Alternative titles; symbols
SNOMEDCT: 130197005, 7259005; ICD10CM: E76.210; ORPHA: 309297, 582; DO: 0111391;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q24.3 | Mucopolysaccharidosis IVA | 253000 | Autosomal recessive | 3 | GALNS | 612222 |
A number sign (#) is used with this entry because mucopolysaccharidosis type IVA (MPS4A; Morquio syndrome A) is caused by homozygous or compound heterozygous mutation in the GALNS gene (612222), which encodes galactosamine-6-sulfate sulfatase, on chromosome 16q24.
See MPS IVB (MPS4B; 253010), also known as Morquio syndrome B, a genetically distinct disorder with overlapping clinical features caused by mutation in the beta-galactosidase gene (GLB1; 611458) on chromosome 3p22.
Mucopolysaccharidosis type IVA is an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system (CNS) involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life (Montano et al., 2008).
McKusick (1972) noted that between 1929 and 1959, a miscellany of skeletal disorders was included in the Morquio category, including various types of spondyloepiphyseal dysplasia (see, e.g., 183900) and multiple epiphyseal dysplasia (see, e.g., 132400).
Nelson et al. (1988) proposed the division of MPS IVA into 3 subgroups: severe classic, intermediate, and mild, reflecting clinical variability observed in 12 enzymatically proven cases. Those who were only mildly affected showed a relatively high residual enzyme activity.
The first cases of Morquio syndrome were likely reported in a French Canadian brother and sister by Osler (1897) as cases of achondroplasia (ACH; 100800) (see McKusick, 1972, p 583, fig 11-23).
Morquio (1929) in Montevideo, Uruguay, and Brailsford (1929) in Birmingham, England, simultaneously and independently described the entity now known to result from a deficiency of galactosamine-6-sulfatase. Morquio (1929) observed the disorder in 4 sibs in a family of Swedish extraction. Notable features included osseous dystrophy, corneal clouding, aortic valve disease, and urinary excretion of keratosulfate.
Greenberg (1968) noted that the dangerous complications of atlantoaxial dislocation due to hypoplasia of the odontoid can occur in Morquio disease and in various forms of spondyloepiphyseal dysplasia.
Gadbois et al. (1973) identified 48 patients from 27 families with Morquio syndrome in the province of Quebec. Total urinary excretion of keratan sulfate was increased 2 to 3 times that of normal, while urinary excretion of total mucopolysaccharide was within normal limits.
Hussels (1974) described an affected woman who had 2 normal children. Her brother was also affected.
Guiney and Stevenson (1982) described a woman with documented Morquio syndrome due to deficiency of N-acetylgalactosamine-6-sulfate sulfatase who survived to the age of 67 years. After suffering for several days from episodes of unexplained and episodic apnea, she was found dead in bed.
Hecht et al. (1984) reported a 14-year-old boy with a very mild form of Morquio syndrome who presented as having nonresolving bilateral Legg-Perthes disease. He had short stature (15th percentile for height) and a short trunk, but did not have pectus carinatum, genu valgum, excessive joint laxity, corneal clouding, or facial changes. Radiographic studies showed mild platyspondyly, anterior wedging of the first lumbar vertebra, and minimal odontoid hypoplasia, as well as abnormal capital femoral epiphyses. N-acetylgalactosamine-6-sulfate sulfatase activity was undetectable in leukocytes and low in fibroblasts. Urine keratan sulfate was increased at 22.9 mg/total volume (normal less than 2 mg/total volume). Together with the cases of Fujimoto and Horwitz (1983) and 2 cases of Holzgreve et al. (1981), this experience suggested the existence of a mild form of MPS IVA.
Beck et al. (1986) suggested that there are severe, intermediate, and mild forms of N-acetylgalactosamine-6-sulfate (GalNAc-6-S) sulfatase deficiency. They described a 30-year-old man who was 156 cm tall and had severe hip disease, fine corneal deposits by slit-lamp, and a wedge-shaped first lumbar vertebra. Although there was no increase in urinary keratosulfate, GALNS activity was markedly decreased in fibroblasts. The authors noted the similarities to so-called 'nonkeratosulfate-excreting Morquio syndrome' (252300), which may be a variant of Morquio A.
In all of 12 patients with MPS IVA, Nelson and Thomas (1988) found odontoid dysplasia in the absence or presence of atlanto-axial instability. In general, the findings correlated well with the overall clinical severity of the condition. The authors emphasized the importance of careful follow-up of these patients for symptoms or signs of cervical cord compression. Proven compromise of the upper cervical cord would be an indication for posterior fusion of the upper cervical spine.
Montano et al. (2008) developed growth curves based on data from 354 patients with Morquio A disease. The mean birth lengths of boys and girls were 52.6 and 52.1 cm, respectively. The mean final heights for males and females at 18 years and older were 122.4 and 113.1 cm, respectively, which corresponded to -7.4 SD for males and -7.7 SD for females compared to controls. The mean body mass index for males and females at or over 18 years of age was 24.7 and 25.6 kg/m(2), respectively. The growth pattern in Morquio A patients was characterized by impaired growth velocity after 1 year of age.
Harmatz et al. (2015) performed a longitudinal analysis of endurance and respiratory function from a natural history study of patients with Morquio A syndrome. The authors used a 6-minute walk test and a 3-minute stair climb test as well as measuring respiratory evaluation by forced vital capacity (FVC) and maximum voluntary ventilation (MVV). At year 0 (baseline), 353 subjects were assessed; at year 1, 184; and at year 2, 78. The overall annualized estimate of change in the 6-minute walk test distance was -4.86 +/- 3.25 m. In contrast, little change (-0.14 +/- 0.60 stairs/min) was observed in the 3-minute stair climb test. Annualized changes in FVC and MVV were 2.44 +/- 0.68% and 1.01 +/- 2.38%, respectively. FVC and MVV increased in patients less than 14 years of age, but decreased in older patients.
Caciotti et al. (2015) reported the clinical data, biochemical assays, molecular analyses, and in silico structural analyses of mutations in 37 MPS IVA patients. Thirty-one patients had the severe phenotype, 3 were intermediate, and 3 were mild. The phenotypic features of the patients were reported in the supplemental material for this paper.
Matalon et al. (1974) concluded that the enzyme deficiency in Morquio disease involves 6-sulfatase, which catalyzes both keratan sulfate and chondroitin sulfate. Di Ferrante et al. (1978) further suggested that the defect concerns galactosamine-6-sulfate sulfatase.
Glossl et al. (1984) found that fibroblasts from some cases of MPS IVA also showed a deficiency of neuraminidase (NEU1; 608272) in addition to the expected deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Residual neuraminidase activity was about 5% of normal, whereas GalNAc-6-S sulfatase activity was less than 1%. Neuraminidase was normal in peripheral leukocytes. Somatic cell hybridization of the patient's fibroblasts with those of another patient with MPS IVA did not correct the sulfatase deficiency, but fusion with sialidosis fibroblasts produced an increase in neuraminidase levels. Restudy of 10 different MPS IVA cell lines showed low neuraminidase in 2 and low normal in 6.
Levin et al. (1975) described the classic oral abnormalities found among 12 patients with Morquio A syndrome. The maxillary anterior teeth were widely spaced and flared, and the posterior teeth were tapered with pointed cusp tips. The enamel was of normal hardness, but some patients had pitted enamel with decreased thickness. The hard palate was broad and flat.
Nelson and Kinirons (1988) found typical dental changes in all of 12 patients with the disorder, although the changes were of variable degree. The dental changes were found only in MPS IVA and not in MPS IVB.
Cahane et al. (1990) reported a brother and sister in their thirties with Morquio syndrome who developed glaucoma, a complication observed in other forms of mucopolysaccharidosis and mucolipidosis.
Borlot et al. (2014) specifically assessed the CNS involvement in 9 Brazilian patients with MPS IVA confirmed by biochemical analysis. The patients ranged in age from 5 to 26 years. All had motor weakness, and 6 had impaired deep sensation. Cognition was normal in all but 1, who had delayed development at age 5. In 7 patients, brain and spinal cord imaging showed variable abnormalities, including clival hypoplasia, basilar invagination, and arachnoid cysts. All patients had odontoid hypoplasia and degenerative features of the neuroaxis, and 8 had spinal cord compression. Borlot et al. (2014) recommended thorough neurologic examination and imaging of all patients with MPS IVA.
In fibroblasts isolated from affected members of 6 families with Morquio syndrome, Danes and Bearn (1967) found no evidence for metachromasia. In contrast, fibroblasts isolated from patients with other forms of mucopolysaccharidosis did show metachromasia. Danes and Bearn (1967) noted that classic Morquio syndrome involves only the skeletal system and postulated that had tissue from the cornea, cartilage, or growing bone been examined, metachromasia may have been present. Based on the findings, the authors suggested that Morquio syndrome should not be classified as a generalized mucopolysaccharidosis.
Nelson et al. (1988) found that examination of urinary glycosaminoglycans by a 2-dimensional electrophoresis technique was a reliable and efficient diagnostic assay with no false-negative results.
Prenatal Diagnosis
Beck et al. (1992) made the diagnosis of MPS IVA in a fetus at 23 weeks of gestation. A previously born child was affected. Ultrasound showed moderate ascites, and keratan sulfate was found in the amniotic fluid. The diagnosis was confirmed after pregnancy termination.
Hendriksz et al. (2014) reported the outcome of a phase 3 randomized placebo-controlled study of elosulfase alfa administered to 176 patients over the age of 5 years with Morquio A syndrome. These patients were randomized (1:1:1) to receive elosulfase alfa 2.0 mg/kg every other week, elosulfase alfa 2.0 mg/kg/week, or placebo for 24 weeks. The primary efficacy measure was a 6-minute walk test distance. Secondary efficacy measures were a 3-minute stair climb test, followed by changes in urine keratan sulfate. Hendriksz et al. (2014) found that elosulfase alfa improved endurance as measured by the 6-minute walk test in the weekly, but not in the every-other-week, dose group; it did not improve endurance on the 3-minute stair climb test, but it did reduce urine keratan sulfate and had an acceptable safety profile.
Charrow et al. (2015) reviewed consensus recommendations for diagnostic evaluation, monitoring, and perioperative management of spinal cord compression that were developed by a multinational, multidisciplinary panel of experts to assess patients with Morquio syndrome.
Hendriksz et al. (2018) reported the outcome of 2 sequential open label studies on treatment with elosulfase alfa in patients with Morquio A syndrome. The first study involved escalating doses of elosulfase alfa of 0.1, 1.0, and 2.0 mg/kg/week in 20 patients, followed by a long-term extension study of 2.0 mg/kg/week in 17 of the first-study participants. Hendriksz et al. (2018) found that urinary keratin sulfate decreased concurrently with increasing doses of elosulfase alfa. Disease stabilization was suggested, as study participants did not seem to have the progressive clinical deterioration that would be expected in an untreated natural history population. Antidrug antibodies were identified in all patients, but this was not associated with changes in clinical parameters, urine keratin sulfate content, or adverse events. There was a favorable safety profile over the 5 years of the studies.
In patients with MPS IVA, Tomatsu et al. (1992) identified 4 different mutations in the GALNS gene (612222.0001-612222.0004).
In 5 unrelated Japanese patients with MPS IVA, Hori et al. (1995) found, in heteroallelic state, 2 separate deletions of nearly 8.0 and 6.0 kb in the GALNS gene. There were Alu repetitive elements near the breakpoints of the 8.0-kb deletion; this deletion had clearly resulted from an Alu-Alu recombination. The 6.0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at the deletion breakpoints. This was the first documentation of a frequently occurring double deletion in a gene that is not a member of a gene cluster. One of the patients was homozygous for the double deletion, and the others were heterozygous. In the 4 heterozygous patients, Tomatsu et al. (1996) identified novel mutations in the GALNS gene on the other allele: 1 nonsense and 3 missense.
Bunge et al. (1997) performed mutation analysis of the GALNS gene in 35 patients with MPS IVA from 33 families, mainly of European origin. By nonradioactive SSCP screening, they identified 35 different gene mutations, 31 of them novel. Together they accounted for 88.6% of the disease alleles of the patients investigated. The great majority of the gene alterations proved to be point mutations, 23 missense, 2 nonsense, and 3 affecting splicing. Six small deletions (1 to 27 bp) and 1 insertion were also characterized. In a Polish family, 2 mildly affected sibs were compound heterozygous for 2 mutations in the GALNS gene: R94G (612222.0008) and R259Q (612222.0009). Their mother, who was homozygous for the R259Q mutation, was found to have greatly reduced enzymatic activity, but only limited manifestations of MPS IVA: short trunk with slight prominence of sternum, and hoarse voice. She had no corneal clouding and was 1.60 m tall.
Analyzing DNA from 21 patients of diverse ethnic and geographic origins by SSCP and sequencing, Tomatsu et al. (1997) detected 16 mutations in the GALNS gene, including 14 new mutations (11 missense, 1 premature termination, 1 splice site alteration, and 1 cryptic site alteration). All 12 missense and nonsense mutations were shown by transient expression to abolish or greatly reduce GALNS activity, thereby providing an explanation as to why they produce MPS IVA. All mutations were readily confirmed by restriction enzyme or allele-specific oligonucleotide analysis. These findings, coupled with previously reported mutations, brought the total of different mutations to 41 among independent families with Morquio syndrome.
Tomatsu et al. (2005) summarized information on 148 unique mutations in the GALNS gene, including 26 novel mutations. Heterogeneity in GALNS mutations accounted for an extensive clinical variability within MPS IVA. They noted that 7 nonsynonymous SNPs and 9 synonymous SNPs had been described. Of the analyzed mutant alleles, missense mutations accounted for 78.4%; small deletions, 9.2%; nonsense mutations, 5.0%; large deletions, 2.4%; and insertions, 1.6%. Transitional mutations at CpG dinucleotides accounted for 26.4% of all the described mutations. Three missense mutations accounted for over 5% of all mutations: R386C (612222.0003), G301C (612222.0010), and I113F (612222.0005).
Caciotti et al. (2015) studied 37 Italian MPS IVA patients and found that standard sequencing procedures failed to characterize the second disease-causing mutation in 16% of patients. Searching for large rearrangements and mRNA defects in this 16% identified splicing defects or large deletions on the other allele in 67% of these. Caciotti et al. (2015) reported 14 novel mutations in GALNS among the 37 patients.
Morquio Syndrome and APRT Deficiency
Wang et al. (1999) described a Czech patient with Morquio syndrome and adenine phosphoribosyltransferase (APRT; 102600) deficiency with subsequent 2,8-dihydroxyadenine urolithiasis, both of which were caused by a 100-kb deletion on chromosome 16q24.3 with breakpoints in intron 2 of the GALNS gene and intron 2 of the APRT gene. Fukuda et al. (1996) described a Japanese patient with a submicroscopic deletion involving GALNS and APRT in one chromosome and a point mutation in the other GALNS allele (R386C; 612222.0003). Wang et al. (1999) concluded that APRT is located telomeric to GALNS on 16q24.3, that GALNS and APRT are transcribed in the same orientation (centromeric to telomeric), and that combined APRT/GALNS deficiency may be more common than hitherto realized.
Sukegawa et al. (2000) studied 15 missense mutations and 2 newly engineered active site mutations (C79S, C79T) in the GALNS gene by transient expression analysis. Mutant proteins, except for C79S and C79T, were destabilized and detected as insoluble precursor forms, while the C79S and C79T mutants were of a soluble mature size. Mutations identified in patients with the severe phenotype had no activity, whereas mutations identified in patients with the mild phenotype had a considerable residual activity (1.3-13.3% of wildtype GALNS activity). Sukegawa et al. (2000) also constructed a tertiary structural model of human GALNS from the x-ray crystal structure of homologous sulfatases and investigated 32 missense mutations. The authors proposed 3 different biochemical models for the severe phenotype: (i) destruction of the hydrophobic core or modification of the packing; (ii) removal of a salt bridge to destabilize the entire conformation; (iii) modification of the active site. In contrast, mild mutations were mostly located on the surface of the GALNS protein.
In British Columbia, between 1952 and 1986, 6 cases of MPS IVA were observed, yielding a frequency of 1 in 216,412 live births (Lowry et al., 1990).
Using multiple ascertainment sources, Nelson et al. (2003) obtained an incidence rate for MPS IVA in western Australia for the period 1969 to 1996 of approximately 1 in 640,000 live births.
Wang et al. (2010) identified 27 GALNS mutations, including 16 novel mutations, among 24 Chinese patients with MPS IVA. Approximately 63% of the mutations found in the Chinese patients were not observed in other countries, suggesting that a different mutational spectrum may exist in the Chinese population. The most common mutation G340D (612222.0018) was present in 8 (16.7%) of 48 mutant alleles and was found only in 5 patients from central eastern China. Haplotype analysis indicated a founder effect.
Caciotti et al. (2015) reported a population incidence for MPS IVA of about 1 in 300,000 live births in Italy.
Khan et al. (2017) analyzed the epidemiology of the mucopolysaccharidoses in Japan and Switzerland and compared them to similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II (309900), accounting for 55% of all MPS. MPS I (see 607014), III (see 252900), and IV accounted for 15%, 16%, and 10%, respectively. MPS VI (253200) and VII (253220) were more rare and accounted for 1.7% and 1.3%, respectively. A retrospective epidemiologic data collection was performed in Switzerland between 1975 and 2008 (34 years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12%, 24%, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3% and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS was also reported to be higher in these countries.
Wiedemann (1992) provided a biographic sketch of Luis Morquio (1867-1935) of Montevideo. Chudley and Chakravorty (2002) published illustrations of 2 Uruguayan postal stamps honoring Morquio, one issued in 1969 and the other in 2001.
Bernal and Briceno (2006) examined pottery artifacts from the Tumaco-La Tolita culture, which existed on the border of present-day Colombia and Ecuador approximately 2,500 years ago, and described multiple figurines of an adult with apparent short stature, coarse facies, short nose, short neck, small thorax, and the left shoulder set higher than the right, findings suggestive of mucopolysaccharidosis IV. Bernal and Briceno (2006) believed these artifacts to be among the earliest artistic representations of disease.
Tomatsu et al. (2003) generated transgenic mice homozygous for a disruption in exon 2 of the Galns gene. These mice had no detectable GALNS enzyme activity, showed increased urinary glycosaminoglycan levels, and accumulated glycosaminoglycans in multiple tissues including liver, kidney, spleen, heart, brain, and bone marrow. At 2 months old, lysosomal storage was present primarily within reticuloendothelial cells. By 12 months old, vacuolar change was observed in glomeruli and heart valves. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage, and keratan sulfate and chondroitin-6-sulfate were more abundant in corneal epithelial cells of Galns -/- mice. Surprisingly, radiographs revealed no change in the skeletal bones of mice up to 12 months old.
Tomatsu et al. (2008) found that weekly treatment of MPS IVA mice for 12 weeks with enzyme replacement using native GALNS or SUMF1-modified GALNS resulted in clinical improvement, manifest by a marked reduction of storage material in visceral organs, bone marrow, heart valves, ligaments, and connective tissue. Pharmacokinetics and biodistribution were assessed and found to be similar for the 2 GALNS enzymes used. There was a dose-dependent clearance of storage material observed in brain, and blood keratan sulfate was reduced to nearly normal levels. The study provided proof of concept for enzyme replacement therapy in MPS IVA.
Tomatsu et al. (2008) had noted lack of improvement in bone pathology in MPS IVA mice treated with long-term enzyme replacement therapy (ERT). Tomatsu et al. (2015) administered recombinant enzymes to newborn mice: the first injection was administered intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from the fifth to fourteenth weeks were intravenous into the tail vein. MPS4A mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was better organized than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to treatment. Levels of serum keratan sulfate were kept normal in newborn ERT-treated mice. Tomatsu et al. (2015) concluded that the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice.
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