Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series

Abstract

BackgroundWe present the disease course and long-term follow-up of two patients who were phenotypically diagnosed with atypical Leber Hereditary Optic Neuropathy (LHON) 14 and 12 years ago, respectively, whereby whole exome sequencing revealed recently described recessive DNAJC30:c.152G>A 152 A>G (p.Tyr51Cys) homozygous pathogenic variant with significant spontaneous visual acuity recovery in one.Case presentationTwo presented unrelated males with atypical LHON with sequential visual acuity (VA) loss were followed for many years. Both patients had negative family history. At the presentation at ages 17 (Case 1) and 18 years (Case 2), both had reduced visual acuity (Snellen): (Case 1) right eye (RE):CF 3m, left eye (LE):0.6, (Case 2) RE:0.2, LE:0.15; and color vision (Ishihara): (Case 1) 1/15 and 13/15; (Case 2) 2/15 and 3/15. Both had hyperemic optic disks (PNO) and central scotoma in their visual fields. Electrophysiology in the acute phase showed reduced and delayed visually evoked potentials (VEP) P100 in both patients, with reduced N95 amplitude in Case 2, and initially normal N95 amplitude in Case 1. Fluorescein angiography showed no early leakage with some late pooling at optic disks. Extensive clinical workout, including brain magnetic resonance imaging (MRI), aquaporin 4 (Aq4), and anti-myelin oligodendrocyte protein (anti-MOG) antibodies, was negative. Intravenous corticosteroids did not improve vision. Both experienced further deterioration several months after the onset accompanied by thinning of the peripapillary retinal nerve fiber layer (RNFL). Genetic testing for typical LHON pathogenic variants and whole mitochondrial DNA (mtDNA) sequencing was negative. 1 year after the onset, modest VA improvement began in Case 2 and continued over the next 3 years. VA improved bilaterally to 0.7, color vision 15/15, and islands of vision appeared within the visual field scotoma. VEP P100 peak time shortened, and amplitude increased, despite further RNFL thinning on optical coherent tomography (OCT). The patient's visual function remained stable during the entire 12-year follow-up period. Case 1 experienced modest VA improvement to 0.1 with some improvement in the visual field seven years after the disease onset, remaining stable during the entire 14-year follow-up period. VEP P100 wave remained undetectable.ConclusionsPresented are two autosomal recessive LHON (arLHON, OMIM:619382) cases with the same DNAJC30:c.152G>A pathogenic variant and different degrees of spontaneous visual recovery despite progressive RNFL thinning during a long-term follow-up. This mutation should be screened in every atypical LHON patient.

Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm

“… 18 , 19 Importantly, arLHON patients carrying DNAJC30 mutations displayed a significantly higher ratio of visual improvement (up to 81%) after idebenone treatment ( Table 3 ). In contrast, DNAJC30 patients who received corticoid boluses during the acute phase of the disease instead of idebenone showed no visual acuity recovery, 4 , 9 ,10 as did the patient carrying MCAT variants. 6 However, a gain of visual acuity upon corticoid treatment has been reported occasionally (one individual with a DNAJC30 mutation 4 and two of three siblings carrying NDUFS2 mutations 3 ; Table 3 ).…”

“… Based on steroid/corticosteroid treatment documented in 12 individuals showing no improvement in 11/12 individuals (10 and 1 carrying the p.Tyr51Cys and p.Leu101Gln mutations in homozygosity, respectively). 4 , 9 , 10 Visual improvement is noted in 1/12 individual carrying the p.Pro78Ser mutation in homozygosity. 4 …”

Electroretinographic oscillatory potentials in Leber hereditary optic neuropathy

“…The changes in RGCs and in the retinal nerve fiber layer (RNFL) strongly impact the central retina leading to low vision or irreversible legal blindness with small number of patients that eventually recover vision partially [ 7 , 8 ]. Equivalent mitochondrial alterations can be also caused by biallelic mutations in genes of the nuclear DNA leading to an autosomal recessive form of LHON, as recently reported [ 9 , 10 ].…”

Leber’s hereditary optic neuropathy: Update on the novel genes and therapeutic options

“…14 In contrast to LHON caused by mtDNA mutations, arLHON tends to have an earlier disease onset age, such as 12 or 14, and a higher rate of visual recovery. 15…”