• By: Karen G. Zaarour, MD; Elias I. Traboulsi, MD
    A Compendium of Inherited Disorders and the Eye, Oxford University Press
    Genetics

    OMIM Numbers

    • 222300 for WOLFRAM Syndrome 1 (WFS1)
      (606201 for WFS1 gene)
    • 604928 for WOLFRAM Syndrome 2 (WFS2)
      (611507 for WFS2 gene)
    • 598500 for Wolfram syndrome, mitochondrial form

    Inheritance

    • Autosomal recessive

    Gene

    • WFS1 gene at 4p16.1
    • WFS2 gene at 4q22-q24

    Epidemiology

    • Wolfram syndrome is a rare disease estimated to affect about 1/100,000 in North America and 1/770,000 in the UK, with a heterozygous carrier state frequency of 1/354 in the UK, and as high as 1/100 in Europe and the US.1,2
    • Its prevalence among patients with juvenile-onset diabetes mellitus varies between 1/148 and 1/175.
    • The incidence of WFS may be significantly higher in populations with consanguineous marriages, such as in the Middle East, estimated at 1/68,000 in the Lebanese population.3
    • The prognosis is in general poor, with a median age at death around 30 years (25-49 years). Most patients die with severe neurological disabilities such as bulbar dysfunction and organic brain syndrome, and usually from respiratory failure as a result of brain stem atrophy.

    Description

    • Wolfram syndrome derives its name from the physician who first reported the association of juvenile-onset diabetes mellitus and optic atrophy, in 4 siblings in 1938.4 Also referred to by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is an autosomal recessive neurodegenerative disease characterized by a combination of diabetes mellitus, optic atrophy, diabetes insipidus, deafness, neurological symptoms, renal tract abnormalities, psychiatric manifestations, and gonadal disorders. A finding of insulin-dependent diabetes mellitus and bilateral progressive optic atrophy can alone establish a clinical diagnosis of Wolfram syndrome.
    • Wolfram syndrome 2 (WFS2) is also an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high-frequency sensorineural hearing loss, and optic atrophy or neuropathy. However, patients with WFS2 lack diabetes insipidus and usually demonstrate a defective platelet aggregation pattern, which can lead to gastrointestinal bleeding.5

    Inheritance and molecular genetics

    • Wolfram syndrome is mainly inherited in an autosomal recessive fashion. Autosomal dominant mutations in the WF1 gene have been found to induce low-frequency non-syndromic deafness (OMIM# 600965), as well as Wolfram syndrome-like phenotype (OMIM# 614296), in which hearing impairment is associated with diabetes mellitus and/or optic atrophy.
    • The majority of patients harbor pathogenic WFS1 mutations. The WFS1 gene, associated with Wolfram syndrome 1, is located on chromosome 4p16.1. The majority of mutations are located in exon 8, but other variants have been identified in exons 3, 4, 5, and 6.6 The gene encodes for wolframin, a hydrophobic transmembrane protein of 890 amino acids. Mutation and loss of the wolframin gene cause chronic endoplasmic reticulum stress-mediated apoptosis of cells with a high secretory demand in different organs of the body, such as pancreatic β cells, neuronal cells, and endocrine cells, which in turn leads to the clinical manifestations of the disease. Although its precise function remains not completely understood, wolframin is thought to be necessary for normal intracellular calcium homeostasis.7–9
    • A missense mutation in the WFS2 gene (or CISD2 –CDGSH iron sulfur domain 2- gene) was first isolated by El-Shanti et al in 3 consanguineous families of Jordanian descent with Wolfram syndrome.10 Other reported variants include a deletion mutation in 1 member of a non-consanguineous Italian family and in 2 other siblings.5,11 The gene associated with Wolfram syndrome 2 is located on chromosome 4q22-q24. The CISD2-encoded zinc-finger protein, ERIS (endoplasmic reticulum intermembrane small protein), localizes to the endoplasmic reticulum.12 Animal model studies suggest that Wolfram syndrome 2 is in part a mitochondria-mediated disorder and provide evidence that the CISD2 gene is involved in mammalian life span control.13 A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype in a Moroccan patient was reported by Rouzier et al. and provides more evidence about the role of the CISD2 gene in calcium homeostasis and ER-mitochondria interaction.14
    • There have also been reports suggesting that some cases of Wolfram syndrome result from mitochondrial DNA mutations. Rotig et al. (1993) described a patient with typical features of Wolfram syndrome phenotype, in association with a 7,6-kb heteroplasmic deletion of mitochondrial-DNA. The presence of mild hyperlactemia in this patient suggested a possible abnormality of mitochondrial origin.15 Pilz et al. (1994) described the case of a 19-year-old man with a clinical diagnosis of Wolfram syndrome and the 11778 mitochondrial DNA mutation, which is the most common cause of Leber hereditary optic neuropathy.16 The significance of this association is unclear and may be coincidental.

    Clinical presentation17

    • Non-autoimmune juvenile-onset diabetes mellitus is typically the first manifestation of the disease, diagnosed around age 6. Optic atrophy often occurs within the first decade of life. Approximately 70% of Wolfram patients develop central diabetes insipidus. About 65% develop progressive high-frequency sensori-neural hearing loss that can range in severity from congenital deafness to mild hearing loss beginning at adolescence and slowly progressing.
    • Patients with Wolfram syndrome develop progressive neurodegenerative signs and symptoms that include:
      • Cerebellar ataxia, which is the most common neurological manifestation
      • Dysphagia and dysarthria, which are also commonly seen, and may lead to aspiration pneumonia
      • Central apnea related to brain stem atrophy, a common cause of death
      • Autonomic neuropathy, resulting in orthostatic hypotension, anhidrosis, hyperhidrosis, gastroparesis, hypothermia, and hyperpyrexia
      • Peripheral neuropathy
      • Headache (may resemble trigeminal neuralgia)
      • Hypo/anosmia
      • Hypersomnolence
      • Tremor
      • Seizures/myoclonus
      • Early dementia
      • Mental retardation (only in some patients)
    • Structural and functional urinary tract abnormalities that are commonly seen in patients with Wolfram syndrome include:
      • An atonic bladder
      • Bladder-sphincter dyssynergia
      • Hydro-ureteronephrosis
      • Recurrent urinary tract infections
    • Apart from the diabetes mellitus and diabetes insipidus, Wolfram syndrome can present with additional endocrine manifestations. We cite mainly:
      • Hyponatremia (frequently exacerbated by desmopressin used for treatment of diabetes insipidus)
      • Hypogonadism, with fertility issues in both sexes, erectile dysfunction in male and oligo/amenorrhea in females
      • Hypothyroidism
    • Anxiety and depression are the most common psychiatric symptoms encountered in these patients. Risk of suicide is increased, as well as impulsive and aggressive behavior. Psychosis is a rare presentation.
    • Additional manifestations include: heart conditions such as cardiomyopathy, hematological disturbances such as anemia, and skeletal abnormalities such as a limited mobility of proximal phalangeal joints.
    • Heterozygous carriers were noted to be at greater risk of psychiatric disturbances, notably mood disorders.18

    Ocular findings

    • The major ophthalmological manifestations of Wolfram syndrome result from non-inflammatory degeneration of the visual pathways. Ophthalmoscopic exam, electrophysiological studies, neuroimaging, and post-mortem examinations indicate that the site of pathology is the optic nerve. In fact, atrophy of the optic nerve, chiasm, and tracts have been postulated to be most commonly the first manifestation of the eventual subsequent more generalized neurodegeneration, including atrophy of the medulla and pons, cerebellum, and vermis.
    • Optic atrophy (Figure 1) usually follows the manifestation of diabetes mellitus, with an average age of appearance of 11 years, ranging from a few weeks of life to late teens. The first signs of visual impairment are loss of the blue/green color vision and progressive alteration of the visual field, which often reveals bilateral cecocentral/paracentral scotomas with early peripheral constriction. A variable period of normal vision precedes the onset of visual symptoms. The rate of progression of visual loss shows a wide variability (1-25 years), unlike, for instance, Leber hereditary optic neuropathy, which progresses rapidly over few weeks/months. Visual prognosis is relatively poor, with most patients developing a visual acuity of 20/200 or worse after 8-10 years of onset of symptoms.19

    Figure 1. Photographs of right and left fundi demonstrating optic atrophy in a teenager with Wolfram syndrome.

    • Visual evoked cortical potentials are found to be dysmorphic, of low-amplitude, or totally absent. Electroretinogram (ERG) is usually normal, although some cases present with slightly altered ERG despite a normal-looking retina.
    • The incidence of diabetic retinopathy has been noted to be lower in the Wolfram syndrome population than in patients with type 1 diabetes mellitus, even though the DIDMOAD syndrome is associated with early diabetes of long evolution and poor metabolic control.20,21 Retinopathy is usually of a moderate level and secondary severe ocular complications are seldom observed, though some complicated instances of proliferative retinopathy requiring pars plana vitrectomy have been reported.22–24 The explanation of this finding could be that retinal vessel attenuation secondary to optic atrophy could perhaps protect the retina from hypertension and glucose toxicity (same as the protective effect of carotid stenosis, for example). One other conceivable reason would be hormonal modulation of the development of diabetic retinopathy, in Wolfram patients with primary gonadal atrophy.19
    • Pupillary responses to light can become absent in patients with severe vision loss. Horizontal nystagmus was seen in patients with other signs of cerebellar degeneration.
    • Other reported ocular findings include:
      • Congenital or early-onset cataracts
      • Microspherophakia
      • Glaucoma
      • Increased optic disc cupping
      • Pigmentary retinal dystrophies
      • Tonic pupil
      • Ptosis

    Differential diagnosis

    • The overlapping of several clinical features in hereditary optic neuropathies, and their broad clinical variability, can complicate the differential diagnosis and sometimes delay the diagnosis, especially in patients with non-classical phenotypes.
    • It should be kept in mind that appropriate investigations to rule out other potentially reversible causes of bilateral optic neuropathy should be performed first.
    • The differential diagnosis includes:
      • Juvenile diabetic papillopathy
      • Dominant optic atrophy (can also be associated with hearing loss/optic atrophy, which occurs likely around the same age)
      • Mitochondrial disorders: Maternally inherited diabetes mellitus and deafness, Leber hereditary optic neuropathy
      • Thiamine-responsive megaloblastic anemia with diabetes and deafness
      • Deafness, dystonia, optic neuropathy syndrome
      • Friedreich’s ataxia
      • Alström syndrome
      • X-linked Charcot-Marie-Tooth disease type 5
      • Bardet-Biedel syndrome

    Therapeutic considerations

    • No specific treatment is available to date for Wolfram syndrome. Since it is a multisystemic disease, its clinical management should be multidisciplinary. Genetic counseling and screening for complications and their management are essential.
    • Patients with diabetes mellitus and optic atrophy should be investigated regularly for diabetes insipidus or other hypothalamic dysregulation.
    • The treatment of diabetes mellitus is not different from that of juvenile-onset diabetes mellitus patients without Wolfram syndrome, mainly by insulin therapy and diet management.
    • Diabetes insipidus is mostly treated by desmopressin acetate (DDAVP).
    • Other systemic clinical manifestations should be promptly screened and treated accordingly.
    • As for optic neuropathy management, it has been suggested that the use of idebenone or docosahexaenoic acid may help delay the progression of optic nerve atrophy; however, the efficacy of these molecules has not been confirmed by large-scale interventional studies.25
    • Novel therapies are being currently investigated:
      • Since it has been well established that Wolfram syndrome is attributed to an endoplasmic reticulum (ER) disease, one strategy of treatment would be to target ER dysfunction via drug repurposing.8 Currently FDA-approved chemical chaperones, such as 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA), are known to stabilize protein conformation during folding and to improve trafficking of mutant proteins through the ER. It is then postulated that these small compounds may improve β cell functions and prevent ER stress-mediated β cell death and neurodegeneration in patients with Wolfram syndrome.26–28
      • Several other FDA-approved molecules have proven to preserve ER calcium levels in response to ER stress. Dantrolene, which targets ryanodine receptor localized to the ER membrane has also recently been shown to reduce cell death in animal and cell models with DIDMOAD syndrome.29 Large-scale interventional studies are therefore needed to explore these treatments.
      • Another strategy is being explored, which is, the creation of novel molecules that target mediators of ER calcium homeostasis.30
      • In the field of regenerative medicine, another strategy would focus on creating induced pluripotent stem cells using patients’ skin cells to replace damaged tissues, such as pancreatic β cells, and neural and retinal cells, and to correct WFS1 gene mutations with genome editing technology, in patients with Wolfram syndrome.7,31

    Resources

    • NIH/National Institute of Diabetes, Digestive and Kidney Diseases
      Office of Communications and Public Liaison
      Bldg 31, Rm 9A06
      Bethesda, MD 20892-2560
      Phone: (301) 496-3583
      Email: NDDIC@info.niddk.nih.gov
      Website: http://www2.niddk.nih.gov

     

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