Wolfram syndrome is a complex of multiple organ disorders caused by genetic causes, including diabetes mellitus and diabetes insipidus, sensorineural hearing loss, optic nerve atrophy. Other components of the syndrome may be urinary tract dilation, ataxia, myoclonia, apnea attacks, etc. The diagnosis is established by sequencing the WFS1 gene. Additional examination includes blood biochemistry (sugar, insulin), pituitary MRI, audiometry, ultrasound, ophthalmoscopy. Symptomatic treatment: insulin therapy, antidiuretic, nootropic therapy, hearing replacement. It is possible to perform a hearing-improving operation (CI).
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As an independent disease, the syndrome was studied and described by the American doctor D. Wolfram in 1938. The acronym abbreviation DIDMOAD-syndrome is formed by the first letters of the classical tetrad of signs: diabetes Insipidus, diabetes mellitus, optic atrophy and deafness. The prevalence in the European population is 1:500 thousand, in the USA – 1:100 thousand, and among diabetics ‒ 1:730. Wolfram syndrome has a progressive course and is associated with the death of patients at a young age.
The genetic mechanisms of Wolfram syndrome were determined in 1998, when the WFS1 gene encoding the wolframin protein of the same name was mapped. The gene is located on the 4th chromosome at locus 16.1 (4p16.1), has 8 exons. To date, over 170 of its mutations leading to DIDMOAD syndrome have been studied. Point missense and nonsense mutations, deletions in the 8th exon are most often detected. The interest of other genes in the development of the disease is under study.
In most cases, Wolfram syndrome is transmitted by autosomal recessive principle (mutant alleles must be obtained from both parents), however, some mutations can be transmitted autosomally dominant (one defective allele inherited from any parent is sufficient for the development of pathology). According to observations, the probability of having children with Wolfram syndrome is higher in families where the parents are in a closely related relationship.
Wolframine is a hydrophobic glycoprotein that is a component of the membrane of the endoplasmic reticulum. It is involved in the regulation of endoplasmic reticulum (ER) stress and intracellular calcium transport in pancreatic and nerve cells. Mutations in the WFS1 gene cause the structural inferiority of wolframine and its inability to support physiological processes at the cellular level.
Insulin-producing beta cells of the pancreas and neurons of the nervous tissue are hypersensitive to ER stress, so their dysfunction and apoptosis in Wolfram syndrome develop first of all. Signs of insulin-dependent non-autoimmune diabetes and atrophy of the heart are noted already in the first decade of life.
Depending on the developing clinical picture in genetics , there are complete and incomplete forms of Wolfram syndrome:
- the full form (classical) includes four components (DM + ND+ sensorineural hearing loss + optic atrophy), accounts for slightly less than half of all clinical observations;
- the incomplete form may include any 2 components of the syndrome, of which diabetes mellitus is mandatory, or 3 components (necessarily DM and optic atrophy). Both options account for a little more than 50% in total.
The symptoms depend on the form of Wolfram syndrome (complete, incomplete) and its variant. The timing of the occurrence of various violations also differs. Diabetes mellitus manifests first of all (usually at the age of 4-6 years). Its course is characterized by polyuria, thirst, unstable glycemia, weakness, ketoacidosis is often noted in the debut. Within a year after the diagnosis of DM, also in the first decade of life, atrophy of the optic nerve disc develops. At the same time, visual acuity decreases rapidly and progressively (up to light perception), myopia, amblyopia, cataract are often detected.
In the second decade of life, diabetes insipidus and bilateral sensorineural hearing loss develop. Despite satisfactory compensation of DM, patients note increased thirst, an increase in the volume of daily urine of 2 liters, increased urination up to 20 or more times a day. In the early stages, hearing loss is detected only with the help of audiometry, but after 5 years or more it becomes clinically significant, and after 15 years it can reach the degree of deafness.
The late manifestations of Wolfram syndrome that occur during the third decade include urinary tract lesions (UT), central nervous system, mental disorders. UT dysfunction most often manifests itself as bladder atony, pyelectasia, ureterohydronephrosis, chronic pyelonephritis.
In rare cases, myoclonic seizures, ataxia, and apnea attacks may occur. Some patients with DIDMOAD syndrome have mental retardaion, oligophrenia, and suffer from depressive disorders. Other concomitant conditions include primary hypogonadism, osteoporosis, anemia, growth retardation, hyperkeratosis.
The early onset and progressive course of Wolfram syndrome lead to complications at a young age, 10-15 years after the manifestation of pathology. In case of violation of self-control of the level of glycemia, ketoacidotic coma may develop. Prolonged unsatisfactory compensation of DM is accompanied by the occurrence of diabetic polyneuropathy, microangiopathy, nephropathy.
A critical decrease in hearing and vision, up to deafness, makes patients profoundly disabled and in need of outside care. Chronic renal failure develops against the background of the UT lesion. Life expectancy in patients with Wolfram syndrome is reduced.
For the first time, pediatric endocrinologists face patients suffering from Wolfram syndrome. Further examination and management of patients is carried out by a group of specialists: an ophthalmologist, an otolaryngologist, a neurologist, a geneticist. The criteria for making a clinical diagnosis of DIDMOAD syndrome are the presence of non-autoimmune INZSD and optic atrophy developed before the age of 16. To confirm the diagnostic hypothesis , the following methods are used:
- Laboratory methods. The necessary laboratory minimum includes the study of carbohydrate metabolism (glucose, HbA1c), hormonal studies (insulin, C-peptide, ADH), the determination of markers of autoimmune diabetes (AT to insulin, AT to GAD, AT to beta cells of the pancreas). To assess kidney function, it is necessary to measure diuresis, conduct blood test, Zimnitsky test, microalbuminuria test, determination of creatinine and urea in the blood.
- Neurological complex. The following findings may occur on the MRI picture of the brain: structural and functional disorders of the pituitary gland, atrophy of the bridge and cerebellum, moderate hydrocephalus. Electroneuromyography detects signs of polyneuropathy of the extremities.
- Ophthalmological diagnostics. Refractive disorders (myopia), a drop in visual acuity are detected. Ophthalmoscopy reveals paleness of the central nervous system, the presence of myelin fibers, narrowing of the retinal arteries.
- Surdological examination. In the early period of Wolfram syndrome, audiometry detects hearing loss only in the high-frequency range. However, as the disease progresses, hearing loss can reach 3-4 degrees.
- Sonography. To identify concomitant disorders on the part of internal organs, ultrasound of the urinary system (bladder, kidneys), pancreas, genitals, thyroid gland is performed. According to the indications, an echocardiogram is performed.
- Genodiagnostics. Direct sequencing of the WFS1 gene, as a rule, detects heterozygous mutations in the 8th or other coding exons. For families planning subsequent pregnancies, a geneticist’s consultation is necessary.
At the moment, there are no radical methods of treatment. The gene therapy of DIDMOAD syndrome is at the stage of preclinical trials. Therefore, patients are offered symptomatic therapy designed to support the most affected organs and functions. In order to achieve compensation of carbohydrate metabolism, insulin therapy is prescribed. Antidiuretic therapy with desmopressin is indicated for patients with diabetes insipidus.
In case of UTL infections, antibiotic therapy is performed. In case of difficulty in self-urination, periodic catheterization of the bladder is performed, a cystostomy is installed. Patients with neuropsychiatric disorders are prescribed nootropics, antidepressants. Correction of hearing loss is carried out by selecting a hearing aid, cochlear implantation is possible.
Prognosis and prevention
The prognosis for the course of the disease is unfavorable. All the violations that have arisen are steadily progressing, leading to the development of complications, loss of self-service opportunities. Patients with Wolfram syndrome, as a rule, rarely live longer than 30-40 years. The main causes of death: aspiration pneumonia, respiratory failure, CRF, suicide.
Prevention involves avoiding closely related marriages, genetic counseling for couples with relatives or children with DIDMOAD syndrome. To improve the quality and prolong life, early diagnosis and proper management of the disease is essential.