An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life

Abstract

IntroductionMucopolysaccharidosis type I (MPS I) is a progressive multisystem lysosomal storage disease caused by deficiency of the enzyme α-L-iduronidase (IDUA). Patients present with a continuous spectrum of disease severity, and the most severely affected patients (Hurler phenotype; MPS I-H) develop progressive cognitive impairment. The treatment of choice for MPS I-H patients is haematopoietic stem cell transplantation, while patients with the more attenuated phenotypes benefit from enzyme replacement therapy.The potential of newborn screening (NBS) for MPS I is currently studied in many countries. NBS for MPS I, however, necessitates early assessment of the phenotype, in order to decide on the appropriate treatment. In this study, we developed an algorithm to predict phenotypic severity in newborn MPS I patients.MethodsThirty patients were included in this study. Genotypes were collected from all patients and all patients were phenotypically categorized at an age of > 18 months based on the clinical course of the disease. In 18 patients, IDUA activity in fibroblast cultures was measured using an optimized IDUA assay. Clinical characteristics from the first month of life were collected from 23 patients.ResultsHomozygosity or compound heterozygosity for specific mutations which are associated with MPS I-H, discriminated a subset of patients with MPS I-H from patients with more attenuated phenotypes (specificity 100%, sensitivity 82%). Next, we found that enzymatic analysis of IDUA activity in fibroblasts allowed identification of patients affected by MPS I-H. Therefore, residual IDUA activity in fibroblasts was introduced as second step in the algorithm. Patients with an IDUA activity of < 0.32 nmol x mg-1 × hr-1 invariably were MPS I-H patients, while an IDUA activity of > 0.66 nmol × mg-1 × hr-1 was only observed in more attenuated patients. Patients with an intermediate IDUA activity could be further classified by the presence of differentiating clinical characteristics, resulting in a model with 100% sensitivity and specificity for this cohort of patients.ConclusionUsing genetic, biochemical and clinical characteristics, all potentially available in the newborn period, an algorithm was developed to predict the MPS I phenotype, allowing timely initiation of the optimal treatment strategy after introduction of NBS.

Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study

“…Such cases could be closely monitored and proceed to HCT as soon as a severe phenotype is suggested. 25 An international expert consensus statement is important for further recommendations. Furthermore, considering the higher and more stable IDUA enzyme levels achieved after HCT, one might argue that patients with MPS type I with a more attenuated phenotype (MPS I Hurler-Scheie) are better off with HCT compared with ERT, 4 especially as HCT has become much safer in recent years.…”

Residual N‐acetyl‐α‐glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB

“…HS levels were determined as described previously (Kingma et al 2013). HS in 25 μg of fibroblast lysate was enzymatically digested into disaccharides.…”

Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management

“…26 These studies require long-term fibroblast cultures and mass spectrometry-based GAG assays. Kingma et al 27 developed an algorithm to predict clinical severity in MPS I based on genotyping and an optimized IDUA assay, however, this assay is not routinely available. In a preliminary proteomic study, the lysosomal protein b-galactosidase was elevated 3.6-to 5.7-fold in severe but not attenuated MPS I, 28 and 1 study has reported that serum heparin-cofactor IIthrombin complex levels can differentiate patients with severe MPS I from patients with attenuated MPS I.…”