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Family study of a novel mutation of mucopolysaccharidosis type VI with a severe phenotype and good response to enzymatic replacement therapy: Case report.

ABSTRACT: RATIONALE:Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is produced by the deficiency of the enzyme arylsulfatase B, responsible for the hydrolysis of N-acetyl-D-galactosamine, chondroitin sulfate, and dermatan sulfate. PATIENT CONCERNS:A 3-year-old male with Moroccan origins is the index case. He had healthy consanguineous parents and 4 healthy brothers and sisters. The patient showed a wide spectrum of symptoms including skeletal dysplasia and short stature with elevated glycosaminoglycans (GAGs) in urine. DIAGNOSES, INTERVENTIONS, AND OUTCOMES:GAGs were quantified by spectrometry method with 1,9-dimethylen blue in 24-hour urine samples. The qualitative analysis of urine GAGs was obtained by thin-layer chromatography to determine the predominant presence of dermatan sulfate. The activities of both arylsulfatase B and beta-galactosidase as well as genetic studies were performed in dried blood spots. The genetic study was performed with deoxyribonucleic acid by massive sequencing a of lisosomal storage diseases. Results showed a new mutation c.263A?>?C with the severe phenotype in homozygous in the patient. The familiar study of ARSB and GLB1 genes presented some asymptomatic SNPs but with a discrete decrease in the activity of arylsulfatase B and beta-galactosidase. After an early detection by pediatricians, and both enzymatic and genetic confirmation, the patient had a good response to substitutive enzymatic treatment with galsulfase. LESSONS:Mucoplysaccharidosis type VI is an autosomal recessive rare disease characterized by a lysosomal storage disorder. Although a number of mutations have been already associated to the disease, we have found a new mutation located in the arylsulfatase B enzyme gene. We have described that this mutation is the ultimate cause of a severe presentation of the disease.

SUBMITTER: Ley-Martos M

PROVIDER: S-EPMC6211882 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Family study of a novel mutation of mucopolysaccharidosis type VI with a severe phenotype and good response to enzymatic replacement therapy: Case report.

Ley-Martos Myriam M Guerrero Juan M JM Lucas-Javato Marta M Remón-García Cristina C García-Lozano J Raúl JR Colón Cristóbal C Crujeiras Pablo P Rodrigues Daniel D Paúl-Sánchez Pedro P Macher Hada C HC

Medicine 20181001 42

<h4>Rationale</h4>Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is produced by the deficiency of the enzyme arylsulfatase B, responsible for the hydrolysis of N-acetyl-D-galactosamine, chondroitin sulfate, and dermatan sulfate.<h4>Patient concerns</h4>A 3-year-old male with Moroccan origins is the index case. He had healthy consanguineous parents and 4 healthy brothers and sisters. The patient showed a wide spectrum of symptoms including skeletal dysplasia and short stature w ...[more]

PMID: 30335002

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Project description:Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 microg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.

Project description:Mucopolysaccharidosis VI (MPS VI) is a hereditary lysosomal storage disease caused by the absence of the enzyme arylsulfatase B (ARSB). Craniofacial defects are common in MPS VI patients and manifest as abnormalities of the facial bones, teeth, and temporomandibular joints. Although enzyme replacement therapy (ERT) is the treatment of choice for MPS VI, the effects on the craniofacial and dental structures are still poorly understood. In this study, we used an Arsb-deficient mouse model (Arsb m/m ) that mimics MPS VI to investigate the effects of ERT on dental and craniofacial structures and compared these results with clinical and radiological observations from three MPS VI patients. Using micro-computed tomography, we found that the craniofacial phenotype of the Arsb m/m mice was characterized by bone exostoses at the insertion points of the masseter muscles and an overall increased volume of the jaw bone. An early start of ERT (at 4 weeks of age for 20 weeks) resulted in a moderate improvement of these jaw anomalies, while a late start of ERT (at 12 weeks of age for 12 weeks) showed no effect on the craniofacial skeleton. While teeth typically developed in Arsb m/m mice, we observed a pronounced loss of tooth-bearing alveolar bone. This alveolar bone loss, which has not been described before in MPS VI, was also observed in one of the MPS VI patients. Interestingly, only an early start of ERT led to a complete normalization of the alveolar bone in Arsb m/m mice. The temporomandibular joints in Arsb m/m mice were deformed and had a porous articular surface. Histological analysis revealed a loss of physiological cartilage layering, which was also reflected in an altered proteoglycan content in the cartilage of Arsb m/m mice. These abnormalities could only be partially corrected by an early start of ERT. In conclusion, our results show that an early start of ERT in Arsb m/m mice achieves the best therapeutic effects for tooth, bone, and temporomandibular joint development. As the MPS VI mouse model in this study resembles the clinical findings in MPS VI patients, our results suggest enzyme replacement therapy should be started as early as possible.

Dataset Information

Family study of a novel mutation of mucopolysaccharidosis type VI with a severe phenotype and good response to enzymatic replacement therapy: Case report.

Publications

Family study of a novel mutation of mucopolysaccharidosis type VI with a severe phenotype and good response to enzymatic replacement therapy: Case report.

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