Mutations in NSUN3, a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy.

Inherited optic neuropathies (IONs) are rare genetic diseases characterized by progressive visual loss due the atrophy of optic nerves. The standard diagnostic workup involving next-generation sequencing panels has a diagnostic yield of about forty percent. In the other 60% of the patients with a clinical diagnosis of ION, the underlying genetic variants remain unknown. In this case study, we describe a potentially new disease-associated gene, NSUN3, for IONs. The proband was a young woman with consanguineous parents. She presented with bilateral optic atrophy and nystagmus at the age of seven years. Genetic testing revealed the homozygous variant c.349_352dup p.(Ala118Glufs*45) in NSUN3, with a segregation in the family compatible with autosomal recessive inheritance. Additional functional analysis showed decreased NSUN3 mRNA levels, slightly diminished mitochondrial complex IV levels, and decreased cell respiration rates in patient fibroblasts compared to healthy controls. In conclusion, pathogenic variants in NSUN3 can cause optic neuropathy. Trio whole-exome sequencing should be considered as a diagnostic strategy in ION cases where standard diagnostic analysis does not reveal disease-causing variants.

Delineating Wolfram-like syndrome: A systematic review and discussion of the WFS1-associated disease spectrum.

Wolfram-like syndrome (WFLS) is a recently described autosomal dominant disorder with phenotypic similarities to autosomal recessive Wolfram syndrome (WS), including optic atrophy, hearing impairment, and diabetes mellitus. We summarize current literature, define the clinical characteristics, and investigate potential genotype phenotype correlations. A systematic literature search was conducted in electronic databases Pubmed/MEDLINE, EMBACE, and Cochrane Library. We included studies reporting patients with a clinical picture consisting at least 2 typical clinical manifestations of WSF1 disorders and heterozygous mutations in WFS1. In total, 86 patients from 35 studies were included. The most common phenotype consisted of the combination of optic atrophy (87%) and hearing impairment (94%). Diabetes mellitus was seen in 44% of the patients. Nineteen percent developed cataract. Patients with missense mutations in WFS1 had a lower number of clinical manifestations, less chance of developing diabetes insipidus, but a younger age at onset of hearing impairment compared to patients with nonsense mutations or deletions causing frameshift. There were no studies reporting decreased life expectancy. This review shows that, within the spectrum of WFS1-associated disorders or "wolframinopathies," autosomal dominantly inherited WFLS has a relatively mild phenotype compared to autosomal recessive WS. The clinical manifestations and their age at onset are associated with the specific underlying mutations in the WFS1 gene.