What Is Wolfram Syndrome

Introduction to wolfram syndrome

Wolfram Syndrome (WS) is a genetic disease that leads to diabetes mellitus, optic nerve damage, hearing loss, and neurological deterioration. With only approximately 1 in 770,000 individuals affected in the United Kingdom, medical advancements in this condition remain overlooked, highlighting the need for more genetic screening to obtain accurate statistics (Urano F, 2016). As this condition is neurodegenerative, no reversible treatment is available, and the prognosis remains low. Death usually occurs around 39 years following neurodegeneration, which often results from respiratory failure (Pallotta et al., 2019). The condition requires an interdisciplinary treatment approach for prompt diagnosis, including genetic counselling to assist in the next steps of treatment.

Historical background

Originating back in 1938, Wolfram and Wagenor first discovered it, naming it Wolfram Syndrome. Back then, four siblings were diagnosed with diabetes mellitus and optic neuropathy (Urano F., 2016). In 1995,  diagnostic criteria were developed due to varying presenting symptoms, helping to categorise individuals with Wolfram Syndrome. Disease prevalence is believed to be higher in regions with consanguineous unions, such as  Sicily (Pallotta M et al., 2019).    

A defective WFS1 gene within the ER causes this autosomal recessive disorder (Pallotta et al., 2019). The WFS1 gene assists in producing the Wolframin protein, which is crucial for calcium regulation in cells. WS symptoms affect various  body systems, including the following:

1. Ophthalmologic
2. Urological 
3. Hearing
4. Neurological
5. Endocrine

The four signature symptoms of WS include diabetes insipidus, diabetes mellitus, optic atrophy, and hearing loss. 

Genetics of wolfram syndrome

The genetics of WS involve an autosomal recessive pattern. Both parents must carry the mutated gene, but they will likely not present with symptoms. The syndrome can be classified into two types due to differing genetic mutations:  WFS1 and WFS2 (known as CISD2). An individual with WS inherits a mutated gene from both parents, such as the WFS1 gene,  associated with symptoms including diabetes and deafness alone (Aggarwal B et al., 2021). WFS1 contains eight exons, and more than 200 mutations are located in exon eight of this gene (Panfilli et al., 2021). High expressions of the WFS1 gene occur in the brain, pancreas, heart, and lung tissues (Li L et al., 2020). For example, the defective  WFS1 gene is largely responsible for DM due to the absence of the protein Wolframin (Aggarwal B et al., 2021). This leads to cell death in pancreatic tissue, where the hormone insulin is manufactured. 

There is a homozygous mutation in the ER intermembrane protein, also referred to as zinc finger-like protein, causing the mutational gene WFS2 (Pallotta M et al., 2018). CISD2 mutations also cause WS2. The ER intermembrane protein functions to maintain the integrity of ER membranes. A mutation of the CISD2 gene results in the production of a non-functional protein that cannot regulate mitochondrial cells, causing a reduced energy supply in the body (Shahin A, 2018). WS2 presents with the same clinical progression as typical WS1, except diabetes insipidus does not occur  (Galvez Ruiz et al., 2017). 

Genetic testing

As a result of the complexity of the syndrome, a clear path of symptom onset is not always evident. It is not uncommon for individuals without neurological and urological symptoms to be affected; however, up to 94% of cases present with DM (Lee J et al., 2022). WS1 diagnostic criteria include the progression of DM and optic atrophy in young children around ten years (Galvez Ruiz et al., 2018). However, without optic atrophy, before it develops, the condition can be misdiagnosed as type one DM. Rigoli et al. reported that in paediatric patients, they were initially misdiagnosed as type one DM for up to seven years. Therefore, a combination of genetic testing and clinical symptoms is a reliable diagnostic method for WS1 cases due to the phenotypic diversity of the condition. There has been difficulty in identifying a clear phenotype-genotype relationship in WS because of genetic homogeneity (Sobhani M et al., 2020). 

Clinical features and symptoms 

1. Optic Atrophy

This is a primary requirement for diagnosing WS1, manifesting in the early days with an average onset at the age of eleven. Optic atrophy eventually leads to blindness following the reduction in colour vision over time. Cataracts, nystagmus, and glaucoma are also symptoms of optic atrophy (Rigoli et al., 2018). Numerous ophthalmic markers,  including the diameter of the nerve fibre layer in the eye, reveal thinner retinal layers in WS1 patients compared to those with insulin-dependent diabetes (Rigoli et al., 2018). It is crucial to conduct eye tests, including colour vision efficiency and visual acuity. The absence of a pharmaceutical treatment for optic atrophy emphasises the need for early diagnosis to prevent further damage. 

1. Neurological Symptoms

Plagiarism Score: 0%             It is common to experience neurological symptoms, which have been reported in around 53% of cases by the age of fifteen (Toppings NB et al., 2018). These symptoms primarily affect the cerebellum and brainstem, often leading to cognitive dysfunction and epilepsy. Cerebellar ataxia results from the cerebellum damaged, causing coordination problems and muscle weakness. MRI scans have revealed atrophy in approximately 54% of cases, where these symptoms progress to neurodegeneration (Toppings NB et al., 2018). Other associated symptoms include a reduced ability to taste and smell alongside seizures. 

Diabetes mellitus (DM)

DM is one of the initial clinical manifestations of the syndrome, typically diagnosed around age six. All patients require insulin administration to prevent hypoglycemia. It may take some time to diagnose diabetes mellitus since it has similar symptoms to diabetes insipidus, including excessive urination and thirst (Aggarwal B. et al., 2021). DM is often detected by high haemoglobin and glucose levels (Bhatt et al., 2021). As urological and ophthalmological manifestations can also occur, early diagnosis of WS is crucial. WS mortality rate is significantly higher than that of diabetes mellitus, so efficient management is paramount (Kinsley et al., 1995).

Hearing loss

Wolfram's Syndrome is characterised by hearing loss resulting from ear damage, accounting for up to 70% of cases (Urano et al., 2017). In some cases, hearing loss can manifest from birth, while in others, it occurs during adolescence. In many cases, low-frequency sensorineural hearing impairment is caused by mutations in the WFS1 gene. Consequently, it is essential to conduct regular hearing tests to evaluate the pathophysiology of the condition and determine an appropriate treatment approach.

Urological complications

There are several clinical complications related to the urinary tract, including structural abnormalities that can lead to persistent infections. Symptoms include bladder pressure with limited urine capacity, along with impaired sphincter coordination (Urano et al., 2016). Urinary tract infections (UTIs)  stand out as one of the first clinical symptoms of a neurogenic bladder associated with  WS1 (Rigoli et al., 2018). The onset of these urological complications typically begins around the age of 10 years (La Vale et al., 2021). Anticholinergic drugs, by blocking signals to the brain via the neurotransmitter acetylcholine, can treat overactive bladder contractions (Chancellor M et al., 2016).

Endocrine complications        

A prevalent symptom involves reduced growth hormone (GH) secretion, potentially leading to growth deficiency in WS1 patients (Rigoli et al., 2018). WS is linked to anterior pituitary dysfunctions, often leading to shrinking testicles in men resulting from testicular atrophy (Frontino G et al., 2023). It is, therefore, critical to monitor hormone levels, as GH supplementation may prevent growth stunting. WS is characterised by hypogonadism, impacting females with fertility complications and males with erectile dysfunction (Urano F., 2016). 

Prognosis and life expectancy

The pathogenesis of this disease remains severe since the prognosis is low, with an average death rate before the age of 40 years. While some patients have exceeded this age, there are cases where individuals have been treated at 62 years (Eljamel et al., 2019). Death is often reported due to atrophy of the brain stem. Some of the largest problems that impact quality of life include disrupted sleep, temperature regulation issues, and urological complications from recurrent UTIs (Doty et al., 2017). 

Current treatment and management 

As there is no cure for WS due to the variety of complications and an array of physiological symptoms, treatment is tailored to the patient's presenting symptoms. For example, diabetes mellitus (DM), one of the first symptoms, is treated with insulin, and diabetes insipidus is addressed using desmopressin drug (Kalra S et al., 2016). Through a multidisciplinary approach, a patient's treatment plan and quality of life can be improved by monitoring disease progression. Various patient support groups, such as The Snow Foundation, exist to provide a voice for WS patients and work toward finding a cure for WS (TheSnowFoundation, 2023).

Potential therapeutic targets

A significant concern in  Wolfram Syndrome is its progression due to cellular stress induced by mutated WFS1 genes. Therapeutic targets are emerging to target endoplasmic reticulum (ER) stress in the body. For example, chemical chaperones are used to assist in the protein stability of the mutated WFS1 genes (Abreu et al., 2019). Therefore, this allows a reduction in ER stress, as there is a lower buildup of mutated WFS1 genes in the body (Abreu et al., 2019). Another potential treatment approach is using gene therapy such as CRISPR to transfer non-defective  WFS1 genes into patients with WS via the retinal ganglion (Abreu et al., 2019). Damaged pancreatic and retinal ganglion cells have a large consequence on patients' quality of life.

Summary

Wolfram Syndrome is a challenging and complex disease caused by mutations in the WFS1 and CISD2 genes. There are several conditions associated with it, including diabetes mellitus, diabetes insipidus, optic atrophy, and hearing loss. Other complications exist, including problems with the urinary tract, psychiatric issues, hormonal imbalances, and neurodegeneration. However, these symptoms vary in each case, and they affect multiple organs throughout the body. Therefore a multidisciplinary approach to care proves the most effective and support groups play an essential role in affected individuals and families.

Despite being one of the rarest autosomal recessive disorders, Wolfram Syndrome serves as a disease model to further understand ER stress and cell damage. As there is currently no cure for this condition, future research is focusing on utilising genetic technology such as CRISPR to improve the quality of life of affected individuals.