Abstract
Background
Wolfram syndrome (WFS) is a rare, monogenic neurodegenerative syndrome characterised by insulin requiring non-autoimmune diabetes mellitus (DM) and optic atrophy which are usually the earliest and commonest manifestations. However, there are other features which are under-recognized, adding to morbidity and premature mortality in these patients.
Methods
Five patients (three males, two females) with genetically confirmed WFS at a single tertiary care centre were prospectively followed up. Their symptomatology, clinical profile, genetic analysis and radiology were analyzed. Multidisciplinary approach was used for comprehensive clinical care of this cohort. Patients with primary gonadal failure were subjected to biopsy and immunohistochemistry (IHC) for wolframin was performed.
Results
DM was the earliest presenting manifestation at 6.2 ± 1.3 years followed by optic atrophy at 10.4 ± 2.3 years, diabetes insipidus at 12 ± 2.1 years and deafness at 12.8 ± 2.1 years. All patients were autoantibody negative with low C-peptide(<0.6 ng/ml). Hypoglycemic episodes were frequent (upto 60%) but there was no instance of diabetic ketoacidosis. Optic atrophy was present alongwith proliferative diabetic retinopathy and cataract in 40%. Uncommon manifestations included neuropsychiatric features, parasuicide, cystopathy, brainstem atrophy and hypergonadotropic hypogonadism only in adult males (n = 2). Testicular biopsy revealed partly hyalinised seminiferous tubules and prominence of Leydig cells. IHC confirmed the presence of mutated wolframin, which was not significantly different from normal testis specimen on protein quantification.
Conclusions
WFS requires a multidisciplinary approach with special emphasis on early diagnosis and management of other endocrine and non-endocrine features so as to improve long-term outcomes. Gonadal functions need periodic assessment, especially in adult males.
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Abbreviations
- WFS:
-
Wolfram syndrome
- DIDMOAD:
-
Diabetes insipidus, Diabetes mellitus, Optic atrophy, Deafness
- IHC:
-
Immunohistochemistry
- DR:
-
Diabetic retinopathy
- PDR:
-
Proliferative diabetic retinopathy
- TRD:
-
Tractional retinal detachment
- OA:
-
Optic atrophy
- ELISA:
-
Enzyme linked immunosorbent assay
- ECLIA:
-
Electrochemiluminescence assay
- RD:
-
Retinal detachment
- PRP:
-
Panretinal photocoagulation
- SNHL:
-
Sensorineural hearing loss
- GAD:
-
Glutamic acid decarboxylase
- PTA:
-
Pure tone audiogram
- BERA:
-
Brainstem evoked response audiometry
- LH:
-
Luteinizing hormone
- FSH:
-
Follicle stimulating hormone
- H&E:
-
Hematoxylin and eosin
- DM:
-
Diabetes mellitus
- UPR:
-
Unfolded protein response
- ER stress:
-
Endoplasmic reticulum stress
- AIP:
-
Aryl hydrocarbon receptor interacting protein
- HbA1c:
-
Glycated hemoglobin
- DKA:
-
Diabetic ketoacidosis
- SMBG:
-
Self-monitoring of blood glucose
- HGMD:
-
Human gene mutation database
- SSRI:
-
Selective serotonin reuptake inhibitors
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Acknowledgement
We are indebted to Prof RJ Dash, our teacher and an esteemed endocrinologist in his own right, who edited and provided invaluable suggestions for improvement of the manuscript. We would also like to sincerely thank all the patients and their families for their support, understanding and patience.
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L.D. did data collection and analysis, patient management, follow-up, drafted the manuscript and did literature review. A.R. performed immunohistochemistry of wolframin and helped in drafting the manuscript. R.M. did gonadal biopsy of patients. K.V. interpreted the histopathology and immunohistochemistry in samples of patients and controls. A.S. did psychological evaluation for patients. V.G. performed ophthalmologic evaluation and fundus photography. S.K.B. supervised patient management and edited the manuscript. S.L. helped patient management. N.P. performed audiologic evaluation of the patients. A.B. oversaw patient management and edited the manuscript. P.S. provided radiologic expertise for the patients. P.D. conceived the idea, supervised patient management and follow-up, designed the experiments, interpreted results and edited the manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Institutional ethical committee clearance was obtained (IEC/2020/002784/SPL-149).
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Das, L., Rai, A., Mavuduru, R. et al. Wolfram syndrome: clinical and genetic profiling of a cohort from a tertiary care centre with characterization of the primary gonadal failure. Endocrine 69, 420–429 (2020). https://doi.org/10.1007/s12020-020-02320-6
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DOI: https://doi.org/10.1007/s12020-020-02320-6