J Neuroophthalmol. 2025 Dec 19. doi: 10.1097/WNO.0000000000002428. Online ahead of print.
ABSTRACT
BACKGROUND: Wolfram syndrome type 1 (WS1), or “DIDMOAD” (diabetes insipidus, diabetes mellitus, optic atrophy (OA), and deafness, OMIM #222300), is a rare neurodegenerative disorder resulting from homozygous, compound heterozygous autosomal recessive (AR), or rarely autosomal dominant mutations in the WFS1 gene. Isolated OA with adult-onset, milder phenotypes in WS1 is rare and typically associated with biallelic AR mutations. We describe 7 patients of pauci-syndromic WS1 presenting with adult-onset OA and compare parameters of visual function with other OA-predominant syndromes.
METHODS: A retrospective review was performed identifying records of patients seen at our institution from January 1, 2020, through December 31, 2024, who were found to have OA secondary to mutations in OPA1 (n = 9), WFS1 (n = 7), POLG (n = 3), mutations causing Leber hereditary optic neuropathy (LHON) (n = 17) or isolated OA from other genetic causes (n = 7). Patients were excluded who harbored confounding causes of vision loss and nongenetic causes of OA. Clinical data of visual function were recorded, including mean deviations and foveal sensitivities on automated visual fields (AVF), and ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT). Visual acuities from initial neuro-ophthalmology consultation were recorded in logMAR format. Statistical analysis was performed on continuous variables. This study was granted exempt status by our institutional IRB.
RESULTS: Compared with other OA syndromes, patients with LHON had the most severe average AVF and foveal sensitivity depressions and the lowest presenting logMAR acuity. Patients with WS1 in our cohort had significantly later onset of symptoms and delayed presentation compared with other OA syndromes. Patients with WS1 were significantly more likely to present with arcuate scotomas compared with other genetic OA syndromes, while patients with LHON and patients with OPA1 mutations (autosomal dominant optic atrophy [ADOA]) presented commonly with central scotomas and blind spot enlargement, respectively. WS1 diagnosis was not significantly associated with any specific pattern of thinning on OCT of the RNFL or GCC. ADOA diagnosis was associated with the most peripapillary RNFL thinning overall of all OA syndromes, most significantly in the superior and inferior quadrants.
CONCLUSIONS: Our cohort of patients with WS1 showed uncharacteristically mild vision loss and minimal syndromic features, suggesting that a milder alternative phenotype with WFS1 mutations is possible in contrast to the traditional DIDMOAD syndrome. Compared with other OA syndromes, these patients with WS1 showed significant associations with arcuate visual field defects and trends toward superior/inferior peripapillary RNFL thinning. This suggests that relative preservation of papillomacular bundle fibers and thus milder central visual acuity loss may be a unifying feature in their phenotype. This series expands the clinical spectrum of WS1 and should encourage further work to study the pathogenic role of wolframin in vision loss. Clinicians should consider Wolfram syndrome in cases of adult-onset, symmetric, near-isolated OA, especially in cases with arcuate field defects, which are more commonly seen than in other genetic syndromes.
PMID:41411089 | DOI:10.1097/WNO.0000000000002428