Mucopolysaccharidosis type 3

Mucopolysaccharidosis, type III (synonyms: Sanfilippo syndrome, insufficiency of lysosomal aN-acetylglucosaminidase - mucopolysaccharidosis SHA, acetyl-CoA-a-glucosaminide-N-acetyltransferase - mucopolysaccharidosis III B, N-acetylglucosamine-6-sulfatase - mucopolysaccharidosis III C, sulfamidase - mucopolysaccharidose III D).

[1], [2], [3], [4], [5]

Epidemiology

The frequency of occurrence of the Sanfilippo syndrome in the population is 1 per 70 000 live births.

[6], [7]

Causes of the mucopolysaccharidosis type 3

Mucopolysaccharidosis, type III - genetically heterogeneous group of diseases inherited by autosomal recessive type. 

[8], [9], [10],

Pathogenesis

The disease is caused by mutations of four different genes: lysosomal aN-acetylglucosaminidase (mucopolysaccharidosis III A), acetyl-CoA-a-glucosaminide-N-acetyltransferase (mucopolysaccharidosis III B), lysosomal N-acetylglucosamine 6-sulfatase (mucopolysaccharidosis III C), sulfamidase (mucopolysaccharidosis III D). All enzymes are involved in the metabolism of heparan sulfate.

The heparan-N-sulfatase gene-SGSH-is located on the long arm of the chromosome 17-17q25.3. 75.3% of the currently known mutations in the SGSH gene are point mutations. Frequent mutations typical for European populations - R74C (56% in Poland and 21% in Germany) and R245H (56% in the Netherlands) are described.

The mutation frequency of R74C is 47.5%, the mutation of R245H is 7.5%. The two other mutations, delll35G and N389S, together account for 21.7% of the mutant alleles.

The aN-acetyl-glucosaminidase gene, NAGLU, is located on the long arm of the chromosome 17-17q21. 69% of the mutations found in the NAGLU gene are missense and nonsense mutations, 26.3% are small deletions and insertions. The acetyl-CoA-cc-glucosaminide-N-acetyltransferase gene, HGSNAT, is located on the short arm of the chromosome 8-8p11. The gene was characterized only in 2006 and to date, it found only a few mutations.

The gene N-acetyl-glucosamine-6-sulfatase - GNS - is located on the long arm of chromosome 12 - 12ql4. There are 12 patients with mucopolysaccharidosis IIID registered in the world. There are 4 mutations in the GNS gene.

With all the subtypes of mucopolysaccharidosis III, the degradation of heparan sulfate, which is part of the structure of cell membranes, including neuronal membranes, is degraded, which correlates with the severe neurodegenerative process caused by cortical atrophy. Chronic diarrhea is explained by involvement in the pathological process of the autonomic nervous system along with dysfunction of the intestinal mucosa. Sensorineural hearing loss is probably due to three causes: frequent otitis, deformities of the auditory ossicles and anomalies of the inner ear. The stiffness of the joints is the result of the deformation of the metaphyses, the thickening of the joint capsule is secondary to the deposition of glycosaminoglycans and fibrosis in it. Intrasyndromic differences in the severity of the disease are due solely to the residual functional activity of the mutant enzyme: the higher it is, the easier the disease progresses.

[11], [12], [13], [14], [15]

Symptoms of the mucopolysaccharidosis type 3

Clinical polymorphism in the syndrome of Sanfilippo is less pronounced than in other types of mucopolysaccharidosis. Characterized by a slow progression of the disease, severe neurologic disorders with severe symptoms from the internal organs and other systems.

The first symptoms of the disease usually appear at the age of 2-6 years in children with a previous normal development. Manifest symptoms include regression of psychomotor and speech development, psychiatric disorders in the form of development of the syndrome of hyperactivity, autistic or aggressive behavior, sleep disturbances; children become careless and inattentive.

Other common symptoms are hirsutism, hard hair, mild hepatosplenomegaly, valgus deformity of the extremities, short neck. The formation of coarse facial features by the type of gargoilism and skeletal deformities by the type of multiple dysostosis is poorly expressed in mucopolysaccharidosis III compared with other types of mucopolysaccharidosis characterized by the Hurler phenotype. Growth, as a rule, corresponds to age, and joint stiffness rarely causes a violation of their functions. Most patients often develop osteoporosis and osteomalacia. Secondary skeletal disorders are a high risk of pathological fractures. Rough psychoneurological disorders are most often observed by the 6-10th year of life, they lead to severe social maladjustment. Progressive neurosensory hearing loss is inherent in all patients with severe and moderate forms of the disease. Seizures are observed in almost all patients as the disease progresses.

The course of the disease is rapidly progressing, most patients do not survive to the age of 20 years. It is believed that mucopolysaccharidosis IIIA is the most common and severe type of this syndrome.

Forms

There are four nosological forms that differ in the degree of manifestation of clinical manifestations and the primary biochemical defect.

[16], [17], [18]

Diagnostics of the mucopolysaccharidosis type 3

The diagnosis of mucopolysaccharidosis III is confirmed by determining the level of urinary glucosamycin excretion and measurement of enzyme activity. In the case of mucopolysaccharidosis III, the total excretion of glycosaminoglycans in the urine increases and the hyperexcretion of heparan sulfate is observed. The activity of lysosome enzymes corresponding to a certain subtype of mucopolysaccharidosis III is measured in leukocytes or a culture of skin fibroblasts using an artificial fluorogenic substrate.

Prenatal diagnosis is possible by measuring the activity of enzymes in the chorionic villus sampling at the 9-11th week of pregnancy and / or by determining the spectrum of glycosaminoglycans in the amniotic fluid at the 20-22nd week of pregnancy. For families with a known genotype, it is possible to carry out DNA diagnostics in the early stages of pregnancy.

[19], [20], [21]

Differential diagnosis

Differential diagnosis is performed both within the mucopolysaccharidosis group and with other lysosomal accumulation diseases: mucolipidosis, galactosialidosis, sialidosis, mannosidosis, fucosidosis, GM1-gangliosidosis.

Treatment of the mucopolysaccharidosis type 3

To date, effective therapies for mucopolysaccharidosis III have not been developed. Symptomatic therapy is indicated.