Here we report a case with a rare heterozygous variant (c.1230_1233delCTCT; p.V412Sfs*29) in exon 8 of the WFS1 gene and extensive leukodystrophy change in the central nervous system with syrinx cavity. This variant has been reported in Clinvar (SCV000582399) in 2017. This mutation was described as homozygous (c.1230 1233 deteCT) in a female patient who had showed all the clinical features of Wolfram syndrome . We diagnosed Wolfram-like syndrome in our patient who had optic atrophy, congenital cataract, nystagmus, ataxia, mild mental disability, epilepsy, leukodystrophy and a heterozygous (frame-shift) mutation in the WFS1. To date, more than 400 different mutations have been identified in WFS1 (https://www.ncbi.nlm.nih.gov/clinvar/?term=WFS1%5Bgene%5D).
They are often located in exon 8 and are inactivating (nonsense or frameshift) mutations. WFS1 mutations can be dominantly or recessively inherited and both the onset of the disorder and degree of severity are highly variable . According to the genetic test results, our patient and his grandmother are likely to have a mild form of this syndrome. Although the patient's father had the same mutation, he did not have diabetes mellitus (DM), visual loss, or hearing problems. The HbA1c value was 5.8% at the last follow-up of the patient, who maintained drug-free glucose control with diet and exercise for the last 3 months. The genotype–phenotype correlation is difficult to establish due to the molecular complexity of WFS1. Bonnycastle et al. have found heterozygous nonsynonymous variant (p.Trp314Arg) in the WFS1 gene with dominantly inherited nonsyndromic adult-onset diabetes mellitus in a large four-generations family . Morikawa et al. have shown a de novo heterozygous mutation (p.N325_I328del) in a patient with Wolfram-like syndrome with insulin-dependent DM, congenital cataract, and severe bilateral hearing loss. In general, cataract is not a typical sign of the syndrome, but most patients associated with WFS1 heterozygous mutations had congenital cataract . Neuro-radiological manifestations of Wolfram syndrome include atrophy of the brainstem, diffuse cerebellar gray and white matter atrophy, thinning of the middle cerebellar peduncle and optic nerve and optic tract atrophy . Leukodystrophies are a group of disorders that involve the myelin tracts in the central nervous system, where myelin involvement is the primary feature and not secondary to any underlying neuronal pathology . Leukodystrophy is classified into peroxisomal disorders, lysosomal storage diseases, diseases caused by mitochondrial dysfunction. Each group of leukodystrophy has distinct clinical, biochemical, pathological, and radiologic features. According to Abdelsalam and colleagues MRS revealed abnormal NAA/Cr (The N-acetylaspartate to creatine), Cho/Cr (Colin to creatine), and Cho/NAA (Colin to N-acetylaspartate) ratios which were highly characteristic in the majority of cases, elevated Cho/Cr, decreased NAA/Cr and elevated Cho/NAA ratios were the dominant finding with leukodystrophies. One-way analysis of variance for the spectroscopic metabolite ratios revealed statistical significance in leukodystrophies. Our patient had no abnormality in MRS . Leukodystrophies have never been reported in Wolfram syndrome before. The application of the next-generation sequencing technology allowed for rapid diagnosis and appropriate evaluations of our patient. Identification of a heterozygous variant (p.V412Sfs*29) found in the patient supports the diagnosis of the Wolfram-like syndrome with dominant inheritance in the patient. The present case also described a new neuroradiologic sign observed on MR imaging in Wolfram-like syndrome. The most common findings of neuroradiologic features in the patients with Wolfram syndrome have involved the posterior pituitary gland, optic nerve and optic chiasm, cerebral white matter, brain stem, and cerebellum [11, 12]. Neuroradiologists should be aware of leukodystrophies and other findings when reading MRI studies of patients with genetically confirmed Wolfram-like syndrome. Variable inheritance pattern together with the progressive character of clinical symptoms complicate the diagnosis and family genetic counseling in Wolfram syndrome.