N-acetyl glucosamine 6-sulfate sulfatase deficiency




N-acetyl glucosamine 6-sulfate sulfatase is a lysosomal enzyme found in all cells. It is encoded by the GNS gene. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of complex carbohydrates in the body's cells and tissues and in the cellular organelles, the lysosomes. These complex carbohydrates, also known as mucopolysaccharides or glycosaminoglycans (GAGs), serve as the building blocks for connective tissues in the body.

Deficiency of the N-acetyl glucosamine 6-sulfate sulfatase is called mucopolysaccharidosis type IIID (Sanfilippo D syndrome), and was first described at the American Pediatric Society Annual Meeting by pediatrician, Sylvester Sanfilippo, in 1963. The approximate incidence of Sanfilippo D syndrome is about 1:1,000,000.


Patients with Sanfilippo syndrome are born without symptoms and typically have normal development for the first 2 years of life. Affected infants are apparently normal, although some mild facial dysmorphism may be noticeable. The stiff joints, hirsuteness and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. Acquisition of speech is often slow and incomplete. The disease progresses to increasing behavioural disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behaviour, pica and sleep disturbance. As affected children have normal muscle strength and mobility, the behavioural disturbances are very difficult to manage. The disordered sleep in particular presents a significant problem to care providers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures.

 Although the clinical features of the disease are mainly neurological, patients may also develop diarrhea, carious teeth, and an enlarged liver and spleen. There is a broad range of clinical severity. The disease may very rarely present later in life as a psychotic episode.

 Of all the MPS diseases, MPS III produces the mildest physical abnormalities. It is important, however, that simple and treatable conditions such as ear infections and toothaches not be overlooked because of behavior problems that make examination difficult. Children with MPS III often have an increased tolerance of pain. Bumps and bruises or ear infections that would be painful for other children often go unnoticed in children with MPS III. Parents may need to search for a doctor with the patience and interest in treating a child with a long-term illness. Some children with MPS III may have a blood-clotting problem during and after surgery.


Deficiency of the N-acetyl glucosamine 6-sulfate sulfatase enzyme is caused by a mutation in the GNS gene and results in the accumulation of undegraded substrate in various organs, leading to the symptoms described above. Over 20 various mutations of the GNS gene have been described to-date.


As the disease is caused by a random mutation in the GNS gene, no prevention is available. 


Clinical picture as described above, the diagnosis may be confirmed by assay of enzyme levels in tissue samples and gene sequencing. Prenatal diagnosis is possible.


N-acetyl glucosamine 6-sulfate sulfatase deficiency is a lifelong, progressive condition. Severe CNS degeneration occurs, with progression to a vegetative state. The treatment remains largely supportive. Most patients do not live beyond age 20 years, with death primarily due to respiratory complications.


The behavioural disturbances of MPS-III respond poorly to medication. If an early diagnosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood–brain barrier and therefore cannot treat the neurological manifestations of the disease.

Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system. Several promising therapies are in development. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

The flavonoid genistein decreases the pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro, animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein. Despite its reported beneficial properties, genistein also has toxic side effects.


[1] http://emedicine.medscape.com/article/948540-overview

[2] https://www.ncbi.nlm.nih.gov/gene/2799

[3] Poorthuis BJ, Wevers RA, Kleijer WJ, et al. (1999). "The frequency of lysosomal storage diseases in The Netherlands". Hum. Genet. 105 (1–2): 151–6.

[4] Valstar MJ et al – Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations. Hum Mutat. 2010 May;31(5):E1348-60.

[5] Piotrowska, E.; Jakóbkiewicz-Banecka, J.; Barańska, S.; Tylki-Szymańska, A.; Czartoryska, B.; Wegrzyn, A.; Wegrzyn, G. (Jul 2006). "Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses". European Journal of Human Genetics. 14 (7): 846–52.

[6] Jin, Y.; Wu, H.; Cohen, EM.; Wei, J.; Jin, H.; Prentice, H.; Wu, JY. (Mar 2007). "Genistein and daidzein induce neurotoxicity at high concentrations in primary rat neuronal cultures". J Biomed Sci. 14 (2): 275–84.