Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape to function properly.

In the pancreas, wolframin may help fold a protein precursor of insulin (called proinsulin) into the mature hormone that controls blood glucose levels.

In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing.

As there is a high level of misfolded protein, unfolded protein response (UPR) is stimulated and lead to transcriptional and translational process that can restore ER homeostasis, However, if the ER stress is present persistently due to physiological or pathophysiological events, the UPR will induce apoptosis.

[10] More than 30 WFS1 mutations have been identified in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA6.

Some researchers suggest that altered wolframin disturbs the balance of charged particles in the inner ear, which interferes with the hearing process.

This syndrome is characterised by childhood-onset diabetes mellitus (DM), which results from the improper control of glucose due to the lack of insulin; a gradual loss of vision caused by optic atrophy (OA), in which the nerve that connects the eye to the brain wastes away; and deafness (D).

Researchers suggest that the loss of wolframin disrupts the production of insulin, which leads to poor glucose control and diabetes mellitus.

CISD2 is a protein coding gene that is primarily found on the endoplasmic reticulum (ER), though some studies have shown that it can also be localized in the mitochondrial outer membrane.

[21] The diagnosis of Wolfram syndrome is multifaceted, involving clinical evaluation, genetic testing, laboratory investigations, and imaging studies.

Clinical evaluation typically begins with a detailed medical history and physical examination, where patients often present with juvenile-onset diabetes mellitus followed by progressive optic atrophy, a condition where the optic nerves, which connect the eyes to the brain, deteriorate over time, leading to vision loss.

[22] The progression of symptoms, starting with type 1 diabetes and subsequent vision loss within the first decade of life, is a critical diagnostic clue.

[23] Imaging studies are essential for understanding the extent of brain and optic nerve damage in Wolfram syndrome.

[24] Additionally, areas of the pons, part of the brainstem, may show increased signal intensity on T2-weighted images, indicating potential damage or changes in tissue composition.

The connections between the cerebellum and the brainstem (middle cerebellar peduncles) can also exhibit atrophy, consistent with Wolfram syndrome.

Furthermore, the absence of the typical T1 hyperintensity in the posterior pituitary lobe suggests a lack of vasopressin-containing neurons, often linked with diabetes insipidus, another symptom of Wolfram syndrome.

[30] Other diagnostic tools include audiological tests to identify sensorineural hearing loss, a common feature of Wolfram syndrome, and psychiatric evaluations to address cognitive or behavioral issues arising from neurodegenerative nature of the disease.

Psychiatric evaluations are important because the neurological aspects of Wolfram syndrome can lead to cognitive decline or behavioral changes, which require appropriate management and support.

Intranasal or oral desmopressin has been shown to improve symptoms for the treatment of diabetes insipidus caused by Wolfram syndrome.

[33] Anticholinergic medications, clean intermittent catheterizations, electrical stimulation, and physiotherapy have been shown to be effective at managing urological abnormalities due to Wolfram syndrome such as neurogenic bladder and upper urinary tract dilation.

Gene and regenerative therapies are currently being studied for their efficacy in replacing damaged tissues due to Wolfram syndrome, such as pancreatic β-cells, neuronal, and retinal cells.

ER stress stimulates the unfolded protein response (UPR), which causes cell apoptosis for pancreatic β-cells.

[36] Chemical chaperones are being investigated for their effect on reducing the UPR response and thus delaying disease progression by preventing cell death.

[37] As of 2023, sodium valproate—an anti-epileptic drug—is being investigated as a therapy for Wolfram syndrome due to studies showing its ability to inhibit ER stress-induced apoptosis, reducing neurodegeneration.

[38] Liraglutide—a glucagon-like peptide-1 receptor (GLP 1-R) agonist—has been hypothesized to be an effective therapy, as it has been shown to improve diabetes mellitus, reduce cell death due to ER stress, reduce neuroinflammation, protect retinal ganglion cell death, and prevent optic nerve degeneration.

[39]  Dipeptidyl peptidase-4 (DPP-4) inhibitors have also been hypothesized to be efficacious in the treatment of Wolfram syndrome due to their ability to activate GLP 1-R, similar to liraglutide.

[41] As of 2021, dantrolene sodium—a medication indicated for the treatment of malignant hyperthermia and muscle spasms—was being investigated in patients with Wolfram syndrome in a phase 2 clinical trial.

[10] The second most common clinical manifestation of the disease is diabetes insipidus, which the kidney is unable to retain water due to renal outflow tract dilation and leads to high level of urine production.

Some most common neurological abnormalities are cerebellar ataxia, peripheral neuropathy, epilepsy, cognitive impairement, dysphagia, dysarthria and diminish sense of taste and smell.

[2] There are other abnormalities that associated with Wolfram Syndrome such as gastrointestinal disorders (gastroparesis and bowel incontinence) and heart disease.