Wolfram Syndrome: The Cross-Link Between Rare and Common Disease
At the age of 10, a boy developed dimness in his vision with difficulty recognizing colours.2 Thereafter, he developed behavioural episodes characterized by a bossy
attitude, increased physical activity, and overt sexual behaviour by age 16.2By the
time he turned 22, he was diagnosed with optic atrophy, bilateral sensorineural deafness, bipolar
disorder, and diabetes mellitus amongst a slew of other diseases.2 Of particular interest was how many of the aforementioned symptoms connected to his clinical diagnosis of
the rare Wolfram Syndrome 1 disease.2
Wolfram Syndrome is a rare disease characterized most commonly by many of the boy’s symptoms: optic atrophy, diabetes mellitus, and deafness.1,9 Wolfram Syndrome is typically inherited in an autosomal recessive pattern.10 Thus, in order to be
diagnosed with this disease, an individual would have to inherit two altered genes. However,some patients have been discovered to carry the dominant mutation, which means that an individual would only have to inherit one altered gene.10There are two main forms of this disease: Wolfram Syndrome 1 (WS1) and Wolfram Syndrome 2 (WS2).10 Both forms are caused by an inactivating (nonsense or frameshift) mutation of either the WFS1
(for WS1) or WFS2 (for WS2) gene.4,8,10 A nonsense mutation produces a shorter than normal nucleotide sequence due to a premature stop codon, whereas a frameshift mutation causes error through the insertion or deletion of nucleotides. Beyond the difference in mutated genes, WS1 differs from WS2 in that it has been shown to have greater connections to psychiatric disorders in addition to typical symptoms.8
The WFS1 gene encodes wolframin, a transmembrane protein in the endoplasmic reticulum (ER) shown to interact and influence much of the ER function.8 The ER pathway is important in the assembly and packaging of proteins such as insulin and in the storage of calcium, which are essential to the function of a cell.8An inactivating mutation to WFS1, which often means a reduced dosage of wolframin, has negative implications on ER function.3 Some of these effects have been found to increase ER stress levels, alter pancreatic beta-cells, and induce apoptosis (cell death).1,8 Beta-cells produce insulin, so alterations to its function, in particular, would likely result in major changes that cause symptoms of diabetes.8; In addition, WS1 patients’ fibroblasts with the mutated WFS1 gene have been suggested to release less calcium through the inositol 1,4,5-trisphosphate receptor (IP 3 R), which directly impacts calcium signalling and homeostasis.1 Such alterations to the functioning of the ER subsequently inhibits mitochondrial dynamics, which may also alter neuronal development.8 The worsening of neuronal development could explain some of the psychiatric disorders, hearing loss, and vision deterioration associated with patient symptoms.
Moreover, the implications of important function loss has drastic effects on the prognosis of patients. Unfortunately, the mortality rate is set as high as 60% with most patients dying by age 35 due to neurological complications.5 Currently, standard therapies such as insulin treatment for diabetes symptoms, hearing aids for hearing loss, general accommodations for eyesight, and psychological counseling are used by WS patients.10 However, none of these provide formal treatment for the disease or directly target the locus of the issue. Nevertheless, current research for treatment is underway with a focus on further understanding the mechanisms and ways to restore a normal ER pathway. One of the most recent studies by a team from Yale University builds off previous studies and shows how wolframin (encoded by WFS1) is a regulator of calcium homeostasis. Thus, wolframin encoded by a mutated WFS1 in pancreatic cells results in a lower secretion of insulin and awry calcium signalling, which
ultimately manifests into the symptoms of WS1.6 Knowing this, they tested two drugs: ibudilast and calpain inhibitor.6 These drugs seemingly restored calcium and cell functions, showing promise for possible treatment. Further studies and research are to be done into the effects of these drugs. In time, it is the team’s hope that research discoveries into how the WFS1 gene and wolframin impact cell signalling and function will help people better understand both Wolfram Syndrome and discover possible treatment.
In regards to the case study previously introduced, it was noted that the boy dealt with a manic personality and was diagnosed with bipolar disorder alongside WS1. Interestingly, the diagnosis of a psychiatric disorder is a common occurrence in the realm of Wolfram Syndrome. In fact, there are studies that suggest a strong connection between WS1 and psychiatric disorders through the WFS1 gene. For instance, neurological abnormalities have been reported in 62% of WS1 patients, likely a result of the faulty functioning of the ER and mitochondria that impact neuronal activity. 8 Furthermore, there have been reports of bipolar, clinically depressed, and schizophrenic patients presenting a mutated WFS1 gene.2 Along with mapping the relationship between WS1 and other diseases, it is important to also consider how future Wolfram Syndrome research could potentially help scientists with breakthroughs beyond the parameters of this particular disease. Essentially, this adds another layer of importance to rare disease research. In the particular Yale study, studies on wolframin’s role as a calcium regulator helps pinpoint a certain faulty mechanism to be treated with existing drugs. This opens multiple doors for both Wolfram Syndrome patients, but also those with bipolar disorder and other more common diseases also affected by similar faulty functions. “Although Wolfram Syndrome is a rare disease caused by genetic mutations in a single gene, it is tied to a number of other diseases that could be viable targets for this treatment, including diabetes and bipolar disorder.”7
Research is invaluable in that its findings can help enlighten patients, family members of patients, physicians, and other researchers alike on rare diseases. In the case of Wolfram
Syndrome, its symptoms and mechanisms are connected to a multitude of other more common diseases. As such, Wolfram Syndrome can be used as a model for evaluating these shared abnormalities in cell function. Finding that mutated WFS1 and wolframin have certain
implications dually aids research and treatment in diseases also impacted by the mutation. Afterall, science and medicine is made up of a myriad of connections. With each new discovery comes another cross-link between diseases and treatment, as well as more questions waiting to be answered.
Tiffany Yu
References
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11. Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic β-cells . Human Molecular Genetics. 2006;15(10):1600-1609. doi:10.1093/hmg/ddl081.
Cite This Article:
Yu T., Ahmed R. & Bhains M. Wolfram Syndrome: The Cross-Link Between Rare and Common Disease. Illustrated by Z. Hasan. Rare Disease Review. August 2021.
