed route is ISCA1–NFU1 delivery of a [4Fe–4S] cluster to METTL17 during small mitoribosomal-subunit assembly. No NFU1-specific clinical effect size reported. Patient-derived fibroblasts and mechanistic cell studies, published October 2023 (zhong2023bola3andnfu1 pages 1-2)
Key 2023 development: neuromuscular signaling Patient-specific C. elegans NFU1 variants caused allele-dependent cholinergic dysfunction: Gly147Arg produced acetylcholine hypersensitivity rescued by reducing acetylcholine release, whereas Gly166Cys predominantly caused postsynaptic hypersensitivity. Reducing acetylcholine release rescued nearly all measured Gly147Arg neuromuscular phenotypes. CRISPR C. elegans model, published February 2023; therapeutic relevance remains preclinical (kropp2023patientspecificvariantsof pages 11-11, kropp2023patientspecificvariantsof pages 1-2)

Table: Concise synthesis of established clinical, biochemical, mechanistic, and model-system evidence for NFU1-related MMDS1, including quantitative cohort findings and major 2023 advances.

1. Disease information

Definition and classification

MMDS1 is a nuclear-encoded mitochondrial Fe–S protein-maturation disorder. It is one of a group of MMDS disorders caused by defects in late mitochondrial [4Fe–4S]-cluster assembly or delivery. It is best regarded as the severe end of the broader NFU1-related disorder spectrum rather than as an invariant infantile phenotype. (lebigot2021areviewof pages 2-4, kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

Identifiers and synonyms

  • MONDO: MONDO:0011582.
  • OMIM phenotype: 605711. Some literature tables label this number directly as MMDS1. (alfadhel2017mitochondrialironsulfurcluster pages 6-6, lebigot2021areviewof pages 4-5)
  • Gene: NFU1, approved name NFU1 iron-sulfur cluster scaffold; Ensembl ENSG00000169599. Open Targets identifies NFU1 as the single associated target for MONDO:0011582. (OpenTargets Search: Multiple mitochondrial dysfunctions syndrome 1-NFU1)
  • Common names: multiple mitochondrial dysfunctions syndrome 1; MMDS1; NFU1 deficiency; NFU1-related mitochondrial disease; NFU1-related disorder; mitochondrial [4Fe–4S]-protein maturation defect.
  • ICD/MeSH: No uniquely specific ICD-10, ICD-11, or MeSH code was established in the retrieved literature. Coding generally falls under inherited mitochondrial/metabolic or neurologic disease categories and should not be treated as MMDS1-specific.

The evidence summarized here is predominantly aggregated disease-level literature, supplemented by small patient cohorts, individual case reports, patient-derived fibroblasts, and engineered animal models. It is not derived from a population-scale EHR dataset.

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

MMDS1 is caused by germline biallelic NFU1 variants—homozygous or compound heterozygous—leading to partial or severe loss of NFU1-mediated Fe–S-cluster delivery. This is a monogenic autosomal-recessive disorder, not an infectious, toxic, lifestyle, or environmentally acquired disease. (kropp2021allelespecificmitochondrialstress pages 1-2, kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

Genetic risk factors

Reported disease alleles include missense, splice-altering, frameshift, and deletion/insertion alleles. Recurrently reported substitutions include p.Gly208Cys, p.Gly189Arg, p.Arg182Gln, p.Arg182Trp, p.Gly190Arg, p.Arg21Pro, and p.Cys210Phe; reported splice/frameshift alleles include c.302+3A>G with predicted p.Val56Glyfs*9. Variant nomenclature has differed across transcripts/publications and should be normalized to the current MANE transcript before database loading. (alfadhel2017mitochondrialironsulfurcluster pages 6-6, ahting2015clinicalbiochemicaland pages 5-6)

The p.Gly208Cys allele alters the region surrounding NFU1’s conserved Cys motif and can increase cluster retention while impairing transfer to recipient proteins. p.Gly189Arg has repeatedly been associated with residual function and, in some patients, later onset or longer survival, although genotype–phenotype prediction remains imperfect. (lebigot2021areviewof pages 6-7)

All established disease variants are germline. No somatic MMDS1 mechanism, repeat expansion, aneuploidy, recurrent translocation, or epigenetic primary cause is established. The retrieved studies do not provide reliable gnomAD allele frequencies, carrier-frequency estimates, or a ClinGen-curated penetrance value; individual pathogenic alleles are expected to be very rare.

Environmental and protective factors

No toxin, diet, smoking behavior, radiation exposure, pathogen, or occupational exposure is known to cause MMDS1. No validated protective genetic variant, diet, supplement, or lifestyle intervention has been demonstrated.

A clinically important interaction is metabolic stress: fever or infection frequently preceded reversible or irreversible neurologic decompensation in the 19-person milder NFU1 cohort, and an infectious episode preceded severe regression in a reported cavitating-leukoencephalopathy case. Infection is therefore a trigger of deterioration in genetically affected individuals, not the underlying cause. (kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

Sex may modify PAH expression: female CRISPR Nfu1-mutant rats developed PAH more often than males, while males showed increased ISCU expression and complex-IV activity. This is compelling model evidence but not a validated human MMDS1 sex-risk estimate. (niihori2020ratswitha pages 1-5)

3. Phenotypes

Classical severe MMDS1

Phenotype Type and course Frequency/evidence Suggested HPO term
Global developmental delay/arrest and regression Sign; neonatal/infantile, severe and progressive or crisis-associated Characteristic across historical cases HP:0001263; HP:0002376
Generalized/axial hypotonia Sign; early, often severe Common in clinical series HP:0001252
Feeding difficulty, poor feeding, vomiting, failure to thrive Symptom/sign; early and progressive Recurrent HP:0011968; HP:0002013; HP:0001508
Respiratory distress, apnea, stridor, respiratory failure Sign; episodic or progressive, potentially fatal Recurrent HP:0002098; HP:0002104; HP:0010307; HP:0002878
Seizures or myoclonus Neurologic sign; variable Reported repeatedly HP:0001250; HP:0001336
Spasticity, dystonia, tetraparesis or motor loss Neurologic sign; progressive or crisis-associated Variable; central in milder HSP spectrum HP:0001257; HP:0001332; HP:0002273
Pulmonary hypertension/right-heart failure Cardiopulmonary sign; severe and sometimes acute/fatal Important MMDS1 clue; approximately 70% quoted for Gly208Cys-associated cases in the rat-study background HP:0002092; HP:0001708
Leukoencephalopathy, sometimes cavitating MRI sign; often symmetric and progressive Highly characteristic HP:0002415; HP:0012444
Lactic/metabolic acidosis Laboratory abnormality; persistent or crisis-related Lactate elevated in 5/6 in Ahting et al. HP:0003128; HP:0001942
Hyperglycinemia Laboratory abnormality Glycine elevated in 7/7 in Ahting et al. HP:0002154
Cardiomyopathy/hepatopathy/tubulopathy Secondary multisystem signs Occasional HP:0001638; HP:0001392; HP:0000124

These manifestations and additional findings—lethargy, abnormal myelination, brainstem or spinal-cord lesions, punctate hemorrhage, basal-ganglia/thalamic lesions, and corpus-callosum abnormalities—are documented across small cohorts and reviews. (lebigot2021areviewof pages 6-7, ahting2015clinicalbiochemicaland pages 5-6, lebigot2021areviewof pages 4-5)

Quantitative clinical evidence

In Ahting et al.’s seven-patient cohort, six patients had fatal infantile encephalopathy and PAH leading to death within the first six months. Biochemical testing showed PDH deficiency in 5/5, respiratory-chain I and II+III defects in 4/5, elevated lactate in 5/6, and elevated glycine in 7/7. (ahting2015clinicalbiochemicaland pages 1-2)

A 2017 literature table summarized 20 neonatal/infantile patients and recorded 20/20 deaths, reflecting ascertainment of the severe historical phenotype rather than present-day survival across all NFU1-related disease. (alfadhel2017mitochondrialironsulfurcluster pages 6-6)

Milder NFU1-related HSP phenotype

The pivotal 2022 multicenter study described 19 affected individuals from ten families with ultra-rare biallelic missense variants: 16/19 had early-onset pure or complex HSP with longer survival, while 3/19 had neurodevelopmental delay with severe hypotonia. Febrile decompensation was common, and white-matter abnormalities were present throughout the cohort. The authors’ central conclusion was that MMDS1 and HSP represent “two ends of the NFU1-related phenotypic continuum.” (kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

Quality of life

No MMDS1-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or health-utility study was located. Functional burden can nevertheless be inferred to be profound: severe cases require respiratory and feeding support and often palliative care; longer-surviving HSP cases experience progressive gait impairment, spasticity, neuropathy, and vulnerability to febrile regression. Formal per-phenotype QoL estimates are unavailable. (ahting2015clinicalbiochemicaland pages 5-6, kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

4. Genetic and molecular information

Causal gene and protein

NFU1 encodes a mitochondrial late-acting Fe–S carrier that assembles or accepts a bridging [4Fe–4S] cluster and transfers it to a restricted set of recipient proteins. ISCU2 and ISCA1 donate [2Fe–2S] precursors; NFU1 dimerization and FDX2-assisted reductive coupling produce the [4Fe–4S] form. A conserved C-terminal hydrophobic patch mediates interactions with ISCU2/ISCA1. (jain2020assemblyofthe pages 2-2)

Suggested annotations include:

  • GO biological process: iron–sulfur cluster assembly (GO:0016226); iron–sulfur cluster transport/transfer; mitochondrial respiratory-chain complex assembly; protein lipoylation; mitochondrial translation.
  • GO molecular function: iron–sulfur cluster binding; metal-cluster carrier activity.
  • GO cellular component: mitochondrial matrix (GO:0005759); mitochondrion (GO:0005739).
  • Chemical entities: [4Fe–4S] cluster; [2Fe–2S] cluster; lipoate/lipoic acid; pyruvate; lactate; glycine; α-ketoglutarate. Appropriate ChEBI identifiers should be validated against the current ontology release.

Variant consequences

Most variants act through loss or reduction of function: impaired protein stability, cluster acquisition, oligomerization, or cluster transfer. Engineered variants form an allelic series rather than behaving as uniform nulls. This helps explain variable expressivity and the MMDS1–HSP continuum. (kropp2021allelespecificmitochondrialstress pages 1-2, kropp2021allelespecificmitochondrialstress pages 2-4)

For clinical curation, each variant requires transcript-normalized HGVS, zygosity, segregation, functional evidence, population frequency, and current ClinVar/ACMG classification. The literature predates uniform application of current ACMG/AMP specifications, so “reported pathogenic” should not automatically be copied as a contemporary laboratory classification.

Modifiers and epigenetics

No human modifier gene has been validated. Increased ISCU expression was associated with relative protection from PAH in male mutant rats, providing a mechanistic modifier hypothesis rather than a human clinical modifier. No reproducible disease-specific DNA-methylation signature, histone alteration, chromatin defect, or pathogenic epimutation is known. (niihori2020ratswitha pages 1-5)

5. Environmental information

Environmental exposures are not etiologic. The main clinically relevant external stressors are fever, infection, fasting/catabolism, dehydration, and other metabolic stresses that may exceed already restricted mitochondrial reserve. The febrile association is supported by human cohorts, whereas fasting and catabolic-risk recommendations are extrapolated from mitochondrial medicine practice rather than MMDS1 trials. (kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

No infectious agent is specifically causal, and MMDS1 is neither communicable nor zoonotic.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic NFU1 pathogenic variants lead to reduced abundance, abnormal oligomerization, impaired cluster acquisition, or defective transfer by mitochondrial NFU1.
  2. Defective NFU1 leads to failure of late [4Fe–4S]-cluster delivery to selected recipient proteins; ISCU2/ISCA1-to-NFU1 transfer and FDX2-assisted cluster formation are upstream biochemical steps. (jain2020assemblyofthe pages 2-2)
  3. Insufficient [4Fe–4S] delivery leads to reduced activity/stability of lipoic-acid synthase and selected respiratory-chain/aconitase targets. (jain2020assemblyofthe pages 2-2, kaiyrzhanov2022phenotypiccontinuumof pages 1-2)
  4. LIAS dysfunction leads to deficient lipoylation of the E2/H components of pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine-cleavage system.
  5. Loss of PDH/KGDH activity leads to impaired carbon entry and flux through the tricarboxylic-acid cycle, reduced oxidative ATP generation, pyruvate-to-lactate diversion, and accumulation of organic-acid intermediates.
  6. Glycine-cleavage failure leads to hyperglycinemia, which may compound neurologic dysfunction.
  7. Respiratory-chain dysfunction leads to reduced oxidative phosphorylation, altered redox state, membrane-potential loss, and variant-dependent reactive oxygen species/reactive iron stress. (kropp2021allelespecificmitochondrialstress pages 11-12, kropp2021allelespecificmitochondrialstress pages 1-2)
  8. NFU1 deficiency also leads to impaired [4Fe–4S] loading of METTL17 during small-mitoribosomal-subunit assembly—proposed rather than fully proven in vivo—and results in attenuated mitochondrial protein synthesis in patient fibroblasts. (zhong2023bola3andnfu1 pages 1-2)
  9. Energy/redox/translation failure leads to dysfunction and injury in high-demand oligodendroglial, neuronal, muscular, respiratory, myocardial, and pulmonary-vascular cells; the exact cell-death sequence is partly inferred.
  10. White-matter injury leads to leukoencephalopathy, regression, hypotonia/spasticity and seizures, while pulmonary-vascular metabolic remodeling leads to PAH, right-ventricular hypertrophy and potentially fatal right-heart failure. The vascular causal link is supported directly in mutant rats. (niihori2020ratswitha pages 1-5)

Cellular and tissue interpretation

The hallmark white-matter disease suggests high vulnerability of oligodendrocytes (CL:0000128), their precursors (CL:0002453), and myelinated axons/neurons (CL:0000540), although human single-cell confirmation is unavailable. Pulmonary arterial endothelial cells (CL:0000115) and vascular smooth-muscle cells (CL:0000359) are implicated by vascular remodeling; cardiomyocytes (CL:0000746) and skeletal myocytes (CL:0000188) are affected through energy failure.

Suggested GO processes include oxidative phosphorylation (GO:0006119), aerobic respiration (GO:0009060), mitochondrial translation (GO:0032543), response to oxidative stress (GO:0006979), axon ensheathment (GO:0008366), and regulation of membrane potential. Inflammation, adaptive immunity, Wnt, MAPK, PI3K–AKT, and mTOR are not established primary disease pathways.

Molecular profiling

  • Proteomic/biochemical: reduced lipoylated mitochondrial proteins and recipient-enzyme activities are the most reproducible molecular signature. (ahting2015clinicalbiochemicaland pages 1-2, jain2020assemblyofthe pages 2-2)
  • Metabolomic: elevated lactate, pyruvate and glycine; occasional urinary α-ketoglutarate, glutarate, or 2-hydroxybutyrate. (lebigot2021areviewof pages 6-7, alfadhel2017mitochondrialironsulfurcluster pages 6-6)
  • Translation profiling: 2023 work demonstrated reduced mitochondrial pulse-label synthesis in NFU1-mutant fibroblasts and connected NFU1 to METTL17/mitoribosome assembly. (zhong2023bola3andnfu1 pages 1-2)
  • Single-cell/spatial transcriptomics/multi-omics: no MMDS1-specific human atlas was located.
  • Functional genomics: CRISPR models in rat and C. elegans are available; no clinically validated genome-wide therapeutic screen was found.

7. Anatomical structures affected

Organ and system level

The primary systems are the central nervous system, neuromuscular system, lungs/pulmonary vasculature, and systemic energy metabolism. Secondary involvement includes heart/right ventricle, skeletal muscle, liver, kidney tubules, and respiratory apparatus. (ahting2015clinicalbiochemicaland pages 5-6, lebigot2021areviewof pages 4-5)

Suggested UBERON mappings include brain (UBERON:0000955), cerebral white matter (UBERON:0002437), corpus callosum (UBERON:0002336), basal ganglion (UBERON:0002420), thalamus (UBERON:0001897), brainstem (UBERON:0002298), spinal cord (UBERON:0002240), lung (UBERON:0002048), pulmonary artery (UBERON:0002012), heart (UBERON:0000948), skeletal muscle tissue (UBERON:0001134), liver (UBERON:0002107), and kidney (UBERON:0002113). Identifier validation against the target ontology version is advised.

Subcellular level

The initiating defect is in the mitochondrial matrix and affects Fe–S carriers, respiratory-chain machinery, TCA-cycle/lipoylated complexes, glycine cleavage, and mitoribosome assembly. No consistent lateralization is expected; MRI abnormalities are generally bilateral/symmetric.

8. Temporal development

Classical disease begins neonatally or in early infancy, sometimes after an initially unremarkable period. The course is usually rapidly progressive, with feeding and respiratory deterioration, metabolic acidosis, encephalopathy, regression, and PAH. Onset from birth to approximately nine months was represented in early clinical literature. (ahting2015clinicalbiochemicaland pages 1-2)

Longer-surviving NFU1 disease may begin in infancy or childhood with motor delay, lower-limb spasticity, gait disturbance, or hypotonia. Its course may be slowly progressive or relapsing/stepwise, with febrile illnesses producing reversible or permanent loss of function. (kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

There are no validated stages. A practical clinical framework is: presymptomatic genetically affected; early developmental/metabolic abnormalities; established neurologic or cardiopulmonary disease; crisis/decompensation; and advanced respiratory/right-heart or severe neurologic failure. Spontaneous remission is not established, although partial recovery after febrile decompensation occurs in some milder patients.

9. Inheritance and population

Inheritance is autosomal recessive. Parents of an affected individual are usually heterozygous carriers; for a couple in whom both partners carry the relevant familial allele, each pregnancy has a 25% affected, 50% carrier, and 25% unaffected/non-carrier probability, assuming ordinary Mendelian segregation.

By 2021, more than 35 MMDS1 patients from multiple continents had been published, but this is a literature count—not prevalence. No reliable incidence per 100,000, prevalence, carrier frequency, sex ratio, or population-based survival estimate exists. (lebigot2021areviewof pages 2-4, lebigot2021areviewof pages 4-5)

Consanguinity is present in some families but is not required; both consanguineous homozygous and non-consanguineous compound-heterozygous families are reported. A recurrent p.Gly208Cys allele occurred in Spanish/French patients and has been described as a founder allele, but its population carrier frequency is not established in the retrieved evidence. (ahting2015clinicalbiochemicaland pages 1-2, ahting2015clinicalbiochemicaland pages 5-6)

Penetrance appears high for individuals with two clearly damaging alleles, but severity is highly variable and formal penetrance estimates are unavailable. There is no evidence of anticipation. Germline mosaicism has not been quantified; standard counseling should acknowledge a small residual recurrence risk after an apparently de novo allele.

10. Diagnostics

When to suspect MMDS1

Consider NFU1 disease in a neonate or infant with combinations of hyperglycinemia, lactic acidosis, hypotonia/regression, respiratory failure, PAH, and symmetric or cavitating leukoencephalopathy. Also consider it in early-onset HSP with white-matter abnormalities, especially where fever precipitates neurologic decline. (ahting2015clinicalbiochemicaland pages 5-6, kaiyrzhanov2022phenotypiccontinuumof pages 1-2)

Recommended investigations

  1. Urgent chemistry/metabolic testing: blood gas, lactate, pyruvate, glucose, electrolytes, liver/renal indices; plasma amino acids with glycine; CSF lactate and amino acids when clinically safe; urine organic acids; acylcarnitines and standard metabolic crisis studies.
  2. Cardiopulmonary evaluation: ECG, echocardiography with PA-pressure/right-heart assessment, oxygenation and respiratory review. PAH may be a decisive clue and requires specialist confirmation.
  3. Neurodiagnostics: brain MRI with diffusion-weighted imaging and spectroscopy where available; EEG for seizures; EMG/nerve-conduction studies in HSP/neuropathy phenotypes.
  4. Biochemical confirmation: PDH activity, respiratory-chain enzyme studies, succinate dehydrogenase/complex-II assessment, and immunoblotting for lipoylated DLAT/DLST/GCSH in fibroblasts or muscle can support pathogenicity. In Ahting et al., the combination of PDH and respiratory-chain testing had high yield, but normal results in one tissue do not exclude milder disease. (ahting2015clinicalbiochemicaland pages 1-2, lebigot2021areviewof pages 6-7)
  5. Genetic confirmation: sequence and deletion/duplication analysis of NFU1, preferably through a mitochondrial disease, leukodystrophy, hyperglycinemia, or HSP multigene panel, or trio WES/WGS. The 2021 review explicitly concluded that large NGS panels or exome sequencing are needed for confirmation. (lebigot2021areviewof pages 2-4)
  6. RNA analysis: fibroblast RNA/cDNA testing is useful for suspected splice variants or when only one pathogenic allele is found.

WGS is useful for deep intronic, structural, or otherwise unresolved variants; WES is effective for coding/splice-region variants. Chromosomal microarray, karyotype, FISH, mtDNA-only sequencing, and repeat-expansion testing are not first-line tests for a classic NFU1 presentation, although mtDNA analysis may be included in a broad mitochondrial workup.

Differential diagnosis

Key alternatives are MMDS2–5/other late Fe–S maturation disorders (BOLA3, IBA57, ISCA2, ISCA1), primary lipoate-synthesis defects (LIAS, LIPT1, LIPT2), glycine-cleavage disorders (GLDC, AMT, GCSH), primary PDH-complex defects, other mitochondrial respiratory-chain disorders, and cavitating leukodystrophies including APOPT1-related disease. NFU1 is favored by combined PDH/lipoylation and respiratory-chain defects, hyperglycinemia, PAH, and characteristic white-matter disease, but molecular confirmation is required. (kropp2021allelespecificmitochondrialstress pages 29-30, ahting2015clinicalbiochemicaland pages 5-6)

There are no validated standalone clinical diagnostic criteria. Prenatal molecular diagnosis is possible only after familial variants are established. MMDS1 is not a standard universal newborn-screening condition; biochemical markers lack adequate specificity and no proven early disease-modifying therapy currently satisfies classic screening criteria.

11. Outcomes and prognosis

Historical prognosis was extremely poor: 6/7 patients in a 2015 cohort died by six months, and an older 20-patient literature summary recorded 20/20 deaths. These figures should not be generalized to every genotype because later cohorts uncovered longer-surviving HSP phenotypes. (ahting2015clinicalbiochemicaland pages 1-2, alfadhel2017mitochondrialironsulfurcluster pages 6-6)

Major causes or mediators of death include respiratory failure, PAH/right-heart failure, severe metabolic decompensation, and progressive encephalopathy. Prognostic indicators likely include age at onset, residual NFU1 activity, variant class, PAH, ventilatory dependence, severity of white-matter disease, and recurrent crises, but no validated prognostic score or biomarker exists.

Survivors may have persistent intellectual, motor, spastic, dystonic, neuropathic, respiratory, and feeding disability. There are no 5- or 10-year survival curves and no controlled treatment-versus-no-treatment survival analysis.

12. Treatment and current applications

Current standard: supportive multidisciplinary care

No therapy has been shown to restore NFU1 function or alter survival in controlled human studies. Published severe cases received interventions such as artificial ventilation and palliative care. (ahting2015clinicalbiochemicaland pages 5-6)

Practical management includes:

  • stabilization of airway, breathing, circulation, glucose and acid–base balance during crises;
  • early enteral nutrition assessment and aspiration prevention;
  • seizure-directed therapy guided by EEG and mitochondrial-drug safety;
  • respiratory support, secretion management, sleep/ventilation studies and vaccination;
  • serial echocardiography and expert PAH/right-heart management;
  • physical, occupational, speech, feeding and spasticity therapies;
  • hearing, vision, orthopedic, hepatic and renal surveillance according to phenotype;
  • early palliative-care involvement in severe disease.

These map broadly to NCIT concepts for supportive care, mechanical ventilation, enteral nutrition, physical therapy, occupational therapy, speech therapy, anticonvulsant therapy, and palliative care. Exact NCIT codes should be verified in the intended terminology release.

Drugs and advanced therapeutics

No NFU1-specific approved drug, established pharmacogenomic rule, gene therapy, cell therapy, ASO/siRNA therapy, or enzyme-replacement therapy exists. Empiric “mitochondrial cocktails,” lipoic acid, thiamine, riboflavin, biotin, carnitine, antioxidants, or dichloroacetate lack MMDS1 efficacy evidence and can carry risks; they should not be represented as proven therapies.

A 2023 C. elegans study found that reducing acetylcholine release rescued nearly all Gly147Arg neuromuscular phenotypes, raising an allele-specific cholinergic-treatment hypothesis. The opposite/partly postsynaptic behavior of Gly166Cys underscores why this is not yet a general treatment recommendation. (kropp2023patientspecificvariantsof pages 11-11, kropp2023patientspecificvariantsof pages 1-2)

The tool-based ClinicalTrials.gov search found no relevant MMDS1/NFU1 interventional trial. Accordingly, response rates, adverse-event frequencies, treatment algorithms, and combination-therapy outcomes are unavailable.

13. Prevention

Primary prevention through lifestyle modification is not possible because MMDS1 is inherited. Effective reproductive prevention options after molecular diagnosis include genetic counseling, carrier testing of the reproductive partner and relatives, cascade testing, prenatal diagnosis, and preimplantation genetic testing for monogenic disease.

Secondary prevention consists of early recognition in siblings and at-risk relatives, baseline cardiopulmonary/MRI/metabolic assessment, and rapid treatment of fever, infection, poor intake, dehydration, and catabolism. Families should receive a written emergency plan. These measures are clinically rational but have not been tested in MMDS1 trials.

Tertiary prevention targets aspiration, contractures, malnutrition, respiratory infections, seizures, PAH/right-heart failure, and avoidable metabolic stress. Routine age-appropriate immunization, including respiratory-pathogen vaccines, is appropriate; no disease-specific vaccine or prophylactic medication exists.

14. Other species and natural disease

NFU1 and mitochondrial Fe–S transfer are evolutionarily conserved. Relevant experimental species include:

  • Rattus norvegicus — NCBI Taxonomy 10116;
  • Caenorhabditis elegans — NCBI Taxonomy 6239;
  • Homo sapiens — NCBI Taxonomy 9606.

No well-established naturally occurring NFU1-MMDS1 veterinary syndrome, breed predisposition, VBO mapping, zoonotic transmission, or cross-species infectious susceptibility was identified. Comparative evidence is therefore principally from induced genetic models rather than natural animal disease.

15. Model organisms and advanced experimental systems

CRISPR Nfu1-G206C rat

The rat mutation corresponds to human p.Gly208Cys. Homozygous rats developed elevated right-ventricular pressure, right-ventricular hypertrophy, pulmonary-artery remodeling, and severe angio-obliterative vascular changes. Both sexes had reduced complex-II activity/expression, PDH activity, and lipoate binding, but PAH was more penetrant in females; males showed preserved NFU1 oligomerization, increased ISCU and increased complex-IV activity. This is strong in-vivo causal evidence linking NFU1 dysfunction to PAH. Its major limitation is incomplete recapitulation of fatal infantile encephalopathy: the animals survived to adulthood. (niihori2020ratswitha pages 1-5)

Patient-variant C. elegans

CRISPR recreation of five patient variants in nfu-1 produced an allelic series of respiratory dysfunction, membrane-potential changes, oxidative stress and reactive mitochondrial iron. Reactive iron occurred only with some alleles, showing that iron dyshomeostasis is a variant-dependent contributor rather than a universal mechanism. DAF-16 and SKN-1 stress responses and body-wall-muscle reporter changes were allele specific. (kropp2021allelespecificmitochondrialstress pages 11-12, kropp2021allelespecificmitochondrialstress pages 1-2)

A subsequent 2023 study found opposite cholinergic effects from Gly147Arg and Gly166Cys. Gly147Arg produced acetylcholine hypersensitivity and was rescued by reducing acetylcholine release; Gly166Cys produced predominantly postsynaptic hypersensitivity through an unresolved mechanism. Limitations include species differences, homozygous modeling of variants that may occur as compound heterozygotes in patients, and inability to model human PAH or white-matter disease. (kropp2023patientspecificvariantsof pages 11-11, kropp2023patientspecificvariantsof pages 1-2)

Human fibroblasts and recent developments

Patient fibroblasts remain the most directly relevant functional system for testing protein lipoylation, respiratory-chain activity, splice effects, and NFU1 abundance. The principal recent advance was Zhong et al. (published October 2023; DOI: https://doi.org/10.1093/nar/gkad842), which identified attenuated mitochondrial protein synthesis in NFU1-mutant fibroblasts and proposed ISCA1–NFU1-mediated [4Fe–4S] insertion into METTL17 during mitoribosome assembly. The abstract states that patient fibroblasts display “previously unrecognized attenuation of mitochondrial protein synthesis.” (zhong2023bola3andnfu1 pages 1-2)

The other major 2023 development was Kropp et al. (published February 2023; DOI: https://doi.org/10.1242/dmm.049594), whose abstract reports that the two modeled variants had “altered acetylcholine signaling at neuromuscular junctions, but opposite effects on activity and motility.” (kropp2023patientspecificvariantsof pages 1-2)

No comparably transformative MMDS1-specific human clinical study from 2024 was identified in the retrieved literature. Thus, the current frontier remains mechanistic—mitoribosome biology, variant-specific stress responses, pulmonary vascular metabolism, and functional classification of rare alleles—rather than clinical therapeutics.

Evidence limitations and knowledge-base cautions

MMDS1 evidence is dominated by small, retrospective, genotype-enriched cohorts and case reports. Historical mortality and PAH frequencies are susceptible to severe-phenotype ascertainment. Variant-level phenotypes can be confounded by compound heterozygosity, tissue-specific residual activity, inconsistent transcript numbering, and heterogeneous biochemical testing. Animal rescue findings must not be presented as human treatment evidence.

Formal prevalence, penetrance, carrier frequency, natural-history curves, standardized QoL data, validated diagnostic criteria, prospective biomarkers, controlled treatment outcomes, and human single-cell or spatial-omics data are unavailable. Claims labeled “not identified” reflect the literature and registry searches conducted for this report, not proof that no unpublished data exist.

Selected primary and authoritative sources

  1. Cameron JM et al. American Journal of Human Genetics. Published October 2011. “Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3…” PMID 21944046; DOI: https://doi.org/10.1016/j.ajhg.2011.08.011. (kropp2021allelespecificmitochondrialstress pages 29-30)
  2. Navarro-Sastre A et al. Original NFU1 fatal mitochondrial disease report. Published 2011. PMID 22077971. (kropp2021allelespecificmitochondrialstress pages 29-30)
  3. Invernizzi F et al. Frontiers in Genetics. Published November 2014. DOI: https://doi.org/10.3389/fgene.2014.00412. Described infection-associated regression, lactic acidosis, hyperglycinemia, complex-II/PDH deficiency and cavitating leukoencephalopathy.
  4. Ahting U et al. Frontiers in Genetics 6:123. Published 13 April 2015. PMID 25918518; DOI: https://doi.org/10.3389/fgene.2015.00123. (OpenTargets Search: Multiple mitochondrial dysfunctions syndrome 1-NFU1, ahting2015clinicalbiochemicaland pages 1-2)
  5. Jain A et al. Human Molecular Genetics 29:3165–3182. Published August 2020. DOI: https://doi.org/10.1093/hmg/ddaa172. (jain2020assemblyofthe pages 2-2)
  6. Niihori M et al. American Journal of Respiratory Cell and Molecular Biology 62:231–242. Published February 2020. DOI: https://doi.org/10.1165/rcmb.2019-0065OC. (niihori2020ratswitha pages 1-5)
  7. Lebigot E et al. Biomedicines 9:989. Published August 2021. DOI: https://doi.org/10.3390/biomedicines9080989. (lebigot2021areviewof pages 2-4, lebigot2021areviewof pages 4-5)
  8. Kropp PA et al. PLOS Genetics 17:e1009771. Published 27 August 2021. DOI: https://doi.org/10.1371/journal.pgen.1009771. (kropp2021allelespecificmitochondrialstress pages 1-2)
  9. Kaiyrzhanov R et al. Annals of Clinical and Translational Neurology 9:2025–2035. Published October 2022. DOI: https://doi.org/10.1002/acn3.51679. (kaiyrzhanov2022phenotypiccontinuumof pages 1-2)
  10. Kropp PA et al. Disease Models & Mechanisms 16. Published February 2023. DOI: https://doi.org/10.1242/dmm.049594. (kropp2023patientspecificvariantsof pages 1-2)
  11. Zhong H et al. Nucleic Acids Research 51:11797–11812. Published October 2023. DOI: https://doi.org/10.1093/nar/gkad842. (zhong2023bola3andnfu1 pages 1-2)

References

  1. (ahting2015clinicalbiochemicaland pages 1-2): Uwe Ahting, Johannes A. Mayr, Arnaud V. Vanlander, Steven A. Hardy, Saikat Santra, Christine Makowski, Charlotte L. Alston, Franz A. Zimmermann, Lucia Abela, Barbara Plecko, Marianne Rohrbach, Stephanie Spranger, Sara Seneca, Boris Rolinski, Angela Hagendorff, Maja Hempel, Wolfgang Sperl, Thomas Meitinger, Joél Smet, Robert W. Taylor, Rudy Van Coster, Peter Freisinger, Holger Prokisch, and Tobias B. Haack. Clinical, biochemical, and genetic spectrum of seven patients with nfu1 deficiency. Frontiers in Genetics, Apr 2015. URL: https://doi.org/10.3389/fgene.2015.00123, doi:10.3389/fgene.2015.00123. This article has 116 citations and is from a peer-reviewed journal.

  2. (kaiyrzhanov2022phenotypiccontinuumof pages 1-2): Rauan Kaiyrzhanov, Maha S. Zaki, Tracy Lau, Sambuddha Sen, Reza Azizimalamiri, Mina Zamani, Gözde Yeşil Sayin, Taru Hilander, Stephanie Efthymiou, Viorica Chelban, Ruth Brown, Kyle Thompson, Maria Irene Scarano, Jaya Ganesh, Kairgali Koneev, Ismail Musab Gülaçar, Richard Person, Dinara Sadykova, Yerdan Maidyrov, Tahereh Seifi, Aizhan Zadagali, Geneviève Bernard, Katrina Allis, Houda Zghal Elloumi, Amanda Lindy, Ehsan Taghiabadi, Sumit Verma, Rachel Logan, Brian Kirmse, Renkui Bai, Shaimaa M. Khalaf, Mohamed S. Abdel‐Hamid, Alireza Sedaghat, Gholamreza Shariati, Mahmoud Issa, Jawaher Zeighami, Hasnaa M. Elbendary, Garry Brown, Robert W. Taylor, Hamid Galehdari, Joseph J. Gleeson, Christopher J. Carroll, James A. Cowan, Andres Moreno‐De‐Luca, Henry Houlden, and Reza Maroofian. Phenotypic continuum of nfu1 ‐related disorders. Annals of Clinical and Translational Neurology, 9:2025-2035, Oct 2022. URL: https://doi.org/10.1002/acn3.51679, doi:10.1002/acn3.51679. This article has 9 citations and is from a peer-reviewed journal.

  3. (lebigot2021areviewof pages 4-5): 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. (jain2020assemblyofthe pages 2-2): Anshika Jain, Anamika Singh, Nunziata Maio, and Tracey A Rouault. Assembly of the [4fe–4s] cluster of nfu1 requires the coordinated donation of two [2fe–2s] clusters from the scaffold proteins, iscu2 and isca1. Human Molecular Genetics, 29(19):3165-3182, Aug 2020. URL: https://doi.org/10.1093/hmg/ddaa172, doi:10.1093/hmg/ddaa172. This article has 27 citations and is from a domain leading peer-reviewed journal.

  5. (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.

  6. (ahting2015clinicalbiochemicaland pages 5-6): Uwe Ahting, Johannes A. Mayr, Arnaud V. Vanlander, Steven A. Hardy, Saikat Santra, Christine Makowski, Charlotte L. Alston, Franz A. Zimmermann, Lucia Abela, Barbara Plecko, Marianne Rohrbach, Stephanie Spranger, Sara Seneca, Boris Rolinski, Angela Hagendorff, Maja Hempel, Wolfgang Sperl, Thomas Meitinger, Joél Smet, Robert W. Taylor, Rudy Van Coster, Peter Freisinger, Holger Prokisch, and Tobias B. Haack. Clinical, biochemical, and genetic spectrum of seven patients with nfu1 deficiency. Frontiers in Genetics, Apr 2015. URL: https://doi.org/10.3389/fgene.2015.00123, doi:10.3389/fgene.2015.00123. This article has 116 citations and is from a peer-reviewed journal.

  7. (OpenTargets Search: Multiple mitochondrial dysfunctions syndrome 1-NFU1): Open Targets Query (Multiple mitochondrial dysfunctions syndrome 1-NFU1, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  8. (lebigot2021areviewof pages 2-4): 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.

  9. (alfadhel2017mitochondrialironsulfurcluster pages 6-6): Majid Alfadhel, Marwan Nashabat, Qais Abu Ali, and Khalid Hundallah. Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease. Neurosciences, 22:4-13, Jan 2017. URL: https://doi.org/10.17712/nsj.2017.1.20160542, doi:10.17712/nsj.2017.1.20160542. This article has 33 citations and is from a peer-reviewed journal.

  10. (lebigot2021areviewof pages 6-7): 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.

  11. (niihori2020ratswitha pages 1-5): Maki Niihori, Cody A. Eccles, Sergey Kurdyukov, Marina Zemskova, Mathews Valuparampil Varghese, Anna A. Stepanova, Alexander Galkin, Ruslan Rafikov, and Olga Rafikova. Rats with a human mutation of nfu1 develop pulmonary hypertension. Feb 2020. URL: https://doi.org/10.1165/rcmb.2019-0065oc, doi:10.1165/rcmb.2019-0065oc. This article has 49 citations and is from a peer-reviewed journal.

  12. (kropp2023patientspecificvariantsof pages 11-11): Peter A. Kropp, Philippa Rogers, Sydney E. Kelly, Rebecca McWhirter, Willow D. Goff, Ian M. Levitan, David M. Miller, and Andy Golden. Patient-specific variants of nfu1/nfu-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1. Feb 2023. URL: https://doi.org/10.1242/dmm.049594, doi:10.1242/dmm.049594. This article has 1 citations and is from a domain leading peer-reviewed journal.

  13. (kropp2023patientspecificvariantsof pages 1-2): Peter A. Kropp, Philippa Rogers, Sydney E. Kelly, Rebecca McWhirter, Willow D. Goff, Ian M. Levitan, David M. Miller, and Andy Golden. Patient-specific variants of nfu1/nfu-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1. Feb 2023. URL: https://doi.org/10.1242/dmm.049594, doi:10.1242/dmm.049594. This article has 1 citations and is from a domain leading peer-reviewed journal.

  14. (kropp2021allelespecificmitochondrialstress pages 1-2): Peter A. Kropp, Jing Wu, Michael Reidy, Sanjay Shrestha, Kyle Rhodehouse, Philippa Rogers, Michael N. Sack, and Andy Golden. Allele-specific mitochondrial stress induced by multiple mitochondrial dysfunctions syndrome 1 pathogenic mutations modeled in caenorhabditis elegans. Aug 2021. URL: https://doi.org/10.1371/journal.pgen.1009771, doi:10.1371/journal.pgen.1009771. This article has 12 citations and is from a domain leading peer-reviewed journal.

  15. (kropp2021allelespecificmitochondrialstress pages 2-4): Peter A. Kropp, Jing Wu, Michael Reidy, Sanjay Shrestha, Kyle Rhodehouse, Philippa Rogers, Michael N. Sack, and Andy Golden. Allele-specific mitochondrial stress induced by multiple mitochondrial dysfunctions syndrome 1 pathogenic mutations modeled in caenorhabditis elegans. Aug 2021. URL: https://doi.org/10.1371/journal.pgen.1009771, doi:10.1371/journal.pgen.1009771. This article has 12 citations and is from a domain leading peer-reviewed journal.

  16. (kropp2021allelespecificmitochondrialstress pages 11-12): Peter A. Kropp, Jing Wu, Michael Reidy, Sanjay Shrestha, Kyle Rhodehouse, Philippa Rogers, Michael N. Sack, and Andy Golden. Allele-specific mitochondrial stress induced by multiple mitochondrial dysfunctions syndrome 1 pathogenic mutations modeled in caenorhabditis elegans. Aug 2021. URL: https://doi.org/10.1371/journal.pgen.1009771, doi:10.1371/journal.pgen.1009771. This article has 12 citations and is from a domain leading peer-reviewed journal.

  17. (kropp2021allelespecificmitochondrialstress pages 29-30): Peter A. Kropp, Jing Wu, Michael Reidy, Sanjay Shrestha, Kyle Rhodehouse, Philippa Rogers, Michael N. Sack, and Andy Golden. Allele-specific mitochondrial stress induced by multiple mitochondrial dysfunctions syndrome 1 pathogenic mutations modeled in caenorhabditis elegans. Aug 2021. URL: https://doi.org/10.1371/journal.pgen.1009771, doi:10.1371/journal.pgen.1009771. This article has 12 citations and is from a domain leading peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 12
On topic 8
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 54
Resolved 54
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 5
Terms named correctly 0
Terms named as a different term 3
Terms whose name is worth a second look 2

Terms the report names something else

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

  • MONDO:0011582 (4 mentions) - the report calls it "if available"; MONDO calls it multiple mitochondrial dysfunctions syndrome 1
  • HP:0001252 (1 mention) - the report calls it "Common in clinical series"; HP calls it Hypotonia
  • HP:0002154 (1 mention) - the report calls it "Glycine elevated in 7/7 in Ahting et al"; HP calls it Hyperglycinemia

Terms whose name is worth a second look

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

  • GO:0016226 (1 mention) - the report calls it "GO biological process: iron–sulfur cluster assembly"; GO calls it iron-sulfur cluster assembly**
  • GO:0005759 (1 mention) - the report calls it "GO cellular component: mitochondrial matrix"; GO calls it mitochondrial matrix**