Morquio‐B disease: Clinical and genetic characteristics of a distinct GLB1‐related dysostosis multiplex

Abstract

Background 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. Methods We analyzed 63 (n = 62 published) cases with MBD to describe their clinical, biochemical and genetic features. Results Forty‐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. Conclusion Data provide a basis for future systematic collection of clinical, biochemical, morphologic, and genetic data of this ultra‐rare condition.

Epidemiology of Mucopolysaccharidoses Update

“…This report showed that pure MPS IVB was also observed in a patient carrying R201H homozygous variant and in the majority of the T500A variant. Furthermore, Y333C, G438E, T82M, R201H, and H281Y variants were also reported in the same study [119].…”

“…If the accumulation of keratan sulfate predominates, patients are diagnosed with MPS IVB [ 1 ]. The most common mutations in the GLB1 gene related to MPS IVB are p.Y183H, p.W273L, and p.T500A [ 117 , 118 , 119 ]. Notably, the p.W273L mutation was found commonly among European MPS IVB patients who were unrelated, of which the frequency was 79% of all alleles [ 120 ].…”

Are GMI gangliosidosis and Morquio type B two different disorders or part of one phenotypic spectrum?

“…A significant amount of patients were primarily diagnosed with MorB, but developed neurological symptoms, ranging from delayed achievements of milestones to intellectual disability, dystonia and spasticity. These patients were classified as having intermediate phenotypes or “MorB plus disease” 7 . It seems, therefore, that intermediate patients exhibit symptoms similar to the spectrum of neurological manifestations of GMI gangliosidosis.…”

“…MorB is characterized by a pronounced skeletal phenotype, including midface hypoplasia, mandibular protrusion, short stature with disproportionally short trunk, kyphoscoliosis, sternal protrusion, coxa and genua valga, platyspondyly, vertebral wedging, odontoid hypoplasia, narrow spinal canal, hip dysplasia and dysplasia of metaphysis, and epiphysis of long bones 7 . The skeletal manifestations in GMI gangliosidosis have a significant overlap with MorB.…”

“…Also, GMI gangliosidosis patients with neither KSuria nor oligosacchariduria have been reported 16 . In MorB, some patients have oligosacchariduria, 7,18 and some patients lack KSuria 7 . GMI gangliosides are probably the cause for neurodegeneration in GMI gangliosidosis but are also involved in the pathogenesis of neurological diseases such as Alzheimer's disease 19,20 .…”