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Wolfram syndrome: clinical and genetic profiling of a cohort from a tertiary care centre with characterization of the primary gonadal failure

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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.

Author information

Author notes

  1. These authors contributed equally: Liza Das, Ashutosh Rai

Authors and Affiliations

  1. Department of Endocrinology, PGIMER, Chandigarh, India

    Liza Das, Sanjay Kumar Bhadada, Anil Bhansali & Pinaki Dutta

  2. Department of Translational and Regenerative Medicine, PGIMER, Chandigarh, India

    Ashutosh Rai

  3. Department of Urology, PGIMER, Chandigarh, India

    Ravimohan Mavuduru

  4. Department of Histopathology, PGIMER, Chandigarh, India

    Kim Vaiphei

  5. Department of Psychiatry, PGIMER, Chandigarh, India

    Akhilesh Sharma

  6. Department of Ophthalmology, PGIMER, Chandigarh, India

    Vishali Gupta

  7. Department of Endocrinology, Eternal Heart Care Centre, Jaipur, India

    Sailesh Lodha

  8. Department of Otorhinolarygology, PGIMER, Chandigarh, India

    Naresh Panda

  9. Department of Radiology, PGIMER, Chandigarh, India

    Paramjeet Singh

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Contributions

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.

Corresponding author

Correspondence to Pinaki Dutta.

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The authors declare that they have no conflict of interest.

Ethical approval

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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Informed consent was obtained from all individual participants included in the study.

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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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