Wolfram Syndrome

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 by Bayan Al Othman, MD on June 30, 2020.


Wolfram Syndrome


Disease Entity

OMIM Numbers

  • 222300 - WFS1
  • 604928 - WFS2
  • 598500 - WFS, mitochondrial form

ICD-10 Code

  • E138 Other specified diabetes mellitus with unspecified complications

Disease/Description

Wolfram Syndrome (WFS1) is a rare genetic cause of juvenile-onset diabetes mellitus characterized by pancreatic β-cell destruction and concurrent optic atrophy. WFS has also been termed DIDMOAD (i.e., diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome due to its association with a constellation of other symptoms. WFS can manifest with various other neurological findings (e.g., peripheral neuropathy, ataxia, and cognitive impairment)[1][2][3] or other systemic findings (e.g., renal tract abnormalities, gonadal atrophy, and psychiatric disturbances).[1][4]

Classically, WFS is linked to mutations of the WFS1 gene[5]; however, other mutations at different loci have been shown to cause similar syndromes.[6][7] Like WFS1, Wolfram Syndrome 2 (WFS2) is characterized by juvenile-onset diabetes mellitus, optic atrophy, and sensorineural deafness. WFS2 is unique however, in that it maps to a different locus, often lacks diabetes insipidus (DI), and more commonly presents with bleeding secondary to defective platelet aggregation.[6][8][9]

Epidemiology

WFS1 is an uncommon disease and, therefore, prevalence estimates vary greatly, ranging from 1 in 770,000 in the UK and 1 in 100,000 in a North American population.[1][10] The prevalence in children has been reported as 1 in 500,000.[1] The highest known prevalence was found in a Lebanese community with greater rates of consanguinity.[11] In juvenile diabetics, the frequency of WFS1 has been estimated at 1/148 to 1/175.[12] Estimates of carrier frequency have been reported as high as 1% of the general population.[4]

Inheritance and molecular genetics

Both WFS1 and WFS2 typically follow an autosomal recessive inheritance pattern. Autosomal dominant mutations in the WFS1 gene have however been implicated in Wolfram-like syndrome, characterized by deafness, optic atrophy and/or diabetes mellitus, as well as low frequency non-syndromic deafness. [13][14]

WFS1 is caused by homozygous or heterozygous loss of function mutations at chromosome 4p16.1, encoding the wolframin protein.[5][15][16] Most mutations involve exon 8 but some have been located in exons 3, 4, 5, and 6, and are usually due to missense mutations, although nonsense, in frame deletions or insertions, and frameshift mutations have also been identified.[17][18] Interestingly, inactivating mutations have been correlated to earlier onset of WFS1 and more severe disease.[2][19]

Wolframin is a transmembrane protein localizing to the endoplasmic reticulum (ER) and is highly expressed in pancreatic β-cells. Although its entire function has yet to fully be understood, loss of function in wolframin results in aggregation of misfolded proteins in the ER, overwhelming the normal protein destruction pathways of the cell and triggering apoptosis.[20][21] Other than the pancreas, wolframin is greatly expressed in the brain, heart and muscle tissues, and, to a lesser degree, in the liver and kidneys.[22] Cells with a high secretory demand, such as pancreatic β-cells and neuronal cells, rely heavily on the ER for correct protein folding. Mutations in wolframin disrupt this process and are thus hypothesized to be the cause of diabetes mellitus (pancreatic β-cell death) and optic atrophy (retinal ganglion cell death) in WFS.[20][23]

In contrast to WFS1, WFS2 has been mapped to mutations in chromosome 4q22-24, but frequently involves the CISD2 gene.[9] This gene encodes a zinc-finger protein of the Endoplasmic Reticulum Intermembrane Small protein (ERIS) which does not interact with wolframin although their histological expression largely overlap.[24] Wolframin and ERIS also overlap in function as they both play a role in calcium homeostasis of the ER.[6][20] Mutations in ERIS and subsequent imbalances in calcium homeostasis are hypothesized to cause ER stress via accumulation of misfolded proteins, triggering apoptosis in affected cells.[6][24] This mechanism and its destruction of retinal ganglion cells is thought to be the cause of optic atrophy in Wolfram syndrome patients.[6] CISD2 has also been shown to impact mitochondrial function and may affect cell lifespan.[25]

WFS1 patients have also been found to have concomitant mutations in mitochondrial DNA (mtDNA), thus implicating WFS1 as a possible ER and mitochondria related disorder.[7][26] mtDNA may impact the severity or phenotype of Wolfram syndrome, although the relationship of mtDNA and nuclear mutations has yet to be fully elucidated.[25][27]

Clinical Presentation

As a general rule in WFS1, patients tend to present with diabetes mellitus in the first decade of life. Optic atrophy follows in the early second decade, and diabetes insipidus and deafness develop later in the second decade. Finally, neurologic and genitourinary tract problems present, on average, in the third decade.[28]

The juvenile-onset diabetes mellitus resulting from WFS1 typically requires less exogenous insulin in management and better glycemic control due to chronic loss of pancreatic β-cell death when contrasted with Type 1 Diabetes Mellitus (T1DM) due to autoimmunity.[19] The optic atrophy typically manifests as decreased visual acuity and loss of color perception (see Ocular Findings).[29] Diabetes insipidus is thought to be due to hypothalamic dysfunction, resulting in a partial central DI secondary to decreased anti-diuretic hormone release.[30] Deafness in WFS1 is mainly characterized as gradual, sensorineural, high-frequency hearing loss, although congenital deafness has been reported.[1]

The common associated neurologic manifestations of WFS1 are truncal ataxia, peripheral neuropathy, and cognitive impairment[1][2], but other neurologic symptoms include anosmia, loss of gag reflex, myoclonus, epilepsy, nystagmus and autonomic neuropathies (i.e. orthostatic hypotension, gastroparesis, and resting tachycardia).[1][31] Psychiatric findings are extremely common in WFS1 patients but present later in the course of the disease, with anxiety and depression being most common. However, severe depression, psychosis, impulsivity, and verbal and physical aggression can result.[4][31]

Genitourinary symptoms vary widely; bladder instability or atony can cause urge or overflow incontinence, respectively. Structural abnormalities include hydroureteronephrosis and sphincter abnormalities, predisposing patients to recurrent urinary tract infections (UTIs).[1][31] Besides diabetes mellitus, hypogonadism is another endocrine abnormality present in WFS1, with erectile dysfunction in men, menstrual cycle irregularity in females, and impaired fertility in both sexes. Hyponatremia is commonly seen in WFS1, and is thought to partly be due to partial central DI. Short stature from growth hormone (GH) deficiency and hypothyroidism can also be seen in WFS1 patients.[1][31] Other manifestations of this disease include structural cardiac abnormalities, such as pulmonary valvular stenosis and cardiomyopathy, anemia, and limited joint mobility.[11][17]

Patients with WFS2 exhibit similar manifestations of juvenile-onset diabetes mellitus and optic atrophy, but have lower rates of diabetes insipidus. The psychiatric findings in WSF2 patients have not been broadly reported, but may be less frequent.[6][9][32] WSF2 patients frequently suffer from peptic ulcer disease and gastritis and can present with severe hemorrhage from gastrointestinal ulcers secondary to decreased platelet aggregation with collagen and/or ADP.[6][8][32]

Ocular Findings

Optic atrophy, due to death of retinal ganglion cell axons, is a diagnostic requirement in WFS. Optic atrophy has a median age of onset of 11 years in WFS1 patients.[33] However, the onset of optic atrophy is delayed and the severity is reduced in patients with missense mutations than those with inactivating mutations.[2] Optical coherence tomography (OCT) scans show retinal thinning of the optic nerve and macula.[34] OCT-angiography shows significant reduction in optic nerve head and peri-papillary microvasculature.[35] Reduced signal from optic nerves and chiasm can be seen on magnetic resonance imaging (MRI) of these patients.[33][36]

Visual acuity generally declines gradually and is severe with most WFS1 patients progressing to 20/200 vision or worse within 8 years after onset of disease.[33] Another cross-sectional study found that most patients with WFS have a best-corrected visual acuity of less than 20/40, although other studies report higher prevalence of vision loss.[29] Visual field loss before visual acuity deterioration has been reported with central scotomas and constricted peripheral vision.[33] The majority of WFS1 patients experience color deficiencies in color perception, specifically in the blue-yellow spectrum. Although less common, patients can present with early-onset cataracts (possibly related to impaired glucose regulation).[29][33]

Interestingly however WFS patients have shown to have lower rates of diabetic retinopathy[29][37][38] when compared to age-matched T1DM patients.[19] One theory proposed to explain this finding is that an attenuated retinal fiber layer has less demand for blood flow and is therefore less likely to be damaged in hypoxic conditions of glycemic instability.[33] Rarely, WFS1 patients can present with pigmentary retinopathy, but is not considered a major contributing factor to reduced visual acuity.[29]

Electroretinography (ERG) results vary by study, but typically show normal values in WFS1 patients, consistent with optic atrophy due to retinal ganglion cell axon loss.[33][37] Visual Evoked Potentials (VEP) in WFS1 patients are also consistent with optic atrophy. The prominent positive deflection (P100) values are typically delayed (up to 146ms) with reduced amplitude and have abnormal curve morphology.[33][37][38] In addition, unaffected heterozygotes can show abnormal curve morphology in the setting of normal P100 latencies.[37]


Diagnosis

The majority of patients do not present with all four symptoms included in the eponym ‘DIDMOAD’. Therefore, the diagnosis of WFS can be made by only having concurrent juvenile-onset DM and optic atrophy.[28][33] However, a minority of patients do not present with DM until after 18 years of age and do not fit these diagnostic criteria. New diagnostic criteria for WFS have been proposed to address this deficit by including all patients with DM, regardless of onset, and optic atrophy. Another proposal is to include all patients presenting with two or more of the DIDMOAD symptoms.[28] The average delay in diagnosis of WFS is 14 years after the onset of symptoms.[2] Thus, it is crucial that physicians suspect WFS in the setting of DM and optic atrophy, especially in the setting of negative anti-glutamic acid decarboxylase and anti-islet cell antibodies commonly found in T1DM.[32]

Molecular genetic testing allows for disease confirmation, genetic counseling, and for screening in high risk, asymptomatic individuals with significant family history. Identification of heterozygotes carriers of WFS1 mutations allows for psychiatric monitoring as these individuals are 26 fold more likely to undergo psychiatric hospitalization than noncarriers.[4] Currently, Sanger sequencing-based genetic testing targeted for the most common gene implicated, WFS1, is the next step in diagnosis when faced with clinical uncertainty. If negative, patients can be tested for CISD2 gene for WFS2. Exome and/or genome sequencing-based diagnostic methods are under development.[31] Prenatal genetic studies can safely be performed via chorionic villus sampling (CVS) for family planning purposes.[39]

MRI findings in WFS1 patients can show generalized atrophy of the brain, hypothalamus, brainstem, cerebellum, and cerebral cortex. Other MRI findings include absence of physiological high signal intensity of the neurohypophysis, shrinkage of the optic nerves, chiasm and tracts, and reduced signal from the posterior pituitary, consistent with partial DI.[36][40] Asymptomatic patients may show MRI changes before clinical symptoms.[2]

Differential diagnosis[17][31]

  • Diabetic papillopathy
  • Mitochondrial disorders: Maternally inherited diabetes-deafness syndrome (MIDD), Leber Hereditary Optic Neuropathy (LHON), and Kearns-Sayre syndrome
  • Thiamine-Responsive Megaloblastic Anemia syndrome (TRMA)
  • Wolfram-like syndrome and low frequency non-syndromic deafness
  • Autosomal dominant optic atrophy
  • Deafness, dystonia, optic neuropathy syndrome
  • Friedreich’s ataxia
  • Alström syndrome
  • X-linked Charcot-Marie-Tooth disease type 5 (CMTX5)
  • Bardet-Biedel syndrome
  • Myotonic dystrophy type 1
  • Deafness-dystonia-optic neuropathy syndrome (DDON)

Management/Therapeutic Considerations

Up to 60% of WFS patients have early mortality (less than 36 years of life)[41] and the most common causes of death are central respiratory failure, autonomic dysfunction, dysphagia, or aspiration pneumonia. Other less common causes of death are progressive renal disease from chronic reflux and recurrent UTIs resulting in urosepsis.[1][41] Multidisciplinary care is necessary due to the complexity and vast array of possible manifestations across organ systems, and no cure is available.

Annual ophthalmologic examination is recommended, including visual acuity, color vision testing, funduscopic examination, visual field testing, and OCT scans.[31] OCT scans of the optic disc and macula have been reported as reliable indicators of disease progression with retinal thinning.[34] Standard monitoring and treatment for diabetic retinopathy in Type 1 diabetics should be implemented in WFS patients as well as regular screening for microalbuminuria. Audiologic examination, including auditory brain stem responses (ABRs) and evoked optoacoustic emissions, is recommended to evaluate for sensorineural hearing loss. Urologic referral with renal and urinary tract imaging and genetic counseling are suggested. Other recommendations include regular neurologic examinations, MRI neuroimaging, developmental assessments, and psychiatric evaluations.[17][31]

Emphasis should be placed on optimization of glycemic control with insulin therapy following standard guidelines for insulin-dependent diabetes mellitus. In specific hormone deficiencies, exogenous replacement may be necessary, such as desmopressin in DI, growth hormone in pathologic short stature, and levothyroxine in hypothyroidism. Other treatments for urologic complications may be warranted, such as intermittent self-catheterizations, placement of an indwelling catheter, and frequent surveillance and/or prophylactic antibiotics for UTIs. Low-vision therapy and adaptive equipment can be implemented and cataract surgery with intraocular lens placement can be performed for significant reductions in visual acuity due to optic atrophy and cataracts, respectively.[17][31]

Idebenone, a coenzyme Q derivative of the mitochondrial respiratory chain, and docosahexaenoic acid have been reported in case reports to may help to delay progression of optic atrophy and improve vision. Mitochondrial dysfunctional has been thought to contribute to disease pathology in addition to ER stress. However, these medications have not been evaluated in WFS by large-scale clinical trials.[31][35][42] As misfolding of proteins in the ER trigger apoptosis in pancreatic β-cells with WFS1 mutations, FDA-approved chemical chaperones, 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) may show clinical improvement in WFS1 patients.[20][31] Thought to be due to regulation of calcium influx during ER dysfunction, dantrolene has been shown to reduce β-cell death in murine models with WFS1 mutations and prevent cell death in induced pluripotent stem cells from a WFS1 patient.[43] Small molecule inhibitors that target important functions in the ER, such as calcium homeostasis, redox regulation, and protein folding, are potential future avenues of study. Another area for potential therapy is by using gene editing technology. Damaged tissues (i.e. pancreatic β-cells and retinal cells) could theoretically be replaced in Wolfram syndrome by generating induced pluripotent stem cells using patients’ skin cells, editing their genome with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology, and transplanting them into target organs.[31]

Additional Resources

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