Title: Wolfram Syndrome
Author: Nathan G. Lambert, BS; Kathleen B. Digre, MD
Keywords: Wolfram Syndrome; WFS1; Wolframin; Diabetes insipidus; Diabetes mellitus; Optic atrophy; Sensorineural deafness;
Diagnosis: Wolfram Syndrome
Wolfram Syndrome, or DIDMOAD, is a rare genetic syndrome consisting of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. It was first reported in 1938 by Wolfram and Wagener who reported a family of 8 siblings, 4 of whom had juvenile diabetes mellitus and optic atrophy.1 We report two cases of siblings who exhibited typical findings of Wolfram Syndrome and describe their disease course and progression.
A 10-year-old boy with a family history of Wolfram Syndrome presented to Moran neuro-ophthalmology clinic after referral for possible hereditary optic atrophy. The patient had a 5-year preceding history of diabetes mellitus and high frequency hearing loss. During elementary school he experienced increased urinary frequency and was eventually diagnosed with diabetes insipidus and treated with DDAVP. His older brother had also recently tested positive for Wolfram Syndrome. His vision was 20/30 OD and 20/20 OS with mild correction. Color vision was 5/6 OD and 6/6 OS, with full stereo 9/9. No APD was noted at the time.
At age 12 later he was noted to have some slight temporal pallor. His color vision was 6/7 with stereoscopic vision of 8/9. At age 14, his genetic testing returned positive for a mutation in the Wolfram gene (WFS1), located at map position 4p16.1. He had also experienced some decrease in hearing. He continued to require insulin therapy for his diabetes mellitus.
Between the age of 16 to 18, he was noted to have some peripapillary atrophy on funduscopic examination, and Humphrey visual field (HVF) testing showed an enlarged blind spot with mean deviation of -4.65 (OD) and -5.07 (OS) (Figure 1). His pupils were noted to be slightly sluggish to light reaction with a slight near dissociation. His color vision had decreased to 7/9 but his stereoscopic vision remained full.
At his most recent appointment, at age 22, his vision continued to be stable, but hearing loss in right ear appeared to be worse than previously. His stereoscopic and color vision were also decreased at 4/9 (stereo) and 1/10 (OD) and 2/10 (OS) (color). OCT revealed thinning of the retinal nerve fiber layer (RNFL) He still showed no APD at this time, however his pupils continued to react sluggishly to light. At this point he had started to report swallowing difficulties.
This the older brother of patient in Case 1 was sdiagnosed with diabetes mellitus at age 7. He was later diagnosed with diabetes insipidus and treated with DDAVP. At age 10 he failed the school eye exam and presented to neuro-ophthalmology clinic where he was found to have decreased color vision and a VA (CC) of 20/200 (OD) and <20/400 (OS). He scored 0/7 for color vision and 6/9 for stereoscopic vision. His pupils were very poorly reactive but showed no afferent pupillary defect (APD). Funduscopic exam showed a pale nerve and OCT showed extensive retinal nerve fiber layer loss. His visual fields showed an enlarged blind spot bilaterally. Later that year an MRI showed atrophy and thinning of the brainstem with cerebellar hemispheric atrophy.
Throughout this process he was found to have depression, anxiety, and obsessive-compulsive disorder (OCD) and had previously been diagnosed with Asperger’s Syndrome. Genetic results at age 14 showed two mutations within exon 8 of the WFS1 gene and he was officially diagnosed with Wolfram Syndrome.
His condition continued to decline over the next 8 years. By age 22 he was placed on a CPAP for obstructive sleep apnea (OSA). By age 23 he exhibited swallowing difficulties and presented to the emergency department on multiple occasions for dysphagia and frequent choking episodes. He had also started to develop an uncoordinated, wide-based gait. At age 25 he experienced another episode of aspiration whereby he eventually died of pneumonia and respiratory failure.
Wolfram Syndrome is neurodegenerative condition due to a loss of function mutation in the WFS1 gene, which codes for the protein wolframin1. This rare genetic disease is thought to occur in 1:770,0002, with an average life expectancy of 40 years3. Although genetic testing is necessary for definitive diagnosis, Wolfram Syndrome should be suspected in any patients with an inherited association of juvenile-onset (before age 16) insulin-dependent diabetes mellitus and progressive bilateral optic atrophy4.
The WFS1 gene codes for the protein wolframin, and endoglycosidase H-sensitive membrane glycoprotein that localizes primarily to the endoplasmic reticulum (ER)5. This protein is thought to function as an ER calcium channel or regulator of calcium channel activity, and as such is important in cell-to-cell communication, muscle contraction, and protein processing6. Fonseca et al. found that WFS1 was upregulated during glucose-induced insulin secretion. They also noted that knockdown of WFS1 resulted in an ER stress signal, leading to beta-cell dysfunction and cell death, and subsequent diabetes7. Deletion or loss-of-function mutations in WFS1 result in ER dysfunction, leading to apoptosis of that associated cell.
Seventy percent of patients with Wolfram Syndrome go on to develop central diabetes insipidus1, due to loss of vasopressin producing neurons. Proper functioning of the WFS1 gene is important for maintenance of neuron’s responsible for vasopressin synthesis and processing. Gabreels et al. found that patients with Wolfram Syndrome had vasopressin neuron loss in the supraoptic nucleus as well as defects in vasopressin precursor proteins8.
Impaired glucose control is usually one of the first signs of Wolfram Syndrome. Diabetes mellitus is often diagnosed by age 61, Wolframin is highly expressed in the pancreatic beta-cells and may assist in folding mechanisms of insulin precursor proteins7. WFS1 deficient mice have destruction of beta-cells resulting in impaired glucose tolerance and diabetes mellitus9. Patients with Wolfram Syndrome often remain insulin dependent throughout the course of their life.
Optic atrophy, noticed as loss of color and peripheral vision, is usually the second symptom behind diabetes mellitus, often occurring by age 111. Optic atrophy occurs in almost all patients10, and most patients eventually go blind1. Wolframin is localized to retinal ganglion cells, inner nuclear layer photoreceptors and glial cells of the retina11. The complete cellular mechanism resulting in optic atrophy is unclear, but is thought to be from issues in proper ER function leading to protein deficits, axonal transport deficiencies, and subsequent optic atrophy1.
The mechanistic etiology of sensorineuronal hearing loss seen from WFS1 mutations has also not been fully elucidated. Some studies suggest that proper wolframin function is necessary for maintenance of cochlear hair cells12. It has also been suggested that calcium dysregulation that occurs secondary to WFS1 mutations is implicated in resultant deafness12. It is likely that both mechanisms are at work, however further study is needed to clarify this process.
Neurologic and psychological complications are also common in patients with Wolfram Syndrome. Takeda et al found that WFS1 mRNA and protein were highly expressed in the amygdala, hippocampus, and other areas of the limbic system13. Patients with Wolframin Syndrome are often affected with severe mental and emotional illness such as anxiety, depression, psychosis, and aggression14. WFS1 gene is also expressed in the raphe nucleus and nucleus ceruleus, making it logical that mutations leading to imbalanced levels of serotonin and norepinephrine could lead to impulsive suicide and psychiatric disease15. One study looking at MRI findings in Wolfram Syndrome patients found associated generalized brain atrophy, especially in the cerebellum, medulla, and pons16. Interestingly, one of the most common causes of death in these patients is central respiratory failure secondary to severe brainstem atrophy17,18.
A variety of other pathologic associations have been seen occur commonly in patients with Wolfram Syndrome. By their early 20’s, many patients with WS experience incontinence1 secondary to neurogenic bladder and other urinary tract or bladder abnormalities19. Many patients develop cerebellar ataxia resulting in gait and balance issues10. Other issues include peripheral neuropathy, loss of gag reflex, myoclonus, mental retardation, seizures, and dementia1.
The two patient cases presented exhibit a variety of common findings of Wolfram Syndrome including, diabetes insipidus, diabetes mellitus, progressive optic atrophy, sensorineural deafness, swallowing difficulties, mental illness (anxiety, depression), bladder incontinence, cerebellar ataxia, and death secondary to aspiration and central respiratory failure. Any patient with a personal and family history of juvenile onset diabetes mellitus and bilateral progressive optic atrophy should be suspected and evaluated for Wolframin Syndrome.
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- Gabreels, B.A., et al. The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2. J Clin Endocrinol Metab 83, 4026-4033 (1998).
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