Follow-up of very attenuated form of mucopolysaccharidosis type Ⅱ detected by newborn screening.
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Mucopolysaccharidosis (MPS) type Ⅱ is an X-linked recessive disease caused by the pathogenic variants in the IDS gene. IDS encodes a lysosomal enzyme, iduronate 2-sulfatase (I2S). Systemic accumulation of dermatan sulfate (DS) and heparan sulfate (HS) can be found in various tissues due to the deficiency of I2S activity. New therapies have become available for MPS II : enzyme replacement therapy (ERT), which has therapeutic effects on the central nervous system. Newborn screening (NBS) for this disease has been initiated in many regions. Aichi Prefecture, Japan, introduced NBS for MPS Ⅱ in June 2019. Predicting the long-term outcome of patients identified by NBS is challenging. Some cases have very mild clinical features without any treatment.
Case Presentation
He was referred for evaluation from the NBS program after screening positive for MPS II. The primary I2S activity in the patient was 0.47 μmol/h/L on DBS (cut-off 1.5 μmol/h/L) and secondary I2S activity was 0.34 μmol/h/L. Physical examination of the patient revealed no significant abnormalities except for extensive dermal melanocytosis and ectopic patches on the dorsal parts of the hands and feet.
Diagnostic Workup
IDS gene sequencing revealed a novel (at the time) hemizygous variant of c.1003C>A ( p.His335Asn). This variant was absent from the database of healthy population and ClinVar. Polyphen 2 predicted this variant as “probably damaging” (score: 0.998-1.0). The ACMG classification of this variant was likely pathogenic (PM2+PM5+PP3+PP4). Urinary glycosaminoglycan (GAG) analysis showed a high uronic acid concentration (102 mg/g creatinine) with a high DS fraction ratio. Based on these results, the patient was diagnosed with MPS II.
Treatment and Management
ERT was initiated 5 months after birth. The parents requested discontinuing ERT at 11 months because his older sibling was also found to have the mild phenotype of MPSⅡ. Upon confirming the genotype of the asymptomatic maternal great-grandfather, the decision was made not to treat.
Outcome and Follow-Up
He had no specific MPS II phenotype, including brain disorder, until the age of 4 years.
Discussion
There is no established treatment policy for asymptomatic MPS Ⅱ patients diagnosed by NBS, although guidelines emphasize the importance of early treatment before disease progression. The wide variety of clinical symptoms in MPS II makes this problem even more complex. Recently, the patient with p.His335Asn was also detected by NBS in Kumamoto Prefecture, Japan, and was initiated on ERT at 4 months of age. It is noteworthy that both cases with p.His335Asn were detected only by NBS and not by family or medical history. This indicates that this variant is associated with a very attenuated form of MPS Ⅱ. In fact, the older brother of our patient, a 6-year-old with normal development and recurrent otitis media, was also diagnosed after the younger brother was detected. During genetic counselling, p.His335Asn was found in their great-grandfather, who was asymptomatic but showed an abnormal increase in urinary excretion of DS and HS. In mild cases, diagnosis solely on urinary uronic acid excretion is challenging. Additional clinical information and DS/HS in DBS would be helpful for accurate diagnosis. The older brother had temporarily discontinued ERT after experiencing injection reactions, and then decided to stop after finding out that their great-grandfather had p.His335Asn. The case highlights the importance of providing parents with appropriate information and discussing the timing of treatment initiation and choice of treatment for cases detected by NBS. The diversity of clinical features in families with MPS II requires careful follow-up in the future.
Conclusion
The phenotype of MPS II detected by NBS may differ from the clinical characteristics previously reported. Patients with p.His335Asn diagnosed biochemically and genetically as MPS Ⅱ may have no difficulties in life.
Mucopolysaccharidosis (MPS) type Ⅱ is an X-linked recessive disease caused by the pathogenic variants in the IDS gene. IDS encodes a lysosomal enzyme, iduronate 2-sulfatase (I2S). Systemic accumulation of dermatan sulfate (DS) and heparan sulfate (HS) can be found in various tissues due to the deficiency of I2S activity. New therapies have become available for MPS II : enzyme replacement therapy (ERT), which has therapeutic effects on the central nervous system. Newborn screening (NBS) for this disease has been initiated in many regions. Aichi Prefecture, Japan, introduced NBS for MPS Ⅱ in June 2019. Predicting the long-term outcome of patients identified by NBS is challenging. Some cases have very mild clinical features without any treatment.
Case Presentation
He was referred for evaluation from the NBS program after screening positive for MPS II. The primary I2S activity in the patient was 0.47 μmol/h/L on DBS (cut-off 1.5 μmol/h/L) and secondary I2S activity was 0.34 μmol/h/L. Physical examination of the patient revealed no significant abnormalities except for extensive dermal melanocytosis and ectopic patches on the dorsal parts of the hands and feet.
Diagnostic Workup
IDS gene sequencing revealed a novel (at the time) hemizygous variant of c.1003C>A ( p.His335Asn). This variant was absent from the database of healthy population and ClinVar. Polyphen 2 predicted this variant as “probably damaging” (score: 0.998-1.0). The ACMG classification of this variant was likely pathogenic (PM2+PM5+PP3+PP4). Urinary glycosaminoglycan (GAG) analysis showed a high uronic acid concentration (102 mg/g creatinine) with a high DS fraction ratio. Based on these results, the patient was diagnosed with MPS II.
Treatment and Management
ERT was initiated 5 months after birth. The parents requested discontinuing ERT at 11 months because his older sibling was also found to have the mild phenotype of MPSⅡ. Upon confirming the genotype of the asymptomatic maternal great-grandfather, the decision was made not to treat.
Outcome and Follow-Up
He had no specific MPS II phenotype, including brain disorder, until the age of 4 years.
Discussion
There is no established treatment policy for asymptomatic MPS Ⅱ patients diagnosed by NBS, although guidelines emphasize the importance of early treatment before disease progression. The wide variety of clinical symptoms in MPS II makes this problem even more complex. Recently, the patient with p.His335Asn was also detected by NBS in Kumamoto Prefecture, Japan, and was initiated on ERT at 4 months of age. It is noteworthy that both cases with p.His335Asn were detected only by NBS and not by family or medical history. This indicates that this variant is associated with a very attenuated form of MPS Ⅱ. In fact, the older brother of our patient, a 6-year-old with normal development and recurrent otitis media, was also diagnosed after the younger brother was detected. During genetic counselling, p.His335Asn was found in their great-grandfather, who was asymptomatic but showed an abnormal increase in urinary excretion of DS and HS. In mild cases, diagnosis solely on urinary uronic acid excretion is challenging. Additional clinical information and DS/HS in DBS would be helpful for accurate diagnosis. The older brother had temporarily discontinued ERT after experiencing injection reactions, and then decided to stop after finding out that their great-grandfather had p.His335Asn. The case highlights the importance of providing parents with appropriate information and discussing the timing of treatment initiation and choice of treatment for cases detected by NBS. The diversity of clinical features in families with MPS II requires careful follow-up in the future.
Conclusion
The phenotype of MPS II detected by NBS may differ from the clinical characteristics previously reported. Patients with p.His335Asn diagnosed biochemically and genetically as MPS Ⅱ may have no difficulties in life.