Kiely et al. Orphanet Journal of Rare Diseases (2017) 12:32 DOI 10.1186/s13023-017-0583-7 RESEARCH Open Access Early disease progression of Hurler syndrome Bridget T. Kiely1, Jennifer L. Kohler1, Hannah Y. Coletti2, Michele D. Poe1 and Maria L. Escolar1* Abstract Background: Newborn screening for mucopolysaccharidosis type I (MPS I) shows promise to improve outcomes by facilitating early diagnosis and treatment. However, diagnostic tests for MPS I are of limited value in predicting whether a child will develop severe central nervous system disease associated with Hurler syndrome, or minimal or no central nervous system involvement associated with the attenuated phenotypes (Hurler–Scheie and Scheie syndromes). Given that the optimal treatment differs between Hurler syndrome and the attenuated MPS I phenotypes, the absence of a reliable prognostic biomarker complicates clinical decision making for infants diagnosed through newborn screening. Information about the natural history of Hurler syndrome may aid in the management of affected infants, contribute to treatment decisions, and facilitate evaluation of treatment effectiveness and prognosis. Thus, the aim of this study was to characterize the progression and timing of symptom onset in infants with Hurler syndrome. Results: Clinical data from 55 patients evaluated at a single center were retrospectively reviewed. Information about each child’s medical history was obtained following a standardized protocol including a thorough parent interview and the review of previous medical records. All patients underwent systematic physical and neurodevelopmental evaluations by a multidisciplinary team. Nearly all patients (98%) showed signs of disease during the first 6 months of life. Common early disease manifestations included failed newborn hearing screen, respiratory symptoms, difficulty latching, and otitis media. Other symptoms such as kyphosis, corneal clouding, cardiac disease, joint restrictions, and enlarged head circumference typically appeared slightly later (median age, 8–10 months). During the first 12 months, gross motor development was the most severely affected area of functioning, and a significant number of patients also experienced language delays. Cognition was typically preserved during this period. Conclusions: In this large cohort of patients with Hurler syndrome, the vast majority showed signs and symptoms of disease during the first months of life. More research is needed to determine the extent to which early clinical manifestations of MPS I can predict phenotype and treatment outcomes. Keywords: Mucopolysaccharidosis type I, MPS I, Hurler syndrome, lysosomal storage disorders, Newborn screening, Natural history Background three clinical phenotypes. Hurler syndrome, the most se- Mucopolysaccharidosis type I (MPS I, OMIM 252800) is vere form, typically manifests during the first year of life. a rare lysosomal storage disorder caused by the defi- Affected children rapidly develop significant cognitive ciency or complete absence of enzyme α-L-iduronidase impairment and somatic disease in multiple organ sys- activity. Inadequate activity of this enzyme leads to the tems, leading to death within the first decade in the ab- accumulation of glycosaminoglycans throughout the sence of treatment. The attenuated forms of MPS I, body, resulting in progressive multisystem deterioration. known as Hurler–Scheie syndrome and Scheie syn- Although MPS I is associated with a continuum of dis- drome, are characterized by later onset of symptoms, ease presentations, it has traditionally been divided into longer life expectancy, and mild or no central nervous system (CNS) involvement. Symptoms found across the * Correspondence: [email protected] entire MPS I spectrum include corneal clouding, orga- 1 Program for the Study of Neurodevelopment in Rare Disorders, Children’s nomegaly, cardiac valve abnormalities, joint contrac- Hospital of Pittsburgh of UPMC, 4401 Penn Ave, Pittsburgh, PA 15224, USA Full list of author information is available at the end of the article tures, and dysostosis multiplex [1]. © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kiely et al. Orphanet Journal of Rare Diseases (2017) 12:32 Page 2 of 10 Treatment for MPS I is based on clinical presentation. proactively monitor all newborns with MPS I for com- Intravenous enzyme replacement therapy (ERT) is the mon early disease manifestations. Characterization of first-line treatment for individuals with the attenuated the earliest manifestations of Hurler syndrome may also forms of this disorder [2]. In these patients ERT has contribute to the identification of prognostic clinical been shown to improve quality of life and ameliorate markers. These markers, in combination with other test hepatomegaly, apnea, joint restrictions, and other som- results, may help clinicians determine which infants are atic symptoms [3–5]. However, because the recombinant the best candidates for HSCT and which should be enzyme cannot cross the blood–brain barrier, ERT alone treated with less aggressive therapies such as ERT. More is generally not sufficient to manage the CNS manifesta- data on the progression of early signs and symptoms of tions associated with Hurler syndrome. For these pa- Hurler syndrome are needed to serve as a comparator tients, hematopoietic stem cell transplantation (HSCT) for the evaluation of treatment effectiveness and to as- is the mainstay of treatment, although ERT may be sess the true clinical benefit of NBS once it is imple- added as an adjunct therapy [2]. Poe et al. (2014) found mented. However, because of the rarity of Hurler that patients with Hurler syndrome who underwent syndrome, there is a paucity of research about its natural HSCT prior to 9 months of age showed relatively nor- history [1, 12–14]. Thus, the aim of this study was to mal trajectories of cognitive development, whereas those characterize the onset and progression of neurological who were transplanted later experienced long-term defi- and somatic disease in a large cohort of patients with cits [6]. These findings suggest that HSCT may be able Hurler syndrome who underwent standardized multidis- to halt the progression of cognitive decline but is less ef- ciplinary evaluations at a single center. fective at reversing pre-existing neurological damage. Thus, early treatment of affected individuals is crucial. Methods Historically, most patients with MPS I were diagnosed Inclusion and exclusion criteria only after the appearance of characteristic disease mani- Clinical data were retrospectively reviewed from all festations. However, pilot newborn screening (NBS) pro- patients with a confirmed diagnosis of Hurler syn- grams for this disorder have recently been implemented drome that were seen at the Program for the Study in a number of locations, including Taiwan and Italy [7– of Neurodevelopment in Rare Disorders between 2000 9]. Moreover, in February 2016 the U.S. Secretary of and 2013 (n = 55). Diagnosis was based on deficiency Health and Human Services approved MPS I for or complete absence of enzyme α-L-iduronidase activ- addition to the Recommended Uniform Screening Panel. ity, increased glycosaminoglycans in urine, and muta- This development is likely to result in increased imple- tion analysis predictive of phenotype, Hurler mentation of newborn screening for this disorder in the phenotype or family history of Hurler syndrome. Only coming years. data collected before treatment with HSCT were in- Early diagnosis of patients with MPS I shows promise cluded in the analysis. to improve outcomes. Nonetheless, the implementation of routine newborn screening for this disorder will likely Data acquisition pose a number of challenges for clinicians. To select the Disease onset and clinical course were characterized by most appropriate disease-modifying therapy (HSCT and/ reviewing available outside medical records, parental re- or ERT) for each patient, clinicians will need to deter- sponses to a detailed questionnaire, and clinical data col- mine which infants are most likely to develop the severe lected at the time of evaluation at our specialized CNS involvement associated with Hurler syndrome. program. The parental questionnaire covered the child’s However, the limited prognostic value of genetic and prenatal and neonatal history, acquisition of develop- biochemical tests complicates phenotype prediction at mental milestones, behaviors, initial signs of disease, and the time of diagnosis for many patients [10–12]. In the prior diagnoses, surgeries, and hospitalizations. When absence of a biomarker that can reliably predict disease available, the results of cardiac evaluations, brain and course, patients diagnosed with MPS I through newborn cervical spine magnetic resonance imaging (MRI) scans, screening must be monitored closely during the first and audiological assessments were also reviewed. months of life. At each clinic visit, the patients underwent compre- Although only