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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 ?-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.

SUBMITTER: Abumansour IS

PROVIDER: S-EPMC7012745 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Morquio-B disease: Clinical and genetic characteristics of a distinct <i>GLB1</i>-related dysostosis multiplex.

Abumansour Iman S IS Yuskiv Nataliya N Paschke Eduard E Stockler-Ipsiroglu Sylvia S

JIMD reports 20191128 1

<h4>Background</h4>Morquio-B disease (MBD) is a distinct <i>GLB1</i>-related dysostosis multiplex involving the trabecular parts of long bones and spine, presenting a mild phenocopy of <i>GALNS</i>-related Morquio-A disease.<h4>Methods</h4>We analyzed 63 (n = 62 published) cases with MBD to describe their clinical, biochemical and genetic features.<h4>Results</h4>Forty-one of 51 cases with informative clinical data had <i>pure MBD</i> including progressive growth impairment, kyphoscoliosis, coxa ...[more]

PMID: 32071837

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Project description:Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.

Dataset Information

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

Publications

Morquio-B disease: Clinical and genetic characteristics of a distinct <i>GLB1</i>-related dysostosis multiplex.

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