Sanfilippo syndrome (mucopolysaccharidosis III) is a genetic disease from the group of mucopolysaccharidoses that occurs due to point mutations and is characterized by a violation of glycosaminoglycan metabolism. Pathology is manifested by progressive delay of psychorechological development, multiple behavioral disorders, gross motor disorders. To diagnose the syndrome, a study of the level of certain enzymes in cell cultures, magnetic resonance imaging of the brain is prescribed. Treatment is symptomatic: correction of behavior, elimination of convulsive syndrome, comprehensive rehabilitation and proper care.
ICD 10
E76.2 Other mucopolysaccharidoses
General information
The disease is named after the American pediatrician Sylvester Sanfilippo, who together with colleagues described its characteristic features in 1963. This syndrome accounts for up to 47% of all cases of mucopolysaccharidoses. The incidence of Sanfilippo disease ranges from 0.28 to 4.1 per 100,000 live births. Scientists believe that the true prevalence of the syndrome is much higher, due to the presence of mild forms with minor clinical symptoms.
Causes
The disease develops due to mutations of genes encoding certain enzymes in the cycle of biochemical transformations of heparan sulfates. Thanks to the improvement of molecular genetic diagnostics, it was possible to detect 4 variants of gene anomalies that occur in different subtypes of Sanfilippo syndrome:
- The SGSH mutation. Deficiency of the enzyme heparan-N-sulfatase is caused by a violation of the structure of the long arm of the 17th chromosome. As a result, mucopolysaccharidosis IIIA occurs — the most common form of the syndrome in North European countries.
- NAGLU mutation. Disorders in the gene located on chromosome 17 and encoding α-N-acetylglucosaminidase provoke mucopolysaccharidosis type IIIB, more common in the Southeastern part of Europe.
- HGSNAT mutation. Such a gene anomaly is localized on the 8th chromosome. At the same time, the work of the enzyme α-glucosaminide N-acetyltransferase is disrupted, resulting in Sanfilippo type IIIC disease, which occurs 5-6 times less often than the previous two types.
- GNS mutation. The defeat of the enzyme N-acetylglucosamine-6-sulfatase, encoded by the gene at the 12q14 locus, causes type IIID MPS, the rarest form of the syndrome.
Pathogenesis
Due to the deficiency of specific lysosomal enzymes in the body, the level of partial degradation products of heparan sulfate increases, which have a toxic effect on the nervous system. Substances accumulate in the neurons of the central nervous system, provoke a progressive increase in the size of lysosomes, dystrophy of nerve cell processes, the formation of axonal spheroids, and also cause thinning of the myelin layer.
The appearance of degraded glycosaminoglycans triggers pathological reactions in the central nervous system, stimulates the formation of free radicals, nitric oxide, pro-inflammatory cytokines. Oxidative stress increases, aggravating the course of the neurodegenerative process. Abnormal gangliosides, cholesterol esters accumulate in cells, which form specific striated corpuscles in the cerebral cortex, amygdala, and midbrain.
Symptoms
Women carrying a child with Sanfilippo syndrome have a complicated course of pregnancy and childbirth: the threat of unauthorized termination, breech presentation of the fetus, weakness of labor, requiring an operative cesarean section. In the neonatal period, children are susceptible to respiratory disorders, breastfeeding disorders, prolonged jaundice, accompanied by an extremely high bilirubin content.
The disease is characterized by some phenotypic features. Patients have an elongated head shape, a narrow high forehead, a thickened turned-out lower lip. The skin is rough and dense to the touch, the hair is dry, hard. Usually there is excessive hair loss (hypertrichosis). The lesion of the spine is manifested by scoliosis, kyphosis, due to the underdevelopment of the femoral heads, gait changes are noted.
The manifestation of a typical clinical picture occurs in early childhood. The main sign of Sanfilippo syndrome are neurodegenerative disorders that go through 3 consecutive stages. In the first phase (1-4 years of the child’s life), delayed speech development and hearing loss prevail. Such symptoms are nonspecific, so at this stage the diagnosis is extremely rare.
The detailed clinical picture is formed in the 2nd phase (4-10 years). The child stops talking, loses previously acquired motor and cognitive skills. Mental disorders are manifested by a decrease in concentration, disinhibition, impulsive or destructive behavior. Insomnia worries, the daily routine is completely lost, at night the patient often chews bed linen, laughs or cries for no reason.
Approximately at the age of 10, phase 3 of Sanfilippo syndrome manifests, which is characterized by severe neurological symptoms. In addition to mental retardation and behavioral disorders, motor disorders are progressing. There is instability when walking, frequent falls, loss of volume of active movements due to hypotension and muscle spasticity. In most cases, a convulsive syndrome occurs.
Complications
Irreversible neurodegenerative process leads to a complete loss of the ability to move independently, regression of all cognitive skills. Such patients eventually become severely disabled and require round-the-clock qualified care. Sometimes patients fall into a vegetative state with a lack of spontaneous mental activity.
Among the somatic complications of Sanfilippo syndrome, hepatosplenomegaly, heart pathology (left ventricular hypertrophy, aortic valve stenosis) are most common. In most patients, chronic diarrhea occurs in phase 1-2. Against the background of swallowing and breathing disorders, protracted infectious diseases of the bronchopulmonary system develop, which are often the cause of death.
Diagnostics
To make a diagnosis, a consultation of a geneticist is required with the involvement of specialized specialists — pediatricians, pediatric neurologists, psychiatrists. It is possible to suspect Sanfilippo disease by specific changes in the phenotype, progressive speech delay in combination with multiple behavioral disorders. The following methods are used for the complex diagnosis of the syndrome:
- Laboratory tests. Biochemical analysis of urine shows an increase in the level of secreted glycosaminoglycans. The study of specific enzyme activity in the culture of fibroblasts or white blood cells is a 100% reliable diagnostic method.
- Neuroimaging. According to the results of MRI of the brain, diffuse atrophic processes, expansion of the ventricular system, degeneration of the corpus callosum are determined. Hypointensivity of the basal ganglia in the T2 mode is less often detected.
- Prenatal diagnosis. With a burdened family history, pregnant women undergo a chorionic villi biopsy (at 12-14 weeks) or amniocentesis (at 14-16 weeks) to confirm or refute the diagnosis by genetic examination.
Treatment
Conservative therapy
Currently, there are no pathogenetic drugs that can stop or slow down neurodegenerative processes in the brain. The selection of symptomatic therapy is carried out differentially, taking into account the severity of the manifestations of MPS III. Patients are prescribed the following therapeutic measures:
- Psychotropic drugs. Correction of behavioral disorders is performed with tranquilizers, sedatives, nootropics. Anticonvulsants are recommended for convulsive syndrome.
- Treatment of insomnia. To normalize circadian rhythms and facilitate falling asleep, the hormone melatonin is mainly used, which provides gentle regulation of sleep, shows high efficiency.
- Antibacterial therapy. Antimicrobials are indicated for bacterial infections of the respiratory tract and middle ear. For the treatment of severe aspiration pneumonia, 2-3 medications and reserve antibiotics are combined.
- Orthopedic correction. To correct posture, eliminate joint stiffness, a comprehensive physiotherapy program is carried out, specially selected orthoses are used.
Proper feeding of patients is necessary to reduce the risk of aspiration complications. The frequency of eating is 8-10 times a day in small portions, with the preserved function of swallowing, feeding with a spoon in a sitting or reclining position is permissible. Gross bulbar disorders, the development of pneumonia or bronchitis are indications for the probe administration of food mixtures.
Experimental treatment
In recent years, the use of substrate-reducing therapy aimed at reducing the synthesis of heparan sulfate has been considered. The issues of intrathecal enzyme replacement and gene therapy are also discussed. Now these methods of treatment are at the stage of multicenter clinical trials, and it is possible that in the future they will be able to be used to effectively eliminate the manifestations of Sanfilippo syndrome.
Rehabilitation
To improve the quality of life, the patient needs constant care at home, comprehensive rehabilitation measures. The program includes massage, physical therapy, physiotherapy (thermotherapy, UVT, biofeedback method). Psychological and pedagogical assistance is necessarily prescribed in order to partially preserve the patient’s ability to adequate mental reactions, non-verbal communication with family members.
Prognosis and prevention
With MPS IIIA, an extremely severe course is observed, most patients die at the age of 15-25 years from somatic complications. A more favorable prognosis for Sanfilippo syndrome types B, C, D, which can occur in a mild form: patients live up to 30-40 years, have the ability to move independently, have a higher level of intellectual development. Specific prevention of mucopolysaccharidosis III has not been developed.
