Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 65764006; ORPHA: 423461, 577; DO: 0080071;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q23.2 | Mucolipidosis III alpha/beta | 252600 | Autosomal recessive | 3 | GNPTAB | 607840 |
A number sign (#) is used with this entry because of evidence that mucolipidosis III alpha/beta, also known as pseudo-Hurler polydystrophy, is caused by homozygous or compound heterozygous mutation in the gene encoding the alpha/beta-subunits precursor gene of GLcNAc-phosphotransferase (GNPTAB; 607840).
Mucolipidosis II alpha/beta, or I-cell disease (252500), is also caused by mutations in the GNPTAB gene. A mucolipidosis III variant, ML III gamma (252605), is caused by mutation in the gene encoding the gamma subunit, GNPTG (607838).
Cathey et al. (2008) reported an updated nomenclature classification system for mucolipidosis II and III. ML II was renamed ML II alpha/beta; ML IIIA was renamed ML III alpha/beta; and ML IIIC was renamed ML III gamma.
Mucolipidosis type III alpha/beta is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically less severe than the allelic disorder mucolipidosis type II alpha/beta (summary by Paik et al., 2005).
Under the designation 'pseudo-polydystrophie de Hurler,' Maroteaux and Lamy (1966) described 4 cases with many of the features of the Hurler syndrome but a much slower clinical evolution and no mucopolysacchariduria. The bone marrow contained cells reminiscent of those in the Hurler syndrome but vacuoles were empty. Hypoplasia of the odontoid was noted in at least 1 case. The authors pointed out that this was probably the condition present in a patient listed among 'cases defying classification' in the report of McKusick et al. (1965). At least 1 brother-sister pair proved to have a form of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome; 253200).
In Freiburg, Germany, Schinz and Furtwaengler (1928) described a sibship of 11, the offspring of a first-cousin marriage, in which a man then 29 years old and 3 of his sisters were identically affected by a disorder in which a striking feature was stiff joints. Flexion contracture in the fingers and toes was combined with reduced mobility in the ankles, wrists, knees, elbows, hips, shoulders and spine. The face was red with somewhat prominent forehead, broad nose and fleshy tongue. Intelligence was normal. Umbilical hernia was present in the male, whose height was 61.4 inches. X-rays showed thick skull, short posterior cranial fossa, and prominent external and internal occipital protuberance. A striking feature was extensive destruction or disturbance in the development of the carpal and tarsal bones. Horsch (1934) described a sister from the same sibship whose features, including those in the carpal and tarsal bones, were identical. The brother was restudied with description of cysts in the head of the humerus and the epiphysis of the radius and digits.
Langer et al. (1966) described a 61-year-old male who appeared to have the same disorder, including changes in the joints, carpal and tarsal bones, and cornea. The urine contained no excess of acid mucopolysaccharide but did have an excess of a glycoprotein. Not surprisingly, in view of the progressive stiffness of the hands and flexion contractures of fingers accompanied by other musculoskeletal changes, these patients are often thought to have a rheumatologic disorder (Brik et al., 1993).
The sibs reported by Steinbach et al. (1968) appear to have had this condition.
Freisinger et al. (1992) described a sister and brother with a very mild form of ML III, manifested only by isolated involvement of the hips and very mild abnormalities of the spine. Discrete opacifications of the cornea were found on slit-lamp examination. Serum levels of several lysosomal hydrolases were considerably increased. Mild disease was reported also by Ward et al. (1993) in 4 sibs from Baluchistan. Ranging from 7 to 12 years of age, they showed claw hands, joint stiffness, aortic valve involvement and radiologic dysostosis multiplex. The patients reported by Ward et al. (1993) were thought to fall into complementation group C.
Tylki-Szymanska et al. (2002) reported 3 patients with ML III who demonstrated the clinical variability of this condition and compared their biochemical results and clinical pictures with cases in the literature. One patient was a 13-year-old girl whose only symptoms were joint stiffness of the hands. The other 2 patients were a 5-year-old boy with a severe form of ML III and his 2-year-old sister who was less affected than he was at the same age.
In a 39-year-old patient with pseudo-Hurler polydystrophy, Shinkai et al. (1994) observed a huge connective tissue nevus on his back. The lesional skin was composed of densely packed, coarse collagen fibers, which were immunohistochemically found to consist of type I, type III, and type VI collagens. The amount of elastic fibers was moderately reduced. The glucosaminoglycan content of lesional skin was similar to that in a normal control. Activities of several glycosidases were markedly decreased in cultured fibroblasts.
It is possible that some cases of ML II (252500) and some cases of ML III represent homozygosity for different mutant genes at the same locus, namely, one determining a 'recognition marker' for multiple lysosomal enzymes. Sialidase deficiency similar to that in ML II was found in ML III by Thomas et al. (1976). Furthermore, Berman et al. (1974) found quantitatively and qualitatively abnormal glycoprotein components in the urine in 2 sibs with ML II. Both ML II and ML III show a marked deficiency of fibroblast UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. As a consequence, the common phosphomannosyl recognition marker of acid hydrolases is not generated, and these enzymes are not directed to the lysosomes.
Varki et al. (1981) developed a sensitive assay for the transferase that uses alpha-methyl mannoside as the acceptor. With the assay, a difference in enzyme activity was found to distinguish the 2 mucolipidoses. Enzyme activity was less than 0.4-2.0 pmol-mg per hr in ML II and 2.9-39.4 pmol-mg per hr in ML III. The difference in clinical severity may be explained thereby. Varki et al. (1981) found that the fibroblasts from 2 sibs with ML III (GM 3391 and GM 3392) had normal enzyme activity when measured with the assay using alpha-methyl mannose as acceptor but a low activity when assayed with endogenous acceptor. Mixing experiments showed the presence of endogenous acceptors and lack of inhibitors in the mutant fibroblasts. The authors concluded that the N-acetylglucosaminylphosphotransferase of the mutant fibroblasts has normal catalytic activity but is defective in its ability to recognize lysosomal enzymes as specific substrates for phosphorylation.
There is more than one cause of the pseudo-Hurler polydystrophy phenotype. Of 18 patients studied by Kelly et al. (1975), only 12 of them met the biochemical and ultrastructural criteria for ML III. One apparently typical case proved to have a form of the Maroteaux-Lamy syndrome. Gericke (1977) described the disorder in 2 sisters, aged 27 and 12 years. Other cases probably represent some disorder not cataloged here.
Gatti et al. (1985) concluded that 3 children with mucolipidosis III were homozygous also for the common variant alpha-L-fucosidase trait (136820), which is accompanied by low activity of the enzyme in plasma but no clinical abnormality as a rule. Thus, plasma alpha-L-fucosidase levels, which are usually elevated in ML III, were normal in these patients.
By cell complementation studies, Gravel et al. (1981) and Honey et al. (1982) demonstrated the existence of 3 complementation groups, designated A, B, and C. Group A appears to be the most common of the 3; many I-cell disease patients fall within this group (Mueller et al., 1983). Group C is less common and group B is probably very rare. Patients with cells showing normal phosphotransferase activity toward alpha-methylmannoside as an acceptor are within complementation group C, and patients with cells showing deficient activity toward both alpha-methylmannoside and lysosomal enzymes are in groups A and B. A possible explanation (Little et al., 1986) of these and other findings is that the phosphotransferase possesses 2 domains: a catalytic site (which is defective in group A patients) and a region important for recognition of lysosomal enzymes (which is defective in group C patients).
Robinson et al. (2002) reported 2 sibs with ML III that suggested the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic, and histologic criteria. Robinson et al. (2002) suggested that bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease.
The transmission pattern of mucolipidosis III alpha/beta is autosomal recessive (Steet et al., 2005, Tiede et al., 2005, Paik et al., 2005).
Canfield et al. (1998) found that in 2 of 2 patients with mucolipidosis IIIA, the GlcNAc-phosphotransferase alpha/beta transcript (GNPTAB; 607840) was present but greatly reduced. In 4 of 4 patients with mucolipidosis II, the GNPTAB transcript was absent. In all ML II and ML III patients examined, the GNPTAG transcript (607838) was present at normal levels.
In a 47-year-old female who presented with dilated cardiomyopathy and mild neuropathy and was found to have mucolipidosis III, Steet et al. (2005) identified a homozygous splice site mutation in the GNPTAB gene (607840.0001). The patient, who exhibited none of the connective tissue anomalies characteristic of mucolipidosis III, was found to have a minimal amount of functional enzyme present in fibroblasts. The authors stated that this was the first example of the disease presenting in an adult patient.
In a 14-year-old boy who had mild clinical, radiographic, and biochemical findings of mucolipidosis III, including joint stiffness, dysostosis multiplex, and elevated serum levels of lysosomal enzymes but no mental retardation, corneal clouding, or valvular heart disease, Tiede et al. (2005) identified homozygosity for a missense mutation in the GNPTAB gene (607840.0002). The patient was also homozygous for an ala663-to-gly substitution in the GNPTAB gene that was deemed a polymorphism because it was found in 5% of normal alleles. Both parents were heterozygous for both mutations.
In 2 unrelated Korean girls with type IIIA mucolipidosis, Paik et al. (2005) identified compound heterozygosity for 3 different mutations in the GNPTAB gene (607840.0008-607840.0009).
Bargal et al. (2006) studied GNPTA mutations in 24 patients. They suggested that there is a clinical continuum between ML III and ML II, and that the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.
Otomo et al. (2009) identified 18 GNPTAB mutations, including 14 novel mutations, among 25 unrelated Japanese patients with ML II and 15 Japanese patients with ML III. The most common mutations were R1189X (607840.0004), which was found in 41% of alleles, and F374L (607840.0015), which was found in 10% of alleles. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the more severe phenotype. In all, 73 GNPTAB mutations were detected in the 80 alleles. In a review of the reported clinical features, most ML II patients had impairment in standing alone, walking without support, and speaking single words compared to those with ML III. The frequencies of heart murmur, inguinal hernia, and hepatomegaly and/or splenomegaly did not differ between ML II and III patients.
Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being a 2-bp deletion (607840.0011) that was found in 45% of the mutant alleles; one patient was homozygous for a missense mutation. Three additional patients with a less severe phenotype consistent with ML III had missense mutations. Encarnacao et al. (2009) concluded that patients with ML II alpha/beta are almost all associated with the presence of nonsense or frameshift mutations in homozygosity, whereas the presence of at least 1 mild mutation in the GNPTAB gene is associated with ML III alpha/beta.
Bargal, R., Zeigler, M., Abu-Libdeh, B., Zuri, V., Mandel, H., Neriah, Z. B., Stewart, F., Elcioglu, N., Hindi, T., Le Merrer, M., Bach, G., Raas-Rothschild, A. When mucolipidosis III meets mucolipidosis II: GNPTA gene mutations in 24 patients. Molec. Genet. Metab. 88: 359-363, 2006. Note: Erratum: Molec. Genet. Metab. 91: 299 only, 2007. [PubMed: 16630736] [Full Text: https://doi.org/10.1016/j.ymgme.2006.03.003]
Berman, E. R., Kohn, G., Yatziv, S., Stein, H. Acid hydrolase deficiencies and abnormal glycoproteins in mucolipidosis III (pseudo-Hurler polydystrophy). Clin. Chim. Acta 52: 115-124, 1974. [PubMed: 4208016] [Full Text: https://doi.org/10.1016/0009-8981(74)90394-5]
Brik, R., Mandel, H., Aizin, A., Goldscher, D., Ziegler, M., Bialik, V., Berant, M. Mucolipidosis III presenting as a rheumatological disorder. J. Rheum. 20: 133-136, 1993. [PubMed: 8441145]
Canfield, W. M., Bao, M., Pan, J., Brewer, A. D. K., Pan, H., Roe, B., Raas-Rothschild, A. Mucolipidosis II and mucolipidosis IIIA are caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene on chromosome 12p. (Abstract) Am. J. Hum. Genet. 63: A15 only, 1998.
Cathey, S. S., Kudo, M., Tiede, S., Raas-Rothschild, A., Braulke, T., Beck, M., Taylor, H. A., Canfield, W. M., Leroy, J. G., Neufeld, E. F., McKusick, V. A. Molecular order of mucolipidosis II and III nomenclature. (Letter) Am. J. Med. Genet. 146A: 512-513, 2008. [PubMed: 18203164] [Full Text: https://doi.org/10.1002/ajmg.a.32193]
Encarnacao, M., Lacerda, L., Costa, R., Prata, M. J., Coutinho, M. F., Ribeiro, H., Lopes, L., Pineda, M., Ignatius, J., Galvez, H., Mustonen, A., Vieira, P., Lima, M. R., Alves, S. Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations. Clin. Genet. 76: 76-84, 2009. [PubMed: 19659762] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01185.x]
Freisinger, P., Padovani, J. C., Maroteaux, P. An atypical form of mucolipidosis III. J. Med. Genet. 29: 834-836, 1992. [PubMed: 1453439] [Full Text: https://doi.org/10.1136/jmg.29.11.834]
Gatti, R., Lombardo, C., Cardo, P. P. Homozygosity for the variant alpha-L-fucosidase trait and mucolipidosis III. Hum. Genet. 70: 71-73, 1985. [PubMed: 3997153] [Full Text: https://doi.org/10.1007/BF00389462]
Gericke, G. J. Mucolipidosis III: two patients displaying genetic pleiotropism. S. Afr. Med. J. 51: 140-144, 1977. [PubMed: 850847]
Gravel, R. A., Gravel, Y. L., Miller, A. L., Lowden, J. A. Genetic complementation analysis of I-cell disease and pseudo-Hurler polydystrophy. In: Callahan, J. W.; Lowden, J. A.: Lysosomes and Lysosomal Storage Diseases. New York: Raven Press (pub.) 1981. Pp. 289-298.
Honey, N. K., Mueller, O. T., Little, L. E., Miller, A. L., Shows, T. B. Mucolipidosis III is genetically heterogeneous. Proc. Nat. Acad. Sci. 79: 7420-7424, 1982. [PubMed: 6961420] [Full Text: https://doi.org/10.1073/pnas.79.23.7420]
Horsch, K. Ueber hereditaere degenerative Osteoarthropathie. Arch. Orthop. Unfallchir. 34: 536-540, 1934.
Kelly, T. E., Thomas, G. H., Taylor, H. A., Jr., McKusick, V. A., Sly, W. S., Glaser, J. H., Robinow, M., Luzzatti, L., Espiritu, C., Feingold, M., Bull, M. J., Ashenhurst, E. M., Ives, E. J. Mucolipidosis III (pseudo-Hurler polydystrophy): clinical and laboratory studies in a series of 12 patients. Johns Hopkins Med. J. 137: 156-175, 1975. [PubMed: 810612]
Langer, L. O., Jr., Kronenberg, R. S., Gorlin, R. J. A case simulating Hurler syndrome of unusual longevity, without abnormal mucopolysacchariduria: a proposed classification of the various forms of the syndrome and similar diseases. Am. J. Med. 40: 448-457, 1966.
Little, L. E., Mueller, O. T., Honey, N. K., Shows, T. B., Miller, A. L. Heterogeneity of N-acetylglucosamine 1-phosphotransferase within mucolipidosis III. J. Biol. Chem. 261: 733-738, 1986. [PubMed: 3001079]
Maroteaux, P., Lamy, M. La pseudo-polydystrophie de Hurler. Presse Med. 74: 2889-2892, 1966. [PubMed: 4958870]
McKusick, V. A., Kaplan, D., Wise, D., Hanley, W. B., Suddarth, S. B., Sevick, M. E., Maumenee, A. E. The genetic mucopolysaccharidoses. Medicine 44: 445-483, 1965. [PubMed: 4221470] [Full Text: https://doi.org/10.1097/00005792-196511000-00001]
McKusick, V. A. Heritable Disorders of Connective Tissue. (4th ed.) St. Louis: C. V. Mosby (pub.) 1972.
Mueller, O. T., Honey, N. K., Little, L. E., Miller, A. L., Shows, T. B. Mucolipidosis II and III: the genetic relationships between two disorders of lysosomal enzyme biosynthesis. J. Clin. Invest. 72: 1016-1023, 1983. [PubMed: 6309902] [Full Text: https://doi.org/10.1172/JCI111025]
Otomo, T., Muramatsu, T., Yorifuji, T., Okuyama, T., Nakabayashi, H., Fukao, T., Ohura, T., Yoshino, M., Tanaka, A., Okamoto, N., Inui, K., Ozono, K., Sakai, N. Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation. J. Hum. Genet. 54: 145-151, 2009. [PubMed: 19197337] [Full Text: https://doi.org/10.1038/jhg.2009.3]
Paik, K. H., Song, S. M., Ki, C. S., Yu, H.-W., Kim, J. S., Min, K. H., Chang, S. H., Yoo, E. J., Lee, I. J., Kwan, E. K., Han, S. J., Jin, D.-K. Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II or type IIIA. Hum. Mutat. 26: 308-314, 2005. [PubMed: 16116615] [Full Text: https://doi.org/10.1002/humu.20205]
Robinson, C., Baker, N., Noble, J., King, A., David, G., Sillence, D., Hofman, P., Cundy, T. The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment. J. Inherit. Metab. Dis. 25: 681-693, 2002. [PubMed: 12705498] [Full Text: https://doi.org/10.1023/a:1022935115323]
Schinz, H. R., Furtwaengler, A. Zur Kenntnis einer hereditaeren Osteoarthropathie mit rezessivem Erbgang. Dtsch. Z. Chir. 207: 398-416, 1928.
Schmidt, R. Eine bisher nicht beschriebene Form familiaerer Hornhautentartung in Verbindung mit Osteoarthropathie. Klin. Monatsbl. Augenheilkd. 100: 616-620, 1938.
Shinkai, H., Katagiri, K., Ishii, Y., Takayasu, S. Connective tissue naevus with pseudo-Hurler polydystrophy. Brit. J. Derm. 130: 528-533, 1994. [PubMed: 8186124] [Full Text: https://doi.org/10.1111/j.1365-2133.1994.tb03392.x]
Steet, R. A., Hullin, R., Kudo, M., Martinelli, M., Bosshard, N. U., Schaffner, T., Kornfeld, S. Steinmann, B. A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy. Am. J. Med. Genet. 132A: 369-375, 2005. [PubMed: 15633164] [Full Text: https://doi.org/10.1002/ajmg.a.30498]
Steinbach, H. L., Preger, L., Williams, H. E., Cohen, P. The Hurler syndrome without abnormal mucopolysacchariduria. Radiology 90: 472-478, 1968. [PubMed: 4230591] [Full Text: https://doi.org/10.1148/90.3.472]
Strecker, G., Peers, M.-C., Michalski, J.-C., Hondi-Assah, T., Fournet, B., Spik, G., Montreuil, J., Farriaux, J.-P., Maroteaux, P., Durand, P. Structure of nine sialyl-oligosaccharides accumulated in urine of eleven patients with three different types of sialidosis (mucolipidosis II and two new types of mucolipidosis). Europ. J. Biochem. 75: 391-403, 1977. [PubMed: 885137] [Full Text: https://doi.org/10.1111/j.1432-1033.1977.tb11540.x]
Thomas, G. H., Tiller, G. E., Jr., Reynolds, L. W., Miller, C. S., Bace, J. W. Sialidase deficiency in mucolipidosis II (I-cell disease) and mucolipidosis III (pseudo-Hurler polydystrophy). (Abstract) 5th International Congress of Human Genetics, Mexico City 1976.
Tiede, S., Muschol, N., Reutter, G., Cantz, M., Ullrich, K., Braulke, T. Missense mutations in N-acetylglucosamine-1-phosphotransferase alpha/beta subunit gene in a patient with mucolipidosis III and a mild clinical phenotype. Am. J. Med. Genet. 137A: 235-240, 2005. [PubMed: 16094673] [Full Text: https://doi.org/10.1002/ajmg.a.30868]
Traboulsi, E. I., Maumenee, I. H. Ophthalmologic findings in mucolipidosis III (pseudo-Hurler polydystrophy). Am. J. Ophthal. 102: 592-597, 1986. [PubMed: 3777077] [Full Text: https://doi.org/10.1016/0002-9394(86)90529-5]
Tylki-Szymanska, A., Czartoryska, B., Groener, J. E. M., Lugowska, A. Clinical variability in mucolipidosis III (pseudo-Hurler polydystrophy). Am. J. Med. Genet. 108: 214-218, 2002. [PubMed: 11891688] [Full Text: https://doi.org/10.1002/ajmg.10224]
Varki, A. P., Reitman, M. L., Kornfeld, S. Identification of a variant of mucolipidosis III (pseudo Hurler polydystrophy): a catalytically active N-acetylglucosaminylphosphotransferase that fails to phosphorylate lysosomal enzymes. Proc. Nat. Acad. Sci. 78: 7773-7777, 1981. [PubMed: 6461005] [Full Text: https://doi.org/10.1073/pnas.78.12.7773]
Ward, C., Singh, R., Slade, C., Fensom, A. H., Fahmy, A., Semrin, A., Sjovall, A., Talat, A., Hasilik, A., Klein, I., Benson, P. F. A mild form of mucolipidosis type III in four Baluch siblings. Clin. Genet. 44: 313-319, 1993. [PubMed: 8131303] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03907.x]