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 ... 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 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.
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 ... 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.
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, ... 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.
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 ... 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 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 ... 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). - 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.
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 ... 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.