Given the limited lifespan and with the recent progress in experimental treatments for WS, timely diagnosis and multidisciplinary treatment for DI/DM, hydronephrosis, and visual/psychiatric status-maintaining quality of life-are of crucial importance

Delides, Alexandros

Dinopoulos, Argyrios

Kleanthous, Kleanthis

Manolakos, Emmanouil

Mastorakos, Georgios

Nikolopoulos, Thomas

Papadimitriou, Anastasios

Papadimitriou, Dimitrios T

Tiulpakov, Anatoly

Urano, Fumihiko

Voros, Gerasimos

Zoupanos, George

English

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker Open Access Publications 12-1-2019 A novel detrimental homozygous mutation in the WFS1 gene in two sisters from nonconsanguineous parents with untreated diabetes insipidus Dimitrios T Papadimitriou Kleanthis Kleanthous Emmanouil Manolakos Anatoly Tiulpakov Thomas Nikolopoulos See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Dimitrios T Papadimitriou, Kleanthis Kleanthous, Emmanouil Manolakos, Anatoly Tiulpakov, Thomas Nikolopoulos, Alexandros Delides, Gerasimos Voros, Argyrios Dinopoulos, George Zoupanos, Anastasios Papadimitriou, Georgios Mastorakos, and Fumihiko Urano Clin Case Rep. 2019;7:2355–2357.    | 2355wileyonlinelibrary.com/journal/ccr3Received: 20 June 2019 | Revised: 1 September 2019 | Accepted: 15 September 2019DOI: 10.1002/ccr3.2494  C A S E  R E P O R TA novel detrimental homozygous mutation in the WFS1 gene in two sisters from nonconsanguineous parents with untreated diabetes insipidusDimitrios T. Papadimitriou1  |   Kleanthis Kleanthous1,2 |   Emmanouil Manolakos3 |   Anatoly Tiulpakov4  |   Thomas Nikolopoulos5 |   Alexandros Delides5,6 |   Gerasimos Voros7 |   Argyrios Dinopoulos8 |   George Zoupanos9 |   Anastasios Papadimitriou2 |   Georgios Mastorakos10 |   Fumihiko Urano111Department of Pediatric Endocrinology & Diabetes, Athens Medical Center, Athens, Greece2Department of Pediatric Endocrinology and Diabetes, Attikon University Hospital, Athens, Greece3Access to Genome, Athens‐Thessaloniki, Athens, Greece4Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russia5Department of Pediatric Otorhinolaryngology, Attikon University Hospital, Athens, Greece6Department of Pediatric Otorhinolaryngology, Athens Medical Center, Athens, Greece7Department of Pediatric Ophthalmology, Athens Medical Center, Athens, Greece8Department of Pediatric Neurology, Attikon University Hospital, Athens, Greece9Department of Pediatric Urology, Athens Medical Center, Athens, Greece10Endocrine Unit, Aretaieion Hospital, Medical School, University of Athens, Athens, Greece11Washington University School of Medicine, St. Louis, MOThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.© 2019 The Authors. Clinical Case Reports published by John Wiley & Sons LtdAll contributors have read and approved the submission to Clinical Case Reports. CorrespondenceDimitrios T. Papadimitriou, Pediatric Endocrinologist at Pediatric Endocrine Clinics, Athens Medical Center, 58, av Kifisias, Marousi, 15125, Athens, Greece.Email: dtpapadimitriou@pedoendo.grAbstractGiven the limited lifespan and with the recent progress in experimental treatments for WS, timely diagnosis and multidisciplinary treatment for DI/DM, hydronephrosis, and visual/psychiatric status—maintaining quality of life—are of crucial importance.K E Y W O R D Sdiabetes insipidus, diabetes mellitus, novel mutation, WFS1 gene, Wolfram syndrome1 |  INTRODUCTIONWS is a rare neurodegenerative disorder. Two sisters, a 19‐yr blind since 13 (died at 21, due to brain stem atrophy) and a 7‐yr‐old, from nonconsanguineous parents originated from Trapezund, had poorly treated DM since 3  years and untreated DI. Genetic testing revealed a novel homozygous c.2069G > A mutation in WFS1.Wolfram syndrome (WS), also called DIDMOAD (diabe-tes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal recessive neurodegenerative genetic dis-order.1 The prevalence of WS has been estimated between 1 2356 |   PAPADIMITRIOU eT Al.in 770 000 in the United Kingdom and 1 in 100 000 in North America.2 Two causative genes have been identified: WFS1 and CISD2 (WFS2).3 Classical WS is the result of autosomal recessive mutations affecting the WFS1 gene, which is im-plicated in endoplasmic reticulum (ER) function,2 although WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mito-chondria to ensure effective Ca++ transfer and lipids transfer, and apoptosis within stabilized and functionalized micro-domains, termed “mitochondria‐associated ER membranes” (MAMs).4 The prognosis of the syndrome is currently poor. The median age at death is 30 years (range, 25‐49 years), usu-ally from respiratory failure as a result of brain stem atrophy.52 |  CASE REPORTTwo sisters from nonconsanguineous parents presented to our pediatric endocrinology clinic due to severe polyuria‐polydipsia. They both had poorly treated diabetes mellitus since the age of 3 years and untreated diabetes insipidus (DI).A 19‐yr‐old girl totally blind since the age of 13 had pri-mary amenorrhea and bladder incontinence. Cranial nerve examination was normal except oculomotion with roving eye movements. Muscle strength was normal with deep tendon re-flexes 2/4. There were no signs of ataxia nor extrapyramidal signs. Mental status was appropriate for age but suffered from insomnia and apparent depression. Her HbA1c was 8.2%, bio-chemical values being normal. Gonadotropins in GnRH test-ing as well as estradiol levels and thyroid function tests were normal. Abdominal ultrasonography revealed normal uterus and ovaries but inappropriate for pubertal stage along with mild (Grade II) hydronephrosis. Comprehensive ophthalmic examination showed “No Light Perception” in both eyes. The pupillary light reflex was completely absent, and both pupils were mid‐dilated. The anterior segment was normal, and the intraocular pressure was 12  mm  Hg in both eyes (Goldman application tonometer). Dilated fundus examination revealed complete optic nerve atrophy. Otologic and audiologic evalua-tion was performed. They included otomicroscopy, tympanom-etry, transient otoacoustic emissions (TOAE), and automated auditory brainstem response (aABR). Her tympanogram was type A, TOAEs “pass” bilateral, as well as aABRs.The patient had severe salt‐wasting diuresis when treatment for diabetes insipidus was started,6 and fludrocortisone was necessary to be added, along with frequent bladder catheteriza-tions for her neurogenic bladder. Six months after appropriate treatment for diabetes mellitus and insipidus, she had menstrual onset. Unfortunately, 2 years after presentation, she died unex-pectedly in her sleep. Autopsy showed severe brain stem atrophy.Her 7‐year‐old sister had normal neurological examina-tion. She was prepubertal. Her HbA1c was 10.1%, the rest biochemical values being normal. Abdominal ultrasonog-raphy revealed mild to severe hydronephrosis (Grade III). Ophthalmic examination showed a visual acuity 6/15 (0.40 LogMAR) in her right eye and 6/19 (0.50 LogMAR) in her left eye with + 1.00 diopters sphere corrective lens in both eyes. The pupillary light reflex was reduced symmetrically in both eyes, but there was not relative afferent pupillary reflex. The anterior segment was normal, and the intraocular pres-sure was 12 mm Hg in the right and 11 mm Hg in the left eye (Goldman application tonometer). Dilated fundus exam-ination revealed moderate optic nerve atrophy. Otologic and audiologic tests revealed a type C tympanogram, right side “pass” and left “fail” of TOAEs, whereas aABRs were “pass” bilateral.She also presented severe salt‐wasting diuresis when treatment for diabetes insipidus was started, and fludrocorti-sone was necessary to be added for 1 month only, along with frequent urinary catheterizations for her neurogenic bladder. On the contrary, we were not able to discontinue fludrocorti-sone in her sister.They both normalized their HbA1c (<7%) under intensi-fied multiple insulin daily injections with the 24‐hr analogue degludec (Tresiba®) and the newest faster formulation of as-part (Fiasp®). Glucose variability was also optimized using the FlashStyle Libre System, minimizing hypoglycemia and confining postprandial hyperglycemic excursions. Adjunctive treatment with idebenone 600 mg × 3 p.o. was given to the younger sister aiming to visual stabilization7—proven suc-cessful for 2.5  years now—while both sisters received ad-ditional pioglitazone therapy 45  mg/d  ×  1 p.o. aiming to mitigate β‐cell death.8Genetic testing was performed to confirm the clinical di-agnosis of WS. DNA was tested with PCR amplification and sequencing analysis (Sanger sequencing) of the entire coding region and all exon‐intron splice junctions of the WFS1 gene (chromosome 4): reference sequence: NM_006005.3, with the A of the ATG start codon at position 1. A homozygous c.2069G > A mutation in WFS1 gene was found in both sis-ters, whereas the parents were carriers. This point mutation is a missense mutation in amino acid position 690 (p.C690Y) replacing cysteine with tyrosine in exon 8. To our knowledge, this is a novel variant in WFS1 gene, not previously reported in patients with WS. According to the Prediction Program PolyPhen‐2, the mutation is predicted to be damaging with a score of 1000. A different heterozygous—not related to dis-ease manifestation—missense mutation at the same codon has been reported (690Cys‐ > Arg).3 |  DISCUSSIONWe have previously reported a novel homozygous WFS1 gene mutation due to maternal uniparental disomy of chromosome    | 2357PAPADIMITRIOU eT Al.4.9 Now we present a novel detrimental homozygous WFS1 gene mutation, adding to the genotype‐phenotype correlation reported so far.10 The two sisters affected were born from nonconsanguineous parents of Greek descent born in dis-tant regions of Russia. However, detailed genealogical his-tory proved that both originated 5‐6 generations before from Trapezund, an ancient Greek colony located in the Greek—until 1922—Pontus, presently in the state of Turkey, indicat-ing a founder mutation effect.Even though a correct diagnosis of WS had been made several years ago, none of the girls had ever received treat-ment for DI. Their diabetes was poorly controlled, and their quality of life was poor. No care had been ever provided for their hydronephrosis nor their psychiatric status. Given the known effect of glycemic control on the neurodegenerative process 10 and the severe consequences of untreated DI such as failure to thrive and hydronephrosis, proper treatment of endocrine dysfunctions is crucial not just to avoid con-sequences but also to improve quality of survival.11 In our center, proper multidisciplinary care along with adjunctive treatment with idebenone 7 and pioglitazone 8,12 has resulted in stabilization of visual status, resume in growth and pu-bertal development, normalization of BMI and improved quality of life in our previously reported patient 9 as well as the younger of the two sisters currently reported. The fact that the life span in WS is limited but progress in ex-perimental treatments—that hopefully will be soon widely available—has been made 13 underlines the importance of timely diagnosis and effective multidisciplinary approach in centers with experience in complex endocrine pathologies such as WS.CONFLICT OF INTERESTAll authors declare no conflict of interest.AUTHOR CONTRIBUTIONSPDT: was the treating physician in Athens Medical Center and wrote the paper. KK: was the treating physician in Attikon University Hospital. ME: performed the genetic analysis in all family members in Greece—Access to Genome. TA: put the initial genetic diagnosis in one of the two sisters in Russia. NT. and DA: performed the oto-logic and audiologic evaluations. VG: performed the oph-thalmic examination and follow‐up. DA: performed the neurological evaluation. ZG: performed the urologic evalu-ations and follow‐up. PA: supervised hospitalization in Attikon University Hospital. MG: followed the older sister in the transition to the adult endocrine unit of Aretaieion University Hospital. UF: coordinated and supervised explo-rations and treatment.ORCIDDimitrios T. Papadimitriou   https://orcid.org/0000-0002-6083-3560 Anatoly Tiulpakov   https://orcid.org/0000-0001-8500-4841 REFERENCES 1. Rigoli L, Bramanti P, Di Bella C, De Luca F. Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative dis-ease. Pediatr Res. 2018;83(5):921‐929. 2. Toppings NB, McMillan JM, Au P, Suchowersky O, Donovan LE. Wolfram syndrome: a case report and review of clinical manifesta-tions, genetics pathophysiology, and potential therapies. Case Rep Endocrinol. 2018;2018:9412676. 3. Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. 2012;24(4):512‐517. 4. Delprat B, Maurice T, Delettre C. Wolfram syndrome: MAMs' connection? Cell Death Dis. 2018;9(3):364. 5. Urano F. Wolfram syndrome: diagnosis, management, and treat-ment. Curr Diab Rep. 2016;16(1):6. 6. Papadimitriou DT, Spiteri A, Attilakos A, Papadimitriou A. Cerebral salt wasting complicated by central diabetes insipidus and growth hormone deficiency. Indian J Pediatr. 2018;85(7):580‐581. 7. Bababeygy SR, Wang MY, Khaderi KR, Sadun AA. Visual im-provement with the use of idebenone in the treatment of Wolfram syndrome. J Neuroophthalmol. 2012;32(4):386‐389. 8. Hara T, Mahadevan J, Kanekura K, Hara M, Lu S, Urano F. Calcium efflux from the endoplasmic reticulum leads to beta‐cell death. Endocrinology. 2014;155(3):758‐768. 9. Papadimitriou DT, Manolakos E, Bothou C, et al. Maternal unipa-rental disomy of chromosome 4 and homozygous novel mutation in the WFS1 gene in a paediatric patient with Wolfram syndrome. Diabetes Metab. 2015;41(5):433‐435. 10. Rohayem J, Ehlers C, Wiedemann B, et al. Diabetes and neurode-generation in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011;34(7):1503‐1510. 11. Gan HW, Bulwer C, Spoudeas H. Pituitary and hypothalamic tumor syndromes in childhood. In Feingold KR, Anawalt B, Boyce A et al., eds. Endotext. South Dartmouth, MA. 2000. Available from https ://www.ncbi.nlm.nih.gov/books/ NBK27 9153/  12. Akiyama M, Hatanaka M, Ohta Y, et al. Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apopto-sis in Wfs1 knockout mice. Diabetologia. 2009;52(4):653‐663. 13. Lu S, Kanekura K, Hara T, et al. A calcium‐dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci USA. 2014;111(49):E5292‐5301.How to cite this article: Papadimitriou DT, Kleanthous K, Manolakos E, et al. A novel detrimental homozygous mutation in the WFS1 gene in two sisters from nonconsanguineous parents with untreated diabetes insipidus. Clin Case Rep. 2019;7:2355–2357. https ://doi.org/10.1002/ccr3.2494

A novel detrimental homozygous mutation in the WFS1 gene in two sisters from nonconsanguineous parents with untreated diabetes insipidus

Dimitrios T. Papadimitriou

Kleanthis Kleanthous

Emmanouil Manolakos

Anatoly Tiulpakov

Thomas Nikolopoulos

Alexandros Delides

Gerasimos Voros

Argyrios Dinopoulos

George Zoupanos

Anastasios Papadimitriou

Georgios Mastorakos

Fumihiko Urano

Crossref

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=9654&amp;context=open_access_pubs

A novel detrimental homozygous mutation in the WFS1 gene in two sisters from nonconsanguineous parents with untreated diabetes insipidus

Abstract

Similar works

Full text

Available Versions

Digital Commons@Becker

Crossref