Jul 15, 2018
Mucopolysaccharidosisis a complex of genetically determined pathologies that has unified pathogenetic mechanisms of development, consisting in incomplete destruction and accumulation of mucopolysaccharides. The clinical picture of mucopolysaccharidosis is formed depending on the lesion of the structure, in which an excessive amount of glucosaminoglycans accumulates. The most common mucopolysaccharidosis in children and scientifically proven is the fact of the pathological gene transfer by heredity.
This pathology is extremely rare, but the attention of researchers is focused on the problem of finding an effective method of its treatment, since the level of mortality from mucopolysaccharidosis is very high.
Causes of mucopolysaccharidosis
All forms and types of mucopolysaccharidosis belong to the category of hereditary pathologies transmitted by an autosomal recessive type of inheritance. The mutation gene is a change in the structure of the lysosomal alpha-irunidase gene, which takes a direct part in the metabolic transformations of glucosaminoglycans.
Due to mutational damage of lysosomal alpha-irunidase, there is a disruption of the process of intralisomal decomposition of dermatan sulfate and its excessive accumulation in hepatic and splenic parenchyma, cartilaginous tissue and periosteum, nerve tissues and vascular wall.
As a result of the progression of the edema of the soft shell of the brain, a partial occlusion of the subarachnoid space develops, which in turn contributes to the progression of hydrocephalus. The cause of the child's signs of mental retardation is the excessive accumulation of gangliosides in neurons.
In addition to severe metabolic abnormalities of mucopolysaccharides, there are signs of metabolic disorders of proteins that manifest themselves in the form of hyperaminoaciduria.
Symptoms of mucopolysaccharidosis
All patients suffering from mucopolysaccharidosis have characteristic distinctive phenotypic signs in the form of development of ugly facial features with an enlarged tongue and large head. Patients with any type of mucopolysaccharidosis have signs of a delay in physometric development, namely, a discrepancy in bone age with a passport, development of an expressed degree of scoliosis and disfiguring contractures of large joints.
Despite the primary lesion of the nervous and / or musculoskeletal system, some types of mucopolysaccharidosis show internal damage.
Characteristic distinctive symptoms of mucopolysaccharidosis is the destruction of neurons in the cortical structures of the brain, as a result of which the child develops signs of impaired intellectual ability of varying degrees of intensity. In the progressive course of the disease, in almost 100% of cases of mucopolysaccharidosis, the optic nerve is damaged, as well as the cornea of one / both eyes, accompanied by a pronounced impairment of visual function.
Types of mucopolysaccharidosis
♦ The most severe form of this pathology is mucopolysaccharidosis type 1, accompanied by profound violations of the neurological status of the child and the complex defeat of virtually all vital organs and systems.
The debut of the disease occurs during the thoracic period and is accompanied by severe disturbances in the shape and size of the cerebral cranium, kyphoscoliotic deformation of the thoracic spine and contractures of small joints. In this category of patients there is an inborn increase in liver size and weakness of the tendon-muscular inguinal ring with the appearance of signs of inguinal hernia.
In the early stages of the disease, the diagnosis of "mucopolysaccharidosis" is rarely established due to the fact that this pathology is classified as rare. However, the progression of physical and mental development disorders in a child in combination with external manifestations makes it possible to put mucopolysaccharidosis type 1 in a differential-diagnostic series.
The neurological status of a child suffering from type 1 mucopolysaccharidosis has characteristic features in the form of development of signs of a hypertensive-hydrocephalic symptom complex, namely, an increase in the size of the cerebral part of the skull, the appearance of an enlarged venous network in the temporal regions and vegetative dysfunctions. When performing the radiography of the skull in the lateral projection, some increase in the sagittal size of the Turkish saddle is worth noting, and lumbar puncture allows to determine the elevated cerebrospinal pressure. The pathogenesis of neurological disorders in patients with type 1 mucopolysaccharidosis is based on changes in the structure of bone tissue in the projection of the skull and increased hydrophilicity of the connective tissue component of the brain tissue.
The defeat of internal organs in type 1 mucopolysaccharidosis occurs in a distant period and consists in the formation of valvular heart disease defects, opacity of the cornea of the eye. In connection with the fact that this pathology is accompanied by severe violations of the brain structures, it is classified as unfavorable for the life of a child, the duration of which does not exceed a ten-year boundary. Laboratory chromatographic studies of urine of children suffering from this type of mucopolysaccharidosis are accompanied by the determination of high glucosamine levels exceeding the threshold of 300 mg per day.
♦ Mucopolysaccharidosis type 2 has clinical manifestations similar to the previous one, but its characteristic feature is the predominant defeat of males in the first year of life. Phenotypic manifestations of this pathology are less pronounced compared to type 1 mucopolysaccharidosis, but they emphasize the genetic origin of the disease: retardation in growth, hypertelorism and flattening of the nose, shortening of the cervical spine and large dimensions of the tongue.
The main distinguishing feature of type 2 mucopolysaccharidosis is the complete absence of signs of static deformation of the spine in the form of development of kyphoscoliosis. Violation of the intellectual-mnestic function of the cerebral cortex has lesser manifestations, however, in most cases, the children develop signs of sensorimotor deafness. Eye damage is only in small stagnant changes in the optic nerve and bilateral dullness of the superficial layers of the cornea.
Type 2 mucopolysaccharidosis is characterized by the manifestation of endocrine and vegetative-trophic changes in the form of development of the abdominal type of obesity, hypertrichosis and acrocyanosis. Children suffering from mucopolysaccharidosis type 2 are classified as a risk for the occurrence of respiratory viral diseases, complicated by bacterial pneumonia. Diagnostic criterion for establishing the diagnosis of mucopolysaccharidosis in this situation is an increase in the chromatographic parameters of heparan sulfate or dermatan sulfate in urine.
♦ Sanifilippo syndrome, or type 3 mucopolysaccharidosis, equally affects both male and female children and is accompanied by the development of a specific phenotypic appearance. Children suffering from type 3 mucopolysaccharidosis have anomalies in the development of the cerebral and facial parts of the skull in the form of enlarged frontal bones, a flattened bridge of nose, a large tongue and thick lips, and closely located eye orbits. The defeat of the osteoarticular apparatus affects small joints more than the spine, and manifests itself in the development of congenital contractures of interphalangeal and metatarsophalangeal joints of the hands and feet. Also for this congenital syndrome is not characterized by the defeat of internal organs, however the neurological status of the child suffers to a great extent.
From an early age, children tend to have increased irritability and emotional instability, memory impairment, and a progressive inhibition of intellectual activity. The diagnosis, as a rule, is established at a late stage of the disease with the help of the involvement of laboratory and instrumental examination techniques( X-ray morphometry, chromatographic determination of acid mucopolysaccharides characterized by a high level of heparan sulfate level).
♦ 4 type of mucopolysaccharidosis, or Morkio syndrome, differs from previous forms in a favorable course, since this pathology is not accompanied by gross neurologic defects and affects the development of the osteoarticular system of the child to a greater degree. Children with Morkio syndrome have gross anomalies in the development of large tubular and flat bones, as well as joint deformities with a pronounced impairment of their function. A laboratory study of the urine of a child suffering from type 4 mucopolysaccharidosis is accompanied by the detection of an elevated dermatan sulfate content.
♦ Scheye syndrome, or type 5 mucopolysaccharidosis, has a clinical and laboratory symptomatology similar to the first type, however, in this pathology more aggressive course of the disease with complete absence of remission periods is noted. In this regard, the Sheyye syndrome occupies a leading position in the structure of infant mortality from mucopolysaccharidosis. The principal difference of this syndrome is the primary defeat of the cardiovascular system with the formation of gross malformations of valvular apparatus of the heart and large vessels.
♦ Children with diagnosed mucopolysaccharidosis type 6 can live with this disease for a long time, since this pathology is not accompanied by a violation of the intellectual and mnestic functions of the brain and manifests itself only in a certain opacification of the cornea, which has a one-sided or two-sided nature. Chromatographic examination of urine, which is included in the algorithm of examination of patients with suspected mucopolysaccharidosis, allows to determine an elevated level of dermatan sulfate in the absence of heparan sulfate.
Treatment of mucopolysaccharidosis
An early diagnosis of the clinical-laboratory type of the pathology is of great importance in the treatment of a child with mucopolysaccharidosis, since each variant of the disease requires an individual approach to the use of an appropriate treatment method. In determining the tactics of conducting and treating a patient suffering from mucopolysaccharidosis of one type or another, a group of specialists, including pediatric neonatologist, plastic surgery specialist, orthopedist, neurosurgeon, ophthalmologist and otolaryngologist, takes part.
As a rule, the treatment of mucopolysaccharidosis consists in the elimination of certain signs of the disease, that is, a symptomatic treatment option is used. The only pathogenetically substantiated method of treatment at the moment is considered hormone therapy, which allows not only to curtail clinical manifestations, but also to level the laboratory manifestations of the disease. The optimal combination, which significantly reduces the activity of synthesis of glucosaminoglycans by fibroblasts, is the combination of thyroidin and prednisolone( the daily dosage is at least 1 mg per 1 kg of the child's weight by the course of 2 months).
It is also advisable to prescribe drugs that improve the function of fibroblasts, which include Methionine in a daily dose of 0.75 mg orally.
Type 1 mucopolysaccharidosis is an absolute indication for bone marrow transplantation, provided there are no contraindications, and this method is more effective at the age of the patient up to two years. Existing extra-neural disorders in the child are justification for the use of replacement therapy with Aldurasim at a dosage of 100 units per kg of body weight by the method of weekly intravenous drip infusion. However, this drug is not used in the treatment of type 2 mucopolysaccharidosis, since the active substance is unable to penetrate the blood-brain barrier.