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Wolfram Syndrome: A Rare Optic Neuropathy in Youth with Type 1 Diabetes

Bucca, Brian C.*; Klingensmith, Georgeanna; Bennett, Jeffrey L.

doi: 10.1097/OPX.0b013e31822f4d8f
Case Report

Wolfram Syndrome (WS) is a rare, autosomal recessive disorder that causes non-autoimmune type 1 diabetes. The etiology involves a single gene mutation of the wolframin protein inducing endoplasmic reticulum stress and apoptosis in selected cell types with resultant diabetes insipidus, diabetes mellitus, optic atrophy, and sensory-neural deafness. Symptoms are initially absent and signs within the posterior segment of the eye are usually the earliest indicator of WS.

These cases characterize unusual and poorly described findings of pigmentary maculopathy in WS and illustrate the importance of collaboration between diabetes and eye care providers; especially in cases of non-autoimmune type 1 diabetes exhibiting atypical human leukocyte-associated antigen haplotypes.




The Barbara Davis Center for Childhood Diabetes (BCB, GK), Departments of Pediatrics and Ophthalmology (BCB), Department of Pediatrics (GK), and Departments of Neurology and Ophthalmology (JLB), University of Colorado, Denver, Aurora, Colorado.

Received March 31, 2011; accepted June 27, 2011.

Brian C. Bucca, University of Colorado, Denver, The Barbara Davis Center for Childhood Diabetes, 1775 Aurora Court, MS A140, PO Box 6511, Aurora, Colorado 80045, e-mail:

First described by Wolfram and Wagener1 in 1938, Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder causing a constellation of signs most often including diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD).2 Other notable complications include a variety of neurological manifestations including gastrointestinal dysfunction, psychiatric illnesses, ataxia, epilepsy, and central apnea.2–4 Because of variable mutations in chromosome 4 (4p16.1 locus),2,3 presentation is variable; however, type 1 diabetes (T1D) mellitus and optic atrophy are omnipresent and present early in the disease course, with diabetes usually preceding eye symptoms.

During initial phases, patients are visually asymptomatic when presenting for diabetes or eye care and consequently, the syndrome often escapes diagnosis until ocular findings become clinically evident. An insensitive clinical sign is the presence of T1D without the typical diabetes-associated autoimmunity, which presents at a median age of 6 years. Optic atrophy is typically the first coexistent manifestation to be noted and is present at a median age of 12 years. Concurrent diagnoses of T1D and optic atrophy should alert the physician to a possible diagnosis of WS.

Although retinal pigmentary changes have been reported in WS, most reported cases fail to describe the location of the pigmentation or describe localization to the peripheral retina.5,6 Pigmentary maculopathy has been noted in rare cases, but characterization of this unusual finding has been limited to date.5–8 To our knowledge, only one report has published images of pigmentary maculopathy in WS.5 To further characterize this rare finding, we present diagnostic images and a discussion of two cases of pigmentary maculopathy in WS.

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Case 1

We report a 6-year-old girl with a 3-year history of T1D who presented to a diabetes specialty eye practice with minor reduced best-corrected visual acuity. The patient had no complaints of blurred vision and no difficulties completing visual tasks. Her general medical history was notable for occasional enuresis and daytime wetting. Family ocular and medical history was negative. She was otherwise healthy, active in ballet, and in a gifted program in school. The most recent glycosylated hemoglobin was 8.8%.

On presentation, best-corrected acuity was 20/40− in both eyes with a minor hyperopic and astigmatic correction in both eyes. Eye alignment, confrontation fields, and extraocular movements were normal, and pupils showed sluggish reactivity without an afferent pupillary defect. Slitlamp examination was normal. Funduscopy was notable for bilateral, temporal disk pallor (Fig. 1a, b) and blunted foveal reflex with subtle foveal retinal pigment epithelial granularity in both eyes (Fig. 1c, d). No diabetic retinopathy was appreciated in both eyes. Ishihara color vision testing was grossly deficient in both eyes with essentially normal results on Farnsworth D-15. The results of the electroretinogram was normal. As the patient's age prevented comparisons with normative data, stratus optical coherence tomography showed what was considered to be normal foveal contour and thickness (136 μm, 138 μm) (Fig. 2a, b). Nerve fiber layer thickness was not assessed.





Findings of bilateral optic atrophy and reduced acuity were communicated with the patient's endocrinologist, which precipitated a thorough review of her case. Her diabetes evaluation showed persistently negative autoantibodies typically associated with T1D (glutamic acid decarboxylase, insulin autoantibodies, islet antigen-2, and zinc transporter-8), and her human leukocyte-associated antigen (HLA) typing was HLA DR2, a low risk HLA for developing T1D. Diabetes insipidus was not present.

Neuro-ophthalmologic consultation confirmed diminished central acuity, color vision loss, and bilateral, temporal disc pallor. She had no history of neurological complaints and her result of neurologic examination was normal. Magnetic resonance imaging of the brain and orbits were normal. Vitamin B12 and folate levels were normal and inflammatory serology was negative. Formalized auditory testing showed no hearing deficit, and genetic testing revealed compound heterozygous mutations in the WFS-1 gene, diagnostic of WS.

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Case 2

A thirteen-year-old female with a 9-year history of T1D, presented to a diabetes specialty eye practice with essentially normal uncorrected vision and without complaint. No coexistent medical or ocular conditions were noted and family ocular history was positive for glaucoma. Immediate family medical history was negative but extended family history was positive for neurological diagnoses including Meniere's disease, myasthenia gravis, multiple sclerosis, and psychological diagnoses. Recent glycosylated hemoglobin was 8.5%.

On presentation, uncorrected acuities were 20/25 in both eyes. Eye alignment, confrontation fields, and extraocular movements were normal and pupils were equal in size and reactivity without an afferent pupillary defect. Slitlamp examination was normal. Funduscopic examination was notable for subtle temporal disk pallor (Fig. 3a, b) and blunted foveal reflex and fine macular retinal pigment epithelial granularity in both eyes (Fig. 3c, d). No diabetic retinopathy was appreciated. Farnsworth D-15 color testing revealed only minor reversals in both eyes and Humphrey 24 to 2 visual field testing was attempted but deemed to be unreliable on two occasions. Spectral domain optical coherence tomography demonstrated what was considered to be normal foveal contour and thickness (126 μm, 123 μm) without retinal pigment epithelial abnormality in both eyes (Fig. 4a, b). Nerve fiber layer analysis revealed suspected temporal thinning (31 μm, 25 μm), but the patient's age prevented comparisons with normative data (Fig. 5). Serum vitamin B12, folate, thallium, and lead levels were normal and inflammatory serology was negative. Fluorescein angiography showed faint, mottled hyperfluorescence in the fovea of the OD without leakage (Fig. 6a, b). Fundus autofluorescence (Fig. 6c, d) and electroretinogram were unremarkable in both eyes.









Findings of bilateral optic atrophy were communicated with the patient's endocrinologist, which precipitated a thorough review of her case. Her diabetes evaluation showed persistently negative T1D auto-antibodies and her HLA typing was atypical for T1D (DR6 and DR1). Diabetes insipidus was not present.

Neuro-ophthalmologic consultation re-affirmed the presence of temporal disc pallor (Fig. 3a) and revealed a mild to moderate color deficit in both eyes as measured with Ishihara color plates. She had no history of neurological complaints and her result of neurologic examination was normal. Magnetic resonance imaging of the brain and orbits showed non-specific, very small areas of T2 hyperintensity in the frontal white matter of uncertain etiology.

Formalized auditory testing showed moderate to severe high frequency sensorineural hearing loss, and genetic testing revealed two heterozygous nucleotide variations in the WFS-1 gene, which were of unknown clinical significance. Because these mutations had not previously been described, WS could not be immediately confirmed; however, both have been predicted to be damaging mutations and likely represent a variant of WS. No mitochondrial mutations specific to Leber's Hereditary Optic Neuropathy were reported.

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Discussion of Wolfram Syndrome

WS (DIDMOAD) is a rare autosomal recessive, single gene mutation of the WFS-1 gene. Investigators historically believed the etiology to be mitochondrial in nature; however, subsequent studies have shown central nuclear mutations localized to chromosome 4 (4p16.1 region) in 90% of Wolfram patients.2 More recent theories hypothesize that central nuclear mutations predispose to mitochondrial dysfunction, which contribute to the overall phenotype.2 Epidemiologic studies have not been conducted in the Unites States, but prevalence estimates range from 1:68,000 in Lebanon to 1:770,000 in the United Kingdom with higher incidence in consanguineous parents.2,3,9

The WFS-1 gene codes for the protein wolframin, which is thought to assist in calcium ion homeostatsis, promotion of cell membrane trafficking, and protein folding in the endoplasmic reticulum of neuronal and pancreatic cells. Up to 50 distinct mutations of the WFS-1 gene have been reported, leading to variable presentations and disease severity.9 Mutational dysfunction of wolframin protein folding induces endoplasmic reticulum stress resulting in impaired cell cycle progression and premature induction of apoptosis. This occurs especially in pancreatic beta cells, the optic nerve, and pituitary vasopression-producing neurons resulting in non-autoimmune T1D, progressive optic neuropathy, and central diabetes insipidus, respectively. Increased apoptosis also has affects in the brain stem, causing other complications including gastrointestinal and bladder dysfunction, trunkal ataxia, epilepsy, anosmia, nystagmus, behavioral disorders, and central apnea.2

Diabetes mellitus and optic atrophy are consistent findings in WS (99 and 97.5% of cases) and present at a median age of 6 and 11 years, respectively.2,6 Diabetes mellitus is the initial sign in 85% of cases and optic atrophy in 9%.6 Other signs can be quite variable in presentation, age of onset, and degree of severity. Diabetes insipidus presents in 73% of cases in the second to third decade of life.2 Sensory-neural hearing loss, usually present by the second to third decade of life, typically affects high frequencies bilaterally in 39 to 62% of patients2,9 and can remain unnoted as voice frequencies are often spared.2,6 Psychiatric and behavioral disorders have been noted in as much as 60% of Wolfram patients,2,6 which often manifest as general depression or suicidal ideation.2 Central neurologic defects including respiratory failure and brain stem atrophy are the usual causes of premature death, which often occurs in the third or fourth decade of life.9

Although diabetes is the most common presenting sign in WS, distinct differences between T1D in WS and classic T1D should be noted. Most notable are the relative absence of insulin autoantibodies in WS as opposed to classic T1D, where antibodies are found in 93% of patients.2 HLA-DR2 is relatively common in Wolfram patients (44%), in contrast to classic T1D patients who typically exhibit HLA-DR3 and/or HLA-DR4 and only rarely (6%) test positive for HLA-DR2. The autosomal recessive inheritance pattern in Wolfram patients results in a 25% chance of inheritance as opposed to 3 to 6% chance for classic T1D.2 Finally, investigations of microvascular disease in patients with WS vs. traditional T1D have reported non-significant trends toward less retinopathy in patients with WS.10

Numerous effects on the visual system have been reported in WS. When symptomatic, patients usually present with complaints of blurred vision, loss of peripheral field, or difficulty distinguishing colors. Bilateral, progressive optic atrophy is the most common presenting ocular sign.2 Additional signs include moderate to severe acuity and color deficiencies along the blue-yellow and/or red-green axes.6 Bilateral diminished pupillary responses, constricted visual field, cataracts (30 to 67%), nystagmus, and peripheral pigmentary retinopathy (30%) have also been described.2 Although visual-evoked potentials consistently show reduced or absent amplitudes and increased latencies, the result of electroretinogram is typically normal. Visual deterioration is usually 20/200 or worse3 with full nadir occurring at a median of 8 years after diagnosis.2

The prevalence of pigmentary maculopathy in WS is currently unknown and has been minimally reported. Cremers et al.7 described one patient in a series of 91 cases with irregular pigmentation of the macula, and Gunn et al.8 noted perimacular granularity in one of four cases. Dhalla et al.5 were the first to publish color and angiographic images of bilateral pigmentary maculopathy in WS where disturbances appeared to be diffusely distributed in the area centralis. In contrast, our cases demonstrate more subtle pigmentary disturbances localized to the foveolar area. It is not clear whether this discrepancy represents a phenotypic variation or that pigmentary changes may become progressively distributed in these atypical cases. Fundus autofluorescence imaging showed no abnormality of lipofuscin deposition in our second case, indicating that either the pigmentary changes are not resultant from pathological mechanisms in retinal pigment epithelial cells or it is too early in the disease process to show abnormal autofluorescence.

Immunohistologic analysis has shown preferential loss of inner retinal layers including the ganglion cell, nerve fiber, inner nuclear, and both plexiform layers with preservation of the outer nuclear layer.11 Magnetic resonance imaging studies have reported marked axonal loss and demyelination of the optic nerve, chiasm, and radiations; atrophy of the superiour colliculus and lateral geniculate nucleus; and structural preservation of the visual cortex.4,11

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Differential Diagnosis

Differential diagnoses for optic atrophy in youths with T1D should initially center on conventional mechanisms more common in this age group: compressive (intraorbital, pituitary/hypothalamic), inflammatory, nutritional [folate, hypovitaminosis (B1,B12)], and toxic (lead, thallium, medication induced).

A variety of inherited optic neuropathies and retinal degenerations begin to manifest in early childhood and in the adolescent age group. Although a family history should raise suspicion, the clinician must be mindful that the variable penetrance or recessive inheritance patterns of these conditions can conceal the presence of inherited disease in family members. Differentiation between inherited optic neuropathies and retinal degenerations require electrodiagnostic testing.12 Although alterations in electroretinogram waveforms are typical in retinal dysrophies and degenerations,13 a normal or minimally affected electroretinogram should alert the clinician to consider optic neuropathy or pathology elsewhere in the visual pathway.

For definitive diagnosis of suspected inherited optic neuropathy, genetic testing for mitochondrial and central nuclear mutations is necessary. Both types of mutations can precipitate mitochondrial dysfunction and result in deficiencies in adenosine triphosphate; the causative mechanism in genetically determined optic neuropathies. The variable susceptibility of other neurologic pathways to adenosine triphosphate deficiencies may produce coexistent systemic neurologic findings known as optic atrophy “plus” syndromes.3,12 As a result, the patient should undergo a complete neurologic work-up. A thorough family history coupled with examination of available family members is extremely important for identifying inheritance pattern and facilitating genetic counseling. Two of the most common hereditary optic neuropathies are discussed below. In cases of bilateral simultaneous or sequential optic atrophy, these should be considered primary diagnoses in patients whom conventional disease mechanisms have been ruled out.

Dominant optic atrophy is the most common hereditary optic atrophy with an estimated prevalence of 1:50,000.3,12 It is caused by a variety of 90 different nuclear mutations of the OPA1 gene (3q28-29), which are thought to disrupt sharing of mitochondrial DNA and destabilization of mitochondrial complexes important in oxidative phosphorylation.3,12,14 Determination of family history is often difficult as penetrance and phenotypic expression within families are highly variable.3,12,14 Although symptoms can be insidious, symptomatic patients typically present in the first to second decades of life with bilaterally reduced vision ranging from 20/20 to hand motion. Although the rate of vision decline is variable, it is progressive and usually stabilizes at 20/200 or better in 80% of patients.3,12 Disk pallor can be either diffuse or temporal; visual field deficits are usually central, paracentral, or ceacocentral; red-green or blue-yellow color vision defects are common3,12; and pupil function is minimally affected.12 Dominant optic atrophy most typically occurs in isolation,3 but other neurologic defects such as ataxia, extraophthalmological abnormalities (ophthalmoplegia and ptosis), and multiple sclerosis-like disease may coexist (dominant optic atrophy “plus”).3,12,14 Sensorineural hearing loss is the most common extra neurologic finding in dominant optic atrophy and has been reported to cluster within families.12 Accordingly, WS-related optic atrophy and dominant optic atrophy plus should be the primary differential diagnoses in patients with concurrent non-autoimmune T1D, optic atrophy, and sensorineural hearing loss.

Lebers hereditary optic neuropathy is the most common primary mitochondrial-inherited disease.12 Ninety-five percent of Lebers sufferers worldwide contain one of three mitochondrial DNA mutations, causing alterations in complex 1 of the mitochondrial respiratory chain almost exclusively in papillomacular retinal ganglion cells.3 The prevalence ranges from 1:31,000 in England to 1:50,000 in Finland,12 and the peak age of onset is between 15 and 35 years. No racial predilection has been described, but males are predominantly affected (80 to 90% of cases), which has raised theories concerning a X-linked influence.3,12 As isolated cases within families are extremely rare, a majority of cases (60%) have a positive family history.12 Three of four cases present with unilateral vision loss of variable severity with sequential involvement of the fellow eye occurring within 1 year in 97% of cases; typically within 6 to 8 weeks.3,12 Although 20% of cases present with normal disk appearance, peripapillary nerve fiber layer swelling and non-fluorescein leaking disk telangiectasia may be present during the acute phases12; optic atrophy usually presents after 6 months causing red-green color vision deficits as well as central or centrocaecal visual field defects. Except in asymmetric cases, or early in the disease when presentation can be unilateral, pupillary function is typically preserved or minimally affected. Visual prognosis is worse than dominant optic atrophy with stabilization over months and acuity deterioration worse than 20/200.3,12 Sensorineural hearing loss is not seen in Lebers hereditary optic neuropathy, but other systemic neurologic features may coexist including cardiac conduction abnormalities, peripheral neuropathy, ataxia myoclonus, dystonia as well as brain stem, and MS-like syndromes (Lebers hereditary optic neuropathy “plus”).3,12 Additionally, a variety of other syndromes presenting with optic atrophy and complex neurological defects may coexist with T1D and must be considered (Table 1).



The cases presented here have advanced the characterization of unusual and poorly described findings of pigmentary maculopathy in WS. In addition, these cases illustrate the importance of integrated care and detailed disclosure of unusual ocular findings to non-eye care providers. In these examples, collaborative care led to an earlier molecular diagnosis of WS allowing for early genetic counseling, provisional and supportive care, and early recognition and treatment of additional anticipated sequela. Although no effective treatment has been identified, as appropriate interventions become available, earlier diagnosis of WS will likely reduce rates of mortality and improve quality of life.

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diabetes insipidus; optic atrophy; non-autoimmune type 1 diabetes; sensory-neural hearing loss; pigmentary maculopathy

© 2011 American Academy of Optometry