Abstract
BackgroundMorquio‐B disease (MBD) is a distinct GLB1‐related dysostosis multiplex involving the trabecular parts of long bones and spine, presenting a mild phenocopy of GALNS‐related Morquio‐A disease.MethodsWe analyzed 63 (n = 62 published) cases with MBD to describe their clinical, biochemical and genetic features.ResultsForty‐one of 51 cases with informative clinical data had pure MBD including progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly, odontoid hypoplasia. Ten of 51 had MBD plus neuronopathic manifestations including intellectual/developmental/speech delay, spasticity, ataxia dystonia. Corneal clouding, cardiac valve pathology, hepatosplenomegaly, spinal cord compression were infrequent and atlantooccipital dislocation, cardiomyopathy and cherry red spot were never reported. Urinary glycosaminoglycan and oligosaccharide excretion was consistently abnormal. Keratan sulphate‐derived oligosaccharides were only detected using LC‐MS/MS‐based methods. Residual β‐galactosidase activities measured against synthetic substrates were 0%‐17%.Among 28 GLB1 variants, W273 L (34/94 alleles) and T500A (11/94 alleles) occurred most frequently. W273L was invariably associated with pure MBD. Pure MBD also was reported in a case homozygous for R201H, and in the majority of cases carrying the T500A variant. Homozygous Y333C and G438E were associated with MBD plus neuronopathic manifestations. T82M, R201H, and H281Y, observed in seven alleles, previously have been found sensitive to experimental chaperones.ConclusionData provide a basis for future systematic collection of clinical, biochemical, morphologic, and genetic data of this ultra‐rare condition.
Highlights
Morquio-B disease (MBD) is a distinct GLB1-related dysostosis multiplex involving the trabecular parts of long bones and spine, presenting a mild phenocopy of GALNS-related Morquio-A disease
Morquio-B disease (MBD) (OMIM 253010)[4] is a distinct form of GLB1related disorder presenting with a specific type of dysostosis multiplex which has been known as Morquio syndrome since its first description by Morquio[5] and Brailsford.[6]
The remaining 10 cases showed additional primary neuronopathic manifestations. These findings indicate that GLB1-related MBD occurs in two forms: pure MBD and MBD plus neuronopathic manifestations
Summary
GLB1-related disorders are caused by a deficiency of β-galactosidase, a lysosomal enzyme facilitating the degradation of complex carbohydrates bound to a variety of structurally unrelated molecules such as gangliosides, proteoglycans, and N- and Olinked glycoproteins. Morquio-B disease (MBD) (OMIM 253010)[4] is a distinct form of GLB1related disorder presenting with a specific type of dysostosis multiplex which has been known as Morquio syndrome since its first description by Morquio[5] and Brailsford.[6]. The β-galactosidase monomer consists of two β-domains and a TIM barrel domain, which together generate appropriate protein folding and Synopsis GLB1-related Morquio-B disease (MBD) is a distinct dysostosis multiplex resembling mild forms of GALNS-related Morquio-A disease and occurs as pure skeletal MBD and as MBD plus neuronopathic phenotype. While accumulation of GM1-gangliosides in the brain seems most responsible for neurologic manifestations in GM1-gangliosidosis, excretion of both skeletal and corneal forms of keratan sulfate has been shown in MBD and type 1 (infantile) GM1-gangliosidosis.[10]. Numerous other alleles have been found in both GM1-gangliosidosis and in MBD.[11,13,15-17] but the type and degree of overlap between pure skeletal and neuronopathic phenotypes is hard to predict. We reviewed published data on potentials of small molecules for allele specific rescue of β-galactosidase activity for those alleles identified in the reported MBD cases
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