Alternative titles; symbols
SNOMEDCT: 15892005; ICD10CM: E76.22; ORPHA: 581, 79272; DO: 0111402, 12801;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q14.3 | Mucopolysaccharidosis type IIID | 252940 | Autosomal recessive | 3 | GNS | 607664 |
A number sign (#) is used with this entry because mucopolysaccharidosis type IIID (MPS3D) is caused by homozygous mutation in the gene encoding N-acetylglucosamine-6-sulfatase (GNS; 607664) on chromosome 12q14.
The mucopolysaccharidoses are a family of lysosomal storage diseases caused by deficiencies of enzymes required for the catabolism of glycosaminoglycans. The defects result in accumulation of excessive intralysosomal glycosoaminoglycans (mucopolysaccharides) in various tissues, causing distended lysosomes to accumulate in the cell and interfere with cell function. Multiple types have been described (Mok et al., 2003).
Kresse et al. (1980) reported a 7-year-old East Indian boy living in England and a 4-year-old girl from Sardinia with Sanfilippo disease type D. The boy was mentally retarded and had 'characteristic behavioral disturbances.' The girl showed coarse facies and hirsutism but was not mentally retarded. Both patients excreted excessive heparan sulfate in the urine. Gatti et al. (1982) concluded that MPS IIID cannot be distinguished clinically from the other forms of Sanfilippo syndrome. Autosomal recessive inheritance was considered confirmed. Stating that only 2 cases of MPS IIID had been reported in detail, Coppa et al. (1983) added 2 more. One of the patients, who presented at age 9 years 8 months with a history of chronic diarrhea, was only mildly retarded. Both patients had a high percentage of heparan sulfate in the urinary glycosaminoglycans and severe deficiency of N-acetylglucosamine-6-sulfate sulfatase in cultured skin fibroblasts.
Siciliano et al. (1991) reported the cases of 2 adolescent sisters, the daughters of first-cousin Italian parents. The elder child was 19 years old. Her early milestones were mildly delayed: she was able to stand at 1 year and to walk by herself at 2 years. Speech began at the age of 2.5 years and was limited to a few words. At the age of 4 the patient started to show progressive speech loss and aggressive behavior. By age 10 she showed complete loss of contact with her environment and was unable to walk unaided. The younger sister was somewhat less retarded and attended elementary school for 5 years, although with little advance. Enzymatic and immunologic characterization of the patients' fibroblasts indicated deficiency of the enzyme; however, Northern blot analysis showed apparently normal mRNA for N-acetylglucosamine 6-sulfatase; thus, abnormal translation or premature degradation may be responsible for the enzyme defect.
Jansen et al. (2007) provided follow-up on 2 affected Italian Canadian brothers originally reported by Kaplan and Wolfe (1987). Both parents originated from a small community in Abruzzo, Italy, but denied consanguinity. Both boys had developmental delay noted by age 2 and 1 year, respectively. The boys needed special education and showed severe oppositional behavior and school regression in adolescence. The older brother had difficulty walking by age 25 and required a wheelchair. At age 31 and 23 years, respectively, they showed loss of or minimal speech, dysphagia and drooling, and were dependent on assistance for activities of daily living. Physical features included low-set ears, coarse facial features, synophrys, low nasal bridge, anteverted nares, hypertrichosis, and joint contractures. The older brother had decreased vision and the younger brother progressive hearing loss. Both had sleep abnormalities. IQ was estimated to be below 50.
Jansen et al. (2007) reported a 15-year-old Turkish English girl with Sanfilippo syndrome type D with a homozygous mutation in the GNS gene (607664.0004). She was severely retarded and fully dependent on assistance for all activities of daily living.
The transmission pattern of MPS3D in the family reported by Beesley et al. (2003) was consistent with autosomal recessive inheritance.
Kresse et al. (1980) found that cultured skin fibroblasts from 2 patients with clinical features of Sanfilippo syndrome accumulated excessive amounts of heparan sulfate and were unable to release sulfate from N-acetylglucosamine-6-sulfate linkages in heparan sulfate-derived oligosaccharides. Keratan sulfate-derived oligosaccharides bearing the same residue at the nonreducing end were normally degraded. Kinetic differences between the sulfatase activities of normal fibroblasts were found. Thus, the N-acetylglucosamine-6-sulfate sulfatases degrading heparan sulfate and keratan sulfate are distinct. The activity directed against heparan sulfate is deficient in this form of Sanfilippo syndrome, designated type D by Kresse et al. (1980).
From genomic DNA of a patient with MPS IIID, Mok et al. (2003) amplified and sequenced the promoter and 14 exons of GNS and found a homozygous nonsense mutation in exon 9 which predicted a premature termination mutation, arg355 to ter (R355X; 252940.0001). They also found 2 common synonymous coding SNPs and genotyped these in samples from 4 ethnic groups.
Independently, Beesley et al. (2003) reported the molecular diagnosis of Sanfilippo disease type D; in an affected 3-year-old boy, the child of consanguineous Pakistani parents, they identified a homozygous 1-bp deletion in the GNS gene (607664.0002).
Jansen et al. (2007) identified a homozygous mutation in the GNS gene (607664.0003) in the brothers reported by Kaplan and Wolfe (1987).
Elcioglu et al. (2009) reported a 10-year-old Turkish boy with Sanfilippo disease, in whom they identified homozygosity for a 1-bp insertion in the GNS gene (607664.0005). The authors stated that this was the twenty-first patient and the eighth mutation reported for the disease.
Thompson et al. (1992) described type D Sanfilippo syndrome in a Nubian goat.
Takahashi et al. (2021) described neuropathologic findings in a mouse model of type D Sanfilippo syndrome, which had a constitutive knockout of the Gns gene, from 12 to 48 weeks of age, compared with heterozygous Gns mice. Progressive gliosis, as shown by increased GFAP immunostaining, was seen at age 12 weeks in the motor cortex, somatosensory cortex, thalamus, striatum, and entorhinal cortex of the mutant mouse brains and was progressive until age 48 weeks. Microglial activation, demonstrated by increased CD68 immunostaining, was increased starting at age 12 weeks. Lysosomal enlargement and proliferation, as demonstrated by increased LAMP1 (153330) staining, was seen in the mutant mouse brains at age 12 weeks and had age-related progression in some regions. Progressive accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a component of the mitochondrial respiratory chain that accumulates in other lysosomal storage disorders, was seen in most brain regions by 24 weeks of age.
Beesley, C. E., Burke, D., Jackson, M., Vellodi, A., Winchester, B. G., Young, E. P. Sanfilippo syndrome type D: identification of the first mutation in the N-acetylglucosamine-6-sulphatase gene. J. Med. Genet. 40: 192-194, 2003. [PubMed: 12624138] [Full Text: https://doi.org/10.1136/jmg.40.3.192]
Coppa, G. V., Giorgi, P. L., Felici, L., Gabrielli, O., Donti, E., Bernasconi, S., Kresse, H., Paschke, E., Mastropaolo, C. Clinical heterogeneity in Sanfilippo disease (mucopolysaccharidosis III) type D: presentation of two new cases. Europ. J. Pediat. 140: 130-133, 1983. [PubMed: 6411475] [Full Text: https://doi.org/10.1007/BF00441662]
Elcioglu, N. H., Pawlik, P., Colak, B., Beck, M., Wollnik, B. A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D. Genet. Counsel. 20: 133-139, 2009. [PubMed: 19650410]
Gatti, R., Borrone, C., Durand, P., De Virgiliis, S., Sanna, G., Cao, A., von Figura, K., Kresse, H., Paschke, E. Sanfilippo type D disease: clinical findings in two patients with a new variant of mucopolysaccharidosis III. Europ. J. Pediat. 138: 168-171, 1982. [PubMed: 6807676] [Full Text: https://doi.org/10.1007/BF00441147]
Jansen, A. C. M., Cao, H., Kaplan, P., Silver, K., Leonard, G., De Meileir, L., Lissens, W., Liebaers, I., Veilleux, M., Andermann, F., Hegele, R. A., Andermann, E. Sanfilippo syndrome type D: natural history and identification of 3 novel mutations in the GNS gene. Arch. Neurol. 64: 1629-1634, 2007. [PubMed: 17998446] [Full Text: https://doi.org/10.1001/archneur.64.11.1629]
Kaplan, P., Wolfe, L. S. Sanfilippo syndrome type D. J. Pediat. 110: 267-271, 1987. [PubMed: 3100754] [Full Text: https://doi.org/10.1016/s0022-3476(87)80171-3]
Kresse, H., Paschke, E., von Figura, K., Gilberg, W., Fuchs, W. Sanfilippo disease type D: deficiency of N-acetylglucosamine-6-sulfate sulfatase required for heparan sulfate degradation. Proc. Nat. Acad. Sci. 77: 6822-6826, 1980. [PubMed: 6450420] [Full Text: https://doi.org/10.1073/pnas.77.11.6822]
Mok, A., Cao, H., Hegele, R. A. Genomic basis of mucopolysaccharidosis type IIID (MIM 252940) revealed by sequencing of GNS encoding N-acetylglucosamine-6-sulfatase. Genomics 81: 1-5, 2003. [PubMed: 12573255] [Full Text: https://doi.org/10.1016/s0888-7543(02)00014-9]
Siciliano, L., Fiumara, A., Pavone, L., Freeman, C., Robertson, D., Morris, C. P., Hopwood, J. J., Di Natale, P., Musumeci, S., Horwitz, A. L. Sanfilippo syndrome type D in two adolescent sisters. J. Med. Genet. 28: 402-405, 1991. [PubMed: 1908010] [Full Text: https://doi.org/10.1136/jmg.28.6.402]
Takahashi, K., Le, S. Q., Kan, S., Jansen, M. J., Dickson, P. I., Cooper, J. D. Neuropathology of murine Sanfilippo D syndrome. Molec. Genet. Metab. 134: 323-329, 2021. [PubMed: 34844863] [Full Text: https://doi.org/10.1016/j.ymgme.2021.11.010]
Thompson, J. N., Jones, M. Z., Dawson, G., Huffman, P. S. N-acetylglucosamine 6-sulphatase deficiency in a Nubian goat: a model of Sanfilippo syndrome type D (mucopolysaccharidosis IIID). J. Inherit. Metab. Dis. 15: 760-768, 1992. [PubMed: 1434515] [Full Text: https://doi.org/10.1007/BF01800018]