КЛИНИЧЕСКИЙ СЛУЧАЙ ПОЛНОЙ ФОРМЫ СИНДРОМА ВОЛЬФРАМА

Белякова Н.A.¹, Силкина М.И.², Ларева А.В.³, Коновалова О.И.⁴, Руденко Е.В.⁵, Лясникова М.Б.⁶

¹Доктор медицинских наук, Профессор, Тверской Государственный медицинский университет, ²Врач-эндокринолог Областной клинической больницы, Тверь, ³Кандидат медицинских наук, Доцент, Тверской Государственный медицинский университет, ⁴Врач-эндокринолог Областная клиническая больница, Тверь, ⁵Врач-эндокринолог Областная клиническая больница, Тверь, ⁶Кандидат медицинских наук, Доцент, Тверской Государственный медицинский университет

КЛИНИЧЕСКИЙ СЛУЧАЙ ПОЛНОЙ ФОРМЫ СИНДРОМА ВОЛЬФРАМА

Аннотация

В статье представлен клинический случай редкой генетической патологии - полной формы синдрома Вольфрама. Синдром Вольфрама, акроним Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness) - тяжелое дегенеративное наследственное заболевание с аутосомно-рецессивным типом наследования и прогрессирующим течением, которое включает в себя 4 составляющих: сахарный диабет, несахарный диабет, атрофию зрительных нервов и сенсоневральную тугоухость. Развитие сахарного диабета в детском возрасте без выраженной микроангиопатии в сочетании с субатрофией диска зрительного нерва обоих глаз,возникновение билатеральной нейросенсорной тугоухости, развившейся вслед за центральной формой несахарного диабета позволили предположить у конкретного пациента полную форму синдрома Вольфрама.

Ключевые слова: синдром Вольфрама, сахарный диабет, несахарный диабет, атрофия зрительных нервов, тугоухость.

Belyakova N.A.¹, Silkina M.I.²,  Lareva A.V.³, Konovalova O.V.⁴, Rudenko E.V.⁵ Lyasnikova M.B.⁶

¹MD, Professor, Tver State Medical University, ²MD, Tver State Clinical Hospital, department of endocrinoljgy, ³MD, Associate professor,Tver State Medical University, ⁴MD, Tver State Clinical Hospital, department of endocrinology, ⁵MD, Tver State Clinical Hospital, department of endocrinoljgy, ⁶MD, Associate professor,Tver State Medical University

WOLFRAM SYNDROM IN CLINICAL PRACTICE

Abstract

This article presents a clinical case of rare genetical disease –Wolfram syndrome, DIDMOAD—Syndrome (stands for Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness) , a hard degenerative hereditary disease  with an autosomal recessive mode of inheritance and a progressive course which includes the following 4 components: diabetes mellitus (DM), diabetes insipidus (DI), optic nerve atrophy and sensorineural hypocusis. Development of diabetes in childhood without the expressed microangiopathy and nearly simultaneous decline of subatrophy optic nerves of both eyes, the emergence of bilateral sensorineural hearing loss, followed by the addition of central diabetes insipidus allowed to assume the presence of DIDMOAD-syndrome, complete form - Wolfram syndrome in actual patient.

Keywords: DIDMOAD –syndrome,Wolfram syndrome, diabetes mellitus, diabetes insipidus, optic nerves atrophy, hearing loss.

Introduction

DIDMOAD—Syndrome (Wolfram syndrome, stands for Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness)—Is a severe degenerative hereditary disease with an autosomal recessive mode of inheritance and a progressive course which includes the following 4 components: diabetes mellitus (DM), diabetes insipidus (DI), optic nerve atrophy and sensorineural hypocusis. The disease was first described in 1938 by Dr. Wolfram D. Jr [1]. According to published data the spread of DIDMOAD—Syndrome in Great Britain and USA was of about 1 in 770 000 and 1 in 100 000 of the population respectively, whereas in Europe it was 1:500 000. Moreover, it reached a ratio of 1:730 among diabetes patients. In Russia, however, the frequency of this disease is unknown [5]. Earlier DIDMOAD—Syndrome was designated as a mitochondrial disease. In 1998 Strom T.M charted a nuclear gene WFS1, which was located on the 4p.16.1 chromosome and consisted of 8 axons. To date, over 170 mutations have been found. The product of the WFS1 gene expression is a  transmembrane glycoprotein called Woframin. It is embedded in the membrane of the endoplasmic reticulum, is connected to a group of transport proteins, and plays a role in regulating intracellular calcium metabolism in pancreatic cells and the nervous system [7]. The clinical portrait of this disease can be quite variable, and a concept of "incomplete form” of the DIDMOAD—Syndrome exists. It is associated with diabetes mellitus and optical atrophy, and there is a complete form, including all four components of the syndrome. It is considered that a necessary and sufficient criteria for the clinical diagnosis of DIDMOAD—Syndrome is a combination of nonautoimmune insulin-dependent diabetes mellitus and optic atrophy, which developed up to 16 years of age [3,4]. Another frequent component of this syndrome is the atony (loss) of the urinary system. The latter develops at a later date after infection (after 20-30 years) and aggravates the prognosis for the patient's life. The rarer manifestations of the syndrome are neurological manifestations (truncal ataxia, monoclonal cramps, severe apnea, dementia) psychiatric disorders, changes in motility of the gastrointestinal tract.

The prognosis of this disease is unfavorable because of blindness, deafness, severe renal and neurological disorders. Average life expectancy is 30-40 years. The causes of death are respiratory failure as a result of damage to the respiratory center, aspiration pneumonia, neurological complications, infection, complications of the urinary system, suicide as a result of severe mental disorders [4]. Wolfram syndrome is included in the etiologic classification of diabetes in a group of other genetic syndromes, sometimes combined with diabetes [6]

Clinical observation

Patient X, is 24 years old, unemployed. On the 24.10.2014 she was admitted to the endocrinology department GBUZ "Regional Hospital" (EDO) Tver with complaints of dry mouth, thirst (up to 10 litres of liquid per day) frequent urination; unstable glycemic indices (3.0 - 20.0 mmol / L); pain, numbness, decreased sensation in extremities; blurred vision; hearing loss in both ears (hearing aids). Permanent tinnitus; general weakness. Hypoglycemia 1-2 times a week.

Case history: The patient suffered from (DI - Type 1) for 18 years. The illness started with a ketoacidotic comma, glucose levels in blood at beginning of the illness where 25mol/L. From the beginning of illness the patient was on insulin therapy. From the age of 10 she had vision deficiency, from the age of 12 a progressive deterioration of hearing in both ears. She was treated at the inpatient and outpatient pediatric endocrinologist, where a correction was performed in 2008. The patient was first admitted to the endocrinology department of OKB, at the same time the share of urinalysis was of 1,004-1,010 g/l and microalbuminuria (60 mg in daily urine), which were considered as diabetic nephropathy in the stage of microalbuminuria. Re-admission in 2011. This diagnosis was not confirmed, and the low density of urine was left unattended. In 2008, diabetic peripheral sensorimotor polyneuropathy was diagnosed, and in 2011 - cardiac autonomic neuropathy.

Changes in the fundus ophthalmologist regarded as neyrooptikopatiya. This deterioration lasted through the course of 4-6 months. When narosla thirst, urination quickened, appetite worsened. The IT scheme hospitalization aspartame 32 units / day, glargine 13 units / day.

Patient's life history: Overcome diseases: SARS. Obstetric and gynecological history: mensis 16 years, regular, was not pregnant. Inheritance: father had diabetes type 2. According to the sisters, the parents are not closely related. Disability from childhood and from the age of 18 - group II disability.

Objectively: The condition is satisfactory. BMI = 21.8 kg / m2. Skin and mucous had normal colouring, dryly. The thyroid gland (TG) didn’t increase in size. RR 17 per minute. Lungs without pathology. Pulse 90 / min., Rhythmic, blood pressure 120/85 mm Hg. Art. The tones are clear, rhythmic, noise no heart. Abdomen soft, painless. The liver and spleen are not enlarged. Effleurage on the lumbar region painless on both sides. Ripple on the arteries of the legs, plantaris maintained.

Neurologist: diabetic distal polyneuropathy sensorimotor form.

Optometrist: subatrophy optic nerves OU.

Blood analysis: giperholesterinemiya, HbA1c - 13.6%, fluctuations in glycemia 8.00-12.00-16.00-20.00 at admission12,2-12,6-13,4-14,5 mmoly / l at discharge at DM (aspart 20 U / CST., 13 glargine units / CST) -3,6-6,8-6,3-6,1 mmoly / l. Uroscopy at admission: density 1.002 to 1.004 g / l with a prevalence of night diuresis over morning diuresis. Osmolarity - 166 mosmol / l plasma Osmolarity - 297 mosmol / l. During treatment desmopressin (0.2 mg / CST) urine density 1.009 to 1.024 g / l, there was a decrease in total diuresis  (with 3950 to 2500 ml) night diuresis did not prevail over daily. Ultrasonography of kidneys, bladder and genitaliy: no pathologies. Ultrasonography of abdominal cavity: dyskinesia of the bladder. Electroneuromyography of lower extremity: motor axonopathy of right peroneal nerve. Ewing’s test: CHSS test and sample with positive isometric exercise.

Discussion

Development of diabetes in childhood without the expressed microangiopathy and nearly simultaneous decline of subatrophy optic nerves of both eyes, the emergence of bilateral sensorineural hearing loss, followed by the addition of central diabetes insipidus allowed to assume the presence of the patient DIDMOAD-syndrome, complete form - Wolfram syndrome.

 

Список литературы / References

1. Wolfram D.J. Diabetes mellitus and simple optic atrophy among siblings:report of four cases/ Wolfram D.J.,Wagener H.P. // J. Mayo Clinic Proceedings. – 1938. – Vol. 13.- Р. 715-718.
2. Кураева Т.Л. Случай нетипичного течения DIDMOAD -синдрома/ Кураева Т.Л., Зильберман Л.И. // Сахарный диабет. – 2000. – №1- С. 43-45.
3. Barrett T.G. Neurodegeneration and diabetes:U.K. nationwide study of Wolfram (DIDMOAD) syndrome / Barrett T.G., Bundey S.E., Macleod A.F.// Lancet. – 1995/ – Vol. 346. - P. 1453-1458.
4. Barrett T.G. Wolfram (DIDMOAD ) syndrome/ Barrett T.G., Bundey S.E. // J. Medical Genetics. – 1997. – Vol. 34. - P. 838-841.
5. Табеева К.И. DIDMOAD-синдром. Клинический случай / Табеева К.И., Белая Ж.Е., Арутюнян Д.Б. и др. // Сахарный диабет. – 2004. – №2.- С. 60-64.
6. Дедов И.И. Сахарный диабет :федеральная целевая программа/Дедов И.И., Шестакова М.В., Максимова // Москва. – 2002.-С. 6-8.
7. Гришина Д.П. Клинические варианты и молекулярные основы DIDMOAD-синдрома; автореферат дисс. … кандидата медицинских наук  по специальности эндокринология -14.01.02., защита 23.04.13 / Гришина  Дарья Павловна- М., 2013.- 28 с.

Список литературы на английском языке / References in English

1. Wolfram D.J. Diabetes mellitus and simple optic atrophy among siblings:report of four cases/ Wolfram D.J.,Wagener H.P. // J. Mayo Clinic Proceedings. – 1938. – Vol. 13.- Р. 715-718.
2. Kuraeva Т.L. Sluchaj netipichnogo techeniya DIDMOAD –sindroma [The case of nontypical form of DIDMOAD -syndrome] Kuraeva Т.L., Zilberman L.I. // Diabetes mellitus – 2000. – Vol. 1.- P. 43-45.[in Russian]
3. Barrett T.G. Neurodegeneration and diabetes:U.K. nationwide study of Wolfram (DIDMOAD) syndrome / Barrett T.G., Bundey S.E., Macleod A.F.// Lancet. – 1995/ – Vol. 346. - P. 1453-1458.
4. Barrett T.G. Wolfram (DIDMOAD ) syndrome/ Barrett T.G., Bundey S.E. // J. Medical Genetics. – 1997. – Vol. 34. - P. 838-841.
5. Tabeeva К.I. DIDMOAD –sindrom. Klinicheskij slutchaj[DIDMOAD-syndrome. Clinical observation] Tabeeva К.I., Belaya J.Е., Аrutyunyan D.B. and others // Diabetes mellitus. – 2004. – Vol. 2.- P. 60-64. [in Russian]
6. Dedov I.I. Sacharnij diabet :federalnaja tselevaya programma [Diabetes mellitus : federal target program ]Dedov I.I., Shestakova М.V., Маksimova М.А. // Мо – 2002.- P. 6-8. [in Russian]
7. Grishina D.P. Klinitcheskije varianty i molecularnije osnovy DIDMOAD –sindroma [Clinical variants and molecular basis of DIDMOAD-syndrome] the abstract of diss… of PhD in medicine - endocrinology -14.01.02. , defence of the thesis 23.04.13/ Grishina Dаrya Pavlovna – M., 2013.- 28 р. [in Russian]