Alternative titles; symbols
SNOMEDCT: 75238000; ICD10CM: E76.22; ORPHA: 581, 79271; DO: 0111393;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p11.21-p11.1 | Mucopolysaccharidosis type IIIC (Sanfilippo C) | 252930 | Autosomal recessive | 3 | HGSNAT | 610453 |
A number sign (#) is used with this entry because mucopolysaccharidosis type IIIC (MPS3C), also known as Sanfilippo syndrome C, is caused by homozygous or compound heterozygous mutation in the HGSNAT gene (610453), encoding heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase, on chromosome 8p11.
Sanfilippo syndrome comprises several forms of lysosomal storage diseases due to impaired degradation of heparan sulfate. The deficient enzyme in Sanfilippo syndrome C, or MPS IIIC, is an acetyltransferase that catalyzes the conversion of alpha-glucosaminide residues to N-acetylglucosaminide in the presence of acetyl-CoA.
For a general phenotypic description and a discussion of genetic heterogeneity of Sanfilippo syndrome, see MPS IIIA (252900).
Kresse et al. (1976) reported 2 related patients of Greek origin with the phenotype of Sanfilippo syndrome who had normal values of heparan sulfamidase (605270) and alpha-N-acetylglucosaminidase (NAGLU; 609701). Metabolic correction was achieved upon cocultivation with Sanfilippo A and Sanfilippo B (252920) fibroblasts. The authors termed the disorder 'Sanfilippo disease type C.'
Klein et al. (1978) identified complete deficiency of acetyl-CoA:alpha-glucosaminide N-acetyltransferase in 3 patients with MPS IIIC. In a note added in proof, they indicated that since submission of the manuscript, they had proved the IIIC defect in 11 cases of the Sanfilippo syndrome.
Sewell et al. (1988) reported 2 affected sisters born from a large consanguineous Turkish family with MPS IIIC. The older child presented at 3 months of age with dysmorphic signs, including coarse facies, hypertelorism, low-set ears, depressed nasal bridge, and coarse hair. She had mild hepatosplenomegaly and high lumbar vertebral bodies radiographically. She demonstrated delayed motor development. The younger sister presented at age 16 months with a similar clinical phenotype. Skeletal radiographs showed iliac flaring, practically flat acetabula, and thickened femoral necks. The lumbar vertebral bodies showed ovoid deformities. Urinary heparan sulfate was increased.
Ruijter et al. (2008) reported 29 patients from the Netherlands with MPS IIIC. Some of the patients were of Turkish or Moroccan descent. Psychomotor development was reported to be normal in all patients during the first year of life. Onset of behavioral problems or psychomotor retardation became apparent between 1 and 6 years of age. Behavioral problems were severe and included restlessness, chaotic behavior, and temper tantrums. Sleep disturbances were common. Other features included diarrhea, inguinal or umbilical hernia, recurrent upper respiratory tract infection, and seizure. Retinitis pigmentosa was present in 3 patients over age 30. Neurologically, patients showed loss of speech development and developmental decline about 10 years before loss of motor function. The mean age at death was 34 years.
Canals et al. (2011) reported 11 unrelated probands with MPS IIIC, including 7 of Spanish origin, 1 from Argentina, and 3 from Morocco. Four of the families were consanguineous. The age at onset ranged between 3 and 6 years. Clinical features included motor deterioration, loss of speech, seizures, and delayed psychomotor development. Most had coarse facial features and hypertrichosis; variable but common additional features included sleep difficulties, kyphoscoliosis, hearing loss, and dysphagia.
The lysosomal-membrane enzyme deficient in MPS IIIC catalyzes the transfer of an acetyl group from cytoplasmic acetyl-CoA to terminal alpha-glucosamine residues of heparan sulfate with lysosomes. It was the first nonhydrolytic activity identified as occurring in lysosomes. Bame and Rome (1985) found that the enzyme carries out a transmembrane acetylation via a ping-pong mechanism. The reaction can be dissected into 2 half reactions: acetylation of the enzyme and transfer of the acetyl group to glucosamine.
Bame and Rome (1986) found that 5 cell lines from 3 affected families with Sanfilippo syndrome type C living in the Netherlands were able to catalyze acetylation of the lysosomal membrane and to carry out acetyl-CoA/CoA exchange, but could not transfer the bound acetyl group to glucosamine; a sixth cell line from a patient of Italian ancestry was devoid of this activity. Acetylation of terminal alpha-linked glucosamine residues inside the lysosome is a required step in the degradation of heparan sulfate. Although acetyl-CoA is the acetyl donor in this reaction, it is unlikely that this cofactor could exist stably in the acidic and hydrolytic ambience of the lysosome. N-acetyltransferase provides a means for cells to use cytoplasmically derived acetyl-CoA in heparan sulfate degradation without transporting the intact molecule across the lysosomal membrane. Vectorial transport of the acetyl group across the lysosomal membrane appears to be a unique solution to a complex enzymatic and compartmental problem. Whether the 2 classes of mutants are allelic remains to be determined. The data are consistent with a model assuming a single subunit (Rome, 1986).
Klein et al. (1981) described an assay for the detection in leukocytes of homozygous and heterozygous carriers of Sanfilippo syndrome type C. Affected individuals had no residual activity of acetyl-CoA:alpha-glucosaminide N-acetyltransferase. The authors noted that the enzyme was strongly membrane-bound.
Prenatal Diagnosis
DiNatale et al. (1987) diagnosed MPS IIIC in a fetus by enzymatic studies of chorionic villus biopsy material obtained at 10 weeks' gestation.
MPS IIIC is an autosomal recessive disorder (Fan et al., 2006).
Ausseil et al. (2004) performed a genomewide scan on 44 MPS IIIC patients and their unaffected relatives from 31 families in 10 countries. Several of the families were consanguineous. Analysis of excess homozygosity in patients and identity in state of genotypes among affected relatives identified chromosome 8. Linkage analysis delineated an 8.3-cM candidate gene interval in the pericentromeric region of chromosome 8 (maximum multipoint lod score of 10.61 at marker D8S519). Affected sibs were identical in state for 15 consecutive markers in this region.
Fan et al. (2006) identified the HGSNAT gene (610453), encoding the human N-acetyltransferase, and identified 2 mutations accounting for 4 alleles in 2 human MPS IIIC cell lines. A splice junction mutation (610453.0001) accounted for 3 mutant alleles, and a single-basepair insertion (610453.0002) accounted for the fourth.
Hrebicek et al. (2006) narrowed the candidate linkage region for Sanfilippo syndrome type C to a 2.6-cM interval between D8S1051 and D8S1831 on chromosome 8p and identified causative mutations in the HGSNAT gene (e.g., 610453.0003-610453.0005). Among 30 probands with MPS IIIC, they identified 4 nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice site mutations, and 14 missense mutations. The probands were geographically and ethnically diverse. In 23 of the 30 probands included in this study for mutation analysis, HGSNAT mutations were identified in both alleles. Five probands were heterozygous for a missense mutation, with a second mutation yet to be identified. In 2 probands, no mutation in the coding regions or immediate flanking regions was identified. These patients were homozygous for the microsatellite markers throughout the entire MPS IIIC locus and may be homozygous for a yet to be identified HGSNAT mutation. Functional expression of human HGSNAT and the mouse ortholog demonstrated that it is the gene that encodes the lysosomal N-acetyltransferase and suggested that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane.
In 3 unrelated Portuguese patients with MPS IIIC, Coutinho et al. (2008) identified 2 different mutations in the HGSNAT gene (610453.0006 and 610453.0007).
Feldhammer et al. (2009) stated that 50 pathogenic mutations in the HGSNAT gene had been reported to date, and the authors identified 10 novel mutations. A review of published mutations showed that they span the entire HGSNAT gene, and there were no obvious genotype/phenotype correlations.
Canals et al. (2011) identified 9 different pathogenic mutations in the HGSNAT gene, including 7 novel mutations, in 11 patients with MPS IIIC, including 7 of Spanish origin, 1 from Argentina, and 3 from Morocco. The most common mutation was 372-2A-G (610453.0007), which was found in 4 Spanish patients, with a frequency of 50% (7 of 14 alleles) for the Spanish patients. The second most common mutation was 234+1G-A (610453.0010), which was found in 1 Spanish and 2 Moroccan patients. Haplotype analysis indicated a founder effect for both of these mutations. Each of the 7 novel mutations was found in only 1 patient. In vitro functional expression assays in COS-7 cells showed that missense mutations had practically no residual enzyme activity (range, 0-1.19%).
Using multiple ascertainment sources, Nelson et al. (2003) obtained an incidence rate for Sanfilippo syndrome (all forms combined) in western Australia for the period 1969 to 1996 of approximately 1 in 58,000 live births; there was a total of 11 cases, including 5 of type A, 5 of type B, and 1 of type C.
Ruijter et al. (2008) reported a high frequency of 2 HGSNAT mutations in the Dutch population (R344C; 610453.0008 and S518F; 610453.0009), which occurred in 22% and 29.3% of mutant alleles, respectively.
The birth prevalence of MPS IIIC in Australia, Portugal, and the Netherlands has been estimated at 0.07, 0.12, and 0.21 per 100,000, respectively (Feldhammer et al., 2009).
Zaremba et al. (1992) identified a presumably balanced Robertsonian translocation in 2 sibs with Sanfilippo disease type IIIC and suggested that the mutant gene was located in the pericentric region of either chromosome 14 or chromosome 21. The mother had the same balanced Robertsonian translocation involving chromosomes 14 and 21. A third, unaffected, child did not receive the translocation chromosome from the mother. Zaremba et al. (1992) raised the possibility that one of the 2 mutated loci necessary for the disorder was the result of rearrangement in the pericentric region of either chromosome 14 or 21 and that only the father was a carrier of the 'regular' mutation.
Ausseil, J., Loredo-Osti, J. C., Verner, A., Darmond-Zwaig, C., Maire, I., Poorthuis, B., van Diggelen, O. P., Hudson, T. J., Fujiwara, T. M., Morgan, K., Pshezhetsky, A. V. Localisation of a gene for mucopolysaccharidosis IIIC to the pericentromeric region of chromosome 8. J. Med. Genet. 41: 941-944, 2004. [PubMed: 15591281] [Full Text: https://doi.org/10.1136/jmg.2004.021501]
Bame, K. J., Rome, L. H. Acetyl coenzyme A:alpha-glucosaminide N-acetyltransferase: evidence for a transmembrane acetylation mechanism. J. Biol. Chem. 260: 11293-11299, 1985. [PubMed: 3897232]
Bame, K. J., Rome, L. H. Acetyl-coenzyme A:alpha-glucosaminide N-acetyltransferase: evidence for an active site histidine residue. J. Biol. Chem. 261: 10127-10132, 1986. [PubMed: 3733705]
Bame, K. J., Rome, L. H. Genetic evidence for transmembrane acetylation by lysosomes. Science 233: 1087-1089, 1986. [PubMed: 3090688] [Full Text: https://doi.org/10.1126/science.3090688]
Bartsocas, C., Grobe, H., van de Kamp, J. J. P., von Figura, K., Kresse, H., Klein, U., Giesberts, M. A. H. Sanfilippo type C disease: clinical findings in four patients with a new variant of mucopolysaccharidosis III. Europ. J. Pediat. 130: 251-258, 1979. [PubMed: 108106] [Full Text: https://doi.org/10.1007/BF00441361]
Canals, I., Elalaoui, S. C., Pineda, M., Delgadillo, V., Szlago, M., Jaouad, I. C., Sefiani, A., Chabas, A., Coll, M. J., Grinberg, D., Vilageliu, L. Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles. Clin. Genet. 80: 367-374, 2011. [PubMed: 20825431] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01525.x]
Coutinho, M. F., Lacerda, L., Prata, M. J., Ribeiro, H., Lopes, L., Ferreira, C., Alves, S. Molecular characterization of Portuguese patients with mucopolysaccharidosis IIIC: two novel mutations in the HGSNAT gene. (Letter) Clin. Genet. 74: 194-195, 2008. [PubMed: 18518886] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01040.x]
DiNatale, P., Pannone, N., D'Argenio, G., Gatti, R., Ricci, R., Lombardo, C. First-trimester prenatal diagnosis of Sanfilippo C disease. Prenatal Diag. 7: 603-605, 1987.
Fan, X., Zhang, H., Zhang, S., Bagshaw, R. D., Tropak, M. B., Callahan, J. W., Mahuran, D. J. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C). Am. J. Hum. Genet. 79: 738-744, 2006. [PubMed: 16960811] [Full Text: https://doi.org/10.1086/508068]
Feldhammer, M., Durand, S., Mrazova, L., Boucher, R.-M., Laframboise, R., Steinfeld, R., Wraith, J. E., Michelakakis, H., van Diggelen, O. P., Hrebicek, M., Kmoch, S., Pshezhetsky, A. V. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) gene. Hum. Mutat. 30: 918-925, 2009. [PubMed: 19479962] [Full Text: https://doi.org/10.1002/humu.20986]
Hopwood, J. J., Elliott, H. The diagnosis of the Sanfilippo C syndrome, using monosaccharide and oligosaccharide substrates to assay acetyl-CoA: 2-amino-2-deoxy-alpha-glucoside N-acetyltransferase activity. Clin. Chim. Acta 112: 67-75, 1981. [PubMed: 6786804] [Full Text: https://doi.org/10.1016/0009-8981(81)90269-2]
Hrebicek, M., Mrazova, L., Seyrantepe, V., Durand, S., Roslin, N. M., Noskova, L., Hartmannova, H., Ivanek, R., Cizkova, A., Poupetova, H., Sikora, J., Urinovska, J., and 18 others. Mutations in TMEM76 cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Am. J. Hum. Genet. 79: 807-819, 2006. [PubMed: 17033958] [Full Text: https://doi.org/10.1086/508294]
Klein, U., Kresse, H., von Figura, K. Sanfilippo syndrome type C: deficiency of acetyl-CoA: alpha-glucosaminide N-acetyltransferase in skin fibroblasts. Proc. Nat. Acad. Sci. 75: 5185-5189, 1978. [PubMed: 33384] [Full Text: https://doi.org/10.1073/pnas.75.10.5185]
Klein, U., van de Kamp, J. J. P., von Figura, K., Pohlmann, R. Sanfilippo syndrome type C: assay for acetyl-CoA: alpha-glucosaminide N-acetyltransferase in leukocytes for detection of homozygous and heterozygous individuals. Clin. Genet. 20: 55-59, 1981. [PubMed: 6794963] [Full Text: https://doi.org/10.1111/j.1399-0004.1981.tb01807.x]
Kresse, H., Von Figura, K., Bartsocas, C. Clinical and biochemical findings in a family with Sanfilippo disease, type C. (Abstract) Clin. Genet. 10: 364, 1976.
Nelson, J., Crowhurst, J., Carey, B., Greed, L. Incidence of the mucopolysaccharidoses in western Australia. Am. J. Med. Genet. 123A: 310-313, 2003. [PubMed: 14608657] [Full Text: https://doi.org/10.1002/ajmg.a.20314]
Rome, L. H., Hill, D. F., Bame, K. J., Crain, L. R. Utilization of exogenously added acetyl coenzyme A by intact isolated lysosomes. J. Biol. Chem. 258: 3006-3011, 1983. [PubMed: 6402508]
Rome, L. H. Personal Communication. Los Angeles, Calif. 9/8/1986.
Ruijter, G. J. G., Valstar, M. J., van de Kamp, J. M., van der Helm, R. M., Durand, S., van Diggelen, O. P., Wevers, R. A., Poorthuis, B. J., Pshezhetsky, A. V., Wijburg, F. A. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The (sic) Netherlands. Molec. Genet. Metab. 93: 104-111, 2008. [PubMed: 18024218] [Full Text: https://doi.org/10.1016/j.ymgme.2007.09.011]
Sewell, A. C., Pontz, B. F., Benischek, G. Mucopolysaccharidosis type IIIC (Sanfilippo): early clinical presentation in a large Turkish pedigree. Clin. Genet. 34: 116-121, 1988. [PubMed: 3142713] [Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb02846.x]
Uvebrant, P. Sanfilippo type C syndrome in two sisters. Acta Paediat. Scand. 74: 137-139, 1985. [PubMed: 3920864] [Full Text: https://doi.org/10.1111/j.1651-2227.1985.tb10936.x]
Zaremba, J., Kleijer, W. J., Huijmans, J. G. M., Poorthuis, B., Fidzianska, E., Glogowska, I. Chromosomes 14 and 21 as possible candidates for mapping the gene for Sanfilippo disease type IIIC. J. Med. Genet. 29: 514, 1992. [PubMed: 1640438]