Optic neuropathy

Gene: NDUFA1

Green List (high evidence)

Comment on list classification: As reviewed by Neringa Jurkute, there are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.

Created: 16 Dec 2025, 11:04 a.m. | Last Modified: 16 Dec 2025, 11:07 a.m.

Panel Version: 5.32

PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (PMID: 25356405, PMID: 29506883).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

Authors highlight the clinical variability between LSS patients harbouring the same variant.

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).

Created: 16 Dec 2025, 9:12 a.m. | Last Modified: 16 Dec 2025, 12:15 p.m.

Panel Version: 5.32

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020; Optic neuropathy, HP:0001138

Publications

• 41234160

Green List (high evidence)

Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFA1 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research

Created: 27 Nov 2025, 9:15 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Optic neuropathy, optic atrophy; LHON-like

Publications

• PMID: 41234160

Mode of pathogenicity
Other