Cockayne syndrome is a genetic disease of a neurodegenerative nature, the causes of which lie in the violation of the processes of DNA repair (recovery after damage). The symptoms of this pathology are severe mental retardation, lack of physical development, visual and hearing impairments, photosensitization of the skin to sunlight. Diagnosis is made on the basis of the data of the patient’s current status, examination of the patient’s skin and eyes, molecular genetic studies. There is no specific treatment for the disease, supportive and symptomatic therapy is used, the skin and eyes of the patient are protected from exposure to ultraviolet radiation.
Cockayne syndrome (Neill-Dingwall disease) is a severe hereditary pathology characterized by a violation of the development of the central nervous system, visual organs, and skin. For the first time this condition was described in 1936 by the English physician E. Cockayne, then he observed another patient in 1946. In 1950, M. Dingwall and K. Neill described a familial (two brothers) form of the disease, but these researchers pointed to the priority of Kokkane in the study of this condition. To date, it is known that Cockayne syndrome is a rare genetic disease belonging to a group of pathologies caused by a violation of DNA repair processes. This pathology affects both boys and girls with equal probability, the average life expectancy of patients is 10-20 years. There are several varieties of Cockayne syndrome, which are caused by mutations of various genes and differ in the clinical course of the disease. The occurrence of this pathology due to its rarity is currently unknown.
Causes and classification
Cockayne syndrome is one of many hereditary diseases, the cause of which lies in the violation of DNA repair processes. In a healthy organism, various defects of genetic material that occur during replication or under the influence of damaging factors (free radicals, ultraviolet and ionizing radiation) are eliminated by numerous protective systems. In this pathology, due to genetic mutations of certain genes, these processes are hindered, resulting in various malformations. However, many aspects of the pathogenesis of Cockayne syndrome currently remain poorly understood and unclear. For example, there is no generally accepted explanation why the nervous system suffers the most from this disease. It is also unclear why violations of DNA repair processes in this case are not accompanied by a high risk of oncological diseases.
Several genetic varieties of Cockayne syndrome have been identified – according to various data, the number of types of this pathology ranges from 3 to 5. Such uncertainty is due to the fact that types 4 and 5 are associated with pigmented xeroderma, a dermatological disease that is also based on DNA molecule repair disorders. And if some geneticists refer them to the XP-CS type (xeroderma-Cockayne syndrome), then other specialists consider these pathology variants to be a complicated variant of the pigmented xeroderma. Individual varieties of the disease differ from each other by etiology (genes in which mutations have occurred) and features of the clinical course, but they all have an autosomal recessive nature of inheritance:
- Type 1 – historically described as the first and most famous (classic) variant of the disease caused by a mutation of the ERCC8 gene. It is located on chromosome 5 and encodes a sequence of the protein of the same name that binds to a number of enzymes that take part in DNA repair (CSB, p44 proteins).
- Type 2 is the most common form of the disease, which is more severe than the classic version. The cause of this type of pathology is mutations of the ERCC6 gene located on chromosome 10 and encoding the CSB protein (the protein of the Cockayne syndrome B). This protein plays a central role in DNA repair processes, in particular, disorders in the first type of disease are indirectly associated with it.
- Type 3 is a rare and insufficiently studied variant of this pathology. The gene whose mutations lead to its development has not been determined to date.
- Type 4 (according to another classification – pigmented xeroderma D) – is caused by mutations of the ERCC2 gene localized on chromosome 19. The product of its expression is the signal protein XPD, which provides the relationship between the individual components of the DNA repair system.
- Type 5 (pigmented xeroderma G) is caused by a defect in the ERCC5 gene, which is located on chromosome 13 and encodes the enzyme endonuclease, which makes a cut of a single–stranded DNA molecule near the site of its damage. It has been found out that this process is particularly actively involved in the repair of DNA defects caused by exposure to ultraviolet radiation.
Despite the genetic heterogeneity of the Cockayne syndrome, the pathogenesis of this disease (at least according to its known stages) has no special differences in various forms of this pathology. Neurological disorders are presumably caused by insufficient development of glial cells and, as a consequence, reduced myelination of nerve fibers. This theory is supported by the presence of leukodystrophy and atrophy of the optic and auditory nerves in Cockayne syndrome. Human skin and eyes are often exposed to ultraviolet rays, which are part of sunlight, so the cells of the cornea, lens, and skin are often damaged. In the absence of normally functioning DNA repair mechanisms, these damages are not eliminated, which leads to the development of characteristic manifestations of the Cockayne syndrome – corneal opacity, cataract, flabby and senile-looking skin.
Manifestations of Cockayne syndrome can be detected at different ages, depending on the form of the disease. Most types of pathology do not manifest themselves at birth and are registered in the first 2-3 years of life, but type 2 is congenital. Otherwise (with the exception of average life expectancy), the various options do not differ in their manifestations. The first symptom of the Cockayne syndrome is the characteristic appearance of patients – in some cases, moderate microcephaly, a thin nose, a pointed chin, and an enlarged size of the auricles are determined. All this gives the patient’s face an elderly expression. The lag of the child in physical and intellectual development from peers with Cockayne syndrome is also pronounced, dwarfism develops with disproportionately long limbs. There are contractures of the joints and atrophy of subcutaneous fat, so patients look thin.
The condition of the skin of patients with Cockayne syndrome depends on how often it is exposed to ultraviolet rays without protective equipment. Immediately after insolation, a skin burn occurs, sometimes with the formation of blisters, in the future hyperpigmentation, telangiectasia, flabbiness and senile appearance of the skin are determined. Dermatological manifestations are especially pronounced in types 4 and 5 of Cockayne syndrome. Common symptoms of this disease are sensorineural hearing loss, clouding of the lens and cornea, retinal detachment or optic nerve atrophy, which leads to the development of blindness. Patients with Cockayne syndrome easily develop hypertension and atherosclerosis, which, in turn, leads to numerous secondary lesions of various organs, mainly the heart and kidneys. Life expectancy in most forms of the disease is no more than 12 years, very rarely patients live to 20. The most severe type 2 of Cockayne syndrome most often leads to death at the age of 7 years.
Diagnosis and treatment
Diagnosis of Cockayne syndrome is based on the results of a general examination of the patient, computer and magnetic resonance imaging of the head, molecular genetic analysis, as well as a number of specific tests (biopsy of the calf nerve, determination of DNA repair activity and thymus hormone levels). Upon examination, a characteristic appearance, atrophic skin changes, disproportionate dwarfism, signs of mental retardation are revealed. Visual pathologies (juvenile cataract, blindness), hearing loss, joint contractures, convulsive seizures and other neurological disorders can also indicate the presence of Cockayne syndrome.
Magnetic resonance imaging with Cockayne syndrome detects leukodystrophy (violation of the structure of the white matter), calcinates in various structures of the brain are almost always detected. Histological examination of the tissues of the gastrocnemius nerve reveals defects in the myelination of nerve fibers. In patients with Cockayne syndrome, there is a decrease in the level of thymus hormones, an increase in blood pressure and atherosclerosis of the vessels of various organs. A specific test to determine the activity of DNA repair processes indicates the presence of defects in this system. The diagnosis can be definitively confirmed by molecular genetic diagnostics by direct sequencing of genes associated with the disease. With this method of modern genetics, prenatal diagnosis of Cockayne syndrome is also possible.
There is no specific treatment for Cockayne syndrome at the moment, all therapeutic measures are reduced to supportive and palliative procedures. It is possible to improve vision in case of cataracts or corneal opacity with the help of surgical intervention. Physiotherapy and therapeutic gymnastics can reduce the severity of joint contractures. With Cockayne syndrome, it is necessary to use sunglasses and special creams that delay ultraviolet radiation every time you go outside – this will reduce the severity of violations. Arterial hypertension and atherosclerosis are treated with traditional hypotensive and antisclerotic drugs, nootropic drugs are prescribed to improve the functioning of the nervous system.
Prognosis and prevention
The prognosis of Cockayne syndrome is unfavorable, since pathological disorders in this disease are steadily progressing, leading to the death of the patient at the age of 5 to 15 years, sometimes a little earlier or later. Supportive therapy and palliative measures can somewhat improve the patient’s quality of life, but are unable to slow down the development of pathology. The main cause of death in Cockayne syndrome is atherosclerosis and hypertension with concomitant secondary disorders (strokes, heart attacks, heart or kidney failure). Patients with this pathology require careful care due to mental retardation and other manifestations of the disease. Prevention of Cockayne syndrome is carried out by medical and genetic counseling of parents before conception of a child and prenatal diagnosis of this disease. Preventive measures are especially justified in cases where relatives have had cases of children being born with this pathology.