Genotype-Based Severity Scoring System in Wolfram Syndrome: Correlation with Onset of Cardinal Symptoms and WFS1 Gene Variant Types

Autosomal dominant pathogenic variants in the WFS1 gene can cause a broad spectrum of WFS1-related disorders. These disorders present with a range of phenotypic manifestations, including isolated low-frequency sensorineural hearing loss, optic nerve atrophy accompanied by low- to mid-frequency sensorineural hearing loss, isolated diabetes mellitus, and early-onset cataracts. In general, WFS1-related disorders represent a milder spectrum of conditions linked to pathogenic WFS1 variants, except for Hattersley-Urano syndrome, which is characterized by early-onset diabetes mellitus, optic nerve atrophy, cataracts, hypotonia, intellectual disability, and developmental delay. By contrast, autosomal recessive WFS1 variants result in Wolfram Syndrome type 1, a rare neurodegenerative disorder characterized by early-onset diabetes mellitus, optic nerve atrophy, arginine vasopressin deficiency, hearing loss, and cerebellar and brainstem atrophy. Although WFS1-related disorders have been increasingly recognized, additional data are needed to understand their clinical progression and long-term outcomes. Our study aims to expand knowledge on the severity and progression of WFS1-related disorders by reviewing clinical data from patients with autosomal dominant pathogenic WFS1 variants. We obtained clinical data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and related disorders and the Endoplasmic Reticulum Disease Patient Registry and Biorepository. We included participants with autosomal dominant WFS1 pathogenic variants who were diagnosed with optic nerve atrophy and sensorineural hearing loss. Eleven participants with autosomal dominant WFS1 variants meeting these criteria were identified. The 11 cases included five distinct autosomal dominant WFS1 variants: c.923C>G (p.Ser308Cys), c.2051C>T (p.Ala684Val), c.2389G>T (p.Asp797Tyr), c.2456A>C (p.Gln819Pro), and c.2590G>A (p.Glu864Lys). Among these, the p.Gln819Pro variant has not been previously reported in the literature. The median age of optic atrophy diagnosis was 10 years (quartiles: 6.0 and 19.0 years). Visual acuity did not significantly differ between the left (OS) and right (OD) eyes (p = 0.8901). The least square best-corrected visual acuity (BCVA) mean for the right eye was 0.2114 ± 0.01903 and for the left eye, 0.2153 ± 0.01903. Age was not significantly related to best eye BCVA (p = 0.9196), with an estimated change of -0.0002 (95% CI [-0.003, 0.003]) per year. Patient age was also not correlated with binocular BCVA (p = 0.5994), with an estimated change of 0.00075 (95% CI [-0.0021, 0.0036]) per year. Mean retinal nerve fiber layer (RNFL) thickness was not significantly related to age (p = 0.1604), with an estimated annual change of 0.1486 (95% CI [-0.659, 0.363]). However, removing an influential outlier resulted in a significant relationship between RNFL thickness and age (p = 0.0160), with an estimated change of 0.2114 (95% CI [0.045, 0.377]) per year. Hearing loss diagnoses occurred at a median age of 2.0 years (quartiles: 1.5 and 2.0 years). All participants used hearing aids (11/11); six (6/11) had cochlear implants, while three (3/11) used external hearing aids. The median time between hearing loss diagnosis and hearing aid use was 4.0 years (quartiles: 2.5 and 8.0 years). This study contributes to the growing understanding of WFS1-related disorders caused by autosomal dominant WFS1 variants. In particular, it highlights two clinical phenotypes of a novel WFS1 variant and provides valuable insights into the progression of optic nerve atrophy and hearing loss management.

Case presentation: A 51-year-old Caucasian male with persistent dysglycemia was diagnosed with insulin-dependent diabetes mellitus at age six. During adolescence, he experienced a progressive decline in visual acuity over months to years, resulting in bilateral blindness. Ophthalmologic evaluation revealed bilateral optic nerve atrophy. In his second decade of life, the patient developed gradual, asymmetric sensorineural hearing loss of neurodegenerative origin. At age 20, a severe hypoglycemic event caused by inadvertent exogenous insulin administration led to hypoglycemic encephalopathy, resulting in transient coma. Due to a family history of Wolfram Syndrome (two siblings), this diagnosis was considered and confirmed through genetic testing. In his fourth decade, he reported neurological complaints, notably forgetfulness related to daily activities, and displayed progressive ambulatory difficulties, including impaired balance and a wide-based gait, requiring wheelchair use by age 45. In subsequent years, following an acute ischemic stroke, the patient developed dysphagia, REM sleep behavior disorder, urinary incontinence, and constipation. Additionally, he experienced focal seizures with secondary generalization, with presumed structural origin. Discussion: Wolfram syndrome (WFS) or DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), is a rare genetic disorder with these primary features. It can also involve neurological and psychiatric disorders and progressive neurodegeneration. The disease’s severe neurological progression often leads to premature death, typically due to respiratory failure. WFS is an autosomal recessive condition associated with mutations in two genes, defining its subtypes: Wolfram syndrome-1 (WFS1) and Wolfram syndrome-2 (WFS2). WFS1, the classical form, is caused by mutations in the WFS1 gene, encoding the wolframin protein. WFS2, caused by mutations in the CISD2 gene, differs from WFS1 by presenting with bleeding, upper intestinal ulcers, defective platelet aggregation, and the absence of diabetes insipidus and psychiatric disorders. In the presented case, typical of WFS1, the initial symptom was diabetes mellitus, followed by visual acuity loss. By the first half of the second decade of life, the patient developed optic nerve atrophy progressing to blindness, consistent with most case reports. During this period, hearing loss unrelated to diabetes mellitus and diabetes insipidus may occur, potentially leading to hydronephrosis and atony of the bladder and ureter. Eventually, neurological symptoms such as reduced or abolished reflexes, dysphagia, and seizures may appear. Final comments: Despite limited understanding of WFS, advancements have been made in understanding the variability in onset and progression. WFS should be suspected in cases of optic nerve atrophy following a diagnosis of diabetes mellitus in children and adolescents, with genetic testing used for confirmation.

The aim of this study was to assess parameters of retinal morphology by using high-definition optical coherence tomography (OCT) in patients with Wolfram syndrome (WFS) and their relation to optic tract atrophy in magnetic resonance imaging (MRI). High-definition OCT and MRI parameters were evaluated in 12 patients with WFS (three males, nine females; median age at examination 12y 8mo, range 10y 2mo-15y 11mo) and referred to 30 individuals with type 1 diabetes (T1D) (12 males, 18 females; median age at examination 20y 5mo, range 16y 8mo-21y 4mo) and 33 typically developing comparison participants (10 males, 23 females; median age at examination 20y 7mo, range 13y-22y 4mo). Total thickness and quadrant thickness of the retinal nerve fibre layer (RNFL), macular full-thickness parameters and macular ganglion cell layer/inner plexiform layer, intraorbital and intracranial thickness of the optical nerve, as well as the optic chiasm and visual tracts were significantly reduced in patients with WFS compared with those having T1D and the typically developing comparison participants. Optic chiasm thickness correlated negatively in patients with WFS with both age (r=-0.79; p=0.002) and duration of diabetes (r=-0.62; p=0.032). Thickness of the intraorbital parts of the optic nerves in patients with WFS correlated positively with thickness of the superior RNFL (r=0.73; p=0.006). High-definition OCT in combination with MRI could become an important tool for evaluating the effectiveness of therapeutic trials in patients with WFS. Provides evidence of significant reduction of retinal parameters and optic nerves in patients with Wolfram syndrome (WFS). Shows correlations between magnetic resonance imaging parameters and retinal morphology parameters in patients with WFS.

During a routine follow-up visit, a 15-year-old male with type 1 diabetes has complained of decreased visual activity and worsening of his polydipsia and polyuria. His past medical history included being diagnosed for type 1 diabetes at the age of eight years and under poor control due to lack of parental supervision. His review of systems was negative for chest pain, claudication and headache. His family history included type 2 diabetes in his paternal grandmother who suffered a vision loss attributed to it. His physical examination showed bilateral mild optic nerve atrophy. There was no thyromegaly. Tanner staging was 4. Laboratory testing showed haemoglobin A1c of 12.8% and negative urine microalbumin. The possibility of diabetes complications affecting the eyes and kidneys was considered, although it was unlikely due to the relatively short duration of diabetes. Ophthalmology consultation confirmed the bilateral optic nerve atrophy without any diabetic retinopathy. This prompted consideration of Wolfram (DIDMOAD) syndrome that consists of diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness. Extensive laboratory work-up including water deprivation test confirmed the diagnosis of diabetes insipidus. The patient was started on DDAVP (desmopressin) therapy; his polydipsia and polyuria resolved. He started complying better with his diabetes care. Genetic testing showed a mutation in the WFS1 gene confirming the diagnosis of Wolfram syndrome type 1. Auditory testing did not show any hearing deficit. The patient and family were sent for genetic counselling. The aetiology and prognosis of different organ involvement of the syndrome were explained, including blindness, deafness and urinary dysfunction as well as the usual prognosis of diabetes. Wolfram syndrome is an autosomal recessive neuro-endocrine degenerative disorder.1 The syndrome is also known as DIDMOAD as mentioned above. The first and major aspect of Wolfram syndrome is a persistent hyperglycaemia that is insulin dependent in a young child most commonly diagnosed as type 1 diabetes.1, 2 Other organ involvement may start occurring later and may present at different times in life.3 Optic nerve atrophy is often the next sign to appear after diabetes.3, 4 Diabetes insipidus affects almost 70% of patients with this syndrome while deafness occurs in around 65%.4 Other conditions that may occur with this syndrome include hypogonadism, urinary tract problems and neuropsychiatric disorders.4 Many cases of Wolfram syndrome may remain misdiagnosed as type 1 diabetes mellitus.5 Some patients may be misdiagnosed with complications of diabetes due to renal and ophthalmic symptoms.6 Diabetes complications, however, are extremely rare in paediatric diabetes patients. Genetically, there are two types of Wolfram syndrome. Type 1 is the most common type (90%) and is due to mutations in the WFS1 gene. This gene provides instructions for producing a protein called wolframin that is thought to regulate the amount of calcium in cells.1, 4 Wolframin's function is important to produce functional proinsulin.4 WFS1 gene mutations lead to the production of a wolframin protein that has reduced or absent function which triggers apoptosis of beta cells in the pancreas causing diabetes and in the optic nerve leading to blindness.1, 4 Wolfram syndrome type 2 is caused by another mutation in the CISD2 gene which causes the production of a defective protein in the mitochondria that leads to its death.4 When multiple organ involvement is seen in young patients with diabetes, certain syndromes should be considered including Wolfram syndrome or mitochondrial disorders.

Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic β cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve β-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation. These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a rare autosomal recessive syndrome (1/770,000 in the United Kingdom), characterised by juvenile onset of diabetes mellitus, optic nerve atrophy, diabetes insipidus, sensorineural deafness, renal tract and neurological abnormalities, and primary gonadal atrophy. WS is caused mainly by biallelic mutations in the WFS1 gene, which encodes wolframin. Wide tissue distribution of wolframin and many mutations in the wolframin gene resulting in Wolfram syndrome may contribute to different phenotypes and the unusual combinations of clinical features. We describe a female patient with Wolfram syndrome diagnosed at the age of 25, with a previous false diagnosis of type 1 diabetes mellitus and misdiagnosed diabetic complications. The patient was found to be a compound heterozygote for two novel mutations in exon 8 of WFS1 gene: a 2-bp deletion AT at nt 1539 leading to a frameshift (Y513fs) and a single-base substitution 1174C > T resulting in a stop codon (Q392X). A detailed analysis of the patient's medical history and a review of the literature suggest that many cases of Wolfram syndrome may remain undiagnosed due to misdiagnosis as type 1 diabetes mellitus and incorrect interpretation of clinical symptoms of neurodegenerative abnormalities, especially in their early stages.

Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome.

Molecular Characterization of WFS1 in Patients with Wolfram Syndrome

Wolfram syndrome is a rare autosomal recessive disorder characterized by diabetes mellitus, optic atrophy, and progressive neurodegeneration, often summarized by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We report a 27-year-old male with a history of diabetes mellitus, progressive visual loss leading to blindness, and bilateral sensorineural hearing loss. His family history was notable for diabetes-related mortalities and visual impairment in multiple members of the family. Clinical evaluation showed uncontrolled blood glucose level, optic atrophy, and high-frequency sensorineural hearing loss. A clinical diagnosis of Wolfram syndrome was made using the Euro-Wolfram, Alström, and Bardet-Biedl (WABB) criteria. Wolfram syndrome should be suspected in young patients with early-onset diabetes mellitus and visual or hearing impairment. This case report highlights the role of timely multidisciplinary management in preventing disease-related complications.

Disclosure: H. Jung: None. G. Kim: None. Y. Park: None. J. Yu: None. Background: This case report explores the presentation, diagnosis, and multidisciplinary management of an 11-year-old female patient with Wolfram syndrome, a rare and progressive genetic disorder. Wolfram syndrome is a rare genetic disorder characterized by early-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. The prevalence of this syndrome is very low, affecting approximately 1 in 770,000 individuals. Prompt diagnosis is essential as early intervention and comprehensive management can improve the patient's quality of life and prognosis. Clinical Case: A female patient aged 9 years and 2 months was brought to our Pediatric Endocrinology Clinic because an elevated blood sugar level (520 mg/dL) was detected during a routine health checkup. She was born at 40 weeks, weighing 3kg, and had no remarkable perinatal history except for cleft lip. At the time of admission due to diabetes mellitus, the patient showed symptoms of developmental delay, language impairment, short stature, and strabismus. During follow-up over 1 year with management of diabetes mellitus, she showed persistent short stature and poor growth velocity. She underwent a growth hormone (GH) stimulation test, which confirmed GH deficiency. Further investigation found optic atrophy through ophthalmological examination and genetic investigation based on whole exome sequencing revealed a homozygous mutation in WFS1 (c.1475C>T, p.Pro492Leu), suggesting Wolfram syndrome. Pure tone audiometry did not reveal specific abnormality but there were some limitations in the interpretation of the study result due to language and communication difficulties. She also showed nocturia, and in the absence of glycosuria, the urine specific gravity was less than 1.005, suggesting diabetes insipidus. She is currently receiving multidisciplinary treatment including pediatrics, otolaryngology, and ophthalmology. Conclusion: This case underscores the importance of increasing clinical awareness regarding Wolfram syndrome, as early intervention through timely diagnosis may lead to improved patient outcomes. This case also suggests that although GH deficiency is uncommon in Wolfram syndrome, growth assessment is important in patients with Wolfram syndrome in addition to managing diabetes mellitus and diabetes insipidus. Presentation: 6/2/2024

Disclosure: D.H. Sacoto: None. C.A. Villavicencio: None. R. Belokovskaya: None. A.A. Franco-Akel, MD: None. Wolfram syndrome (WS) is a rare and fatal condition with a median age of death of about 39 years and affecting around 1 of 100,000 people in North America. Insulin is the mainstay of treatment in WS though, access to it may affect adherence and glycemic control which is correlated with neurodegenerative progression. We present a patient with WS whose complications exacerbated due to insulin access. A 19-year-old African American male with a history of type 1 diabetes mellitus (T1DM), presented to the ED with a 2 day-history of general malaise and emesis. Diabetic ketoacidosis (DKA) (blood glucose 802 mg/dL, pH 7.2, positive serum ketones) was diagnosed upon arrival. Right optic nerve atrophy was diagnosed at age of seven. At age of eight, patient was diagnosed with bilateral sensory-neuronal hearing loss (SNHL) which led to school withdrawal. It was then when suspicion of WS arose. Single nucleotide polymorphism microarray confirmed homozygosity from the region of linkage on chromosome 4p16.1, where the WFS1 gene lies. At the age of eighteen, patient was diagnosed with neurogenic bladder for which he requires frequent self-catheterization. Since his T1DM diagnosis, patient has faced multiple barriers accessing insulin secondary to insurance issues and lack of social support resulting in multiple hospital admissions for DKA and urinary retention episodes. WS is an autosomal recessive disorder resulting from WFS1 or WFS2 gene mutation on chromosome 4p. WS commonly presents as childhood-onset diabetes mellitus, optic atrophy, SNHL, and neurogenic bladder. Insulin is the first line treatment for optimal glycemic control in WS. Despite optimal glycemic control, WS symptoms and neurodegenerative progression may be influenced by other factors. First, treatment access for rare diseases has shown to be impacted by medical unconscious bias, in addition to systemic, linguistic, and socioeconomic challenges patients may face. Furthermore, Medicaid insurance covering rare diseases still varies widely between 15-67%, and in those insured, there is still a 61% chance of delay or denial due to pre-approval requirements. In addition, poor glycemic control has been correlated with lower socioeconomic status, lack of access to devices such as insulin pumps, migratory status, social support and environment, food security, and ethnic background. Since diabetes control in WS patients is paramount to a better quality of life, additional studies are needed to understand the full scope of barriers that can contribute to policies that facilitate better treatment access for patient and families living with WS. Presentation: Saturday, June 17, 2023

Wolfram syndrome is an autosomal recessive disorder characterized by early-onset diabetes mellitus, diabetes insipidus, optic atrophy and deafness. The aim of this study was to scan the WFS1 gene mutations in a Chinese Wolfram syndrome pedigree. Eight exons and flanking introns of WFS1 gene were screened using PCR-DNA direct sequencing. Effects of the mutation on the structure and function of the WFS1 gene product, Wolframin, were evaluated by bioinformatics. A novel mutation, F417del, in the WFS1 gene was identified. The patient was homozygous of this mutation and the consanguineous parents were heterozygous. The mutation causes the lose of a non-polar amino acid, which was located in the transmembrane domain of the protein product. Bioinformatics predicted that the mutation altered the secondary structure of the transmembrane domain and decreased the hydrophobicity of F417del protein. This study identified a novel mutation of WFS1 gene and represented the first cause of molecular characterization of Chinese Wolfram syndrome patients.

Wolfram syndrome is the condition characterized by juvenile onset diabetes mellitus and optic atrophy, which is also known as DIDMOAD. Classical Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in WFS1, a gene involved in endoplasmic reticulum and mitochondrial function. Patients present with type 1 diabetes mellitus followed by optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts as early as in the third decade, and various neurological abnormalities in the early fourth decade. We describe a case report of 14-year-old male child diagnosed as wolfram syndrome with type 1 diabetes mellitus, diabetes insipidus, deafness, optic atrophy and severe urological abnormalities. Patients who present with early onset insulin-dependent diabetes mellitus and optic atrophy together should be evaluated with respect to Wolfram Syndrome. If a patient, who is a known case of diabetes mellitus, presents with persistent polyuria or neurogenic bladder despite good glycemic control, suspicion of wolfram syndrome and further evaluation regarding the same must be made. Recognizing and timely management of this condition will help to improve the quality of life in the patient.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.

Wolfram syndrome, also known as DIDMOAD, is a relatively rare inherited neurodegenerative disorder, first evident in childhood as an association of juvenile-onset diabetes mellitus and optic atrophy, followed by diabetes insipidus and deafness. The aim of the study was to examine the clinical profile of patients with DIDMOAD syndrome presenting to a tertiary care hospital in north India. Clinical presentation of juvenile-onset diabetes mellitus fulfilling the diagnosis of Wolfram syndrome was studied using a prepared standardized form. Subjects with juvenile-onset non-autoimmune diabetes mellitus attending the diabetic clinic at a tertiary care centre in north India were followed for 10 years and a diagnosis of fully developed Wolfram syndrome was confirmed in seven individuals. The series consisted of five male and two female patients with a mean age of 17.5 ±7.34 years. Two subjects had consanguinity and none had any other family member affected. Optic atrophy was present in all, sensorineural hearing loss in 4/7, central diabetes insipidus in 4/7 and nephrogenic diabetes insipidus in 2/7 subjects. The new associations found were: spastic myoclonus, short stature with pancreatic malabsorption, nephrogenic diabetes insipidus, cyanotic heart disease and choledocholithiasis with cholangitis. Genetic analysis revealed mutation in exon 8 of the WFS1 gene in all the cases studied. The present clinical series of Wolfram syndrome reveals a varied clinical presentation of the syndrome and some new associations.