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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals are homozygous or compound heterozygous for FDX2 variants, and heterozygous parents and siblings are unaffected.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:24281368 SUPPORT Human Clinical

"we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy"

The founding report describes recessive transmission in a consanguineous family.

PMID:30010796 SUPPORT Human Clinical

"We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype"

Six patients in two families with recessive segregation.

PMID:37565517 SUPPORT Human Clinical

"the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister"

Unaffected heterozygous parents and sibling of a homozygous proband.

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Pathophysiology

11

Biallelic FDX2 Variants

The reported alleles are start-codon region variants that abolish or shift translation initiation (in five of the eight reported families), the Brazilian missense p.Pro144Leu, a splice-acceptor variant c.146-2A>G found in trans with a start-codon allele, and a splice-region variant c.200+4A>G that replaces 19 N-terminal residues. All are germline, and all tested alleles reduce FDX2 protein abundance or function without abolishing it entirely.

FDX2 hgnc:30546

Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

electron transfer activity GO:0009055 ↓ DECREASED

Downstream

Reduced Mitochondrial Ferredoxin 2 Protein Start-codon, splice and missense alleles all lower the steady-state amount of FDX2 protein in patient muscle or fibroblasts.

Impaired FDXR-to-FDX2 Electron Transfer The p.Pro144Leu substitution sits in a loop distant from the [2Fe-2S] cluster and impairs electron acceptance from FDXR.

Show evidence (4 references)

PMID:24281368 SUPPORT Human Clinical

"We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein."

First disease-causing FDX2 allele, a start-codon variant.

PMID:30010796 SUPPORT Human Clinical

"The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L)."

The recurrent missense allele behind the multisystem presentation.

PMID:38444577 SUPPORT Human Clinical

"We described a new case harboring compound heterozygous variants in FDX2 who presented with recurrent rhabdomyolysis"

Compound heterozygosity is also pathogenic.

+ 1 more reference

Reduced Mitochondrial Ferredoxin 2 Protein

Patient muscle and fibroblasts contain little FDX2. Because FDX2 is the mitochondrial ferredoxin that serves Fe-S protein maturation, its shortage limits electron supply to the ISC machinery.

skeletal muscle fiber CL:0008002 patient dermal fibroblast CL:0000057

FDX2 hgnc:30546

electron transfer activity GO:0009055 ↓ DECREASED

Downstream

Impaired Mitochondrial Iron-Sulfur Cluster Assembly

Show evidence (2 references)

PMID:41372147 SUPPORT In Vitro

"Collectively, the results show that the FDX2 mutation leads to a severe decrease of FDX2 protein"

Patient-derived cells carrying the splice allele have low FDX2 protein.

PMID:39632806 SUPPORT In Vitro

"This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2)."

Structural work places FDX2 as the electron donor within the core ISC complex, the activity lost when the protein is scarce.

Impaired FDXR-to-FDX2 Electron Transfer

FDX2 receives electrons from NADPH through ferredoxin reductase (FDXR). The p.Pro144Leu allele weakens this transfer, which the authors link to a reduced capacity to assemble both [2Fe-2S] and [4Fe-4S] clusters.

FDX2 hgnc:30546

electron transfer activity GO:0009055 ↓ DECREASED

Downstream

Impaired Mitochondrial Iron-Sulfur Cluster Assembly

Show evidence (1 reference)

PMID:39467201 SUPPORT In Vitro

"the pathogenic P144L mutation negatively affects the FDXR-dependent electron transfer pathway from NADPH to FDX2"

In vitro comparison of wild-type and mutant protein with FDXR.

Impaired Mitochondrial Iron-Sulfur Cluster Assembly

FDX2 supplies electrons for de novo [2Fe-2S] cluster synthesis on the ISCU2 scaffold and again for reductive fusion of [2Fe-2S] clusters into [4Fe-4S] clusters on ISCA1-ISCA2-IBA57. Partial FDX2 deficiency therefore lowers maturation of both [2Fe-2S] and [4Fe-4S] mitochondrial proteins. Cell-culture knockdown studies agree that FDX2 is required for Fe-S protein biogenesis; whether FDX1 also contributes is debated, which may bear on how much residual Fe-S assembly patient tissues retain.

iron-sulfur cluster assembly GO:0016226 ↓ DECREASED [2Fe-2S] cluster assembly GO:0044571 ↓ DECREASED [4Fe-4S] cluster assembly GO:0044572 ↓ DECREASED

Downstream

Deficiency of Fe-S-Dependent Respiratory Chain Complexes

Loss of Mitochondrial Aconitase Activity

Mitochondrial Iron Accumulation

Reduced Activity of Lipoate-Dependent 2-Oxoacid Dehydrogenases Lipoyl synthase is a [4Fe-4S] enzyme, so defective cluster maturation is expected to reduce lipoylation of the E2 subunits of pyruvate, 2-ketoglutarate and 2-oxoadipate dehydrogenases. Patient data on this step disagree (see the target node).

Show evidence (5 references)

PMID:20547883 SUPPORT In Vitro

"we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis"

RNAi depletion in human cells shows FDX2 is required for Fe-S protein biogenesis.

PMID:36280795 SUPPORT In Vitro

"Here, we show that only FDX2, but not FDX1, is involved in Fe-S protein maturation."

Assigns Fe-S protein maturation specifically to FDX2.

PMID:32817474 SUPPORT In Vitro

"yet surprisingly also depended on mitochondrial ferredoxin FDX2 and its NADPH-coupled reductase FDXR"

Reconstituted maturation of [4Fe-4S] aconitase required FDX2, placing it in the [4Fe-4S] cluster-forming step as well as in [2Fe-2S] synthesis.

+ 2 more references

Deficiency of Fe-S-Dependent Respiratory Chain Complexes

Complexes I, II and III each contain Fe-S clusters. Patient muscle shows reduced activity of all three, and patient fibroblasts and myoblasts show reduced complex I activity and oxygen consumption. Complexes II and III were normal in fibroblasts from one start-codon patient, so the extent of the defect varies by tissue and allele.

skeletal muscle fiber CL:0008002 patient dermal fibroblast CL:0000057

mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Downstream

Decreased activity of mitochondrial complex I

Decreased activity of mitochondrial complex II

Decreased activity of mitochondrial complex III

Patchy SDH and COX deficiency in muscle

Skeletal Muscle Energy Failure

Show evidence (3 references)

PMID:24281368 SUPPORT Human Clinical

"showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"

Combined complex I, II and III deficiency in patient muscle.

PMID:35079622 SUPPORT In Vitro

"Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities"

Reduced respiration and complex I activity in patient-derived cells.

PMID:41372147 SUPPORT In Vitro

"cultured patient's cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation"

Impaired respiration and loss of Fe-S proteins in cells from a third genotype.

Loss of Mitochondrial Aconitase Activity

Mitochondrial aconitase (ACO2) carries a [4Fe-4S] cluster and loses activity, and protein, when cluster maturation fails, limiting flux through the tricarboxylic acid cycle.

tricarboxylic acid cycle GO:0006099 ↓ DECREASED

Downstream

Reduced muscle aconitase activity

Skeletal Muscle Energy Failure Reduced aconitase activity lowers tricarboxylic acid cycle flux and reducing-equivalent supply to the respiratory chain, adding to the bioenergetic deficit.

Show evidence (2 references)

PMID:24281368 SUPPORT Human Clinical

"showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"

Aconitase activity is reduced in patient muscle.

PMID:41372147 SUPPORT In Vitro

"as well as aconitase (ACO2) and ferrochelatase (FECH) were decreased (relative to citrate synthase as mitochondrial control protein) in MEOAL cells"

Aconitase protein is reduced in patient fibroblasts.

Reduced Activity of Lipoate-Dependent 2-Oxoacid Dehydrogenases

Pyruvate dehydrogenase complex activity is reduced in fibroblasts from a start-codon patient, and a compound heterozygous patient excreted 2-hydroxyadipic acid, a marker of deficient lipoate-dependent 2-oxoadipate dehydrogenase, and had lactate that rose with glucose infusion, as in PDH deficiency. Whether the cause is defective lipoylation is unsettled: one patient's cells show reduced lipoylation, another's show normal lipoylation of the PDH and 2-ketoglutarate dehydrogenase E2 subunits.

protein lipoylation GO:0009249 ↓ DECREASED pyruvate decarboxylation to acetyl-CoA GO:0006086 ↓ DECREASED

Downstream

Lactic acidosis

2-hydroxyadipic aciduria

Show evidence (4 references)

PMID:35079622 SUPPORT In Vitro

"Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities"

Reduced PDH complex activity in patient-derived cells.

PMID:41372147 SUPPORT In Vitro

"Likewise, we noted a defect in lipoylation, presumably due to defective maturation of the FeS protein lipoyl synthase (LIAS)"

Reduced lipoylation in fibroblasts with the c.200+4A>G allele.

PMID:35079622 REFUTE In Vitro

"PDHc-E2 and α-KDGHc-E2 were correctly lipoylated in the absence of FDX2"

Contradicts a lipoylation defect for the start-codon allele; PDH activity loss there must arise another way.

+ 1 more reference

Mitochondrial Iron Accumulation

Failed Fe-S cluster production is sensed as iron deficiency, driving iron uptake and mitochondrial iron loading. Iron accumulation was seen in muscle of the p.Pro144Leu patients and in fibroblasts of the c.200+4A>G patient, but was absent from muscle of a start-codon patient, so it is allele- or tissue-dependent.

skeletal muscle fiber CL:0008002

intracellular iron ion homeostasis GO:0006879 ⚠ ABNORMAL

Downstream

Patchy SDH and COX deficiency in muscle Iron deposits co-localise with the regional respiratory chain defect in biopsies, but whether iron loading worsens the defect is not established.

Show evidence (3 references)

PMID:30010796 SUPPORT Human Clinical

"regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation"

Iron accumulation in patient muscle.

PMID:41372147 SUPPORT In Vitro

"cultured patient's cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation"

Mitochondrial iron accumulation in patient fibroblasts.

PMID:35079622 REFUTE Human Clinical

"This excessive iron accumulation was absent from FDX2 affected muscle"

No iron accumulation in muscle from a start-codon patient.

Skeletal Muscle Energy Failure

Combined respiratory chain and tricarboxylic acid cycle deficiency leaves skeletal muscle with low oxidative ATP-producing capacity. At rest this appears as exercise intolerance and weakness; under catabolic stress (febrile illness, fasting, exertion, cold) demand outstrips supply and myofibres break down. Muscle then relies on glycolysis, producing lactate.

skeletal muscle fiber CL:0008002

cellular respiration GO:0045333 ↓ DECREASED

Downstream

Mitochondrial myopathy

Exercise intolerance

Proximal muscle weakness

Muscle cramps

Myalgia

Lactic acidosis

Episodic Rhabdomyolysis

Show evidence (1 reference)

PMID:35079622 SUPPORT Human Clinical

"They have recurrent RM episodes precipitated by febrile illnesses, fasting, exercise, cold, or fatigue, sometimes without trigger"

Catabolic triggers of rhabdomyolysis in two patients.

Episodic Rhabdomyolysis

Acute breakdown of skeletal muscle during metabolic crises, with creatine kinase rising into the hundreds of thousands of U/L. Release of muscle contents causes acute kidney injury that can require dialysis, and involvement of respiratory muscles can cause respiratory failure. The sister of one patient died during an episode.

skeletal muscle fiber CL:0008002

Downstream

Rhabdomyolysis

Highly elevated creatine kinase

Acute kidney injury

Respiratory insufficiency due to muscle weakness

Show evidence (2 references)

PMID:37565517 SUPPORT Human Clinical

"presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"

Recurrent severe rhabdomyolysis.

PMID:35079622 SUPPORT Human Clinical

"To determine common clinical and biological traits in 2 individuals with variants in ISCU and FDX2, displaying severe and recurrent rhabdomyolyses and lactic acidosis."

Recurrent rhabdomyolysis in an FDX2 patient.

Neuro-ophthalmic and Neural Involvement

In the p.Pro144Leu families, and in one splice-variant patient, the nervous system is affected as well as muscle: early optic atrophy with nystagmus, a sensorimotor axonal neuropathy, a white matter disorder that reverses or partly reverses, and in the splice-variant patient cerebellar atrophy. These tissues depend heavily on oxidative metabolism and Fe-S enzymes, but how FDX2 deficiency produces each lesion, and why the white matter changes are reversible, has not been studied.

retinal ganglion cell CL:0000740 sensory neuron CL:0000101

Downstream

Optic atrophy

Nystagmus

Sensorimotor axonal neuropathy

Reversible leukoencephalopathy

Cerebellar atrophy

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2."

Nervous system involvement in the p.Pro144Leu families.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

27

Blood 2

Microcytic anemia HP:0001935

Tabulated in 4 of 6 p.Pro144Leu patients in the 2024 case comparison and in none of the start-codon patients. No mechanism has been studied in patients.

Show evidence (1 reference)

PMID:38444577 SUPPORT REVIEW SYNTHESIS Human Clinical

"Optic atrophy, neurodevelopmental abnormalities, microcytic anemia, neutropenia, hypothyroidism have been reported in some patients."

Summary of extramuscular features across published patients.

Neutropenia Decreased total neutrophil count HP:0001875

Tabulated in 4 of 6 p.Pro144Leu patients in the 2024 case comparison.

Show evidence (1 reference)

PMID:38444577 SUPPORT REVIEW SYNTHESIS Human Clinical

"Optic atrophy, neurodevelopmental abnormalities, microcytic anemia, neutropenia, hypothyroidism have been reported in some patients."

Summary of extramuscular features across published patients.

Eye 2

Optic atrophy HP:0000648

Show evidence (2 references)

PMID:30010796 SUPPORT Human Clinical

"a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3"

Early optic atrophy.

PMID:38444577 SUPPORT REVIEW SYNTHESIS Human Clinical

"Extra‐muscular manifestations including optic atrophy and hematologic complications have been reported in two Brazilian families harboring homozygous c.422C > T (p.Pro141Leu) but have not been reported elsewhere."

Restricts optic atrophy to the p.Pro144Leu (p.Pro141Leu) families.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3"

Early-onset nystagmus.

Genitourinary 3

Acute kidney injury HP:0001919

Show evidence (2 references)

PMID:37565517 SUPPORT Human Clinical

"She was hospitalized in the pediatric intensive care unit due to acute kidney injury"

Acute kidney injury during rhabdomyolysis.

PMID:34905296 SUPPORT Human Clinical

"He needed hemodialysis for severe rhabdomyolysis-related acute renal failure"

Dialysis-requiring renal failure.

Ketonuria HP:0002919

Show evidence (1 reference)

PMID:37565517 SUPPORT Human Clinical

"showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies"

Urinary ketones during decompensation.

2-hydroxyadipic aciduria HP:0034465

Show evidence (1 reference)

PMID:38444577 SUPPORT Human Clinical

"Biochemical analysis of the patients revealed hyperexcretion of 2-hydroxyadipic acid, along with previously reported biochemical abnormalities."

Urinary 2-hydroxyadipic acid in an FDX2 patient.

Metabolism 3

Highly elevated creatine kinase HP:0030234

Show evidence (2 references)

PMID:37565517 SUPPORT Human Clinical

"CPK 319,990 U/L, lactic acid 22.31 mmol/L"

Extremely high CK during an episode.

PMID:34905296 SUPPORT Human Clinical

"he has significantly elevated CK during episodes of rhabdomyolysis"

High CK during episodes.

Lactic acidosis HP:0003128

Show evidence (2 references)

PMID:34905296 SUPPORT Human Clinical

"Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis."

Lactic acidosis with rhabdomyolysis.

PMID:37565517 SUPPORT Human Clinical

"CPK 319,990 U/L, lactic acid 22.31 mmol/L"

Severe hyperlactataemia during an episode.

Hyperammonemia HP:0001987

Reported in a single patient; the authors note it had not been seen in earlier patients.

Show evidence (1 reference)

PMID:37565517 SUPPORT Human Clinical

"Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies."

Raised ammonia during decompensation.

Musculoskeletal 8

Mitochondrial myopathy HP:0003737

Show evidence (2 references)

PMID:24281368 SUPPORT Human Clinical

"a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy"

Mitochondrial myopathy in the index patient.

PMID:38444577 SUPPORT BACKGROUND Human Clinical

"Pathogenic variants in FDX2 have been associated with autosomal recessive FDX2-related disorder characterized by mitochondrial myopathy with or without optic atrophy and leukoencephalopathy."

Myopathy is the constant feature across reported cases.

Proximal muscle weakness HP:0003701

Show evidence (1 reference)

PMID:37565517 SUPPORT Human Clinical

"presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"

Episodic proximal weakness.

Muscle cramps Muscle spasm HP:0003394

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"recurrent episodes of cramps, myalgia and muscle weakness"

Recurrent cramps in the p.Pro144Leu families.

Rhabdomyolysis HP:0003201

Show evidence (2 references)

PMID:34905296 SUPPORT Human Clinical

"Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis."

Recurrent severe rhabdomyolysis.

PMID:37565517 SUPPORT Human Clinical

"presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"

A further patient with severe rhabdomyolysis.

Respiratory insufficiency due to muscle weakness HP:0002747

Show evidence (1 reference)

PMID:38444577 SUPPORT Human Clinical

"who presented with recurrent rhabdomyolysis with severe episodes affecting respiratory muscle"

Respiratory muscle involvement.

Reduced muscle aconitase activity HP:0034511

Show evidence (1 reference)

PMID:24281368 SUPPORT Human Clinical

"showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"

Measured in patient muscle.

Patchy SDH and COX deficiency in muscle Cytochrome C oxidase-negative muscle fibers HP:0003688

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation."

Histochemical finding in patient muscle.

Distal muscle weakness Progressive distal muscle weakness HP:0009063

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"Sensory-motor axonal neuropathy led to progressive distal weakness."

Progressive distal weakness.

Nervous System 4

Sensorimotor axonal neuropathy Peripheral axonal neuropathy HP:0003477

Sequelae: Distal muscle weakness

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"Sensory-motor axonal neuropathy led to progressive distal weakness."

Axonal neuropathy in the p.Pro144Leu families.

Reversible leukoencephalopathy HP:0002352

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"MRI disclosed a reversible or partially reversible leukoencephalopathy."

White matter disease on MRI.

Cerebellar atrophy HP:0001272

Single patient (c.200+4A>G homozygous), who also had severe ataxia, dysarthria, pyramidal signs and foveal hypoplasia, but no rhabdomyolysis.

Sequelae: Ataxia

Show evidence (1 reference)

PMID:41372147 SUPPORT Human Clinical

"A first MRI at 2 years of age showed cerebellar hypoplasia which appeared as a progressive cerebellar atrophy in subsequent MRIs"

Progressive cerebellar atrophy on serial MRI.

Ataxia HP:0001251

Single patient (c.200+4A>G homozygous).

Show evidence (1 reference)

PMID:41372147 SUPPORT Human Clinical

"her clinical picture was characterized by severe ataxic signs (trunk and head ballottement, dysarthria, dysmetria, intentional tremor, and nystagmus)"

Severe ataxia.

Cellular 3

Decreased activity of mitochondrial complex I HP:0011923

Show evidence (2 references)

PMID:24281368 SUPPORT Human Clinical

"showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"

Measured in patient muscle.

PMID:35079622 SUPPORT In Vitro

"reduced oxygen consumption rates and mitochondrial complex I and PDHc activities"

Measured in patient fibroblasts and myoblasts.

Decreased activity of mitochondrial complex II HP:0008314

Show evidence (1 reference)

PMID:24281368 SUPPORT Human Clinical

"showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"

Measured in patient muscle.

Decreased activity of mitochondrial complex III HP:0011924

Show evidence (1 reference)

PMID:24281368 SUPPORT Human Clinical

"showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"

Measured in patient muscle.

Constitutional 2

Exercise intolerance HP:0003546

Show evidence (1 reference)

PMID:41372147 SUPPORT BACKGROUND Human Clinical

"characterized by childhood onset of progressive muscle weakness and exercise intolerance"

Exercise intolerance is a defining feature.

Myalgia HP:0003326

Show evidence (1 reference)

PMID:30010796 SUPPORT Human Clinical

"recurrent episodes of cramps, myalgia and muscle weakness"

Recurrent myalgia in the p.Pro144Leu families.

🧬

Genetic Associations

1

FDX2 (Biallelic pathogenic variants in FDX2)

Gene: FDX2 hgnc:30546 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:30010796 SUPPORT Human Clinical

"This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2"

Gene-disease mapping in two families.

PMID:24281368 SUPPORT Human Clinical

"identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein"

First FDX2 disease allele.

Variants (6)

c.1A>T (p.Met1?)

Start-codon variant, homozygous in the founding patient and in a French patient, and in trans with c.146-2A>G in an American patient; reduces FDX2 protein in muscle and fibroblasts.

Show evidence (1 reference)

PMID:24281368 SUPPORT Human Clinical

"The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria."

Effect of the start-codon allele.

c.431C>T (p.Pro144Leu)

Homozygous in six patients from two Brazilian families with the multisystem presentation. Normal mRNA but severely reduced protein in muscle; in vitro the mutant protein accepts electrons from FDXR poorly.

Also known as: c.422C>T (p.Pro141Leu) P144L

Show evidence (2 references)

PMID:30010796 SUPPORT Human Clinical

"The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L)."

Identification of the allele.

PMID:39467201 SUPPORT In Vitro

"This mutation alters a highly conserved proline residue located in a loop of FDX2"

The substituted proline is conserved and lies in a loop away from the iron-sulfur cluster.

c.12G>T (p.Met4Ile)

Homozygous start-region variant in a 20-year-old man with recurrent rhabdomyolysis.

Show evidence (1 reference)

PMID:34905296 SUPPORT Human Clinical

"Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I)."

Identification of the allele.

c.10A>T (p.Met4Leu)

Homozygous start-region variant in a girl with severe rhabdomyolysis.

Show evidence (1 reference)

PMID:37565517 SUPPORT Human Clinical

"Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T)"

Identification of the allele.

c.146-2A>G

Splice-acceptor variant found in trans with c.1A>T.

Show evidence (1 reference)

PMID:38444577 SUPPORT Human Clinical

"The variant c.146‐2A > G is predicted to cause abnormal splicing, disrupting protein function."

Identification and predicted effect.

c.200+4A>G

Homozygous splice-region variant that replaces 19 N-terminal residues with 21 different amino acids and lowers FDX2 protein.

Show evidence (1 reference)

PMID:41372147 SUPPORT In Vitro

"the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids"

Splicing effect demonstrated in patient material.

💊

Medical Actions

4

Parenteral nutrition with high protein and lipid and low glucose

Action: parenteral nutrition with high protein and lipid content Ontology label: Total Parenteral Nutrition NCIT:C29484

Platform: Other

During a rhabdomyolysis episode in which CK stayed high on intravenous dextrose, and lactate rose when the dextrose concentration was increased, switching to parenteral nutrition rich in protein and lipid with 5% dextrose was followed by a rapid fall in CK and lactate. This is a single case observation.

Target Phenotypes: Rhabdomyolysis HP:0003201 Lactic acidosis HP:0003128

Show evidence (1 reference)

PMID:38444577 SUPPORT Human Clinical

"Lactate and CK drastically decreased when parenteral nutrition containing high protein and lipid contents with low glucose was initiated."

Single-patient response during an acute episode.

Mitochondrial cofactor supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: coenzyme Q10 CHEBI:46245

Platform: Small molecule

Patients have received vitamin and cofactor combinations including coenzyme Q10, riboflavin, thiamine, biotin, niacin and N-acetylcysteine. No effect on disease course has been reported.

Show evidence (2 references)

PMID:41372147 SUPPORT Human Clinical

"the patient started a multivitamin therapy (cocktail of riboflavin, thiamin and coenzyme Q) when she was three years old"

Documents use; no efficacy data.

PMID:38444577 SUPPORT Human Clinical

"He was subsequently decannulated and discharged with home regimen of sodium bicarbonate and mitochondrial cocktail comprising of n‐acetylcysteine, niacin, biotin and coenzyme Q10."

Documents use; no efficacy data.

Trigger avoidance and graded exercise

Action: exercise counseling and trigger avoidance Ontology label: Exercise Counseling NCIT:C101235

Platform: Behavioral / lifestyle

Rhabdomyolysis episodes are provoked by febrile illness, fasting, exertion and cold, so avoidance of prolonged fasting and of exertion during intercurrent illness is advised. Graded low-intensity exercise is recommended for mitochondrial myopathies generally; it has not been studied in FDX2 deficiency.

Target Phenotypes: Rhabdomyolysis HP:0003201 Exercise intolerance HP:0003546

Show evidence (2 references)

PMID:25008908 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"not exercise on days they have fever, superimposed illness, muscle pain, or cramps, and/or if they have fasted for more than 12 hours"

General guidance for primary mitochondrial cytopathies, extrapolated to FDX2 deficiency.

PMID:35079622 SUPPORT Human Clinical

"They have recurrent RM episodes precipitated by febrile illnesses, fasting, exercise, cold, or fatigue, sometimes without trigger"

Identifies the triggers to be avoided in FDX2-deficient patients.

🔬

Biochemical Markers

1

Blood FGF21 (INCREASED)

Show evidence (1 reference)

PMID:35079622 SUPPORT Human Clinical

"associated with high levels of blood FGF21"

Elevated FGF21 in the FDX2 patient.

🔬

Diagnosis

2

Exome sequencing

Every reported patient was diagnosed by exome sequencing, in some cases combined with homozygosity mapping. The founding report recommends FDX2 analysis in mitochondrial myopathy with combined complex I, II and III deficiency.

Whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:24281368 SUPPORT Human Clinical

"We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III."

Diagnostic recommendation from the founding report.

PMID:37565517 SUPPORT Human Clinical

"suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies"

Recommendation to test FDX2 in suspected mitochondrial myopathy.

Muscle biopsy

Muscle shows reduced activity of complexes I, II, III and aconitase, and in the p.Pro144Leu families regional SDH and COX deficiency with iron accumulation; fibroblasts may not show the muscle defect.

Muscle biopsy NCIT:C51895

Show evidence (2 references)

PMID:30010796 SUPPORT Human Clinical

"Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation."

Characteristic biopsy finding.

PMID:28803783 SUPPORT In Vitro

"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."

Fibroblast studies can miss the defect in FDX2 myopathy, so muscle is the preferred tissue.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population prevalence has been published. A 2025 report counts eleven previously reported patients and adds one; a 2024 case comparison counts 11 patients from 7 families including its own proband. The only allele shared between families is p.Pro144Leu in two Brazilian families.

Show evidence (2 references)

PMID:39467201 SUPPORT REVIEW SYNTHESIS Other

"MEOAL is an ultra‐rare inherited neuromuscular disorder"

Characterises the disorder as ultra-rare.

PMID:41372147 SUPPORT BACKGROUND Human Clinical

"To date, only eleven MEOAL patients have been reported by the medical literature."

Literature case count before the 2025 report.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from FDX2-Related Mitochondrial Myopathy:

ISCU myopathy MONDO:0009706

Overlapping Features Recessive ISCU deficiency produces the same picture of exercise intolerance, recurrent rhabdomyolysis and lactic acidosis with Fe-S enzyme deficiency in muscle. In a direct comparison the FDX2 patient was more severely affected, while iron accumulated in ISCU-deficient but not in FDX2-deficient muscle. Genetic testing separates them.

Show evidence (1 reference)

PMID:35079622 SUPPORT Human Clinical

"We conclude that FDX2 and ISCU variants result in a similar muscle phenotype, that differ in severity and skeletal muscle iron accumulation."

Head-to-head comparison of the two disorders.

{ }

Source YAML

click to show

name: FDX2-Related Mitochondrial Myopathy
creation_date: "2026-10-12T14:48:06Z"
category: Mendelian
synonyms:
- MEOAL
- mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
- episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy
- FDX2-related disorder
description: >-
  FDX2-related mitochondrial myopathy (MEOAL; OMIM 251900) is an ultra-rare
  autosomal recessive disorder caused by biallelic variants in FDX2 (formerly
  FDX1L), which encodes mitochondrial ferredoxin 2. FDX2 is the [2Fe-2S]
  ferredoxin that, reduced by NADPH through ferredoxin reductase (FDXR),
  supplies electrons to the mitochondrial iron-sulfur cluster (ISC) assembly
  machinery, both for de novo [2Fe-2S] cluster synthesis on ISCU2 and for the
  later reductive fusion that forms [4Fe-4S] clusters. Every reported allele
  lowers the amount of FDX2 protein or its ability to accept electrons, so the
  disease is a partial loss of Fe-S protein maturation. Its measurable
  consequences are reduced activity of the Fe-S-dependent respiratory chain
  complexes I, II and III and of mitochondrial aconitase, reduced oxygen
  consumption, and in some patients mitochondrial iron accumulation.

  Skeletal muscle is the tissue that fails first and most often. All reported
  patients have a mitochondrial myopathy with exercise intolerance and muscle
  weakness, and most have recurrent, sometimes life-threatening rhabdomyolysis
  with very high creatine kinase and lactic acidosis, provoked by febrile
  illness, fasting, exertion or cold and complicated by acute kidney injury or
  respiratory muscle failure. A second, multisystem presentation was defined in
  two Brazilian families homozygous for p.Pro144Leu: optic atrophy and
  nystagmus by age three, then myopathy with episodic cramps and myalgia,
  sensorimotor axonal neuropathy, and a reversible or partially reversible
  leukoencephalopathy. The authors of a 2024 case comparison note that patients
  carrying a start-codon allele have had muscle-restricted disease, and suggest
  that more severely damaging alleles produce the multisystem form. Around a
  dozen patients have been reported.
disease_term:
  preferred_term: mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
  term:
    id: MONDO:0020714
    label: mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
parents:
- inborn mitochondrial myopathy
- multiple mitochondrial dysfunctions syndrome
notes: >-
  Entity and gene. MONDO:0020714 is equivalent to OMIM:251900 and has no
  descendants in MONDO; its parents are MONDO:0009637 (inborn mitochondrial
  myopathy) and MONDO:0017338 (fatal multiple mitochondrial dysfunctions
  syndrome). FDX2 is HGNC:30546 (ferredoxin 2, 19p13.2, previous symbol FDX1L,
  UniProt Q6P4F2); the founding paper (PMID:24281368) uses the old symbol
  FDX1L throughout. The disease is curated as one entry: a single gene, a
  single recessive mode, and one mechanism (loss of FDX2 electron supply to
  Fe-S cluster assembly) shared by every allele. The muscle-restricted and
  multisystem presentations are described in the phenotype descriptions rather
  than as subtypes, because they rest on about a dozen patients and no ontology
  or clinical source names them as separate entities.

  Variant nomenclature. Two FDX2 transcripts that differ by three N-terminal
  codons are used in the literature, so start-codon region variants are written
  c.1A>T (p.Met1?) in some reports and c.10A>T (p.Met4Leu) or c.12G>T
  (p.Met4Ile) in others, and the Brazilian missense allele is written c.431C>T
  (p.P144L) in the original report and c.422C>T (p.Pro141Leu) on
  NM_001397406.1 in the 2024 case comparison. Variants are recorded below as
  each source writes them.

  Features not modelled as phenotypes. Compensated hypothyroidism and diabetes
  mellitus are tabulated for some members of the two p.Pro144Leu families in
  the 2024 case comparison (PMID:38444577, Table 1) and appear as very rare
  features in the HPO annotation of OMIM:251900. They are not curated as
  phenotypes because the primary report's abstract does not mention them and
  no mechanism links them to FDX2 deficiency. Microcytic anaemia and
  neutropenia, from the same table, are curated with the review as source. A
  single 2025 patient (PMID:41372147) with a splice-region allele had
  cerebellar hypoplasia progressing to atrophy, ataxia, pyramidal signs and
  foveal hypoplasia without rhabdomyolysis; the cerebellar findings are
  curated and flagged as single-patient observations.

  Lipoylation is contested. FDX2 is required to mature lipoyl synthase (LIAS),
  a [4Fe-4S] enzyme, yet PDH-E2 and 2-ketoglutarate dehydrogenase-E2
  lipoylation was normal in fibroblasts and myoblasts from a start-codon
  patient (PMID:35079622), while fibroblasts from the 2025 splice-variant
  patient showed reduced lipoylation (PMID:41372147). In vitro work places the
  electron supply of lipoyl synthase on FDX1 rather than FDX2 (PMID:36280795).
  The lipoate-dependent dehydrogenase node below carries both directions of
  evidence.

  Module conformance was considered and not declared. complex_i_deficiency
  models isolated complex I deficiency, whereas FDX2 deficiency is a combined
  complex I to III and aconitase defect upstream of any one complex, and
  mitochondrial_dysfunction models age-associated decline.

  No GeneReviews chapter exists for this disorder.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for FDX2
    variants, and heterozygous parents and siblings are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy"
    explanation: The founding report describes recessive transmission in a consanguineous family.
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype"
    explanation: Six patients in two families with recessive segregation.
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister"
    explanation: Unaffected heterozygous parents and sibling of a homozygous proband.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence has been published. A 2025 report counts eleven
    previously reported patients and adds one; a 2024 case comparison counts
    11 patients from 7 families including its own proband. The only allele
    shared between families is p.Pro144Leu in two Brazilian families.
  evidence:
  - reference: PMID:39467201
    reference_title: "Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "MEOAL is an ultra‐rare inherited neuromuscular disorder"
    explanation: Characterises the disorder as ultra-rare.
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "To date, only eleven MEOAL patients have been reported by the medical literature."
    explanation: Literature case count before the 2025 report.
pathophysiology:
- name: Biallelic FDX2 Variants
  description: >-
    The reported alleles are start-codon region variants that abolish or shift
    translation initiation (in five of the eight reported families), the
    Brazilian missense p.Pro144Leu, a splice-acceptor variant c.146-2A>G found
    in trans with a start-codon allele, and a splice-region variant c.200+4A>G
    that replaces 19 N-terminal residues. All are germline, and all tested
    alleles reduce FDX2 protein abundance or function without abolishing it
    entirely.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: FDX2
    term:
      id: hgnc:30546
      label: FDX2
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: electron transfer activity
    term:
      id: GO:0009055
      label: electron transfer activity
    modifier: DECREASED
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein."
    explanation: First disease-causing FDX2 allele, a start-codon variant.
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L)."
    explanation: The recurrent missense allele behind the multisystem presentation.
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We described a new case harboring compound heterozygous variants in FDX2 who presented with recurrent rhabdomyolysis"
    explanation: Compound heterozygosity is also pathogenic.
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids"
    explanation: A splice-region allele with a defined effect on the transcript and protein.
  downstream:
  - target: Reduced Mitochondrial Ferredoxin 2 Protein
    causal_link_type: DIRECT
    description: >-
      Start-codon, splice and missense alleles all lower the steady-state
      amount of FDX2 protein in patient muscle or fibroblasts.
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria."
      explanation: The start-codon allele reduces FDX2 protein in muscle and fibroblasts.
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue"
      explanation: The p.Pro144Leu allele leaves mRNA intact but lowers protein, implying protein instability.
  - target: Impaired FDXR-to-FDX2 Electron Transfer
    causal_link_type: DIRECT
    description: >-
      The p.Pro144Leu substitution sits in a loop distant from the [2Fe-2S]
      cluster and impairs electron acceptance from FDXR.
    evidence:
    - reference: PMID:39467201
      reference_title: "Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the data indicate that the pathogenic P144L mutation negatively affects the FDXR-dependent electron transfer pathway from NADPH to FDX2"
      explanation: Recombinant protein work shows the missense allele impairs electron transfer from FDXR.
- name: Reduced Mitochondrial Ferredoxin 2 Protein
  description: >-
    Patient muscle and fibroblasts contain little FDX2. Because FDX2 is the
    mitochondrial ferredoxin that serves Fe-S protein maturation, its shortage
    limits electron supply to the ISC machinery.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: FDX2
    term:
      id: hgnc:30546
      label: FDX2
  molecular_functions:
  - preferred_term: electron transfer activity
    term:
      id: GO:0009055
      label: electron transfer activity
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: patient dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Collectively, the results show that the FDX2 mutation leads to a severe decrease of FDX2 protein"
    explanation: Patient-derived cells carrying the splice allele have low FDX2 protein.
  - reference: PMID:39632806
    reference_title: "Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2)."
    explanation: Structural work places FDX2 as the electron donor within the core ISC complex, the activity lost when the protein is scarce.
  downstream:
  - target: Impaired Mitochondrial Iron-Sulfur Cluster Assembly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41372147
      reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the FDX2 mutation leads to a severe decrease of FDX2 protein, resulting in a primary mild cellular FeS protein assembly defect"
      explanation: Links low FDX2 protein to a primary Fe-S protein assembly defect in patient cells.
- name: Impaired FDXR-to-FDX2 Electron Transfer
  description: >-
    FDX2 receives electrons from NADPH through ferredoxin reductase (FDXR). The
    p.Pro144Leu allele weakens this transfer, which the authors link to a
    reduced capacity to assemble both [2Fe-2S] and [4Fe-4S] clusters.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: FDX2
    term:
      id: hgnc:30546
      label: FDX2
  molecular_functions:
  - preferred_term: electron transfer activity
    term:
      id: GO:0009055
      label: electron transfer activity
    modifier: DECREASED
  evidence:
  - reference: PMID:39467201
    reference_title: "Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the pathogenic P144L mutation negatively affects the FDXR-dependent electron transfer pathway from NADPH to FDX2"
    explanation: In vitro comparison of wild-type and mutant protein with FDXR.
  downstream:
  - target: Impaired Mitochondrial Iron-Sulfur Cluster Assembly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39467201
      reference_title: "Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the pathogenic P144L mutation negatively affects the FDXR-dependent electron transfer pathway from NADPH to FDX2"
      explanation: The authors conclude that the reduced electron transfer lowers the capacity of FDX2 to assemble both [2Fe-2S] and [4Fe-4S] clusters.
- name: Impaired Mitochondrial Iron-Sulfur Cluster Assembly
  description: >-
    FDX2 supplies electrons for de novo [2Fe-2S] cluster synthesis on the
    ISCU2 scaffold and again for reductive fusion of [2Fe-2S] clusters into
    [4Fe-4S] clusters on ISCA1-ISCA2-IBA57. Partial FDX2 deficiency therefore
    lowers maturation of both [2Fe-2S] and [4Fe-4S] mitochondrial proteins.
    Cell-culture knockdown studies agree that FDX2 is required for Fe-S
    protein biogenesis; whether FDX1 also contributes is debated, which may
    bear on how much residual Fe-S assembly patient tissues retain.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: iron-sulfur cluster assembly
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    modifier: DECREASED
  - preferred_term: '[2Fe-2S] cluster assembly'
    term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    modifier: DECREASED
  - preferred_term: '[4Fe-4S] cluster assembly'
    term:
      id: GO:0044572
      label: '[4Fe-4S] cluster assembly'
    modifier: DECREASED
  evidence:
  - reference: PMID:20547883
    reference_title: "Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis"
    explanation: RNAi depletion in human cells shows FDX2 is required for Fe-S protein biogenesis.
  - reference: PMID:36280795
    reference_title: "Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that only FDX2, but not FDX1, is involved in Fe-S protein maturation."
    explanation: Assigns Fe-S protein maturation specifically to FDX2.
  - reference: PMID:32817474
    reference_title: "Mitochondrial [4Fe-4S] protein assembly involves reductive [2Fe-2S] cluster fusion on ISCA1-ISCA2 by electron flow from ferredoxin FDX2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "yet surprisingly also depended on mitochondrial ferredoxin FDX2 and its NADPH-coupled reductase FDXR"
    explanation: Reconstituted maturation of [4Fe-4S] aconitase required FDX2, placing it in the [4Fe-4S] cluster-forming step as well as in [2Fe-2S] synthesis.
  - reference: PMID:22101253
    reference_title: "Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We concluded that both FDX1 and FDX2 were important in iron-sulfur cluster biogenesis."
    explanation: Supports a role for FDX2 in Fe-S biogenesis, while arguing that FDX1 contributes too.
  - reference: PMID:12970193
    reference_title: "Components involved in assembly and dislocation of iron-sulfur clusters on the scaffold protein Isu1p."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Depletion of the cysteine desulfurase Nfs1p, the ferredoxin Yah1p or the yeast frataxin homologue Yfh1p by regulated gene expression causes a strong decrease in the de novo synthesis of Fe/S clusters on Isu1p."
    explanation: Depleting Yah1, the yeast FDX2 orthologue, blocks de novo Fe-S cluster synthesis on the scaffold; inferred to hold for human FDX2.
  downstream:
  - target: Deficiency of Fe-S-Dependent Respiratory Chain Complexes
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase."
      explanation: The Fe-S-containing complexes are the ones affected in patient muscle.
  - target: Loss of Mitochondrial Aconitase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"
      explanation: Aconitase, a [4Fe-4S] enzyme, is deficient in patient muscle.
  - target: Mitochondrial Iron Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20547883
      reference_title: "Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Fdx2 deficiency had a severe impact, via impaired Fe/S protein biogenesis, on cellular iron homeostasis, leading to increased cellular iron uptake and iron accumulation in mitochondria"
      explanation: FDX2 depletion in cultured cells causes mitochondrial iron accumulation through impaired Fe-S biogenesis.
  - target: Reduced Activity of Lipoate-Dependent 2-Oxoacid Dehydrogenases
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Lipoyl synthase is a [4Fe-4S] enzyme, so defective cluster maturation is
      expected to reduce lipoylation of the E2 subunits of pyruvate,
      2-ketoglutarate and 2-oxoadipate dehydrogenases. Patient data on this
      step disagree (see the target node).
    evidence:
    - reference: PMID:41372147
      reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Likewise, we noted a defect in lipoylation, presumably due to defective maturation of the FeS protein lipoyl synthase (LIAS)"
      explanation: Reduced lipoylation in fibroblasts from a splice-variant patient, attributed to LIAS maturation failure.
- name: Deficiency of Fe-S-Dependent Respiratory Chain Complexes
  description: >-
    Complexes I, II and III each contain Fe-S clusters. Patient muscle shows
    reduced activity of all three, and patient fibroblasts and myoblasts show
    reduced complex I activity and oxygen consumption. Complexes II and III
    were normal in fibroblasts from one start-codon patient, so the extent of
    the defect varies by tissue and allele.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: patient dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
    explanation: Combined complex I, II and III deficiency in patient muscle.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities"
    explanation: Reduced respiration and complex I activity in patient-derived cells.
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cultured patient's cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation"
    explanation: Impaired respiration and loss of Fe-S proteins in cells from a third genotype.
  downstream:
  - target: Decreased activity of mitochondrial complex I
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
      explanation: Direct biochemical measurement in muscle.
  - target: Decreased activity of mitochondrial complex II
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
      explanation: Direct biochemical measurement in muscle.
  - target: Decreased activity of mitochondrial complex III
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
      explanation: Direct biochemical measurement in muscle.
  - target: Patchy SDH and COX deficiency in muscle
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation."
      explanation: Histochemical readout of the respiratory chain defect in patient muscle.
  - target: Skeletal Muscle Energy Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness"
      explanation: Frames the respiratory chain defect as reducing muscle energy production in this disease class.
    - reference: PMID:35079622
      reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates"
      explanation: Reduced oxidative capacity measured in patient myoblasts.
- name: Loss of Mitochondrial Aconitase Activity
  description: >-
    Mitochondrial aconitase (ACO2) carries a [4Fe-4S] cluster and loses
    activity, and protein, when cluster maturation fails, limiting flux through
    the tricarboxylic acid cycle.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"
    explanation: Aconitase activity is reduced in patient muscle.
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "as well as aconitase (ACO2) and ferrochelatase (FECH) were decreased (relative to citrate synthase as mitochondrial control protein) in MEOAL cells"
    explanation: Aconitase protein is reduced in patient fibroblasts.
  downstream:
  - target: Reduced muscle aconitase activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"
      explanation: Measured in patient muscle.
  - target: Skeletal Muscle Energy Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced aconitase activity lowers tricarboxylic acid cycle flux and
      reducing-equivalent supply to the respiratory chain, adding to the
      bioenergetic deficit.
    evidence:
    - reference: PMID:28803783
      reference_title: "Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "LIAS is an iron‑sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III."
      explanation: Places aconitase alongside the respiratory chain among the Fe-S enzymes that fail together in ISC defects; the energetic consequence is inferred.
- name: Reduced Activity of Lipoate-Dependent 2-Oxoacid Dehydrogenases
  description: >-
    Pyruvate dehydrogenase complex activity is reduced in fibroblasts from a
    start-codon patient, and a compound heterozygous patient excreted
    2-hydroxyadipic acid, a marker of deficient lipoate-dependent 2-oxoadipate
    dehydrogenase, and had lactate that rose with glucose infusion, as in PDH
    deficiency. Whether the cause is defective lipoylation is unsettled: one
    patient's cells show reduced lipoylation, another's show normal lipoylation
    of the PDH and 2-ketoglutarate dehydrogenase E2 subunits.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein lipoylation
    term:
      id: GO:0009249
      label: protein lipoylation
    modifier: DECREASED
  - preferred_term: pyruvate decarboxylation to acetyl-CoA
    term:
      id: GO:0006086
      label: pyruvate decarboxylation to acetyl-CoA
    modifier: DECREASED
  evidence:
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities"
    explanation: Reduced PDH complex activity in patient-derived cells.
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Likewise, we noted a defect in lipoylation, presumably due to defective maturation of the FeS protein lipoyl synthase (LIAS)"
    explanation: Reduced lipoylation in fibroblasts with the c.200+4A>G allele.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "PDHc-E2 and α-KDGHc-E2 were correctly lipoylated in the absence of FDX2"
    explanation: Contradicts a lipoylation defect for the start-codon allele; PDH activity loss there must arise another way.
  - reference: PMID:36280795
    reference_title: "Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "In the latter pathway, FDX1 provides electrons to kickstart the radical chain reaction catalyzed by lipoyl synthase."
    explanation: Lipoyl synthase draws its electrons from FDX1, so FDX2 loss would affect lipoylation only through LIAS cluster maturation.
  downstream:
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38444577
      reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The proband also demonstrated increased blood lactate with the increase of glucose infusion rate. This phenomenon has been known in PDH deficiency"
      explanation: Glucose-provoked hyperlactataemia suggests a PDH-type block contributes to the lactic acidosis.
  - target: 2-hydroxyadipic aciduria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38444577
      reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "2-Hydroxyadipic acid can serve as a potential adjunct biomarker for iron-sulfur assembly defects and lipoic acid biosynthesis disorders."
      explanation: The authors interpret 2-hydroxyadipic acid as a readout of failed lipoate-dependent dehydrogenase activity.
- name: Mitochondrial Iron Accumulation
  description: >-
    Failed Fe-S cluster production is sensed as iron deficiency, driving iron
    uptake and mitochondrial iron loading. Iron accumulation was seen in muscle
    of the p.Pro144Leu patients and in fibroblasts of the c.200+4A>G patient,
    but was absent from muscle of a start-codon patient, so it is allele- or
    tissue-dependent.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: intracellular iron ion homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation"
    explanation: Iron accumulation in patient muscle.
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cultured patient's cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation"
    explanation: Mitochondrial iron accumulation in patient fibroblasts.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "This excessive iron accumulation was absent from FDX2 affected muscle"
    explanation: No iron accumulation in muscle from a start-codon patient.
  downstream:
  - target: Patchy SDH and COX deficiency in muscle
    causal_link_type: UNKNOWN
    description: >-
      Iron deposits co-localise with the regional respiratory chain defect in
      biopsies, but whether iron loading worsens the defect is not established.
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation."
      explanation: Co-occurrence in the same biopsies, not a causal demonstration.
- name: Skeletal Muscle Energy Failure
  description: >-
    Combined respiratory chain and tricarboxylic acid cycle deficiency leaves
    skeletal muscle with low oxidative ATP-producing capacity. At rest this
    appears as exercise intolerance and weakness; under catabolic stress
    (febrile illness, fasting, exertion, cold) demand outstrips supply and
    myofibres break down. Muscle then relies on glycolysis, producing lactate.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: cellular respiration
    term:
      id: GO:0045333
      label: cellular respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They have recurrent RM episodes precipitated by febrile illnesses, fasting, exercise, cold, or fatigue, sometimes without trigger"
    explanation: Catabolic triggers of rhabdomyolysis in two patients.
  downstream:
  - target: Mitochondrial myopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III."
      explanation: Links the respiratory chain deficiency to the mitochondrial myopathy phenotype.
  - target: Exercise intolerance
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41372147
      reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "characterized by childhood onset of progressive muscle weakness and exercise intolerance"
      explanation: Exercise intolerance is a core feature of the disorder.
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37565517
      reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"
      explanation: Episodic weakness accompanies the metabolic decompensations.
  - target: Muscle cramps
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life"
      explanation: Episodic cramps are part of the myopathy.
  - target: Myalgia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life"
      explanation: Episodic myalgia is part of the myopathy.
  - target: Lactic acidosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34905296
      reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis."
      explanation: Lactic acidosis accompanies muscle energy failure during episodes.
  - target: Episodic Rhabdomyolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35079622
      reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "They have recurrent RM episodes precipitated by febrile illnesses, fasting, exercise, cold, or fatigue, sometimes without trigger"
      explanation: Energy demand under catabolic stress precipitates rhabdomyolysis.
- name: Episodic Rhabdomyolysis
  description: >-
    Acute breakdown of skeletal muscle during metabolic crises, with creatine
    kinase rising into the hundreds of thousands of U/L. Release of muscle
    contents causes acute kidney injury that can require dialysis, and
    involvement of respiratory muscles can cause respiratory failure. The
    sister of one patient died during an episode.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"
    explanation: Recurrent severe rhabdomyolysis.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To determine common clinical and biological traits in 2 individuals with variants in ISCU and FDX2, displaying severe and recurrent rhabdomyolyses and lactic acidosis."
    explanation: Recurrent rhabdomyolysis in an FDX2 patient.
  downstream:
  - target: Rhabdomyolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34905296
      reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We present the case of a 20-year-old male with a history of myopathy and multiple episodes of rhabdomyolysis, and lactic acidosis."
      explanation: Clinical rhabdomyolysis.
  - target: Highly elevated creatine kinase
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34905296
      reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "he has significantly elevated CK during episodes of rhabdomyolysis"
      explanation: CK release from damaged myofibres.
  - target: Acute kidney injury
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34905296
      reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years)."
      explanation: The source attributes the renal failure to rhabdomyolysis.
  - target: Respiratory insufficiency due to muscle weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38444577
      reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "who presented with recurrent rhabdomyolysis with severe episodes affecting respiratory muscle"
      explanation: Rhabdomyolysis of respiratory muscles caused respiratory failure.
- name: Neuro-ophthalmic and Neural Involvement
  description: >-
    In the p.Pro144Leu families, and in one splice-variant patient, the
    nervous system is affected as well as muscle: early optic atrophy with
    nystagmus, a sensorimotor axonal neuropathy, a white matter disorder that
    reverses or partly reverses, and in the splice-variant patient cerebellar
    atrophy. These tissues depend heavily on oxidative metabolism and Fe-S
    enzymes, but how FDX2 deficiency produces each lesion, and why the white
    matter changes are reversible, has not been studied.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2."
    explanation: Nervous system involvement in the p.Pro144Leu families.
  downstream:
  - target: Optic atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3"
      explanation: Optic atrophy in the p.Pro144Leu families.
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3"
      explanation: Nystagmus in the p.Pro144Leu families.
  - target: Sensorimotor axonal neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sensory-motor axonal neuropathy led to progressive distal weakness."
      explanation: Axonal neuropathy in the p.Pro144Leu families.
  - target: Reversible leukoencephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MRI disclosed a reversible or partially reversible leukoencephalopathy."
      explanation: White matter disease on MRI.
  - target: Cerebellar atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41372147
      reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A first MRI at 2 years of age showed cerebellar hypoplasia which appeared as a progressive cerebellar atrophy in subsequent MRIs"
      explanation: Single-patient observation.
phenotypes:
- name: Mitochondrial myopathy
  category: Musculoskeletal
  description: >-
    A mitochondrial myopathy is present in every reported patient, with onset
    from infancy to adolescence; between crises there is fixed weakness and
    poor exercise tolerance.
  phenotype_term:
    preferred_term: Mitochondrial myopathy
    term:
      id: HP:0003737
      label: Mitochondrial myopathy
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy"
    explanation: Mitochondrial myopathy in the index patient.
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Pathogenic variants in FDX2 have been associated with autosomal recessive FDX2-related disorder characterized by mitochondrial myopathy with or without optic atrophy and leukoencephalopathy."
    explanation: Myopathy is the constant feature across reported cases.
- name: Exercise intolerance
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by childhood onset of progressive muscle weakness and exercise intolerance"
    explanation: Exercise intolerance is a defining feature.
- name: Proximal muscle weakness
  category: Musculoskeletal
  description: >-
    Proximal weakness, worst during metabolic crises; one patient showed a
    Gowers sign from age 6.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"
    explanation: Episodic proximal weakness.
- name: Muscle cramps
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Muscle cramps
    term:
      id: HP:0003394
      label: Muscle spasm
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent episodes of cramps, myalgia and muscle weakness"
    explanation: Recurrent cramps in the p.Pro144Leu families.
- name: Myalgia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent episodes of cramps, myalgia and muscle weakness"
    explanation: Recurrent myalgia in the p.Pro144Leu families.
- name: Rhabdomyolysis
  category: Musculoskeletal
  description: >-
    Recurrent rhabdomyolysis, often severe, occurs in most patients and is the
    presenting feature with start-codon genotypes. In the 2024 case comparison
    it is tabulated in 6 of 11 patients (1 of the 6 p.Pro144Leu patients and
    all 5 others).
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:34905296
    reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis."
    explanation: Recurrent severe rhabdomyolysis.
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis"
    explanation: A further patient with severe rhabdomyolysis.
- name: Highly elevated creatine kinase
  category: Laboratory
  description: >-
    Peak CK during episodes ranged from about 3,000 U/L to over 1,000,000 U/L;
    CK is normal or near-normal between episodes.
  phenotype_term:
    preferred_term: Highly elevated creatine kinase
    term:
      id: HP:0030234
      label: Highly elevated creatine kinase
  evidence:
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CPK 319,990 U/L, lactic acid 22.31 mmol/L"
    explanation: Extremely high CK during an episode.
  - reference: PMID:34905296
    reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he has significantly elevated CK during episodes of rhabdomyolysis"
    explanation: High CK during episodes.
- name: Lactic acidosis
  category: Metabolic
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:34905296
    reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis."
    explanation: Lactic acidosis with rhabdomyolysis.
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CPK 319,990 U/L, lactic acid 22.31 mmol/L"
    explanation: Severe hyperlactataemia during an episode.
- name: Acute kidney injury
  category: Renal
  description: >-
    Rhabdomyolysis-related acute kidney injury, sometimes requiring
    hemodialysis.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was hospitalized in the pediatric intensive care unit due to acute kidney injury"
    explanation: Acute kidney injury during rhabdomyolysis.
  - reference: PMID:34905296
    reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He needed hemodialysis for severe rhabdomyolysis-related acute renal failure"
    explanation: Dialysis-requiring renal failure.
- name: Respiratory insufficiency due to muscle weakness
  category: Respiratory
  description: >-
    Rhabdomyolysis involving respiratory muscles caused prolonged respiratory
    failure requiring tracheostomy in one patient.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who presented with recurrent rhabdomyolysis with severe episodes affecting respiratory muscle"
    explanation: Respiratory muscle involvement.
- name: Hyperammonemia
  category: Metabolic
  notes: Reported in a single patient; the authors note it had not been seen in earlier patients.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies."
    explanation: Raised ammonia during decompensation.
- name: Ketonuria
  category: Metabolic
  phenotype_term:
    preferred_term: Ketonuria
    term:
      id: HP:0002919
      label: Ketonuria
  evidence:
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies"
    explanation: Urinary ketones during decompensation.
- name: 2-hydroxyadipic aciduria
  category: Metabolic
  description: >-
    Increased urinary 2-hydroxyadipic acid, with 3-methylglutaconic acid and
    2-hydroxyisovaleric acid, persisting between episodes in one compound
    heterozygous patient.
  phenotype_term:
    preferred_term: 2-hydroxyadipic aciduria
    term:
      id: HP:0034465
      label: 2-hydroxyadipic aciduria
  evidence:
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analysis of the patients revealed hyperexcretion of 2-hydroxyadipic acid, along with previously reported biochemical abnormalities."
    explanation: Urinary 2-hydroxyadipic acid in an FDX2 patient.
- name: Decreased activity of mitochondrial complex I
  category: Cellular
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex I
    term:
      id: HP:0011923
      label: Decreased activity of mitochondrial complex I
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
    explanation: Measured in patient muscle.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "reduced oxygen consumption rates and mitochondrial complex I and PDHc activities"
    explanation: Measured in patient fibroblasts and myoblasts.
- name: Decreased activity of mitochondrial complex II
  category: Cellular
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex II
    term:
      id: HP:0008314
      label: Decreased activity of mitochondrial complex II
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
    explanation: Measured in patient muscle.
- name: Decreased activity of mitochondrial complex III
  category: Cellular
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex III
    term:
      id: HP:0011924
      label: Decreased activity of mitochondrial complex III
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III"
    explanation: Measured in patient muscle.
- name: Reduced muscle aconitase activity
  category: Cellular
  phenotype_term:
    preferred_term: Reduced muscle aconitase activity
    term:
      id: HP:0034511
      label: Reduced muscle aconitase activity
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"
    explanation: Measured in patient muscle.
- name: Patchy SDH and COX deficiency in muscle
  category: Cellular
  description: >-
    Regional loss of succinate dehydrogenase and cytochrome c oxidase staining
    with iron deposits in muscle biopsies from the p.Pro144Leu families. Muscle
    histology was reported normal in a start-codon patient.
  phenotype_term:
    preferred_term: regional cytochrome c oxidase-deficient muscle fibres
    term:
      id: HP:0003688
      label: Cytochrome C oxidase-negative muscle fibers
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation."
    explanation: Histochemical finding in patient muscle.
- name: Optic atrophy
  category: Ophthalmological
  description: >-
    Optic atrophy developing by age 3 in all six p.Pro144Leu patients; not
    reported with start-codon genotypes.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3"
    explanation: Early optic atrophy.
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Extra‐muscular manifestations including optic atrophy and hematologic complications have been reported in two Brazilian families harboring homozygous c.422C > T (p.Pro141Leu) but have not been reported elsewhere."
    explanation: Restricts optic atrophy to the p.Pro144Leu (p.Pro141Leu) families.
- name: Nystagmus
  category: Ophthalmological
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3"
    explanation: Early-onset nystagmus.
- name: Sensorimotor axonal neuropathy
  category: Neurological
  phenotype_term:
    preferred_term: Sensorimotor axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensory-motor axonal neuropathy led to progressive distal weakness."
    explanation: Axonal neuropathy in the p.Pro144Leu families.
  sequelae:
  - target: Distal muscle weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sensory-motor axonal neuropathy led to progressive distal weakness."
      explanation: The source attributes the distal weakness to the neuropathy.
- name: Distal muscle weakness
  category: Neurological
  phenotype_term:
    preferred_term: Progressive distal muscle weakness
    term:
      id: HP:0009063
      label: Progressive distal muscle weakness
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensory-motor axonal neuropathy led to progressive distal weakness."
    explanation: Progressive distal weakness.
- name: Reversible leukoencephalopathy
  category: Neurological
  description: >-
    A leukoencephalopathy that reverses or partly reverses on follow-up MRI,
    in 4 of the 6 p.Pro144Leu patients per the 2024 case comparison. Brain MRI
    was normal in the start-codon patients examined.
  phenotype_term:
    preferred_term: Reversible leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI disclosed a reversible or partially reversible leukoencephalopathy."
    explanation: White matter disease on MRI.
- name: Cerebellar atrophy
  category: Neurological
  notes: >-
    Single patient (c.200+4A>G homozygous), who also had severe ataxia,
    dysarthria, pyramidal signs and foveal hypoplasia, but no rhabdomyolysis.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A first MRI at 2 years of age showed cerebellar hypoplasia which appeared as a progressive cerebellar atrophy in subsequent MRIs"
    explanation: Progressive cerebellar atrophy on serial MRI.
  sequelae:
  - target: Ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41372147
      reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "her clinical picture was characterized by severe ataxic signs (trunk and head ballottement, dysarthria, dysmetria, intentional tremor, and nystagmus)"
      explanation: Cerebellar signs in the same patient.
- name: Ataxia
  category: Neurological
  notes: Single patient (c.200+4A>G homozygous).
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "her clinical picture was characterized by severe ataxic signs (trunk and head ballottement, dysarthria, dysmetria, intentional tremor, and nystagmus)"
    explanation: Severe ataxia.
- name: Microcytic anemia
  category: Hematological
  notes: >-
    Tabulated in 4 of 6 p.Pro144Leu patients in the 2024 case comparison and
    in none of the start-codon patients. No mechanism has been studied in
    patients.
  phenotype_term:
    preferred_term: Microcytic anemia
    term:
      id: HP:0001935
      label: Microcytic anemia
  evidence:
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Optic atrophy, neurodevelopmental abnormalities, microcytic anemia, neutropenia, hypothyroidism have been reported in some patients."
    explanation: Summary of extramuscular features across published patients.
- name: Neutropenia
  category: Hematological
  notes: Tabulated in 4 of 6 p.Pro144Leu patients in the 2024 case comparison.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Optic atrophy, neurodevelopmental abnormalities, microcytic anemia, neutropenia, hypothyroidism have been reported in some patients."
    explanation: Summary of extramuscular features across published patients.
biochemical:
- name: Blood FGF21
  presence: INCREASED
  notes: >-
    Raised in a start-codon patient, more so than in an ISCU myopathy patient;
    plasma GDF15 was also markedly raised in the compound heterozygous
    patient. Both are non-specific markers of mitochondrial myopathy.
  evidence:
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with high levels of blood FGF21"
    explanation: Elevated FGF21 in the FDX2 patient.
genetic:
- name: FDX2
  gene_term:
    preferred_term: FDX2
    term:
      id: hgnc:30546
      label: FDX2
  association: Biallelic pathogenic variants in FDX2
  relationship_type: CAUSATIVE
  notes: >-
    Previous symbol FDX1L. Six families carry start-codon or splice variants
    and two Brazilian families carry p.Pro144Leu. No ClinGen gene-disease
    validity assertion was found in the local cache.
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2"
    explanation: Gene-disease mapping in two families.
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein"
    explanation: First FDX2 disease allele.
  variants:
  - name: c.1A>T (p.Met1?)
    description: >-
      Start-codon variant, homozygous in the founding patient and in a French
      patient, and in trans with c.146-2A>G in an American patient; reduces
      FDX2 protein in muscle and fibroblasts.
    evidence:
    - reference: PMID:24281368
      reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria."
      explanation: Effect of the start-codon allele.
  - name: c.431C>T (p.Pro144Leu)
    synonyms:
    - c.422C>T (p.Pro141Leu)
    - P144L
    description: >-
      Homozygous in six patients from two Brazilian families with the
      multisystem presentation. Normal mRNA but severely reduced protein in
      muscle; in vitro the mutant protein accepts electrons from FDXR poorly.
    evidence:
    - reference: PMID:30010796
      reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L)."
      explanation: Identification of the allele.
    - reference: PMID:39467201
      reference_title: "Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This mutation alters a highly conserved proline residue located in a loop of FDX2"
      explanation: The substituted proline is conserved and lies in a loop away from the iron-sulfur cluster.
  - name: c.12G>T (p.Met4Ile)
    description: Homozygous start-region variant in a 20-year-old man with recurrent rhabdomyolysis.
    evidence:
    - reference: PMID:34905296
      reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I)."
      explanation: Identification of the allele.
  - name: c.10A>T (p.Met4Leu)
    description: Homozygous start-region variant in a girl with severe rhabdomyolysis.
    evidence:
    - reference: PMID:37565517
      reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T)"
      explanation: Identification of the allele.
  - name: c.146-2A>G
    description: Splice-acceptor variant found in trans with c.1A>T.
    evidence:
    - reference: PMID:38444577
      reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variant c.146‐2A > G is predicted to cause abnormal splicing, disrupting protein function."
      explanation: Identification and predicted effect.
  - name: c.200+4A>G
    description: >-
      Homozygous splice-region variant that replaces 19 N-terminal residues
      with 21 different amino acids and lowers FDX2 protein.
    evidence:
    - reference: PMID:41372147
      reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids"
      explanation: Splicing effect demonstrated in patient material.
treatments:
- name: Parenteral nutrition with high protein and lipid and low glucose
  description: >-
    During a rhabdomyolysis episode in which CK stayed high on intravenous
    dextrose, and lactate rose when the dextrose concentration was increased,
    switching to parenteral nutrition rich in protein and lipid with 5%
    dextrose was followed by a rapid fall in CK and lactate. This is a single
    case observation.
  treatment_term:
    preferred_term: parenteral nutrition with high protein and lipid content
    term:
      id: NCIT:C29484
      label: Total Parenteral Nutrition
  therapeutic_modality: OTHER
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  - preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lactate and CK drastically decreased when parenteral nutrition containing high protein and lipid contents with low glucose was initiated."
    explanation: Single-patient response during an acute episode.
- name: Hemodialysis for rhabdomyolysis-related renal failure
  description: >-
    Acute supportive care during rhabdomyolysis includes intravenous fluids and
    alkalinisation, with dialysis when renal failure develops.
  treatment_term:
    preferred_term: Hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  therapeutic_modality: DEVICE
  target_phenotypes:
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:34905296
    reference_title: "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years)."
    explanation: Dialysis for rhabdomyolysis-related renal failure.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the episodes, treatment with IV fluids and alkalinization was proposed, associated in a few cases with dialysis."
    explanation: Acute management in two patients.
- name: Mitochondrial cofactor supplementation
  description: >-
    Patients have received vitamin and cofactor combinations including
    coenzyme Q10, riboflavin, thiamine, biotin, niacin and N-acetylcysteine.
    No effect on disease course has been reported.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:41372147
    reference_title: "A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient started a multivitamin therapy (cocktail of riboflavin, thiamin and coenzyme Q) when she was three years old"
    explanation: Documents use; no efficacy data.
  - reference: PMID:38444577
    reference_title: "Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was subsequently decannulated and discharged with home regimen of sodium bicarbonate and mitochondrial cocktail comprising of n‐acetylcysteine, niacin, biotin and coenzyme Q10."
    explanation: Documents use; no efficacy data.
- name: Trigger avoidance and graded exercise
  description: >-
    Rhabdomyolysis episodes are provoked by febrile illness, fasting, exertion
    and cold, so avoidance of prolonged fasting and of exertion during
    intercurrent illness is advised. Graded low-intensity exercise is
    recommended for mitochondrial myopathies generally; it has not been
    studied in FDX2 deficiency.
  treatment_term:
    preferred_term: exercise counseling and trigger avoidance
    term:
      id: NCIT:C101235
      label: Exercise Counseling
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:25008908
    reference_title: "Exercise as a therapeutic strategy for primary mitochondrial cytopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "not exercise on days they have fever, superimposed illness, muscle pain, or cramps, and/or if they have fasted for more than 12 hours"
    explanation: General guidance for primary mitochondrial cytopathies, extrapolated to FDX2 deficiency.
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They have recurrent RM episodes precipitated by febrile illnesses, fasting, exercise, cold, or fatigue, sometimes without trigger"
    explanation: Identifies the triggers to be avoided in FDX2-deficient patients.
diagnosis:
- name: Exome sequencing
  description: >-
    Every reported patient was diagnosed by exome sequencing, in some cases
    combined with homozygosity mapping. The founding report recommends FDX2
    analysis in mitochondrial myopathy with combined complex I, II and III
    deficiency.
  diagnosis_term:
    preferred_term: Whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:24281368
    reference_title: "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III."
    explanation: Diagnostic recommendation from the founding report.
  - reference: PMID:37565517
    reference_title: "Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies"
    explanation: Recommendation to test FDX2 in suspected mitochondrial myopathy.
- name: Muscle biopsy
  description: >-
    Muscle shows reduced activity of complexes I, II, III and aconitase, and in
    the p.Pro144Leu families regional SDH and COX deficiency with iron
    accumulation; fibroblasts may not show the muscle defect.
  diagnosis_term:
    preferred_term: Muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:30010796
    reference_title: "A novel complex neurological phenotype due to a homozygous mutation in FDX2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation."
    explanation: Characteristic biopsy finding.
  - 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: Fibroblast studies can miss the defect in FDX2 myopathy, so muscle is the preferred tissue.
differential_diagnoses:
- name: ISCU myopathy
  disease_term:
    preferred_term: ISCU myopathy
    term:
      id: MONDO:0009706
      label: hereditary myopathy with lactic acidosis due to ISCU deficiency
  description: >-
    Recessive ISCU deficiency produces the same picture of exercise
    intolerance, recurrent rhabdomyolysis and lactic acidosis with Fe-S enzyme
    deficiency in muscle. In a direct comparison the FDX2 patient was more
    severely affected, while iron accumulated in ISCU-deficient but not in
    FDX2-deficient muscle. Genetic testing separates them.
  evidence:
  - reference: PMID:35079622
    reference_title: "FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that FDX2 and ISCU variants result in a similar muscle phenotype, that differ in severity and skeletal muscle iron accumulation."
    explanation: Head-to-head comparison of the two disorders.
- name: FDXR-related auditory neuropathy and optic atrophy
  disease_term:
    preferred_term: auditory neuropathy-optic atrophy syndrome
    term:
      id: MONDO:0060582
      label: auditory neuropathy-optic atrophy syndrome
  description: >-
    Biallelic variants in FDXR, the reductase that supplies electrons to FDX2,
    cause optic atrophy with auditory neuropathy and mitochondrial iron
    overload. Auditory neuropathy has not been reported in FDX2 deficiency.
  evidence:
  - reference: PMID:28965846
    reference_title: "FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family."
    explanation: Defines the FDXR phenotype that overlaps the optic atrophy of the p.Pro144Leu families.

📚

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 (1)

Create: FDX2-Related_Mitochondrial_Myopathy · 2026-10-12T15:55:38Z · View source

New Disease entry for MEOAL (MONDO:0020714, OMIM:251900), autosomal recessive FDX2 (hgnc:30546, previously FDX1L) deficiency. LUMP/SPLIT: DISEASE. MONDO:0020714 has no descendants, one causal gene and one recessive mode; the muscle-restricted (start-codon alleles) and multisystem (p.Pro144Leu) presentations are described in phenotype descriptions rather than as subtypes because they rest on about a dozen patients and no source names them as separate entities. CONTENT: an 11-node causal chain from biallelic FDX2 variants through reduced FDX2 protein and impaired FDXR-to-FDX2 electron transfer to impaired mitochondrial Fe-S cluster assembly, then four arms (combined complex I-III deficiency, aconitase loss, lipoate-dependent 2-oxoacid dehydrogenase deficiency, mitochondrial iron accumulation) converging on skeletal muscle energy failure and episodic rhabdomyolysis, plus a neuro-ophthalmic node for the p.Pro144Leu families. The lipoylation step carries both SUPPORT (PMID:41372147) and REFUTE (PMID:35079622, PMID:36280795) evidence, and muscle iron accumulation carries a REFUTE item from PMID:35079622. 27 phenotypes (23 causally connected; hyperammonemia, ketonuria, microcytic anaemia and neutropenia left unwired because no source links them to a mechanism), six variants, four treatments (high-lipid/protein parenteral nutrition from a single case, haemodialysis, cofactor supplementation, and trigger avoidance with graded exercise extrapolated from general mitochondrial cytopathy guidance), two diagnostic rows and two differentials (ISCU myopathy, FDXR auditory neuropathy-optic atrophy). No module conformance: complex_i_deficiency models isolated complex I deficiency. KEY PMIDS: 24281368, 30010796, 35079622, 34905296, 37565517, 38444577, 39467201, 41372147, 20547883, 36280795, 32817474. DEEP RESEARCH: one openscientist report (research/FDX2-Related_Mitochondrial_Myopathy-deep-research-openscientist.md). It arrived without reference or term validation sections, so just validate-research-reference and just validate-research-terms were run on it in place: 16/16 references resolved, 0 unresolved, 0 off topic (9 judged on topic); 31 terms checked, 29 resolved, 0 unresolved, 2 unverifiable, 11 flagged as named differently, all table-parsing artifacts (frequency-column text read as the label) or the MedGen xref. No CURIE was copied from the report; every binding was looked up in OLS or the committed caches. just preflight-dr could not run because the local MONDO build is absent; a manual check found FDX2 named 71 times and FDX1L 13 times, OMIM 251900 and MEOAL named correctly, and no competing disease gene, so the report is about this disease. From the report the entry uses PMID:39632806 (cryo-EM of FDX2 in the core ISC complex), PMID:12970193 (yeast Yah1), PMID:28965846 (FDXR differential) and PMID:25008908 (exercise guidance); its gnomAD constraint figures were not used because they could not be checked against a cached source. VALIDATION: just validate-disorders passed with 128/128 snippets and 128 reference titles verified; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-block-scalar-comments, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-reference-titles and check-gene-activity-grounding pass. No GeneReviews chapter exists.

OpenScientist ▸

FDX2-Related Mitochondrial Myopathy (MEOAL) — Comprehensive Disease Report

openscientist-autonomous 16 citations 2026-10-12T15:33:15.627750

FDX2-Related Mitochondrial Myopathy (MEOAL) — Comprehensive Disease Report

Disease: FDX2-Related Mitochondrial Myopathy Primary synonym: MEOAL — Mitochondrial myopathy, Episodic, with or without Optic Atrophy and reversible Leukoencephalopathy MONDO: MONDO:0020714 · OMIM: #251900 · Gene: FDX2 (alias FDX1L), 19p13.2 Category: Mendelian (autosomal recessive)

Autonomous literature-based research report. Evidence types indicated as: [HUMAN] clinical case/cohort; [IN VITRO] cell/biochemistry; [MODEL] model organism; [COMP] computational/database.

Summary

FDX2-Related Mitochondrial Myopathy, catalogued as MEOAL (OMIM #251900; MONDO:0020714), is an ultra-rare autosomal-recessive inborn error of mitochondrial metabolism caused by biallelic loss-of-function variants in FDX2 (FDX1L) on chromosome 19p13.2. FDX2 encodes mitochondrial ferredoxin-2, a small [2Fe-2S] electron-transfer protein that serves as the dedicated electron donor for iron-sulfur (Fe-S) cluster biogenesis. When FDX2 function is lost, cells cannot efficiently assemble [2Fe-2S] and [4Fe-4S] clusters, crippling every Fe-S-dependent enzyme — most importantly respiratory chain complexes I, II and III, and the TCA-cycle enzyme aconitase. The downstream consequence is mitochondrial energy (ATP) failure accompanied by disordered cellular iron homeostasis and mitochondrial iron overload.

Clinically, the disease presents in childhood with optic atrophy and nystagmus (by age ~3), followed within the first and second decades by an episodic/progressive myopathy featuring exercise intolerance, cramps, myalgia, and recurrent crises that can escalate to severe rhabdomyolysis (CK up to ~320,000 U/L), lactic acidosis, and acute kidney injury. A sensorimotor axonal neuropathy and reversible (or partially reversible) leukoencephalopathy on MRI complete the characteristic multisystem picture. Muscle biopsy shows a distinctive pattern of regional succinate dehydrogenase (complex II) and cytochrome c oxidase deficiency with iron accumulation. The disorder is genetically and biochemically related to, but distinct from, other Fe-S/ISC-biogenesis diseases such as FDXR-related neuropathy, ISCU myopathy, and Friedreich ataxia (FXN).

There is no disease-specific or curative therapy. Management is supportive and follows general mitochondrial-cytopathy principles: trigger avoidance (fasting, fever, intercurrent illness), graded low-intensity aerobic/resistance exercise, aggressive hydration and renal protection during rhabdomyolysis crises, empirical "mitochondrial cocktail" supplements, and genetic counseling for affected families. The evidence base is derived almost entirely from a small number of consanguineous/founder families plus mechanistic work in human cells, yeast (Yah1), and structural biology (cryo-EM of the ferredoxin–ISC complex); no dedicated vertebrate animal model of FDX2 disease has yet been published.

Key Findings

Finding 1 — Biallelic FDX2 (FDX1L) variants cause autosomal-recessive MEOAL [HUMAN]

FDX2-related disease is a classic Mendelian autosomal-recessive condition. The gene was first implicated by Spiegel and colleagues in 2014, who used exome sequencing combined with homozygosity mapping in a consanguineous family with adolescent-onset mitochondrial myopathy and identified a homozygous c.1A>T variant that disrupts the ATG start codon of FDX1L/FDX2 (PMID: 24281368). The abstract states: "We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein."

Subsequent families confirmed the gene and broadened the allelic spectrum: a recurrent homozygous missense c.431C>T (p.Pro144Leu / P144L) was reported in six patients from two unrelated Brazilian families (PMID: 30010796; mechanism in PMID: 39467201, which notes "the homozygous mutation c.431C>T (p.P144L) described in six patients from two unrelated families"). A homozygous splice variant c.200+4A>G was described in a pediatric multiorgan case (PMID: 41372147), and an additional homozygous case presented with severe rhabdomyolysis (PMID: 37565517). The consistent requirement for two defective alleles, the frequent consanguinity, and the unaffected heterozygous parents all confirm recessive inheritance.

Finding 2 — Pathomechanism: FDX2 deficiency impairs Fe-S cluster biogenesis, disabling Fe-S-dependent respiratory complexes and aconitase [HUMAN / IN VITRO]

The core lesion is a failure of iron-sulfur cluster assembly. In patient skeletal muscle, FDX2 loss severely impairs the activities of the Fe-S-dependent respiratory complexes I, II and III and mitochondrial aconitase (PMID: 24281368: "severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase"). FDX2 is the electron donor that promotes assembly of both [2Fe-2S] and [4Fe-4S] clusters (PMID: 39467201).

Structural work has defined precisely how FDX2 acts within the biogenesis machinery. Cryo-EM shows FDX2 binds the core ISC complex (ISCU2–NFS1–ISD11/LYRM4–ACP1) and competes with frataxin (FXN) for overlapping binding sites, delivering electrons to the nascent cluster (PMID: 39632806: "FDX2 and FXN compete for overlapping binding sites"). Patient cells carrying the c.200+4A>G splice allele show impaired mitochondrial respiration, defects in many Fe-S proteins, enhanced mitochondrial iron accumulation, and reduced SOD2 (PMID: 41372147), tying the molecular defect directly to multisystem energy failure and redox imbalance.

Finding 3 — Clinical phenotype: childhood optic atrophy, episodic myopathy, neuropathy, reversible leukoencephalopathy [HUMAN]

The best-characterized cohort (two Brazilian families, 6 patients) defines the syndrome: optic atrophy and nystagmus developing by age 3, followed by myopathy with recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade, a sensory-motor axonal neuropathy with progressive distal weakness, and a reversible/partially reversible leukoencephalopathy on MRI (PMID: 30010796: "a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life").

Muscle histopathology is distinctive: "Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation" (PMID: 30010796). Acute metabolic crises can be life-threatening: one patient showed CK up to ~320,000 U/L, lactate 22.3 mmol/L, and acute kidney injury during a rhabdomyolysis episode (PMID: 37565517), and multiorgan involvement has been documented in pediatric disease (PMID: 41372147).

Finding 4 — FDX2 is functionally distinct from FDX1 (adrenodoxin) [IN VITRO]

Humans possess two mitochondrial ferredoxins. RNAi depletion established that FDX2 — not FDX1 — is essential for heme A and Fe/S protein biosynthesis, whereas FDX1 (adrenodoxin) reduces P450 enzymes for steroidogenesis (PMID: 20547883: "we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis"). FDX2 cannot efficiently reduce P450s or convert steroids, explaining why FDX2 patients have a mitochondrial Fe-S disease rather than a steroidogenic disorder.

Crucially, FDX2 deficiency deranges iron homeostasis: "Fdx2 deficiency had a severe impact, via impaired Fe/S protein biogenesis, on cellular iron homeostasis, leading to increased cellular iron uptake and iron accumulation in mitochondria" (PMID: 20547883). Both ferredoxins receive electrons from the single ferredoxin reductase FDXR (NADPH → FDXR → FDX) (PMID: 28747430).

Finding 5 — Genomic/constraint data confirm a LoF-tolerant, recessive gene [COMP]

FDX2 (ENSG00000267673) maps to chr19:10,310,045–10,316,015 (cytoband 19p13.2). gnomAD constraint metrics indicate the gene is tolerant of heterozygous loss-of-function: pLI = 0.0006, observed/expected LoF (oe_lof) = 0.70 (90% CI 0.46–1.12), missense oe = 0.95, mis_z = 0.34. This LoF-tolerance is exactly what is expected for an autosomal-recessive disorder in which single-allele carriers are unaffected and two defective alleles are required to produce disease. The protein (UniProt Q6P4F2, FDX2_HUMAN) is a 186-amino-acid mitochondrial [2Fe-2S] ferredoxin with an N-terminal mitochondrial targeting presequence.

Finding 6 — Differential diagnosis: FDX2 disease within the ISC-biogenesis disorder spectrum [HUMAN]

FDX2 disease belongs to a broader family of mitochondrial Fe-S/ISC-biogenesis disorders with overlapping clinical features. The most important differential is FDXR (the upstream electron donor to FDX2), whose biallelic mutations cause auditory neuropathy and optic atrophy with mitochondrial iron overload (PMID: 28965846: "FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation"). Other differentials include ISCU (hereditary myopathy with exercise intolerance / Swedish myopathy, with similar SDH/aconitase deficiency), FXN (Friedreich ataxia), and NFU1/BOLA3/ISCA2/IBA57 (multiple mitochondrial dysfunctions syndrome with glycine elevation).

A pragmatic diagnostic strategy for suspected mitochondrial disease combines biochemical markers (plasma/CSF lactate, alanine, proline) and neuroimaging to predict disease, then applies first-line clinical exome sequencing, reserving muscle biopsy for urgent or inconclusive cases (PMID: 34056100: "apply first-line clinical exome sequencing to identify a definite diagnosis").

Finding 7 — Model organisms: yeast Yah1 is the key ortholog; no dedicated vertebrate model [MODEL / IN VITRO]

The S. cerevisiae ortholog of FDX2 is Yah1 (yeast adrenodoxin homolog). Yah1 depletion causes a strong decrease in de novo Fe/S cluster synthesis on the scaffold Isu1p (PMID: 12970193: "Depletion of the cysteine desulfurase Nfs1p, the ferredoxin Yah1p or the yeast frataxin homologue Yfh1p by regulated gene expression causes a strong decrease in the de novo synthesis of Fe/S clusters on Isu1p"). The Yah1–Arh1 ferredoxin/ferredoxin-reductase pair is essential for heme A biosynthesis and FeSC assembly (PMID: 15211518). No dedicated mouse or zebrafish model of FDX2 disease has been published; mechanistic insight derives from RNAi knockdown in human cells, patient-derived fibroblasts/myoblasts, yeast complementation, and recombinant-protein biophysics/cryo-EM. The pathway framework is summarized by Braymer & Lill, who note "some 30 proteins involved in the synthesis of cellular [2Fe-2S] and [4Fe-4S] clusters and their incorporation into numerous apoproteins" (PMID: 28615445).

Finding 8 — Treatment is supportive/symptomatic; no curative therapy [HUMAN]

No gene-specific or curative treatment exists. Management follows general mitochondrial-cytopathy principles. Endurance exercise training increases VO2max, respiratory chain enzyme activity, muscle strength, and quality of life, and is well tolerated (PMID: 25008908: "Endurance exercise training increases Vo2 max, respiratory chain enzyme activity, and improves quality of life."). Patients are advised to avoid exercise during metabolic stress: "not exercise on days they have fever, superimposed illness, muscle pain, or cramps, and/or if they have fasted for more than 12 hours" (PMID: 25008908). Cochrane review found no evidence of harm from moderate training in muscle disease (PMID: 20091552); creatine monohydrate gives mixed/modest benefit in mitochondrial cytopathies (PMID: 18652078). Acute rhabdomyolysis crises require aggressive IV hydration and renal protection (PMID: 37565517).

Finding 9 — Verified identifiers [COMP]

EBI OLS4 confirms MONDO:0020714 = "mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy" (MEOAL), cross-referenced to OMIM:251900, GARD:0025221, MedGen:1679560 (UMLS C5193223).

The 15-Section Disease Knowledge Report

1. Disease Information

FDX2-Related Mitochondrial Myopathy (MEOAL) is an ultra-rare, autosomal-recessive mitochondrial disorder of iron-sulfur cluster biogenesis. It manifests as a multisystem neuromuscular syndrome combining optic atrophy, episodic/progressive myopathy with exercise intolerance and rhabdomyolysis, axonal neuropathy, and reversible leukoencephalopathy.

Key identifiers:

Resource	Identifier
MONDO	MONDO:0020714
OMIM	#251900
GARD	0025221
MedGen	1679560
UMLS	C5193223
Gene (HGNC)	FDX2 (alias FDX1L)
UniProt	Q6P4F2 (FDX2_HUMAN)
Ensembl	ENSG00000267673
ICD-10	G71.3 (mitochondrial myopathy, NEC) — closest applicable; no FDX2-specific code
ICD-11	8C73 / 5C53.1 (disorders of mitochondrial energy metabolism) — closest applicable

Synonyms / alternative names: MEOAL; mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy; FDX1L-related mitochondrial myopathy; ferredoxin-2 deficiency.

Information source: Disease-level, derived from aggregated case reports and small consanguineous/founder families (individual patient genotype–phenotype correlations) plus mechanistic in vitro and model-organism data — not from large EHR cohorts.

2. Etiology

Causal factor (genetic): Biallelic loss-of-function or hypomorphic variants in FDX2/FDX1L. Reported variants include start-loss c.1A>T (PMID: 24281368), missense c.431C>T (p.P144L) (PMID: 30010796), and splice c.200+4A>G (PMID: 41372147).

Genetic risk factors: The disease is monogenic; "risk" is fully determined by biallelic FDX2 genotype. Consanguinity and founder effects (e.g., the recurrent Brazilian p.P144L allele) are the principal population-level risk contexts.

Environmental risk factors: None cause the disease, but environmental/metabolic stressors act as crisis triggers — fasting (>12 h), fever, intercurrent infection, and strenuous exercise can precipitate rhabdomyolysis and metabolic decompensation (PMID: 25008908; PMID: 37565517).

Protective factors: No specific genetic or environmental protective alleles are established. Trigger avoidance is protective against acute crises.

Gene–environment interactions: The underlying genetic Fe-S/energy deficit interacts with metabolic demand — energy-stress states (fasting, fever, exertion) unmask or worsen the biochemical defect, producing the episodic phenotype.

3. Phenotypes

Phenotype	Type	Onset	Severity / course	Frequency	Suggested HPO
Optic atrophy	Clinical sign	Early childhood (~age 3)	Progressive	Characteristic (majority)	HP:0000648
Nystagmus	Clinical sign	Early childhood	Stable/progressive	Frequent	HP:0000639
Exercise intolerance	Symptom	1st–2nd decade	Episodic	Characteristic	HP:0003546
Myalgia / muscle cramps	Symptom	1st–2nd decade	Episodic	Frequent	HP:0003326 / HP:0003394
Muscle weakness (myopathy)	Clinical sign	1st–2nd decade	Progressive	Characteristic	HP:0003198
Rhabdomyolysis	Lab/clinical	Episodic (crises)	Severe when present	Reported (subset)	HP:0003201
Elevated creatine kinase	Lab abnormality	During crises	Severe (up to ~320,000 U/L)	Frequent in crises	HP:0003236
Lactic acidosis / elevated lactate	Lab abnormality	During crises	Severe (up to 22.3 mmol/L)	Frequent	HP:0003128
Sensorimotor axonal neuropathy	Clinical sign	Childhood–adolescence	Progressive, distal	Characteristic	HP:0007141
Reversible leukoencephalopathy	Imaging/lab	Variable	Reversible/partially reversible	Characteristic	HP:0002352
Acute kidney injury	Lab/clinical	During rhabdomyolysis crises	Severe	Subset	HP:0001919

Quality-of-life impact: Progressive visual loss (optic atrophy), muscle weakness and exercise intolerance, and neuropathy impair mobility, education/employment, and independence. Acute crises are life-threatening and require hospitalization. Formal QoL instrument data (EQ-5D/SF-36) specific to FDX2 disease are not available given the rarity.

4. Genetic / Molecular Information

Causal gene: FDX2 (FDX1L), 19p13.2, ENSG00000267673; UniProt Q6P4F2; 186-aa mitochondrial [2Fe-2S] ferredoxin with N-terminal targeting presequence.

Pathogenic variants (ACMG-consistent, germline, homozygous in reported cases):

Variant (cDNA)	Protein	Class	Consequence	Reference
c.1A>T	start-loss (p.Met1?)	Pathogenic	Loss of function (no initiation)	PMID: 24281368
c.431C>T	p.Pro144Leu	Likely pathogenic/Pathogenic	Missense, impaired function (founder, Brazil)	PMID: 30010796, PMID: 39467201
c.200+4A>G	splice (exon 2 skip → 19 aa replaced by 21)	Pathogenic	Aberrant splicing, low FDX2 protein	PMID: 41372147

Allele frequency: All reported pathogenic variants are rare/private; FDX2 is LoF-tolerant in gnomAD (pLI = 0.0006; oe_lof = 0.70). Origin: germline (no somatic disease role). Functional consequence: loss of function — reduced protein level and/or impaired electron-donor activity. Notably, the P144L and c.200+4A>G mutant proteins may retain near-normal structure, implicating reduced abundance/activity rather than gross misfolding (PMID: 41372147; PMID: 39467201).

Modifier genes / epigenetics / chromosomal abnormalities: None established; no large-scale structural variants reported.

5. Environmental Information

Not a primary driver of this monogenic disease. Non-genetic triggers of acute metabolic crises include fasting, fever, intercurrent illness, and strenuous/eccentric exercise. No infectious agent causes the disease (though infection/fever can precipitate crises). No toxic or occupational exposures are implicated.

6. Mechanism / Pathophysiology

Ordered causal chain:

Biallelic FDX2/FDX1L loss-of-function variant (c.1A>T start-loss, p.P144L missense, or c.200+4A>G splice) → reduced level/activity of mitochondrial ferredoxin-2 protein.
Reduced FDX2 leads to loss of the dedicated [2Fe-2S] electron donor within the core ISC assembly complex (ISCU2–NFS1–ISD11/LYRM4–ACP1), where FDX2 normally competes with frataxin for binding and feeds electrons to the nascent cluster (PMID: 39632806).
Loss of electron donation results in defective de novo assembly of [2Fe-2S] and [4Fe-4S] clusters on the scaffold (inferred from patient cells + yeast Yah1 depletion; PMID: 41372147, PMID: 12970193).
Fe-S deficiency leads to loss of activity of Fe-S-dependent apoproteins — respiratory complexes I, II, III and aconitase (PMID: 24281368).
Branch A (bioenergetic): Respiratory chain failure results in impaired oxidative phosphorylation and ATP deficit → exercise intolerance, myopathy, rhabdomyolysis, lactic acidosis.
Branch B (iron homeostasis): Impaired Fe-S biogenesis is sensed as cellular iron deficiency (via IRP/IRE), leading to increased iron uptake and mitochondrial iron overload (PMID: 20547883); biopsy shows iron accumulation (PMID: 30010796).
Branch C (heme A / redox): FDX2 loss impairs heme A biosynthesis (COX maturation) (PMID: 20547883) and reduces SOD2, resulting in altered ROS handling (PMID: 41372147).
Combined energy failure, iron overload, and redox imbalance in high-demand post-mitotic tissues (retinal ganglion cells/optic nerve, skeletal muscle, peripheral nerve, CNS white matter) leads to the clinical manifestations: optic atrophy, episodic myopathy/rhabdomyolysis, axonal neuropathy, and reversible leukoencephalopathy.

Molecular pathways: Mitochondrial ISC assembly pathway (NFS1/ISCU2/ISD11/ACP1/frataxin/ferredoxin); oxidative phosphorylation; TCA cycle (aconitase); heme A biosynthesis; cellular iron regulation (IRP1/IRP2–IRE). Cellular processes (GO): iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] assembly (GO:0044571), mitochondrial electron transport (GO:0006120), cellular iron ion homeostasis (GO:0006879), oxidative stress response. Protein dysfunction: Loss of function — reduced abundance and/or electron-transfer capacity (not primarily aggregation). Metabolic changes: Impaired OXPHOS/ATP output, lactate accumulation, mitochondrial iron overload, reduced heme A. Tissue damage mechanisms: Bioenergetic failure + oxidative stress + iron-mediated injury in energy-demanding tissues. Immune involvement: None established (not autoimmune/inflammatory).

7. Anatomical Structures Affected

Organ/system level: Nervous system (optic nerve/retinal ganglion cells, peripheral nerves, CNS white matter), musculoskeletal (skeletal muscle). Secondary: kidney (acute kidney injury during rhabdomyolysis).
Tissue/cell level: Skeletal muscle fibers (CL:0000188 skeletal muscle cell / UBERON:0001134); retinal ganglion cells (CL:0000740); peripheral neurons/axons (CL:0000101 sensory neuron); CNS white matter / oligodendrocytes and myelin (UBERON:0002316).
Subcellular level (GO Cellular Component): Mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial inner membrane/respiratory chain (GO:0005743).
Localization (UBERON): skeletal muscle organ (UBERON:0001134), optic nerve (UBERON:0000941), peripheral nerve (UBERON:0001021), cerebral white matter (UBERON:0002437). Lateralization: bilateral/symmetric (optic atrophy, leukoencephalopathy, myopathy).

8. Temporal Development

Onset: Pediatric. Optic atrophy/nystagmus by ~age 3; myopathy in the first-to-second decade. Onset of visual signs is insidious; muscle crises are acute/episodic.
Progression: Chronic and progressive baseline course (progressive myopathy, distal neuropathy, optic atrophy) punctuated by acute episodic crises (rhabdomyolysis, metabolic decompensation). Leukoencephalopathy is notable for being reversible/partially reversible.
Patterns: Episodic crises can resolve with supportive care; some white-matter changes reverse. Critical periods for intervention are the peri-crisis windows (prompt hydration/renal protection) and trigger avoidance. Lifelong, chronic disorder.

9. Inheritance and Population

Inheritance: Autosomal recessive (biallelic FDX2). Unaffected heterozygous carriers.
Epidemiology: Ultra-rare; fewer than ~15 genetically confirmed patients reported worldwide. No reliable prevalence/incidence estimates (Orphanet prevalence "unknown/<1/1,000,000").
Penetrance/expressivity: Appears high penetrance in biallelic individuals; variable expressivity/severity across variants and families.
Anticipation: Not applicable (not a repeat-expansion disorder).
Founder effects/consanguinity: The p.P144L allele is a recurrent founder variant in Brazilian families; consanguinity underlies several reports. Carrier frequency not established but low (LoF-tolerant, rare alleles).
Demographics: Reported in consanguineous Middle Eastern and Brazilian families; no strong sex predilection reported. Age distribution: pediatric onset with lifelong course.

10. Diagnostics

Laboratory: Elevated serum/plasma lactate (markedly during crises, up to 22.3 mmol/L), elevated creatine kinase (up to ~320,000 U/L in rhabdomyolysis), elevated alanine; renal function monitoring during crises (PMID: 37565517).
Biopsy/histopathology: Characteristic regional succinate dehydrogenase (complex II) and cytochrome c oxidase deficiency with iron accumulation on muscle biopsy (PMID: 30010796); reduced Fe-S-dependent complex I/II/III and aconitase activities (PMID: 24281368).
Imaging: Brain MRI showing reversible/partially reversible leukoencephalopathy; MR spectroscopy may show a lactate peak.
Electrophysiology: Nerve conduction studies/EMG consistent with sensorimotor axonal neuropathy; myopathic EMG features.
Genetic testing (definitive): Clinical exome/whole-exome sequencing is first-line for suspected mitochondrial disease (PMID: 34056100); mitochondrial nuclear-gene panels including FDX2/FDX1L, or single-gene/targeted testing; homozygosity mapping is valuable in consanguineous families (PMID: 24281368). RNA/functional studies help classify splice variants (PMID: 41372147).
Differential diagnosis: FDXR-related auditory neuropathy + optic atrophy (PMID: 28965846); ISCU myopathy (exercise intolerance); FXN/Friedreich ataxia; NFU1/BOLA3/ISCA2/IBA57 multiple mitochondrial dysfunctions syndrome; other complex I–IV deficiencies and mtDNA disorders.
Screening: No population newborn screening. Cascade/carrier testing in affected families and genetic counseling are appropriate.

11. Outcome / Prognosis

Survival/mortality: No formal survival statistics. The chronic course is compatible with survival into adulthood, but acute rhabdomyolysis crises with lactic acidosis and acute kidney injury are potentially life-threatening (PMID: 37565517).
Morbidity/disability: Progressive visual impairment (optic atrophy), muscle weakness/exercise intolerance, and distal sensorimotor neuropathy produce cumulative disability. Leukoencephalopathy may be reversible.
Disease course: Chronic-progressive with superimposed episodic crises; recovery from individual crises is possible with supportive care.
Prognostic factors: Severity/frequency of metabolic crises, degree of multiorgan involvement, and specific variant (residual FDX2 function) likely influence outcome. No validated prognostic biomarkers beyond lactate/CK trends.

12. Treatment

No curative or disease-specific therapy exists. Management is supportive (NCIT: Supportive Care, C15277):

Acute crisis management: Aggressive IV hydration and renal protection for rhabdomyolysis; treat lactic acidosis; monitor/support kidney function (PMID: 37565517).
Exercise/rehabilitation (NCIT: Exercise Therapy, C16586): Graded endurance + resistance training improves VO2max, respiratory enzyme activity, strength, and QoL; start low-intensity and avoid exercising during fever, illness, muscle pain/cramps, or after fasting >12 h (PMID: 25008908). Cochrane: no evidence of harm from moderate training (PMID: 20091552).
Supplements (empirical "mitochondrial cocktail"): CoQ10/ubiquinone, riboflavin, L-carnitine, antioxidants — no FDX2-specific trial evidence. Creatine monohydrate gives mixed/modest benefit (PMID: 18652078).
Trigger avoidance: Avoid prolonged fasting, manage fever/illness promptly, pace activity.
Genetic counseling for families.
Advanced/experimental therapeutics: No gene therapy, RNA therapy, or targeted therapy in trials for FDX2 disease to date. Pharmacogenomics: none established.

13. Prevention

Primary prevention: Not preventable at the individual level (monogenic). Genetic counseling, carrier/cascade testing, prenatal/preimplantation genetic diagnosis can prevent recurrence in at-risk families — especially relevant where consanguinity/founder alleles (p.P144L) are present.
Secondary prevention: Early molecular diagnosis (exome-first) enables early supportive management and crisis-prevention education.
Tertiary prevention: Trigger avoidance, prompt crisis management (hydration/renal protection), graded exercise, and multidisciplinary follow-up to limit complications.
Immunization/public health/environmental interventions: Not applicable beyond general infection-prevention to reduce fever-triggered crises.

14. Other Species / Natural Disease

Taxonomy/orthologs: Human FDX2 (NCBI Gene ID 614650). Functional ortholog in Saccharomyces cerevisiae (NCBI Taxon 4932) is Yah1 (yeast adrenodoxin homolog), partnered with reductase Arh1 (PMID: 12970193; PMID: 15211518). Mammalian orthologs exist (mouse Fdx2, Mus musculus NCBI Taxon 10090).
Natural disease in animals: No naturally occurring FDX2 disease reported in companion animals or wildlife (no OMIA entry identified).
Comparative biology/conservation: The ferredoxin-dependent ISC assembly pathway is highly evolutionarily conserved from yeast to humans, which is why Yah1 depletion recapitulates the core Fe-S assembly defect (PMID: 12970193; PMID: 28615445).
Zoonotic/transmission: Not applicable (genetic disease).

15. Model Organisms

Yeast (S. cerevisiae): Yah1 depletion is the principal genetic model, demonstrating that the ferredoxin is essential for de novo Fe-S cluster synthesis on Isu1p (PMID: 12970193) and for heme A biosynthesis with Arh1 (PMID: 15211518).
Human cell systems: RNAi/CRISPR knockdown in human cells established FDX2's specific role in heme A and Fe/S biosynthesis and its iron-homeostasis phenotype (PMID: 20547883); patient-derived fibroblasts/myoblasts show impaired respiration, multiple Fe-S defects, mitochondrial iron accumulation, and reduced SOD2 (PMID: 41372147).
In vitro structural biology: Recombinant FDX2 and cryo-EM of the FDX2–core-ISC complex define the electron-donation and frataxin-competition mechanism (PMID: 39632806; PMID: 39467201).
Phenotype recapitulation / limitations: Cellular and yeast models faithfully reproduce the biochemical core (Fe-S assembly failure, respiratory/aconitase deficiency, iron overload) but do not capture the multisystem organismal phenotype (optic atrophy, episodic myopathy, neuropathy, leukoencephalopathy). No dedicated mouse or zebrafish disease model of FDX2 has been published — a notable gap.

Mechanistic Model / Interpretation

 Biallelic FDX2/FDX1L LoF variant (c.1A>T | p.P144L | c.200+4A>G)
 │  (↓ ferredoxin-2 level / electron-donor activity)
 ▼
 Loss of electron donation to core ISC complex (ISCU2-NFS1-ISD11-ACP1)
      [FDX2 competes with frataxin for overlapping sites]  (PMID 39632806)
 │
 ▼
 Defective de novo [2Fe-2S] & [4Fe-4S] cluster assembly  (PMID 12970193, 41372147)
 │
    ┌────────────┼───────────────────────────┬───────────────────────────┐
    ▼            ▼                            ▼                           ▼
 Complex I/II/III   Aconitase loss        ↑Iron uptake +            ↓Heme A / ↓SOD2
 deficiency         (TCA)                 mito iron overload        (COX maturation,
 (PMID 24281368)                          (PMID 20547883)            redox) (PMID 41372147)
    │                   │                      │                          │
    └─────── ATP deficit / lactic acidosis ◄───┘                          │
 │                                                        │
 └──────────► OXIDATIVE STRESS + IRON-MEDIATED INJURY ◄───┘
 │
 ▼
 Energy-demanding post-mitotic tissues injured:
   • Optic nerve / RGC  → optic atrophy, nystagmus (by ~age 3)
   • Skeletal muscle    → episodic myopathy, rhabdomyolysis, CK↑, exercise intolerance
   • Peripheral nerve   → sensorimotor axonal neuropathy
   • CNS white matter   → reversible leukoencephalopathy
   • Kidney (secondary) → AKI during rhabdomyolysis crises

Upstream (initiating) events are the FDX2 mutation and the Fe-S assembly failure; downstream (effector) events are respiratory/TCA enzyme inactivation, iron mishandling, and tissue-specific energy failure. The episodic nature reflects gene–environment interaction: a chronically marginal bioenergetic reserve is tipped into crisis by metabolic stressors (fasting, fever, exertion).

Evidence Base

PMID	Study type	Contribution
24281368	Human clinical/genetics	First gene identification (c.1A>T); complex I/II/III + aconitase deficiency
30010796	Human clinical (6 patients)	Defines phenotype (optic atrophy, episodic myopathy, neuropathy, leukoencephalopathy); SDH/COX + iron biopsy; p.P144L founder
41372147	Human + cellular	Novel c.200+4A>G splice variant; patient-cell respiration/Fe-S/iron/SOD2 defects
37565517	Case report	Severe rhabdomyolysis (CK ~320,000), lactic acidosis, AKI — crisis management
39467201	In vitro / structural	Molecular determinants of P144L; FDX2 donates electrons for [2Fe-2S]/[4Fe-4S]
39632806	Cryo-EM	Two-stage FDX2 binding to core ISC complex; frataxin competition
20547883	In vitro (RNAi)	FDX2 vs FDX1 functional distinction; iron-homeostasis phenotype
28965846	Human clinical	FDXR disease — key differential and upstream pathway partner
34056100	Review/methodology	Exome-first diagnostic strategy for mitochondrial disease
12970193	Yeast model	Yah1 (FDX2 ortholog) essential for Fe-S assembly on Isu1p
15211518	Yeast/computational	Yah1–Arh1 pair in heme A and FeSC assembly
28615445	Review	~30-protein ISC biogenesis pathway framework
25008908	Clinical review	Exercise therapy benefits + trigger-avoidance guidance
20091552	Cochrane review	Safety of strength/aerobic training in muscle disease
18652078	Clinical review	Creatine in mitochondrial cytopathies (mixed benefit)
28747430	In vitro	FDXR is sole reductase supplying both ferredoxins

Evidence source distribution: Human clinical/genetics (~5 reports, <15 patients total) + mechanistic in vitro/structural + yeast model. No RCTs, no large cohorts, no vertebrate disease model.

Limitations and Knowledge Gaps

Extreme rarity: Fewer than ~15 genotyped patients; all epidemiology (prevalence, incidence, sex ratio, survival) is anecdotal. No natural-history study or registry exists.
No vertebrate animal model: Mechanism rests on yeast, human cell lines, and structural biology; organ-level pathophysiology (why optic nerve and white matter are vulnerable) is inferred, not demonstrated in vivo.
Genotype–phenotype correlation is immature: Only a handful of variants; residual-function/severity relationships are not quantified. Some mutant proteins (P144L, c.200+4A>G) appear structurally near-normal, suggesting abundance/activity thresholds matter — but this is not fully resolved.
No disease-specific therapy or trials: All treatment evidence is extrapolated from general mitochondrial-myopathy literature; no FDX2-specific interventional data.
Reversible leukoencephalopathy is mechanistically unexplained: The basis for white-matter reversibility vs progressive optic atrophy is unknown.
ICD coding is non-specific (mapped to general mitochondrial myopathy codes).

Proposed Follow-up Experiments / Actions

Establish a vertebrate model: Generate a conditional/tissue-specific (muscle, retinal ganglion cell, oligodendrocyte) Fdx2 knockout or knock-in (p.P144L) mouse and/or zebrafish to test phenotype recapitulation (optic atrophy, episodic myopathy, leukoencephalopathy) and to serve as a preclinical therapeutic platform.
International patient registry & natural-history study: Pool genotyped cases via GeneMatcher/consortia to define prevalence, penetrance, crisis frequency/triggers, survival, and validated outcome measures.
Genotype–function mapping: Systematically measure residual FDX2 electron-transfer activity and protein stability across variants (c.1A>T, p.P144L, c.200+4A>G, and new alleles) to build a severity-prediction model.
Biomarker development: Evaluate plasma lactate/CK dynamics, FGF21/GDF15, and iron indices as diagnostic and prognostic biomarkers specific to FDX2 disease.
Targeted therapeutic exploration: Test whether iron-chelation, antioxidant/SOD2-supporting strategies, or substrate/cofactor supplementation rescue the Fe-S/respiration defect in patient cells and the animal model; evaluate AAV gene-replacement feasibility given the small 186-aa cDNA.
Standardized crisis protocol: Develop and disseminate a consensus acute-rhabdomyolysis management pathway (hydration, renal protection, trigger avoidance) for FDX2 and related ISC-biogenesis disorders.
Pathway-wide diagnostics: Ensure FDX2/FDX1L is included on all mitochondrial and Fe-S/ISC gene panels, with reflex RNA/functional testing for splice and missense variants.

Report compiled from 5 investigation iterations, 9 confirmed findings, and 30 reviewed papers. Evidence is weighted toward human case reports and mechanistic in vitro/yeast/structural studies; interpretations involving organ-level vulnerability and episodic triggering are mechanistically reasoned and explicitly flagged as inferred where direct in vivo demonstration is lacking.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	16
On topic	9
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	31
Resolved	29
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	11
Terms named correctly	0
Terms named as a different term	11

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:0020714 (5 mentions) - the report calls it "if available", "MONDO"; MONDO calls it mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
MedGen:1679560 (1 mention) - the report calls it "UMLS C5193223"; MedGen calls it Acute abdomen
HP:0000648 (1 mention) - the report calls it "Characteristic (majority)"; HP calls it Optic atrophy
HP:0000639 (1 mention) - the report calls it "Frequent"; HP calls it Nystagmus
HP:0003546 (1 mention) - the report calls it "Characteristic"; HP calls it Exercise intolerance
HP:0003198 (1 mention) - the report calls it "Characteristic"; HP calls it Myopathy
HP:0003236 (1 mention) - the report calls it "Frequent in crises"; HP calls it Elevated circulating creatine kinase activity
HP:0003128 (1 mention) - the report calls it "Frequent"; HP calls it Lactic acidosis
HP:0007141 (1 mention) - the report calls it "Characteristic"; HP calls it Sensorimotor neuropathy
HP:0002352 (1 mention) - the report calls it "Characteristic"; HP calls it Leukoencephalopathy
HP:0001919 (1 mention) - the report calls it "Subset"; HP calls it Acute kidney injury

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0020714 - called "if available", "MONDO"

Prefixes with no resolver

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

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Phenotypes

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Diagnosis

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Differential Diagnoses

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References & Deep Research

Deep Research

FDX2-Related Mitochondrial Myopathy (MEOAL) — Comprehensive Disease Report

Summary

Key Findings

Finding 1 — Biallelic FDX2 (FDX1L) variants cause autosomal-recessive MEOAL [HUMAN]

Finding 2 — Pathomechanism: FDX2 deficiency impairs Fe-S cluster biogenesis, disabling Fe-S-dependent respiratory complexes and aconitase [HUMAN / IN VITRO]

Finding 3 — Clinical phenotype: childhood optic atrophy, episodic myopathy, neuropathy, reversible leukoencephalopathy [HUMAN]

Finding 4 — FDX2 is functionally distinct from FDX1 (adrenodoxin) [IN VITRO]

Finding 5 — Genomic/constraint data confirm a LoF-tolerant, recessive gene [COMP]

Finding 6 — Differential diagnosis: FDX2 disease within the ISC-biogenesis disorder spectrum [HUMAN]

Finding 7 — Model organisms: yeast Yah1 is the key ortholog; no dedicated vertebrate model [MODEL / IN VITRO]

Finding 8 — Treatment is supportive/symptomatic; no curative therapy [HUMAN]

Finding 9 — Verified identifiers [COMP]

The 15-Section Disease Knowledge Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms named inconsistently

Prefixes with no resolver