Wolfram syndrome

By Marcello Cherchi, MD PhD

For patients

Wolfram syndrome (WS) is an inherited neurodegenerative disorder that begins in infancy or childhood with diabetes and visual loss. Some patients later develop additional problems such as hearing loss, urinary incontinence, mood disorders and other symptoms. If your doctor suspects Wolfram syndrome, then they may check several tests of vision, hearing and balance, as well as several blood tests and imaging, followed by referral to a medical genetics counselor regarding genetic testing. Hearing aids may help with the hearing loss.

For clinicians

Overview

In 1938 Dr. Don J. Wolfram (1910 – 1991) and H. Wagener published cases of four siblings with diabetes and optic atrophy (Wolfram and Wagener 1938). Subsequent descriptions added other features to this syndrome, such that it came to be known by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness), though much literature continues to use the eponymous designation of Wolfram syndrome (WS).

Introduction

Wolfram syndrome (WS), also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness) presents in infancy or childhood with insulin-dependent diabetes mellitus and optic atrophy. Some patients additionally develop diabetes insipidus (due to dysfunction of the supraoptic nucleus) and sensorineural hearing loss. This autosomal recessive neurodegenerative disorder with incomplete penetrance results from mutations in genes encoding either for wolframin (WS type 1) or for CDGSH iron sulfur domain protein (WS type 2). Its prevalence has been estimated at 1 in 770,000. The visual deficits are due to optic atrophy, but sometimes worsened by the presence of pigmentary retinopathy or diabetic retinopathy, and can manifest with central scotomata and constriction of peripheral vision. Visual evoked responses are usually reduced, and electroretinography amplitudes may also be reduced. Audiometry usually shows sensorineural hearing loss that is bilateral, symmetrical, and typically affects the high (greater than low) frequencies), sometimes corroborated on otoacoustic emissions (OAE). Pathologic nystagmus is reported in 8% – 75% of patients; the nystagmus is usually compatible with cerebellar dysfunction (gaze-evoked nystagmus; spontaneous up beat nystagmus), less commonly with visual loss (see-saw nystagmus). Instrumented vestibular testing may identify vestibular weakness. MRI shows prominent atrophy of the brainstem, cerebellum and anterior visual pathways (optic nerves and optic chiasm), milder cortical and subcortical atrophy with ventricular dilation. If a patient experiences disequilibrium it is likely multifactorial and due to visual, cerebellar and sometimes vestibular deficits. It is reasonable to offer amplification for the hearing loss; cochlear implantation is sometimes offered.

Epidemiology

The prevalence of WS has been estimated at 1 in 770,000 (Boutzios et al. 2011).

Genetics

WS is inherited in an autosomal recessive fashion with incomplete penetrance.

Wolfram syndrome type 1 (OMIM 222300) (WS1) is caused by a mutation in the gene encoding for wolframin (OMIM 606201) on chromosome 4p16.1. Wolframin is a transmembrane glycoprotein expressed in the endoplasmic reticulum of cells in the brain, pancreas and heart (Hofmann et al. 2003). A variety of mutations in the WS1 gene have been identified (Kobayashi et al. 2018).

Wolfram syndrome type 2 (OMIM 604928) (WS2) is caused by a mutation in the gene encoding for CISD2 (OMIM 611507). The CDGSH iron sulfur domain protein 2 (CISD2) is expressed in the endoplasmic reticulum and mitochondrial membranes (Amr et al. 2007). Other mutations in WS2 have also been reported (Amr et al. 2007).

Pathophysiological mechanism of disease

The diabetes insipidus (also known as arginine vasopressin deficiency) may result from the loss of neurons in the supraoptic nucleus that would otherwise secrete vasopressin. Gabreels and colleagues (Gabreels et al. 1998) additionally report “a defect in VP [vasopressin] precursor processing.”

The mechanism of nystagmus found in some WS patients is unknown. Al-Till and colleagues (Al-Till et al. 2002) speculate that, “Nystagmus… could be related to the underlying cerebellar degeneration.”

Clinical presentation

Affected patients usually develop insulin-dependent diabetes mellitus and optic atrophy in early childhood, less commonly as teenagers and young adults.

Diabetes mellitus and optic atrophy occur in all patients. The full tetrad of features occurs in 13% of patients (Barrett et al. 1997).

Barrett and colleagues (Barrett et al. 1997) report that deafness occurred in 62% (28/45) of patients, with a median onset of 16 years (range 5 – 39 years). Pennings and colleagues (Pennings et al. 2004) report that the hearing loss in WS1 is worse in females.

In the WS case series of 45 patients described by Barrett and colleagues (Barrett et al. 1997), the age of onset of each feature is displayed in the Figure below.

Additional clinical features may include genitourinary problems (neurogenic bladder, urinary incontinence, urinary tract infections, hypogonadism with decreased libido), hyposmia, psychiatric disorders (depression, anxiety, panic attacks), dysphagia, ataxia and others (Urano 2016).

The “ataxia” reported with WS is usually ascribed to cerebellar deficits (since MRI usually shows prominent cerebellar atrophy). However, if this “ataxia” is more broadly experienced as disequilibrium, then there may be more than one component. There are probably multiple mechanisms by which patients with Wolfram syndrome may experience disequilibrium, including:

• Visual loss (see below).
• Nystagmus (see below).
• Cerebellar dysfunction (see below).
• Complications from diabetes (such as diabetic peripheral neuropathy).

Ocular motor examination

Most descriptions of WS make no comment about nystagmus, and the scarcity of observations may account for the variability in its reported frequency, ranging from 8% (Al-Till et al. 2002) to 28% (Marshall et al. 2013) to 75% (Gunn et al. 1976).

Most of the literature on WS does not describe the associated nystagmus well. For example:

• Gunn and colleagues (Gunn et al. 1976) reported nystagmus in 75% (3/4) patients, but did not provide further details.
• Marshall and colleagues (Marshall et al. 2013) studied a series of 18 WS1 patients and reported “abnormal… nystagmus” in 28% (5/18), without further details.

Some studies report “horizontal nystagmus” or “end-gaze nystagmus,” such as:

• Al-Till and colleagues say that one patient in their series had “horizontal jerky nystagmus” (Al-Till et al. 2002).
• Barrett and colleagues (Barrett et al. 1997) state that out of 11 patients with absent pupillary light reflexes, 9 had “horizontal nystagmus,” adding that, “these were older patients with other cerebellar signs including ataxia and dysarthria.”
• Kabanovski and colleagues studied 5 WS patients and reported “end-gaze nystagmus” (Kabanovski et al. 2022).

Other studies additionally report vertical or torsional nystagmus:

• Grosse Aldenhovel and colleagues (Grosse Aldenhovel et al. 1991) reported one patient who, “had vertical nystagmus in the primary position of the eyes and on up-gaze as well as horizontal nystagmus to both sides.”
• Hoekel and colleagues (Hoekel et al. 2014) studied a series of 18 WS patients and reported nystagmus in 39% (7/18). They further commented, “Nystagmus was observed in 7 subjects (39%), 6 of whom had horizontal conjugate jerk nystagmus when gaze was directed more than 15˚ from primary gaze (gaze-evoked nystagmus). One patient (6%) had rotary/torsional/see-saw nystagmus.”
• Rando and colleagues (Rando et al. 1992) reported on two WS patients, of whom one had “clockwise rotatory nystagmus” and the other had “gaze-evoked horizontal nystagmus.”
• Megighian and Savastano (Megighian and Savastano 2004) reported a case of WS in which, “Two types of nystagmus are present: one is a horizontal jerky nystagmus towards the left with a rotary component and the other one is an upbeat vertical nystagmus.” They also reported that horizontal optokinetic nystagmus was “bilaterally altered” (without further details) and vertical optokinetic responses were normal.

Most of these ocular motor findings (gaze-evoked horizontal nystagmus, spontaneous up beat nystagmus) are compatible with cerebellar dysfunction. The finding of see-saw nystagmus may reflect the visual loss associated with optic nerve and optic chiasm atrophy.

Testing: auditory

Audiometry shows approximately symmetrical sensorineural hearing loss predominantly in the high frequencies. The Figure below from Higashi (Higashi 1991) shows a composite audiogram of multiple patients.

Less commonly, low frequencies are affected greater than high frequencies (Jung et al. 2024).

Fujikawa and colleagues reported on two WS patients and found that “DPOAE [distortion product otoacoustic emissions] amplitudes were decreased to the noise level only at the mid-frequencies… which corresponded to the audiometric configurations” in both ears of each patient (Fujikawa et al. 2010).

Pennings and colleagues (Pennings et al. 2004) reported on a series of 11 WS1 patients. Of these, two underwent auditory brainstem evoked responses (ABR), and the results were reported as normal.

Testing: vestibular

Fujikawa and colleagues reported on two WS patients and found SP/AP ratios were increased (Fujikawa et al. 2010) on electrocochleography (ECoG).

Fujikawa and colleagues reported that in one WS patient tested, “a normal caloric response was observed for both ears”(Fujikawa et al. 2010), and that this was tested with air calorics.

Karzon and Hullar studied a series of 11 WS patients (Karzon and Hullar 2013), of whom three underwent rotatory chair testing (RCT). They reported that:

• On slow harmonic acceleration:
  • One patient had “abnormally low gains” and “low-frequency phase lead was pathologically elevated,” which suggests vestibular weakness.
  • One patient had “borderline low gains across frequencies tested.”
• On step velocity testing:
  • All three patients “had borderline low gains in at least one direction.”
  • One patient “had a markedly decreased time constant in both directions.”

In short, the RCT findings reported by Karzon and Hullar suggest some degree of vestibular weakness, but they added, “Our finding that profound bilateral vestibular loss was not common is typical of patients with WS” (Karzon and Hullar 2013). On review of other literature, Karzon and Hullar found only one report (Barjon et al. 1964) of a patient whose vestibular loss was more pronounced than the sensorineural hearing loss.

Pennings and colleagues (Pennings et al. 2004) reported on a series of 11 WS1 patients, of whom six “underwent vestibular examination with a rotatory chair and electronystagmography.” Of those six patients, “One individual had a hyperactive vestibulo-ocular reflex with asymmetry. One individual… had vestibular areflexia and an enhanced cervico-ocular reflex.”

Testing: other

WS patients generally have one or more factors impairing vision.

Al-Till and colleagues (Al-Till et al. 2002) report optic atrophy in 93% of eyes, pigmentary retinopathy in 30% of eyes and diabetic retinopathy in 20% of eyes.

On visual field testing, the initial visual deficits from optic atrophy include central scotomata with peripheral constriction (Barrett et al. 1997).

Barrett and colleagues (Barrett et al. 1997) reported that electroretinography showed reduced amplitude in 50% (3 out of 6) patients.

Barrett and colleagues (Barrett et al. 1997) reported that visual evoked responses were abnormal in 100% (10 out of 10 patients, showing reduced amplitude to flash and pattern stimulation.

Imaging

Barrett and colleagues (Barrett et al. 1997) reported that out of 11 patients who underwent brain MRI, 8 (73%) showed abnormalities, and “the commonest finding was a generalized atrophy, particularly of the brainstem and cerebellum.”

Rando and colleagues (Rando et al. 1992) reported imaging findings in two WS patients as follows:

• “MRI revealed moderate atrophy of the brainstem and cerebellum… There was mild, diffuse atrophy of the cerebral hemispheres, and the entire ventricular system was dilated. With narrow cuts through the midline, the anterior visual pathway appeared shrunken, thinning of the hypothalamic region was evident, and the posterior lobe of the pituitary could not be identified.”
• “MRI… revealed atrophy of the brainstem and the cerebellum. There was mild, diffuse cortical atrophy and the ventricular system was moderately dilated. The optic nerves and chiasm, the hypothalamus, and the pituitary gland appeared atrophic.”

To summarize, brain MRI shows prominent atrophy of the brainstem, cerebellum and anterior visual pathway (optic nerves and optic chiasm), and milder cortical and subcortical atrophy with ventricular dilation. Representative images are shown in the Figures below.

Histopathology

Barrett and colleagues (Barrett et al. 1997) reported that autopsy findings in one patient “revealed atrophy of the optic nerves, chiasm, cerebellum and brainstem.”

Differential diagnosis

Referral to a medical genetics counselor regarding genetic testing for WS is appropriate.

The differential diagnosis of Wolfram syndrome includes several mitochondrial disorders, autosomal dominant optic nerve atrophy, Friedreich ataxia, Bardet-Biedl syndrome and Alstrom syndrome (Urano 2016).

Treatment

There is no curative or arrestive treatment. Amplification may help with the hearing loss. Cochlear implantation is sometimes offered (Alías et al. 2022; Fehrmann et al. 2024; Lim et al. 2023; Marfatia et al. 2024).

Prognosis

The prognosis is poor.

References

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