Wolfram syndrome, also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can begin to appear as early as childhood to adult years (2–65 years old). There is a 25% recurrence risk in children.
It was first described in four siblings in 1938 by Dr. Don J. Wolfram, M.D. In 1995, diagnostic criteria were created based on the profiles of 45 patients. Wolfram syndrome was subsequently established as a prototype endoplasmic reticulum disorder caused by dysregulated unfolded protein response by Dr. Fumihiko Urano, M.D., Ph.D. at Washington University in St. Louis.
Signs and symptoms
The first symptom is typically diabetes mellitus, which is usually diagnosed around the age of 6. Insulin-dependent diabetes mellitus associate with Wolfram syndrome is differed from type 1 diabetes mellitus by having earlier diagnosis, rarely having positive auto-antibodies and ketoacidosis, having longer remission, needing less daily insulin, having lower average HbA1c level and more frequent hypoglycemia. This condition affects around 70% of people with WSF1 mutations (CISD2 mutations do not typically associate with diabetes insipidus). Since patients with Wolfram syndrome can experience diabetes mellitus, diabetes insipidus and urinary tract disorder, they are treated with desmopressin, which can lead to the development of hyponatremia.
Within cells, wolframin is located the endoplasmic reticulum. Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape to function properly. The endoplasmic reticulum also helps transport proteins, fats, and other materials to specific sites within the cell or to the cell surface. The function of wolframin is unknown. Based on its location in the endoplasmic reticulum, however, it may play a role in protein folding or cellular transport. In the pancreas, wolframin may help fold a protein precursor of insulin (called proinsulin) into the mature hormone that controls blood glucose levels. Research findings also suggest that wolframin may help maintain the correct cellular level of charged calcium atoms (calcium ions) by controlling how much is stored in the endoplasmic reticulum. In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing. Mutation in the WFS1 lead to ER stress due to an increase in the accumulation of misfolded proteins. 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.
Other disorders - caused by mutations in the WFS1 gene
Mutations in the WFS1 gene cause Wolfram syndrome. Researchers have identified more than 100 WFS1 mutations that cause Wolfram syndrome. Some mutations delete or insert DNA from the WFS1 gene. As a result, little or no wolframin is present in cells. Other mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. These mutations appear to reduce wolframin activity dramatically. Researchers suggest that the loss of wolframin disrupts the production of insulin, which leads to poor glucose control and diabetes mellitus. It is unclear how WFS1 mutations lead to other features of Wolfram syndrome.
CISD2-Wolfram Syndrome
CISD2-Wolfram Syndrome is a subtype of Wolfram Syndrome caused by a mutation in the CDGSH iron-sulfur domain-containing protein 2 gene (CISD2 gene). 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. Mutation of this gene effects the protein folding of the ER and functions of the mitochondria, which leads to the signs and symptoms seen in those with CISD2-Wolfram Syndrome. In some cases, mutation of the gene can lead to premature aging, mitophagy and mitochondrial dysfunction. In studies using mice, loss of function of CISD2 caused a decrease in ER Ca2+ and increase in mitochondrial Ca2+. This causes an increase in stress to the ER and activates an unfolded protein response (UPR). Further studies are still needed to better understand CISD2-Wolfram Syndrome and the neurodegenerative effects it has.
Clinical features of both WFS1-Wolfram syndrome and CISD2-Wolfram syndrome are diabetes mellitus, optic atrophy/neuropathy, sensorineural deafness, and genitourinary problems. Although both types have some overlapping symptoms, there are some differences that help us distinguish between the two. One of the main ones is that WFS2, it is not associated with diabetes insipidus or psychiatric disorders but is instead associated with higher bleed risks and peptic ulcers.
CISD2 gene consists of 3 exons on chromosome 4q24, which encodes the protein NAF-1 (nutrient deprivation autophagy factor-1). Therefore, if WFS2 were suspected in a patient, it may help to do a gene sequencing of the three exons and their intronic regions for a genetic analysis. More specifically, the disease prevalence is 1 in 770,000 in the UK, 1 in 710,000 in Japan, 1 in 100,000 in North America, 0.74 in 1,000,000 in Italy, 1 in 68,000 in Lebanon and the highest prevalence is 1 in 54,478 in a small area of Sicily (Italy). The frequency of WSF1 mutation carrier is estimated to be 1 in 354 in the UK population and the disease is estimated to affect 1 out of 150 patient with juvenile-onset insulin-independent diabetes mellitus.
Diagnosis
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. There is increased suspicion when diabetes is diagnosed in children under 16. More evidence shows that Wolfram syndrome varies in how it appears.
The syndrome can present with various symptoms. In addition to diabetes and optic atrophy, the patient may exhibit diabetes insipidus, a condition where the kidneys cannot retain water, leading to frequent urination and excessive thirst. They might also have sensorineural hearing loss, which is a type of hearing loss caused by damage to the inner ear or the nerves that connect the ear to the brain. Neurological abnormalities such as ataxia (lack of muscle coordination) or myoclonus (sudden, involuntary muscle jerks) may also be observed. The progression of symptoms, starting with type 1 diabetes and subsequent vision loss within the first decade of life, is a critical diagnostic clue. 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. Changes in the optic radiations, which are the pathways transmitting visual information from the eyes to the brain, can be detected, aligning with the optic atrophy characteristic of 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. Optical coherence tomography (OCT) is used to measure retinal nerve fiber layer thickness, aiding in the assessment of optic atrophy and monitoring disease progression.
Nowadays, genetic testing is used commonly to confirm the diagnosis of Wolfram syndrome. Initially, people with hereditary optic neuropathy who tested negative for mutation in the common optic neuropathy genes OPA1, OPA3 and LHON were selected for further genetic testing for WS. The primary genetic lotus associated with this syndrome is WFS1, and Sanger sequencing of this gene typically confirms the diagnosis. Most patient exhibit recessive mutation in WFS1, meaning they inherited two copies of the mutated genes, one from each parents. However, some dominant mutation, such as H313Y, have been identified, where one copy of the mutated gene can cause the disorder. These dominant mutations are often linked to low-frequency sensorineural hearing loss, which affects the ability to hear low-pitched sounds. Additionally, there have been recent discoveries of autosomal dominant diabetes, where diabetes is inherited in a dominant manner, in patients with WFS1 mutations. Interpreting genetic testing results requires specialized knowledge due to the complexity of the mutation.
Detailed family history is important as WS2 inherited in an autosomal recessive manner, and genetic counseling is recommended for affected individuals and their families to understand the inheritance pattern, risks to other family members, and reproductive options. A minority of patients have recessive mutation in the CISD2 gene, and for those without WFS1 mutations, sequencing of CISD2 is conducted. Efforts are underway to develop diagnosis methods based on exome (sequencing all the protein-coding regions of the genes) and genome sequencing (sequencing the entire genetic code) for Wolfram syndrome and related disorder.
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. Audiological tests help assess the extent of hearing loss and guide interventions like hearing aids or other assistive devices. 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. While there are no therapies currently available to slow the progression of neurological manifestations, swallowing therapy and esophagomyotomy have been shown to be useful in alleviating some of the neurological symptoms. 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.
While there are no direct treatments, many therapies are currently being investigated for their efficacy at treating Wolfram syndrome. 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.
WFS1 mutations cause proteins in the ER to fold improperly, leading to ER stress. ER stress stimulates the unfolded protein response (UPR), which causes cell apoptosis for pancreatic β-cells. Chemical chaperones are being investigated for their effect on reducing the UPR response and thus delaying disease progression by preventing cell death. The FDA has approved 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as chemical chaperones to reduce ER stress to delay neurodegeneration in patients with Wolfram syndrome. 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. 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. However, the efficacy and safety of using liraglutide and DPP-4 inhibitors for the treatment of Wolfram syndrome has not been well studied yet.
ER calcium levels have also been identified as a target for Wolfram syndrome therapy. WFS1 mutations increase cytosolic calcium, leading to the activation of cysteine proteases known as calpains. Increased calpains activation is associated which cell death. 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.
Prognosis
Wolfram Syndrome prognosis is very poor with a median mortality rate of 65% before the age of 35 (age range 25–39). Currently, there is no effective treatment that can delay or reverse the progression of the disease.