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IEMbase 0696: NDUFA4-related cytochrome c oxidase subunit NDUFA4 (COXFA4) deficiency

Scope

Field Value
IEMbase ID 696
Nosology 7.4.18.01
Nosology code IEM1149
Gene NDUFA4, current HGNC symbol COXFA4
External IDs OMIM:619065; ORPHA:255241
Generated mapping MAPPED to COXFA4-Related_COX_Deficiency.yaml
Candidate DisMech targets Exact COXFA4/NDUFA4 target; broad Leigh context is secondary
Review date 2026-07-07

IEMbase phenotype signal

IEMbase represents autosomal recessive NDUFA4-related cytochrome c oxidase subunit deficiency. This is the complex IV disease now curated under the HGNC-approved symbol COXFA4; the historical NDUFA4 name reflects the older misassignment of the protein to complex I.

The biochemical rows include increased plasma alanine, increased CSF lactate, and increased plasma lactate. Clinical rows include brainstem MRI lesions, developmental delay, failure to thrive, hypertension, regression, peripheral neuropathy, nystagmus, optic atrophy, renal tubular acidosis, respiratory failure, and characteristic dystonia.

DisMech phenotype coverage

COXFA4-Related_COX_Deficiency.yaml is the correct local target. It explicitly models COXFA4/NDUFA4 as a complex IV structural subunit, explains the historical complex I naming problem, records OMIM:619065/MONDO:0033656, and covers failed complex IV assembly, impaired terminal electron transfer, lactic acidosis, and a Leigh-syndrome neurologic phenotype with leukoencephalopathy/brainstem involvement.

Coverage is high for identity and mechanism, but not complete for every IEMbase phenotype row. The local entry is leaner for plasma alanine, CSF lactate as a separate row, failure to thrive, hypertension, regression, peripheral neuropathy, nystagmus, optic atrophy, renal tubular acidosis, respiratory failure, and dystonia.

Concordance and completeness

Judgement: mapped with high identity/mechanism concordance and phenotype-detail gaps.

This is the key exception in the batch: although the record is named NDUFA4 in IEMbase, it belongs with the complex IV COXFA4 entry rather than the complex I NDUFA/NDUFB gap set. DisMech is stronger on the corrected mechanism and gene symbol; IEMbase adds granular clinical rows that should be reviewed if the COXFA4 entry is expanded.

Curation actions

  • Keep COXFA4-Related_COX_Deficiency.yaml as the canonical target.
  • Preserve the NDUFA4 synonym because IEMbase, OMIM, and older literature use it.
  • Consider adding IEMbase-specific phenotype detail for alanine, CSF lactate, failure to thrive, regression, peripheral neuropathy, nystagmus, optic atrophy, renal tubular acidosis, respiratory failure, dystonia, and hypertension if supported by evidence.
  • Do not treat COXFA4/NDUFA4 as a complex I subunit disease.