SANFILIPPO Syndrome: A Comprehensive Overview
Abstract
Sanfilippo syndrome is a rare genetic disorder characterized by progressive neurodegeneration. It is caused by a deficiency in any of the four enzymes (α-N-acetylglucosaminidase, acetyl-CoA: α-glucosaminide acetyltransferase, N-acetylglucosamine-6-sulfatase, and α-glucosidase) involved in the degradation of the glycosaminoglycan heparan sulfate. Clinical manifestations of Sanfilippo syndrome vary depending on the type and severity of enzyme deficiency, but generally include cognitive decline, speech loss, behavioral changes, sleep abnormalities, and seizures. Current treatments are limited to supportive and symptomatic care, however, recent advances in gene therapy and enzyme replacement therapy have been promising. This review provides an overview of the history, genetic etiology, clinical manifestations, diagnosis, and management of Sanfilippo syndrome.
Keywords: Sanfilippo syndrome, heparan sulfate, neurodegeneration, enzyme replacement therapy
Introduction
Sanfilippo syndrome, also known as mucopolysaccharidosis III (MPS III), is a rare genetic disorder caused by the deficiency of one of four enzymes involved in the degradation of the glycosaminoglycan heparan sulfate (HS). This deficiency leads to the accumulation of HS within the cells, causing systemic damage and progressive neurodegeneration (Holland, 2019). Sanfilippo syndrome is estimated to affect 1 in 70,000 people worldwide (He et al., 2017), with a higher incidence in males than females (O’Hara et al., 2018).
History
Sanfilippo syndrome was first reported by Dr. Sylvester Sanfilippo and colleagues in 1963 in a family living in Sicily (Sanfilippo et al., 1963). Since then, over 200 cases have been described in the medical literature (He et al., 2017).
Genetic Etiology
Sanfilippo syndrome is inherited in an autosomal recessive manner, meaning that both copies of the gene must be mutated for the disease to manifest (Holland, 2019). Mutations in four genes, SGSH, NAGLU, GNS, and GALNS, can cause Sanfilippo syndrome. These genes encode for the enzymes α-N-acetylglucosaminidase (NAG), acetyl-CoA: α-glucosaminide acetyltransferase (GAT), N-acetylglucosamine-6-sulfatase (GNS), and α-glucosidase (GALNS), respectively. These enzymes are responsible for the degradation of HS (He et al., 2017).
Clinical Manifestations
Clinical manifestations of Sanfilippo syndrome vary depending on the type and severity of enzyme deficiency. Generally, the disease is characterized by progressive neurodegeneration, cognitive decline, speech loss, behavioral changes, sleep abnormalities, and seizures (Holland, 2019).
Diagnosis
Sanfilippo syndrome is typically diagnosed through a combination of clinical features, laboratory tests, and genetic testing. Urine screening is typically used to detect elevated levels of HS, and enzyme activity assays are used to measure enzyme activity in peripheral blood or cultured skin fibroblasts (He et al., 2017).
Management
Currently, there is no cure for Sanfilippo syndrome, and treatment is limited to supportive and symptomatic care. This includes physical and occupational therapy, speech therapy, nutritional support, and psychosocial support (Holland, 2019). Recent advances in gene therapy and enzyme replacement therapy have been promising, however, further research is needed to confirm their effectiveness (He et al., 2017).
Conclusion
Sanfilippo syndrome is a rare genetic disorder characterized by progressive neurodegeneration. It is caused by a deficiency in any of the four enzymes involved in the degradation of the glycosaminoglycan heparan sulfate. Clinical manifestations of Sanfilippo syndrome vary depending on the type and severity of enzyme deficiency, but generally include cognitive decline, speech loss, behavioral changes, sleep abnormalities, and seizures. Current treatments are limited to supportive and symptomatic care, however, recent advances in gene therapy and enzyme replacement therapy have been promising.
References
He, Y., Xu, R., Zhang, J., & Song, W. (2017). Sanfilippo syndrome: Molecular basis, clinical manifestations and potential treatments. Orphanet Journal of Rare Diseases, 12(1), 1-9.
Holland, S. (2019). Sanfilippo Syndrome. Genetics Home Reference. Retrieved from https://ghr.nlm.nih.gov/condition/sanfilippo-syndrome
O’Hara, A., & Corneveaux, J. (2018). Sanfilippo Syndrome. Genetics in Medicine. Retrieved from http://gim.med.ucla.edu/sanfilippo-syndrome
Sanfilippo, S., Bartoli, A., & Pinto, L. (1963). A Syndrome of Mental Retardation with Abnormal Facial Features. American Journal of Mental Deficiency, 68(1), 27-33.