This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The Wellcome Trust, UK funded genetic testing.Published version, Accepted version (12 month embargo), Submitted versio

De Franco, Elisa

Ellard, Sian

English

Published version, Accepted version (12 month embargo), Submitted versionThe Wellcome Trust, UK funded genetic testing.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site

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C L I N I C A L P I C T U R EJuvenile diabetes and visual impairment:Wolfram syndromeThe presence of diabetes and visual impairment in a young in-dividual is a good diagnostic criterion to suspect Wolfram syn-drome (WS) or Diabetes insipidus, Diabetes mellitus, opticatrophy and deafness.1,2 WS is a rare autosomal recessive dis-ease due to mutations in the Wolframin (WFS1) gene. Thesemutations lead to endoplasmic reticulum stress-related declineof pancreatic beta-cell number and a decrease in endogenousinsulin secretion. Affected individuals are therefore usuallyinsulin-dependent, with a few rare exceptions reported.3–5 Herewe describe a 9-year-old boy who presented with visual impair-ment and diabetes, with a novel homozygous WFS1 frameshiftmutation p.(Ala671fs) confirming WS. This patient has a normalendogenous insulin level necessitating a very low total daily in-sulin requirement for good glycaemic control.A 9-year-old boy presented to our endocrine clinic withdecreased vision for 6 months and polyuria for 4 months. Hisparents were non-consanguineous and there was no family his-tory of diabetes. His visual acuity was 1/6 on both eyes and ret-inal examination revealed bilateral optic atrophy withoutdiabetic retinopathy (Figure 1A and B). His fasting blood glucoselevels were elevated at 14.43 mmol/l with no ketonuria andHbA1C of 9.2%. Anti-glutamic acid decarboxylase antibody lev-els were normal with a normal c-peptide. An audiogram and anabdomen ultrasound were normal and there were no learningdifficulties. An overnight water deprivation test was normal. Inview of the optic atrophy and juvenile diabetes a genetic ana-lysis was done to confirm WS. Sanger sequencing analysis ofthe WFS1 gene (NM_006005.3) detected a homozygous frame-shift mutation p.(Ala671fs), c.2010dup, in the last exon. Thisvariant is predicted to result in insertion of a premature termin-ation codon after 41 amino acids, resulting in possible transla-tion of a truncated protein and loss of >10% of the normal WFS1protein. The patient’s parents were both heterozygous for themutation. The patient was treated with small doses of insulinwith remarkable glycaemic and visual improvement. He is cur-rently requiring five units of biphasic insulin daily for the past24 months with an HbA1c of 6% and no further neuro-degenerative progression.WS is a neuro-degenerative disorder due to mutations in theWFS1 gene leading to non-autoimmune insulin-deficient dia-betes mellitus. Due to the variable presentation there is no diag-nostic marker available for this syndrome and, as in our case,juvenile diabetes with optic atrophy remain the best availableclinical diagnostic criteria, even in the absence of other neuro-degenerative features.1,2 However, partial phenotypes in the ab-sence of diabetes and optic atrophy have been previouslydescribed.6 A possible genotype–phenotype relationship hasbeen suggested, which could have implications for early diagno-sis and management. Diabetic ketoacidosis and microvascularcomplications are seen less frequently in individuals with WSFigure 1. (A) Right eye retinal images showing optic atrophy without retinopathy. (B) Left eye retinal images showing optic atrophy without retinopathy.VC The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved.For permissions, please email: journals.permissions@oup.com803QJM: An International Journal of Medicine, 2019, 803–804doi: 10.1093/qjmed/hcz066Advance Access Publication Date: 19 March 2019Clinical picturethan Type 1 diabetes.5 Although it is common to have insulin defi-ciency, there have been a few reports similar to our case docu-menting an intact pancreatic reserve with normal c-peptide levelsand very low insulin requirements.3–5 Early identification withgood glycaemic control in individuals with WS has been found toslow the progression of neuro-degenerative symptoms.4 An asso-ciation was found between HbA1c levels and neuro-degenerativesyndromes and endocrine symptoms in WS.4 Our patient is youngand hence could progressively develop additional neurologicalfeatures of WS later in life. However, poor glycaemic control andchronic hyperglycaemia is associated with a quicker progressionof WS.4 Our patient and larger series of subjects with WS need tobe regularly monitored and followed up to promptly recogniseprogression, and confirm whether good glycaemic control resultsin a slower progression and better prognosis.This case highlights the need for an increased vigilance to-wards early identification, genetic testing and treatment of WSin a young individual with visual symptoms and diabetes irre-spective of the endogenous insulin reserve. A strict glycaemiccontrol with a lower HbA1c target at follow up warrants a betterquality of life with a slow progression of WS. Our case also illus-trates the possible partial phenotypic presentation of this dis-order confirming the variable spectrum of features at the timeof presentation.FundingThe Wellcome Trust, UK funded genetic testing.Photographs and text from: A.K. Annamalai, Department ofEndocrinology, Ashwin Speciality Hospital, Madurai, India;S. Ellard, Department of Molecular Genetics, University of ExeterMedical School, UK; M. Shanmugam, Department of Neuro-Ophthalmology, Aravind Eye Care Hospitals, Madurai, India;T.P. Jai Juganya, Department of Medicine, Meenakshi MissionHospital and Research Centre, Madurai, India; E. De Franco,Department of Molecular Genetics, University of Exeter MedicalSchool, UK. email: ak_md2000@yahoo.comConflict of interest: None declared.References1.Barrett TG, Bundey SE, Macleod AF. Neurodegeneration anddiabetes: UK nationwide study of Wolfram (DIDMOAD) syn-drome. Lancet 1995; 346:1458–63.2.Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J MedGenet 1997; 34:838–41.3.Fishman L, Ehrlich RM. Wolfram syndrome: report of four newcases and a review of literature. Diabetes Care 1986;9:405–8.4.Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexle K,Kordonouri O, et al. Diabetes and neurodegeneration inWolfram syndrome: a multicenter study of phenotype andgenotype. Diabetes Care 2011; 34:1503–10.5.Cano A, Molines L, Valero R, Simonin G, Paquis-Flucklinger V,Vialettes B, et al. Microvascular diabetes complications inWolfram syndrome (diabetes insipidus, diabetes mellitus,optic atrophy, and deafness [DIDMOAD]): an age- andduration-matched comparison with common type 1 diabetes.Diabetes Care 2007; 30:2327–30.6.Perrotta S, Di Iorgi N, Ragione FD, Scianguetta S, Borriello A, AllegriAE, et al. Early-onset central diabetes insipidus is associated withde novo arginine vasopressin-neurophysin II or Wolfram syn-drome 1 gene mutations. Eur J Endocrinol 2015; 172:461–72.804 | QJM: An International Journal of Medicine, 2019, Vol. 112, No. 10

Juvenile diabetes and visual impairment: Wolfram syndrome

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Juvenile diabetes and visual impairment: Wolfram syndrome

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