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Wolfram syndrome: for professionals

Overview

Prevalence1 in 770,000
InheritanceAutosomal recessive
Genes involved (OMIM No.)WFS1 (#222300), CISD2 (#604928)
SymptomsFrequent dilute urination (from diabetes insipidus)
Hearing loss
Progressive visual acuity loss
Central scotomas
Ataxia
Neuropathy
Depression/anxiety
Ocular featuresOptic atrophy
Reduced retinal sensitivity
Diffuse optic disc pallor
Early stage keratoconus
Systemic featuresNeurological dysfunction
Urinary tract abnormalities
Diabetes mellitus and insipidus
Key investigationsOphthalmic:
– Fundoscopy
– Visual evoked potentials (VEP)
– Optical coherence tomography (OCT)
– Electroretinography (ERG)

Systemic:
– endocrine evaluation
– MRI brain
– Audiometry
– Renal ultrasound
Molecular diagnosisWhole genome sequencing with targeted panels for WFS1 and CISD2 genes
ManagementOcular:
– Regular ophthalmic monitoring
– Low vision aids
– Monitoring and management of optic atrophy

Systemic:
– Optimisation of glycaemic control with insulin therapy
– Management of diabetes insipidus with desmopressin
– Hearing aids for sensorineural hearing loss
– Management of urinary tract abnormalities
– Multidisciplinary approach including endocrinologists, neurologists, urologists, and genetic counsellors
Therapies under researchOngoing research on medications which may delay optic atrophy.

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Clinical phenotype

Wolfram syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a highly variable multisystemic disorder. It is an important cause of infantile or juvenile-onset diabetes and is primarily associated with biallelic variants in the WFS1 gene or, less commonly, in the CISD2 gene.

Presenting features

Ocular:

  • Gradual visual acuity loss due to optic nerve involvement, often severe within a decade of onset.1
  • Central Scotomas2
  • Diffuse reduction in retinal sensitivity with variable peripheral field involvement.3
  • Changes in corneal morphology compatible with early-stage keratoconus.

Systemic

  • Diabetes mellitus: Insulin-dependent, typically presenting in childhood.4
  • Diabetes insipidus: Often emerging in the second decade, leading to excessive thirst and urination.
  • Sensorineural hearing loss: High-frequency hearing loss that progresses over time.1,5
  • Urinary tract abnormalities: Bladder instability, ureteric obstruction, and hydronephrosis.
  • Neurological manifestations: Ataxia, peripheral and autonomic neuropathy, anosmia, myoclonus, and cognitive impairment.
  • Psychiatric issues: Depression and dementia in advanced cases.1

Fundus

  • Optic atrophy: Characterised by a pale optic disc, which is a hallmark of Wolfram syndrome and leads to progressive vision loss.1
  • Thinning of the retinal nerve fibre layer: Observed using optical coherence tomography (OCT), indicating loss of ganglion cell axons.
  • Macular thinning: Noted in OCT images, suggesting atrophy of the central retina.
  • Pigmentary changes: Possible mottling or clumping of the retinal pigment epithelium, sometimes leading to a ‘salt-and-pepper’ appearance.
  • Peripheral retinal degeneration: Often less pronounced than central changes but can include areas of atrophy and pigment clumping.

Genetics

Gene: WFS1 (4p16.1)

  • OMIM No.: #606201
  • Inheritance Pattern: Autosomal recessive
  • Effect: Biallelic mutations in the WFS1 gene lead to Wolfram syndrome (DIDMOAD). This gene encodes wolframin, a transmembrane glycoprotein primarily localised in the endoplasmic reticulum. Wolframin is highly expressed in pancreatic β-cells, neurons in the brain, and retinal cells, including retinal ganglion cells, photoreceptors, and Müller cells. Mutations in WFS1 result in elevated endoplasmic reticulum stress and misfolded protein accumulation, triggering apoptosis particularly in cells reliant on the endoplasmic reticulum for protein folding, such as pancreatic β-cells and retinal ganglion cells.6-8

Gene: CISD2 (4q24)

  • OMIM No.: #611507
  • Inheritance Pattern: Autosomal recessive
  • Effect: Biallelic mutations in CISD2 are a rarer cause of Wolfram syndrome. This gene encodes a small protein localised to the mitochondrial and endoplasmic reticulum membranes, involved in mitochondrial function and endoplasmic reticulum homeostasis. Mutations in CISD2 lead to optic atrophy, diabetes mellitus, and hearing impairment, typically developing later in life compared to WFS1 mutations. Diabetes insipidus is generally absent. Additional features can include upper intestinal ulcers and defective platelet aggregation, leading to a broader range of systemic manifestations.9

Whilst wolfram syndrome is usually inherited in an autosomal recessive manner, a milder form, often termed ‘Wolfram-like’ syndrome, can occur with heterozygous dominant WFS1 mutations, presenting with one or more features such as diabetes mellitus, progressive hearing loss, and optic atrophy.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Optical coherence tomography (OCT): progressive thinning of the retinal nerve fibre layer and the macular ganglion cell layer. In some cases, a characteristic lamination pattern at the outer plexiform layer may be observed, especially in those with heterozygous WFS1 mutations. This pattern includes distinct sub-layers and a nearly confluent ring centred at the fovea.10
  2. Fundus autofluorescence (FAF): reduced autofluorescence corresponding to areas of optic atrophy. This can help delineate the extent of retinal pigment epithelium (RPE) involvement and atrophic changes.11
  3. Visual evoked potential (VEP): typically show reduced amplitudes, reflecting the impaired function of the visual pathway due to optic nerve atrophy. This reduction in amplitude is consistent with the progressive nature of the optic neuropathy seen in Wolfram syndrome.12
  4. Visual field: often reveals central scotomas and a generalised reduction in retinal sensitivity. The extent of peripheral field involvement can vary, with some patients showing more diffuse loss.
  5. Colour vision: Colour vision is significantly affected early in the disease course. Patients may exhibit a marked reduction in colour discrimination, which progresses in parallel with optic atrophy.
  6. Genetic testing: whole genome sequencing

Systemic

  1. Endocrine evaluation: evaluation of hormonal status, including assessments of diabetes mellitus, diabetes insipidus, and other endocrine abnormalities.1
  2. Neurological assessment: MRI of the brain may show brainstem atrophy.
  3. Audiometry: sensorineural hearing loss, primarily affecting high frequencies, is often detected.
  4. Renal ultrasound: structural abnormalities such as hydronephrosis, hydroureter, and bladder atony or instability. These findings are associated with urinary tract dysfunctions commonly seen in Wolfram syndrome.

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Diagnosis

The diagnosis of Wolfram syndrome is based on clinical features, genetic testing, and laboratory investigations. Molecular genetic testing for mutations in the WFS1 gene is the gold standard for confirming the diagnosis.

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Differential Diagnoses

Distinguishing Wolfram syndrome from other genetic or acquired disorders that cause diabetes mellitus, optic atrophy, and hearing loss is essential. Conditions such as mitochondrial disorders and other rare neurodegenerative diseases may have overlapping features.

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Management

Ocular

  1. Regular monitoring: Ophthalmic follow-up to monitor optic atrophy progression.
  2. Low vision aids: Support for visual impairment.12

Systemic

  1. Optimisation of glycaemic control: Insulin therapy for diabetes mellitus.
  2. Management of diabetes insipidus: Desmopressin treatment.
  3. Hearing aids: For sensorineural hearing loss.
  4. Management of urinary tract abnormalities: Urological interventions as needed.
  5. Multidisciplinary approach: Involving endocrinologists, neurologists, urologists, and genetic counsellors.

Family management and counselling

Wolfram syndrome is inherited in an autosomal recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research. There is a specialist centre in Birmingham for recessive Wolfram syndrome where clinicians in the UK may refer patients.

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Current research

Chemical Chaperones

  • Mechanism: Chemical chaperones aid in protein folding within the endoplasmic reticulum (ER), stabilising the native conformation of WFS1 mutant proteins.13
  • Examples: 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA), both FDA-approved, improve β-cell function and reduce neuronal death by alleviating ER stress.
  • Research: AMX0035, an orphan drug, shows promise in reducing neuronal death in preclinical studies.
  • Clinical trial:
    • AMX0035 in Adult Patients With Wolfram Syndrome
      • NCT number: NCT05676034
      • Phase: Phase 2
      • Study focus: Evaluates the safety and efficacy of AMX0035, targeting neuronal death pathways.
      • Primary outcomes: Changes in C-peptide levels and safety/tolerability.
      • Secondary outcomes: Effects on visual acuity, daily insulin dose, and glucose range.

ER Calcium Stabilizers

  • Therapeutic agents: Calpain inhibitor XI and ibudilast preserve cytosolic calcium levels and enhance insulin secretion in WFS1-KO cells. Dantrolene sodium, which stabilises ER calcium levels, is also being explored for its neuroprotective effects.14
  • Mechanism: These drugs target pathways involved in calcium homeostasis, crucial for cellular function in WS1 patients.
  • Clinical trial:
    • A Clinical Trial of Dantrolene Sodium in Paediatric and Adult Patients With Wolfram Syndrome
      • NCT number: NCT02829268
      • Phase: Phase 1/2
      • Study focus: Assessing the safety and efficacy of dantrolene sodium on cardinal manifestations of Wolfram syndrome, including visual acuity, residual beta-cell function, and neurological functions.
      • Primary outcome: Safety and tolerability assessed by liver function tests.
      • Secondary outcomes: Changes in C-peptide levels, visual functioning, visual acuity, and neurological functions.

Targeting ER Stress

  • Agents: Valproic acid (VPA) increases the expression of p21Cip1, protecting cells from ER stress-induced apoptosis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as liraglutide, improve glycaemic control and reduce neuroinflammation.15,16
  • Mechanism: These treatments aim to mitigate the cellular stress responses that contribute to WS1 pathology.
  • Clinical trials:
    • Evaluation of the Safety and Efficacy of Sodium Valproate in the Treatment of Wolfram Syndrome
      • NCT number: NCT03717909
      • Phase: Phase 2
      • Study focus: This trial assesses the safety and efficacy of sodium valproate (VPA) in patients with Wolfram syndrome, specifically targeting its potential to delay neurodegeneration and visual alterations.
      • Primary outcome: Evaluate the safety of sodium valproate in patients with Wolfram syndrome.
      • Secondary outcomes: Include assessments of efficacy in preserving visual function and reducing neurodegeneration. This encompasses measures of visual acuity, retinal nerve fibre layer thickness, insulin and desmopressin requirements, and overall neurological function.
    • Efficacy Study of Daily Administration of VPA in Patients Affected by Wolfram Syndrome (AUDIOWOLF)
      • NCT number: NCT04940572
      • Phase: Phase 2
      • Study Focus: Evaluates the efficacy of sodium valproate in preserving auditory function and assessing its impact on insulin and desmopressin requirements.
      • Primary Outcome: Preservation of auditory function.
      • Secondary Outcomes: Safety, ventral pons volume, insulin and desmopressin requirements, visual acuity, retinal nerve thickness, balance, and sleep quality.
    • Tirzepatide Monotherapy in Patients With Wolfram Syndrome Type 1
      • NCT number: NCT05659368
      • Phase: Phase 2
      • Study focus: Investigating the efficacy of tirzepatide, a dual GIP/GLP-1 receptor agonist, in improving insulin production and managing glycemic variability.
      • Primary outcomes: Changes in endogenous insulin production and insulin requirements.
      • Secondary outcomes: Changes in glucose variability, time in range, and HbA1c levels.

Mitochondrial Modulators

  • Hypothesis: Drugs targeting mitochondrial dynamics could potentially ameliorate symptoms by correcting mitochondrial dysfunction.17
  • Current research: Limited studies, but the hypothesis suggests potential efficacy in managing WS1 pathology.

Other Therapeutic Approaches

  • Gene therapy: Techniques such as CRISPR and adeno-associated viral systems (AAVs) are being explored to correct WFS1 mutations and generate functional neurons, retinal cells, and β-cells from induced pluripotent stem cells (iPSCs).
  • Regenerative medicine: iPSCs are being developed to replace damaged tissues, including pancreatic β-cells and retinal ganglion cells. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is investigated for its role in enhancing cell survival and function under ER stress conditions.

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Further information and support

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References

  1. de Heredia ML, Cleries R, Nunes V. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med. 2013;15(7):497-506.
  2. Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diabetes Rep. 2016;16:6. doi: 10.1007/s11892-015-0702-6.
  3. Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458-63.
  4. Cano A, Molines L, Valéro R, et al. Microvascular diabetes complications in Wolfram syndrome (DIDMOAD): An age- and duration-matched comparison with common type 1 diabetes. Diabetes Care. 2007;30:2327-2330. doi: 10.2337/dc07-0380.
  5. Rigoli L, Bramanti P, Di Bella C, De Luca F. Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease. Pediatr Res. 2018;83:921-929. doi: 10.1038/pr.2018.17.
  6. Inoue H, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998;20(2):143-8.
  7. Strom TM, Hörtnagel K, Hofmann S, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet. 1998;7:2021-2028. doi: 10.1093/hmg/7.13.2021.
  8. Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. 2012;24:512-517. doi: 10.1097/MOP.0b013e328354ccdf.
  9. Rouzier C, Moore D, Delorme C, et al. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet. 2017;26(9):1599-1611. doi: 10.1093/hmg/ddx060.
  10. Asanad S, et al. Optical coherence tomography-angiography in Wolfram syndrome: a mitochondrial etiology in disease pathophysiology. Can J Ophthalmol. 2019;54(1).
  11. Zmyslowska A, et al. Retinal thinning as a marker of disease progression in patients with Wolfram syndrome. Diabetes Care. 2015;38(3).
  12. Rigoli L, Caruso V, Salzano G, Lombardo F. Wolfram Syndrome 1: From Genetics to Therapy. Int J Environ Res Public Health. 2022;19(6):3225. doi: 10.3390/ijerph19063225.
  13. Shang L, Hua H, Foo K, et al. β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome. Diabetes. 2014;63:923-933. doi: 10.2337/db13-0717.
  14. Nguyen LD, Fischer TT, Abreu D, et al. Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome. Proc Natl Acad Sci USA. 2020;117:17389-17398. doi: 10.1073/pnas.2007136117.
  15. Kakiuchi C, Ishigaki S, Oslowski CM, et al. Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94. PLoS ONE. 2009;4. doi: 10.1371/journal.pone.0004134.
  16. Kondo M, Tanabe K, Amo-Shiinoki K, et al. Activation of GLP-1 receptor signalling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome. Diabetologia. 2018;61:2189-2201. doi: 10.1007/s00125-018-4679-y.
  17. Cagalinec M, Liiv M, Hodurova Z, et al. Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. PLoS Biol. 2016;14. doi: 10.1371/journal.pbio.1002511.

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Updated on July 5, 2024
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