• Journal of Genetic Medicine
• /
• v.19 no.1
• /
• pp.32-37
• /
• 2022

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase B due to mutations in the ARSB gene. Here, we report the case of a Korean female with a novel variant of MPS VI. A Korean female aged 5 years and 8 months, who is the only child of a healthy non-consanguineous Korean couple, presented at our hospital for severe short stature. She had a medical history of umbilical hernia and recurrent otitis media. Her symptoms included snoring and mouth breathing. Subtle dysmorphic features, including mild coarse face, joint contracture, hepatomegaly, and limited range of joint motion, were identified. Radiography revealed deformities, suggesting skeletal dysplasia. Growth hormone (GH) provocation tests revealed complete GH deficiency. Targeted exome sequencing revealed compound heterozygous mutations in the ARSB genes c.512G>A (p.Gly171Asp; a pathogenic variant inherited from her father) and c.1157C>T (p.Ser386Phe; a novel variant inherited from her mother in familial genetic testing). Quantitative tests revealed increased urine glycosaminoglycan (GAG) levels and decreased enzyme activity of arylsulfatase B. While on enzyme replacement therapy and GH therapy, her height increased drastically; her coarse face, joint contracture, snoring, and obstructive sleep apnea improved; urine GAG decreased; and left ventricular mass index was remarkably decreased. We report a novel variant-c.1157C>T (p.Ser386Phe)-of the ARSB gene in a patient with MPS VI; these findings will expand our knowledge of its clinical spectrum and molecular mechanisms.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.16 no.1
• /
• pp.24-33
• /
• 2016

Mucopolysaccharidosis type VI (MPS VI) is a rare disease caused by the mutation of ARSB with prevalence range from 1/5,000 in northeast Brazil to 1/2,057,529 births in Czech Republic. In Asia, there is only one published figure in Taiwan of about 1/833,000 births. The exact prevalence in the Korean population is unknown, but we estimated the incidence of MPS VI is about 0.03/100,000 live births. Enzyme replacement therapy (ERT) with recombinant human Arylsulfatase B (rhASB) is a modality for the treatment of MPS VI that reduces the excretion of urine glycosaminoglycan (GAG) and improves joint motion, pulmonary function, and endurance. We presented the clinical features, molecular analysis and outcome of ERT in three Korean MPS VI patients. All patients had the typical characteristic clinical features of MPS IV. Short stature, dysostosis multiplex, corneal opacity and valvular heart disease were found at first presentation, while restrictive lung disease and carpal tunnel syndrome developed later in all patients. Molecular analysis demonstrated novel missense and nonsense mutation in the patients, including p.Ile 67Ser, p.Gly328Arg, $p.Arg191^*$, p.Asp352Asn, and p.Gly17Asp. After ERT, urine GAG was decreased in all patients. Skeletal involvement, corneal opacity, heart valve abnormalities and pulmonary function were not improved with ERT, but it had a better outcome on regarding joint motion and endurance. One patient underwent allogeneic bone marrow transplantation (BMT) prior to ERT, but their clinical response was not improved much after BMT. This study demonstrates clinical phenotypes and molecular analysis of the severe form of MPS VI in Korean patients.

• Journal of mucopolysaccharidosis and rare diseases
• /
• v.3 no.1
• /
• pp.14-19
• /
• 2017

Lysosomal storage diseases (LSDs) are a group of rare inherited metabolic disorders caused by the deficiency of specific lysosomal enzymes and subsequent accumulation of substrates. Enzyme deficiency leads to progressive intra-lysosomal accumulation of the incompletely degraded substances, which cause dysfunction and destruction of the cell and eventually multiple organ damage. Patients have a broad spectrum of clinical phenotypes which are generally not specific for some LSDs, leading to missed or delayed diagnosis. Due to the availability of treatment including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation for some LSDs, early diagnosis is important. ERT products have been approved with optimal outcomes for some LSDs in the recent decades, including Gaucher, Fabry, mucopolysaccharidosis (MPS) I, Pompe, MPS VI, MPS II, and MPS IVA diseases. ERT can stabilize the clinical condition, prevent disease progression, and improve the long-term outcome of these diseases, especially if started prior to irreversible organ damage. Based on the availability of therapy and suitable screening methods in the recent years, some LSDs, including Pompe, Fabry, Gaucher, MPS I, MPS II, and MPS VI diseases have been incorporated into nationwide newborn screening panels in Taiwan.

• Journal of mucopolysaccharidosis and rare diseases
• /
• v.4 no.1
• /
• pp.11-13
• /
• 2018

In Malaysia, diagnosis and treatment of patients with mucopolysaccharidoses (MPS) is mainly localized at Hospital Kuala Lumpur, which is the national referral center for rare diseases. To date there are 83 patients diagnosed with MPS in our center, with MPS II being the commonest. The Malaysian National Medicines Policy second edition has a specific section on the orphan drugs which includes recombinant human enzyme for enzyme replacement therapy (ERT) in MPS. So far, National Pharmaceutical Regulatory Agency Malaysia has approved recombinant human enzyme for MPS types I (Loranidase), II (idursulfase), IVA (elosulfase alfa), and VI (Galsufase). Access to Idursulfase beta (another recombinant human enzyme for MPS II) and vestronidase alfa-vjbk (MPS VII) required special authorization on named patient basic. Currently there are 25 patients receiving ERT, 70% of the funding are from Ministry of Health (MOH), the remaining 30% are from various charitable funds and humanitarian programs. Thirteen newly diagnosed patients have to queue for an additional fund. Four patients have been treated with Hematopoietic stem cell transplant. MOH has also published guidelines regarding the patient selection criteria for ERT and treatment monitoring schedule.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.14 no.2
• /
• pp.178-181
• /
• 2014

Hunter syndrome (mucopolysaccharidosis type II, MPS II) is a X-linked lysosomal storage disease caused by a deficiency in the lysosomal enzyme, iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans within lysosomes of many organs and tissues. Since the enzyme replacement therapy was approved and available in the treatment of MPS I, II, VI, early diagnosis and early therapy can bring the better prognosis of disease and the better quality of life in patients. We described a 2.5 year old child presented with frequent otitis media and developmental delay including speech impairment, who was diagnosed as Hunter syndrome with IDS NM_000202.5:c. 263G>A(p.Arg88His) mutation.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.10 no.1
• /
• pp.59-66
• /
• 2010

Enzyme replacement of therapy (ERT) is one of the most promising therapeutic strategies for the treatment of lysosomal storage disorders. ERT is available in three types of Mucopolysaccharidosis (MPS): for MPS I (Aludrazyme$^{(R)}$), MPS II (Elaprase$^{(R)}$) and MPS VI (Naglazyme$^{(R)}$) patients who are over 5 years old. But recently, early diagnosis can be done by expert clinicians and even in prenatal case. We describe the case of ERT under 5 years old MPS patients. Up to June, 2010 in Samsung Medical Center, there are 6patients who were diagnosed as MPS and started ERT under 5 years old. 3 patients were MPS I, 3 patients were MPS II. 2 patient who was diagnosed as MPS I was female and others were male. Their age at diagnosis were 4 to 37month-old (4, 13, 16, 25, 27, 37 month-old) and they are now 9 to 60 month-old (9, 39, 32, 81, 60 month-old). The youngest patient was started ERT at 4 month-old and others were started at their 13 to 49 month-old (13, 29, 27, 28, 49 month-old). First manifested symptoms of patients were macrocephaly, kyphosis and coarse face appearance. Especially, in 2 of them, one was MPS I and the other was MPS II had elder brother with same disease. And the youngest one was diagnosed by the iduronate-2-sulfatase (IDS) gene analysis from chorionic villi sampling. His mother knew that she was a heterozygous carrier of IDS gene mutation because her younger brother died from MPS II. All of them confirmed as MPS by the enzyme assay in leukocytes and fibroblast skin culture. We started ERT with ${\alpha}$-L-iduronidase(Aldurazyme$^{(R)}$) to MPS I and did recombinant human iduronate-2-sulfatase (Elaprase$^{(R)}$) to MPS II patients as recommended dose as over 5 years old. But for MPS II patient who was 4 month old, we started ERT by recombinant human IDS (Elaprase$^{(R)}$) with reduced dose 0.1 mg/kg and increased dose every 2 weeks by 0.1mg/kg up to 0.5mg/kg IV infusion. During ERT, all patients had no adverse effects and the excretion of GAGs were decreased. We have evaluated other clinical symptoms such as liver/ spleen volume, heart function and neurologic evaluation. We describe a successful ERT to MPS I and MPS II patient under 5 years old without any adverse event. It indicates that ERT in young children are well tolerated and that it has several effects which may confer clinical benefits with long-term therapy.