Discussion and Conclusions
Wolfram syndrome (OMIM #222300) is an autosomal recessive disorder also known as DIDMOAD for its typical clinical features of Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness [10]. The minimum criteria for the diagnosis of Wolfram syndrome are the presence of diabetes mellitus and optic atrophy, both of which usually occur by the age of fifteen [11]. The disorder is also associated with diverse neurologic and psychiatric symptoms, including cognitive impairment [12]. Though with genetic data in hand the diagnosis of Wolfram syndrome now seems clear for the patient presented here, his late age of onset and the prominence of his amnesia are quite atypical for this syndrome and made the diagnosis seem less likely. Furthermore, the clinical presentation, mtDNA deletions, and biochemical data were highly suggestive of a mitochondrial disorder.
Given the multiple organ system dysfunction characteristic of Wolfram syndrome, it was initially thought by a number of clinicians to be a bona fide mitochondrial disorder [13]. Further supporting this hypothesis was the observation of mtDNA deletions in some patients with Wolfram syndrome [14-16]. However, in 1998 two groups identified WFS1, which encodes an 890 amino acid trans-membrane protein localized to the endoplasmic reticulum, as the gene responsible for the majority of Wolfram syndrome cases, thereby arguing against a mitochondrial etiology [17,18]. Mechanistic studies of WFS1 have revealed an important role in dampening the ER stress response in pancreatic beta cells and neurons, and loss of the gene has been shown to result in an exaggerated stress response and accelerated cell death [19]. However, given the shared clinical features between Wolfram syndrome and many mitochondrial disorders, as well as the presence of mtDNA deletions in some patients, many unanswered questions remain about the biology of WFS1 and its impact on mitochondrial function and mtDNA maintenance.
Mutations in residue 558 of WFS1, as identified in the patient described here, have been previously reported. Our patient's p.R558C mutation was first reported as a heterozygous variant in a cohort of psychiatric patients, though it is unclear whether the variant contributed to disease pathogenesis in that population [20]. Our patient's p.R558C mutation, as well as a p.R558H mutation, have been reported in multiple patients with Wolfram syndrome [9,21,22]. Exome databases suggest that the allele frequency of WFS1 c.1672C > T (p.R558C) is quite rare; specifically, the variant is not found in the 1,000 Genomes Project [23] nor in over 2,500 publicly available European and African American exomes [24].
Chaussenot et al. specifically discuss the phenotype of a Wolfram case with the same p.R558C mutation identified in our patient in compound heterozygosity with a p.F354del frameshift mutation [12]. Like our patient, Chaussenot et al.'s case had significant cerebellar atrophy by MRI, neurogenic bladder symptoms, dementia, DM, OA, as well as the absence of diabetes insipidus. However, unlike our patient, the compound heterozygote case had earlier onset of DM, OA, and neurologic symptoms (at ages 9, 10, and 27 respectively), lacked hearing impairment, and developed cerebellar ataxia and nystagmus as part of her neurologic presentation. Of note, the profound amnestic syndrome seen in our patient was not reported for the compound heterozygote case, and is atypical for Wolfram syndrome patients in general. These cases demonstrate that phenotypic heterogeneity is present even among patients with similar mutations, likely attributable to different genetic and environmental backgrounds.
Some WFS1 mutations have been suggested to function in an autosomal dominant manner yielding symptoms such as optic atrophy and hearing impairment in a heterozygous state [25,26]. The patient has one daughter who struggled with Tourette syndrome and ADHD, but the family history is otherwise unremarkable, with no close family members suffering from symptoms associated with Wolfram syndrome. No familial DNA was available to determine the carrier status of his daughter. It is unlikely that his daughter's symptoms are related to WFS1, and we suspect that the p.R558C variant likely acts in a recessive manner.
One of the most striking aspects of the case presented here is the profound thiamine deficiency, and its devastating impact on the patient's memory. The symptom complex of diabetes mellitus, deafness, and optic atrophy has been found in association with defects in thiamine metabolism previously in the context of thiamine-responsive megaloblastic anemia syndrome, or Rogers syndrome (OMIM # 249270) [27-29]. Rogers syndrome, a recessive condition caused by mutations in the thiamine transporter SLC19A2, is characterized by thiamine-responsive megaloblastic anemia, sensorineural deafness, and DM; its phenotypic similarity to Wolfram syndrome suggests the possibility that disruption of thiamine metabolism may contribute to the pathophysiology of Wolfram syndrome. The coding exons of SLC19A2 were sequenced in our patient and no rare mutations were detected, although the presence of non-coding variants cannot be excluded. Given that there was no dietary reason for our patient to develop thiamine deficiency, his case suggests that WFS1 may impact thiamine transport or utilization. Furthermore, given that there are no therapies available for the treatment of Wolfram syndrome, assessment of thiamine sufficiency and possibly empiric thiamine supplementation should be considered for these patients.
The patient presented here had a diagnostic journey that is not unusual for disorders involving dysfunction across multiple organ systems, in that several years elapsed and numerous costly genetic tests were performed without a molecular diagnosis. The application of MitoExome sequencing in this case illustrates how clinical application of next-generation sequencing technology can allow for rapid, simultaneous evaluation for multiple genetic disorders with a single test thereby accelerating the diagnostic process. Furthermore, this case demonstrates how careful study of an individual patient with a rare disorder can yield potentially new insight into gene function and disease pathogenesis.