Publications by authors named "Paul R Harmatz"

25 Publications

  • Page 1 of 1

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

Mol Genet Metab 2019 08 2;127(4):355-360. Epub 2019 Jul 2.

BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address:

Objective: To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI.

Methods: In 2005, the multi-national, MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A sub-analysis was performed in patients who started ERT at ≥16 years of age and had received galsulfase for ≥6 months. Urinary glycosaminoglycans (uGAG), 6-min walk test (6MWT), 3-min stair climb test (3MSCT), pulmonary function measures, cardiac function, ophthalmology measures, liver and spleen sizes, and safety were evaluated.

Results: Of 223 patients enrolled in the CSP, 51 were included in the sub-analysis. Patients were between 16 and 63 years of age at first infusion. From pre-treatment baseline, uGAG level decreased by a mean (±standard deviation [SD]) of 66 (±45)% (N = 29) after a median follow-up of 7.2 years. 6MWT distance decreased slightly by a mean of 17 (±107) meters (N = 23) after 6.6 years. Stairs/min in the 3MSCT increased by a mean of 26 (±33) (N = 14) after 2.8 years. Pulmonary function measures, forced expiratory volume in 1 second and forced vital capacity, increased by a mean of 0.06 (±0.21) L after 7.3 years and 0.05 (±0.28) L after 7.2 years, respectively (N = 19 for both measures). Overall, galsulfase was well tolerated, with most adverse events reported being MPS-related clinical manifestations and not related to galsulfase.

Conclusions: Results of this sub-analysis of the CSP suggest that initiation of galsulfase in adulthood is well tolerated and can possibly stabilize MPS VI in the long term.
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http://dx.doi.org/10.1016/j.ymgme.2019.06.008DOI Listing
August 2019

Enzyme replacement therapy outcomes across the disease spectrum: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

J Inherit Metab Dis 2019 05 8;42(3):519-526. Epub 2019 Apr 8.

BioMarin Pharmaceutical Inc., Novato, California, USA.

The impact of galsulfase enzyme replacement therapy in patients with mucopolysaccharidosis (MPS) VI with phenotypes at either end of the disease spectrum was evaluated. The MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A subanalysis of the CSP was performed in patients with pretreatment urinary glycosaminoglycan (uGAG) levels <100 μg/mg and ≥200 μg/mg creatinine (low- and high-uGAG) who had received galsulfase for ≥6 months. uGAG, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function measures, height/growth, cardiac function, and safety were evaluated. Patients with a high-uGAG level at pre-treatment baseline (N = 68) showed greater impairments in endurance and pulmonary function than those with low-baseline uGAG levels (N = 39). From pre-treatment baseline, the distance walked on the 6MWT in the low- and high-uGAG groups increased by a mean (±SD) of 49 (±151) meters and 42 (±165) meters (median follow-up 5.5 and 7.7 years), respectively. The number of stairs/min climbed in the 3MSCT in the low- and high-uGAG groups increased by a mean of 18 (±33) and 30 (±45) (median follow-up 2.8 and 3.5 years), respectively. Overall, pulmonary function remained unchanged for both groups. No impact was seen on cardiac function. Galsulfase was generally well tolerated in both groups, with most adverse events being MPS-related complications unrelated to galsulfase. Results of this CSP sub-analysis suggest that galsulfase stabilizes MPS VI in the long-term and has an acceptable safety profile, regardless of baseline disease severity.
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http://dx.doi.org/10.1002/jimd.12079DOI Listing
May 2019

Spinal cord issues in adult patients with MPS: transition of care survey.

Childs Nerv Syst 2018 09 27;34(9):1759-1765. Epub 2018 May 27.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Purpose: This study aims to raise awareness of the need for research and appropriate guidelines for managing spinal cord issues in adult patients with mucopolysaccharidosis (MPS) and transition of these patients from pediatric to adult care.

Methods: Pediatric/adult neurosurgeons, orthopedic spine surgeons, and treating physicians with expertise in metabolic disorders and spinal cord issues were invited to complete a survey to assess their experience with spinal cord problems in MPS and their opinion on transitioning routes from pediatric to adult care.

Results: Twenty specialists completed the survey; 16 had treated spinal cord issues in patients with MPS. Foramen magnum and cervical stenosis (87%), atlanto-axial instability (67%), and lumbar spine instability (33%) were the main spinal cord issues encountered; 28% had treated adult patients for one or more spinal cord issues. In 40% of cases, this concerned an intervention or procedures performed during childhood. The main specialist responsible for the care of adult patients with MPS differed considerably between institutions and included both pediatric and adult specialists (30% pediatric neurosurgeons, 10% pediatric spine orthopedic surgeons, 30% adult spine neurosurgeons, 20% general adult surgeons). The preferred option (> 50%) for the transition of care was an interdisciplinary team of pediatric and adult specialists.

Conclusions: Further work needs to be done to address problems of managing spinal cord issues in adult patients with MPS. Currently, the responsibility for the care of patients with MPS with spinal cord issues is inconsistent. The best strategy for transitioning these patients from pediatric to adult care is likely an interdisciplinary approach.
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http://dx.doi.org/10.1007/s00381-018-3834-6DOI Listing
September 2018

Impact of long-term elosulfase alfa on activities of daily living in patients with Morquio A syndrome in an open-label, multi-center, phase 3 extension study.

Mol Genet Metab 2018 02 5;123(2):127-134. Epub 2017 Dec 5.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, United States. Electronic address:

Background: Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR-004). Changes in efficacy endpoints were evaluated over 120weeks, from MOR-004 baseline to MOR-005 week 96. We report the impact of ERT on activities of daily living (ADL) across three domains (mobility, self-care, and caregiver-assistance), as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ) after 72 and 120weeks or approximately 1 and 2years.

Results: Mean baseline MPS-HAQ domain scores showed impairments in mobility, self-care, and independence. The MOR-005 intent-to-treat population (ITT; N=169, including 158 with 2years follow-up) showed sustained significant reductions (representing improvements) in mobility and self-care domain least square (LS) mean scores vs. baseline at 1 and 2years and a non-significant decrease in the caregiver-assistance domain at 2years. At week 120, LS mean (SE) changes from baseline were -0.5 (0.1) for mobility (P=0.002), -0.4 (0.1) for self-care (P=0.001), and -1.0 (0.5) for caregiver-assistance (P=0.06) (ITT population). Improvements in MPS-HAQ domain scores vs. baseline at 1 and 2years were greater in patients continuously treated with the weekly dosing regimen than in the total MOR-005 population and statistically significant across domains. A comparable untreated cohort of patients from the Morquio A Clinical Assessment Program (MorCAP) natural history study (ITT population, N=94, including 37 with 2years follow-up) showed no improvement over 2years, with two of the three domains worsening (LS mean (SE) changes from baseline: 0.3 (0.3) for mobility, 0.4 (0.2) for self-care, -0.5 (0.8) for caregiver-assistance). Changes in LS mean scores vs. baseline were statistically significantly different between MOR-005 and MorCAP for the mobility domain (-0.7 (SE 0.4), P=0.0490) and the self-care domain (-0.7 (SE 0.3), P=0.0146) at 2years.

Conclusions: Together, these findings suggest that long-term elosulfase alfa ERT is associated with partial recovery of functional abilities, improving Morquio A patients' abilities to perform ADL.

Trial Registration: ClinicalTrials.govNCT01415427. Registered 8 August 2011, retrospectively registered.
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http://dx.doi.org/10.1016/j.ymgme.2017.11.015DOI Listing
February 2018

Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa.

JIMD Rep 2018 21;42:9-17. Epub 2017 Nov 21.

BioMarin Pharmaceutical Inc., Novato, CA, USA.

Objective: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities.

Methods: Morquio A patients aged ≥7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined).

Results: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO/work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost.

Conclusions: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.
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http://dx.doi.org/10.1007/8904_2017_70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226396PMC
November 2017

Surgical management of neurological manifestations of mucopolysaccharidosis disorders.

Mol Genet Metab 2017 12 28;122S:41-48. Epub 2017 Sep 28.

Department of Neuroradiology, DASA Group, São Paulo, Brazil.

The mucopolysaccharidosis (MPS) disorders are ultra-rare lysosomal storage disorders associated with progressive accumulation of glycosaminoglycans (GAGs) in cells and tissues throughout the body. Clinical manifestations and progression rates vary widely across and within the different types of MPS. Neurological symptoms occur frequently, and may result directly from brain damage caused by infiltration of GAGs, or develop secondary to somatic manifestations such as spinal cord compression, hydrocephalus, and peripheral nerve entrapment. Management of secondary neurological manifestations often requires surgical correction of the underlying somatic cause. The present review discusses the surgical management of neurological disease in patients with MPS, including diagnostic imaging. Background information is derived from presentations and discussions during a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches.
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http://dx.doi.org/10.1016/j.ymgme.2017.09.011DOI Listing
December 2017

Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: An open-label, phase 2 study.

Am J Med Genet A 2017 Feb 24;173(2):375-383. Epub 2016 Oct 24.

BioMarin Pharmaceutical Inc., Novato, California.

Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open-label, phase 2, multi-national study in Morquio A patients aged ≥5 years unable to walk ≥30 meters in the 6-min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25-foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug-related adverse events, the other was not drug-related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received ≥80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298029PMC
February 2017

Pregnancy in patients with mucopolysaccharidosis: a case series.

Mol Genet Metab Rep 2016 Sep 29;8:111-5. Epub 2016 Aug 29.

Birmingham Women's NHS Foundation Trust, Birmingham, UK.

The mucopolysaccharidoses (MPS disorders) are rare inherited diseases associated with multi-organ accumulation of glycosaminoglycans, leading to musculoskeletal, respiratory, cardiac, neurological, ophthalmological, otolaryngological, and gastrointestinal abnormalities. As a result of improvements in diagnosis, multi-disciplinary care, and therapies such as enzyme replacement therapy and hematopoietic stem cell transplantation, an increasing number of patients with MPS are reaching adulthood and are involved in family planning. Data on fertility and pregnancy outcome in MPS is sparse and comprises primarily isolated case reports. To address this evidence gap, we present a case series on fertility and pregnancy in eight mothers and five fathers with MPS. This case series demonstrates that women with MPS have high-risk pregnancies and deliveries secondary to their underlying disease. However, with appropriate pre-conceptual multi-disciplinary evaluation, optimization and discussion regarding potential risks, combined with regular multi-disciplinary maternal and fetal surveillance in a tertiary center, the outcome of most pregnancies in this case series seems to be favorable with all babies developing normally. Partners of fathers with MPS had uncomplicated pregnancies and deliveries. All children were healthy, with normal growth and development.
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http://dx.doi.org/10.1016/j.ymgmr.2016.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007877PMC
September 2016

Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome.

J Inherit Metab Dis 2016 11 23;39(6):839-847. Epub 2016 Aug 23.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Objective: To present long-term respiratory function outcomes from an open-label, multi-center, phase 3 extension study (MOR-005) of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio A syndrome.

Methods: In part 1 of MOR-005, patients initially randomized to ERT in the 24-week pivotal study (MOR-004) remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two regimens. During part 2, all patients received elosulfase alfa 2.0 mg/kg/week. Respiratory function was one of the efficacy endpoints evaluated in MOR-005. Change from MOR-004 baseline to 120 weeks of treatment for the combined population was determined and compared with results from untreated patients from a Morquio A natural history study (MorCAP).

Results: Maximum voluntary ventilation (MVV) improved up to week 72 and then stabilized; forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV) increased continuously over 120 weeks. Mean increases in the modified per-protocol population was 9.2 % for FVC, 8.8 % for FEV, and 6.1 % for MVV after 120 weeks. All patients ≤14 years showed respiratory improvements, presumably in part related to growth; however, these were greater in treated patients. For those >14 years, treated patients showed improvements, while deterioration occurred in untreated. Altogether, the improvements were significantly greater (P < 0.05) in treated patients.

Conclusions: Long-term ERT is associated with sustained improvements in respiratory function in Morquio A. In younger patients (≤14 years), some improvement may be ascribed to growth. In older patients, other mechanisms, e.g., decreased glycosaminoglycan storage, are likely involved.
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http://dx.doi.org/10.1007/s10545-016-9973-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065598PMC
November 2016

Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome.

Mol Genet Metab 2016 09 16;119(1-2):131-43. Epub 2016 Jun 16.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, United States.

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N=173), analyses were also performed for a modified per-protocol (MPP) population (N=124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3)m and 39.9 (10.1)m for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study (N=56) and 15.1 (7.1)m and 31.7 (6.8)m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0)stairs/min for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3)stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was -59.4 (1.8)% and -62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P<0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified.
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http://dx.doi.org/10.1016/j.ymgme.2016.05.018DOI Listing
September 2016

Cervical cord compression in mucopolysaccharidosis VI (MPS VI): Findings from the MPS VI Clinical Surveillance Program (CSP).

Mol Genet Metab 2016 08 3;118(4):310-8. Epub 2016 Jun 3.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Objectives: To gain insight into the frequency, age of onset, and management of cervical cord compression in mucopolysaccharidosis VI (MPS VI).

Methods: Cervical spine magnetic resonance imaging (MRI) data and/or cervical decompression surgery data collected between 30 June 2005 and 1 September 2015 were analyzed from subjects enrolled in the MPS VI Clinical Surveillance Program (CSP) (ClinicalTrials.gov: NCT00214773), an ongoing multicenter, observational, retrospective and prospective registry.

Results: Of 213 subjects enrolled in the CSP, 134 (62.9%) had at least one documented cervical spine MRI assessment. An additional four subjects were identified through surgery records alone to yield a study population comprising 138 subjects (mean age at enrollment =15.1years; age range=0.80-65.0years). Cervical cord compression was documented in 101 (75.4%) of the 134 subjects with ≥1 MRI assessment, the majority (95.0%) by the time of the first recorded MRI. In general, subjects with cervical cord compression had significantly lower height Z-scores compared to those without cervical cord compression (p<0.0001); nevertheless, a few subjects of taller stature had documented cervical cord compression at a young age. Most subjects >20years of age (31/33, 93.9%) presented with cervical cord compression. There was an insufficient number of subjects with both pre- and post-enzyme replacement therapy (ERT) MRI data to determine any association between ERT and cervical cord compression. Surgical decompression was performed on 58 subjects (42.0%), with mean age at first surgery of 13.1years. Decompression plus stabilization procedures accounted for 12.1% of surgeries. Eight subjects (13.8%) underwent reoperation. Complications during or following surgery were reported in 3 subjects, with anesthesia-related complications resulting in two deaths.

Conclusions: All individuals with MPS VI are at high risk of developing cervical cord compression at an early age. Routine MRI assessments should be initiated from the time of MPS VI diagnosis. The perioperative management of MPS VI patients can be challenging. This study contributes to the understanding of the natural history of MPS VI.
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http://dx.doi.org/10.1016/j.ymgme.2016.06.001DOI Listing
August 2016

The natural history of growth in patients with Hunter syndrome: Data from the Hunter Outcome Survey (HOS).

Mol Genet Metab 2016 Apr 25;117(4):438-46. Epub 2016 Jan 25.

Department of Medical Genetics, Children's Hospitals and Clinics of Minnesota, 2525 Chicago Ave South, CSC 560, Minneapolis, MN 55404, USA; Department of Pediatrics, Division of Genetics, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Hunter syndrome (mucopolysaccharidosis type II) affects growth but the overall impact is poorly understood. This study investigated the natural history of growth and related parameters and their relationship with disease severity (as indicated by cognitive impairment). Natural history data from males followed prospectively in the Hunter Outcome Survey registry and not receiving growth hormone or enzyme replacement therapy, or before treatment start, were analysed (N=676; January 2014). Analysis of first-reported measurements showed short stature by 8years of age; median age-corrected standardized height score (z-score) in patients aged 8-12years was -3.1 (1st, 3rd quartile: -4.3, -1.7; n=68). Analysis of growth velocity using consecutive values found no pubertal growth spurt. Patients had large head circumference at all ages, and above average body weight and body mass index (BMI) during early childhood (median z-score in patients aged 2-4years, weight [n=271]: 1.7 [0.9, 2.4]; BMI [n=249]: 2.0 [1.1, 2.7]). Analysis of repeated measurements over time found greater BMI in those with cognitive impairment than those without, but no difference in height, weight or head circumference. Logistic regression modelling (data from all time points) found that increased BMI was associated with the presence of cognitive impairment (odds ratio [95% CI], 3.329 [2.313-4.791]), as were increased weight (2.365 [1.630-3.433]) and head circumference (1.749 [1.195-2.562]), but not reduced height. Unlike some other MPS disorders, there is no evidence at present for predicting disease severity in patients with Hunter syndrome based on changes in growth characteristics.
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http://dx.doi.org/10.1016/j.ymgme.2016.01.009DOI Listing
April 2016

Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome.

Mol Genet Metab 2015 Feb 1;114(2):186-94. Epub 2014 Nov 1.

BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address:

Objectives: Baseline data from the Morquio A Clinical Assessment Program (MorCAP) revealed that individuals with Morquio A syndrome show substantial impairment in multiple domains including endurance and respiratory function (Harmatz et al., Mol Genet Metab, 2013). Here, 1- and 2-year longitudinal endurance and respiratory function data are presented.

Methods: Endurance was assessed using the 6-minute walk test (6MWT) and the 3-minute stair climb test (3MSCT). Respiratory function was evaluated by measuring forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Data were analyzed using repeated measures ANCOVA models. Annualized estimates of change were determined using model estimates and interpolation.

Results: 353, 184, and 78 subjects were assessed at Year 0 (baseline), Year 1, and Year 2, respectively. The overall annualized estimate of change (SE) in 6MWT distance was -4.86±3.25m; a larger decline of -6.84±5.38m was observed in the subset of subjects meeting the inclusion/exclusion criteria of the Phase 3 clinical trial of elosulfase alfa (≥5years of age with baseline 6MWT distance ≥30 and ≤325m). In contrast, little change (-0.14±0.60stairs/min) was observed in 3MSCT. Annualized changes (SE) in FVC and MVV were 2.44±0.68% and 1.01±2.38%, respectively. FVC and MVV increased in patients aged ≤14years, but decreased in older patients.

Conclusions: The natural history of Morquio A syndrome is characterized by progressive impairment of endurance as measured by the 6MWT. Longitudinal trends in FVC and MVV showing increase in younger patients, but decrease in older patients, are likely to be influenced by growth. Changes in 6MWT may represent a sensitive measure of disease progression in ambulatory Morquio A patients.
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http://dx.doi.org/10.1016/j.ymgme.2014.10.015DOI Listing
February 2015

Mechanisms of plasma non-transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients.

Br J Haematol 2014 Dec 11;167(5):692-6. Epub 2014 Sep 11.

Department of Haematology, University College London, London, UK.

In transfusional iron overload, extra-hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non-transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond-Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin-iron utilization (DBA).
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http://dx.doi.org/10.1111/bjh.13081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577015PMC
December 2014

Orthopedic management of the extremities in patients with Morquio A syndrome.

J Child Orthop 2014 Aug 8;8(4):295-304. Epub 2014 Jul 8.

Department of Orthopaedic Surgery and Sports Medicine, Seattle Children's Hospital, University of Washington, Seattle, WA, USA,

Background: Musculoskeletal involvement in Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) contributes significantly to morbidity and mortality. While the spinal manifestations of the disorder have received considerable attention in the literature, there have been few reported studies to date to guide the management of the orthopedic problems associated with the lower and upper extremities.

Purpose: The objective was to develop recommendations for the management of the extremities in patients with Morquio A syndrome.

Methods: A group of specialists in orthopedics, pediatrics and genetics with experience in the management of Morquio A patients convened to review and discuss current clinical practices and to develop preliminary recommendations. Evidence from the literature was retrieved. Recommendations were further refined until consensus was reached.

Results And Conclusions: This present article provides a detailed review and discussion of the lower and upper extremity deformities in Morquio A syndrome and presents recommendations for the assessment and treatment of these complications. Key issues, including the importance of early diagnosis and the implications of medical therapy, are also addressed. The recommendations herein represent an attempt to develop a uniform and practical approach to managing patients with Morquio A syndrome and improving their outcomes.
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http://dx.doi.org/10.1007/s11832-014-0601-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128951PMC
August 2014

Galsulfase (Naglazyme®) therapy in infants with mucopolysaccharidosis VI.

J Inherit Metab Dis 2014 Mar 10;37(2):277-87. Epub 2013 Oct 10.

Children's Hospital & Research Center Oakland, 747 52nd Street, Oakland, CA, USA,

Objective: To evaluate the efficacy and safety of two dose levels of galsulfase (Naglazyme®) in infants with MPS VI.

Study Design: This was a phase 4, multicenter, multinational, open-label, two-dose level study. Subjects were randomized 1:1 to receive weekly infusions of 1.0 or 2.0 mg/kg of galsulfase for a minimum of 52 weeks. Progression of skeletal dysplasia was determined by monitoring physical appearance, radiographic changes, and growth. Urinary glycosaminoglycan (GAG) levels, gross and fine motor function, cardiac function, vision, hearing, and health resource utilization were evaluated. Safety assessments were performed.

Results: Four infants (aged 3.3-12.7 months) participated in the study. Galsulfase was well tolerated at 1.0 and 2.0 mg/kg/week dose levels with no drug-related serious adverse events. Two subjects experienced a total of four possible treatment-related adverse events which were all considered mild. Length and weight remained within age-expected norms. Skeletal abnormalities continued to progress in all subjects. High baseline urinary GAG levels (mean: 870 μg/mg creatinine) decreased by approximately 70%; these reduced levels were maintained (mean: 220 μg/mg creatinine at week 52) despite the development of anti-galsulfase antibodies. Hearing, cardiac function, hepatosplenomegaly, and facial dysmorphism stabilized or improved, but corneal clouding progressed. There was no clear difference in safety or efficacy between the two doses.

Conclusions: Galsulfase at two dose levels was safe and well tolerated in infants. Normal growth was maintained but skeletal abnormalities continued to progress. Urinary GAG levels decreased with treatment. Early initiation of galsulfase may prevent or slow progression of some disease manifestations.
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http://dx.doi.org/10.1007/s10545-013-9654-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976509PMC
March 2014

Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure.

Orphanet J Rare Dis 2013 Oct 3;8:155. Epub 2013 Oct 3.

Department of Pediatrics and Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, H7-270, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Background: Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder characterized by progressive multi-organ disease. The standard of care for patients with the severe phenotype (Hurler syndrome, MPS I-H) is early hematopoietic stem cell transplantation (HSCT). However, skeletal disease, including hip dysplasia, is almost invariably present in MPS I-H, and appears to be particularly unresponsive to HSCT. Hip dysplasia may lead to pain and loss of ambulation, at least in a subset of patients, if left untreated. However, there is a lack of evidence to guide the development of clinical guidelines for the follow-up and treatment of hip dysplasia in patients with MPS I-H. Therefore, an international Delphi consensus procedure was initiated to construct consensus-based clinical practice guidelines in the absence of available evidence.

Methods: A literature review was conducted, and publications were graded according to their level of evidence. For the development of consensus guidelines, eight metabolic pediatricians and nine orthopedic surgeons with experience in the care of MPS I patients were invited to participate. Eleven case histories were assessed in two written rounds. For each case, the experts were asked if they would perform surgery, and they were asked to provide information on the aspects deemed essential or complicating in the decision-making process. In a subsequent face-to-face meeting, the results were presented and discussed. Draft consensus statements were discussed and adjusted until consensus was reached.

Results: Consensus was reached on seven statements. The panel concluded that early corrective surgery for MPS I-H patients with hip dysplasia should be considered. However, there was no full consensus as to whether such a procedure should be offered to all patients with hip dysplasia to prevent complications or whether a more conservative approach with surgical intervention only in those patients who develop clinically relevant symptoms due to the hip dysplasia is warranted.

Conclusions: This international consensus procedure led to the construction of clinical practice guidelines for hip dysplasia in transplanted MPS I-H patients. Early corrective surgery should be considered, but further research is needed to establish its efficacy and role in the treatment of hip dysplasia as seen in MPS I.
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http://dx.doi.org/10.1186/1750-1172-8-155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852175PMC
October 2013

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

J Inherit Metab Dis 2013 Mar 6;36(2):339-55. Epub 2013 Feb 6.

Department of Paediatric Neurosurgery, Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, UK.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed.
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http://dx.doi.org/10.1007/s10545-013-9586-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590412PMC
March 2013

Anaesthesia and airway management in mucopolysaccharidosis.

J Inherit Metab Dis 2013 Mar 30;36(2):211-9. Epub 2012 Nov 30.

Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.

This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can't intubate, can't ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support.
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http://dx.doi.org/10.1007/s10545-012-9563-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590422PMC
March 2013

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management.

J Inherit Metab Dis 2011 Dec 9;34(6):1183-97. Epub 2011 Jul 9.

Pediatric Cardiology, University of Minnesota, Minneapolis, MN 55455, USA.

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality.The clinical examination of individuals with MPS is often difficult due to physical and, sometimes, intellectual patient limitations. The absence of precordial murmurs does not exclude the presence of cardiac disease. Echocardiography and electrocardiography are key diagnostic techniques for evaluation of valves, ventricular dimensions and function, which are recommended on a regular basis. The optimal technique for evaluation of coronary artery involvement remains unsettled.Standard medical and surgical techniques can be modified for MPS patients, and systemic therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) may alter overall disease progression with regression of ventricular hypertrophy and maintenance of ventricular function. Cardiac valve disease is usually unresponsive or, at best, stabilized, although ERT within the first few months of life may prevent valve involvement, a fact that emphasizes the importance of early diagnosis and treatment in MPS.
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http://dx.doi.org/10.1007/s10545-011-9359-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228957PMC
December 2011

Diagnosis and management of ophthalmological features in patients with mucopolysaccharidosis.

Br J Ophthalmol 2011 May 18;95(5):613-9. Epub 2010 Sep 18.

The Veneto Eye Bank Foundation, Venice, Italy.

Ocular pathology is common in patients with mucopolysaccharidosis (MPS), a hereditary lysosomal storage disorder, where the eye as well as other tissues accumulate excessive amounts of glycosaminoglycans. Despite genetic and phenotypic heterogeneity within and between different types of MPS, the disease symptoms and clinical signs often manifest during the first 6 months of life with increasing head size, recurrent infections, umbilical hernia, growth retardation and skeletal problems. Typical ocular features include corneal clouding, ocular hypertension/glaucoma, retinal degeneration and optic nerve atrophy. Visual deterioration and sensitivity to light may substantially reduce the quality of life in MPS patients, particularly when left untreated. As an early intervention, haematopoietic stem cell transplantation and/or enzyme replacement therapy are likely to improve patients' symptoms and survival, as well as visual outcome. Thus, it is of utmost importance to ensure proper detection and accurate diagnosis of MPS at an early age. It is of fundamental value to increase awareness and knowledge among ophthalmologists of the ocular problems affecting MPS patients and to highlight potential diagnostic pitfalls and difficulties in patient care. This review provides insight into the prevalence and severity of ocular features in patients with MPS and gives guidance for early diagnosis and follow-up of MPS patients. MPS poses therapeutic challenges in ocular management, which places ophthalmologists next to paediatricians at the forefront of interventions to prevent long-term sequelae of this rare but serious disease.
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http://dx.doi.org/10.1136/bjo.2010.179937DOI Listing
May 2011

Non-invasive assessment of tissue iron overload.

Hematology Am Soc Hematol Educ Program 2009 :215-21

University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

In recent years, there has been increasing interest in non-invasive iron measurement, especially of the liver and heart, in patients with iron overload. Serum ferritin still remains an essential monitoring parameter in intervals between liver iron measurements; however, confounding factors such as inflammation, chelation treatment changes and the specific disease have to be taken into account. Liver iron measurements can now routinely be performed in clinical applications either by quantitative magnetic resonance imaging (MRI) using the transverse magnetic relaxation rate R(2) or R(2)* (1/T(2)*) or by biomagnetic liver susceptometry. For iron measurements in the heart, the single-breathhold multi-echo MRI-R(2)* method has become a standard modality and is now applied in clinical settings beyond research studies. In other tissues like the pancreas, pituitary, and brain, different MRI methods are employed, but their clinical benefit has yet to be proven.
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http://dx.doi.org/10.1182/asheducation-2009.1.215DOI Listing
March 2010

Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions.

Transfusion 2008 Sep 29;48(9):1971-80. Epub 2008 May 29.

Department of Hematology, The Children's Hospital & Research Center, Oakland, California, USA.

Background: Transfusion therapy is frequently used to prevent morbidity in sickle cell disease (SCD), and subsequent iron overload is common. The objective of this study was to evaluate the current standard of care in monitoring iron overload and related complications in patients with SCD compared to thalassemia (Thal).

Study Design And Methods: A cross-sectional study was conducted at 31 hematology clinics in the United States, Canada, or the United Kingdom. Patients who received transfusions with a mean serum ferritin level of least 2000 ng per mL were eligible. A total of 199 patients with SCD (113 female; 24.9 +/- 13.2 years) and 142 with Thal (66 female; 25.8 +/- 8.1 years) were recruited, and data were collected between 2001 and 2003 by interview and medical record review.

Results: Although both groups were recruited on the basis of significant iron overload, the likelihood of performing a liver biopsy for routine iron monitoring was significantly higher (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.2-5.3) in Thal than SCD. Thal patients were also more likely to be screened for iron-related organ injury including an echocardiograph for cardiomyopathy (OR, 2.6; p < 0.001; 95% CI, 1.6-4.2), alanine aminotransferase for liver function (OR, 8.3; CI, 1.05-64.4), and thyroid-stimulating hormone for hypothyroidism (OR, 12.3; CI, 7.0-21.5). For adult SCD patients, those maintained on simple transfusion with a serum ferritin level of greater than 2500 ng per mL were the least likely to have a liver biopsy (p < 0.03).

Conclusions: These data highlight the unsystematic monitoring of iron and related organ injury in SCD. Until the relationship between iron and related comorbidities is better understood, routine monitoring of iron overload in SCD patients who receive transfusions should be considered a standard part of clinical care.
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http://dx.doi.org/10.1111/j.1537-2995.2008.01775.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613769PMC
September 2008

Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia.

Bone 2008 Jul 15;43(1):162-168. Epub 2008 Mar 15.

Department of Hematology at the Children's Hospital & Research Center, Oakland, CA, USA.

Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age> or =12 years and liver iron concentration> or =10 mg/g dry wt or serum ferritin> or =2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin<500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6+/-0.7 years), 203 subjects with TxSCD (44% Male, 24.7+/-0.9 years: Mean+/-SE), and 65 NonTxSCD (50% Male, 22.2+/-1.3 years) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2-4.6; 95%CI), male gender (OR: 2.6; 1.5-4.5), hypothyroidism (OR: 3.3; 1.1-9.8) and age (OR: 1.1; 1.03-1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.
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http://dx.doi.org/10.1016/j.bone.2008.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2500183PMC
July 2008

Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease.

Br J Haematol 2006 Nov 10;135(4):574-82. Epub 2006 Oct 10.

Department of Hematology, Children's Hospital and Research Centre, Oakland, CA, USA.

Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P = <0.001) and growth failure (33% vs. 7%, P < 0.001), versus Tx-SCD. Fifty-six per cent of Thal had more than one endocrinopathy compared with only 13% of Tx-SCD (P < 0.001). In contrast, Tx-SCD was not different from non-Tx-SCD. Multivariate analysis indicated that endocrinopathy was more likely in Thal than SCD [Odds Ratio (OR) = 9.4, P < 0.001], with duration of chronic transfusion a significant predictor (OR = 1.4 per 10 years of transfusion, P = 0.04). Despite iron overload, endocrinopathy was not increased in Tx-SCD versus non-Tx-SCD, suggesting that the underlying disease may modulate iron-related endocrine injury. However, because transfusion duration remained a significant predictor of endocrinopathy, these data should be confirmed in SCD subjects that have been chronically transfused for longer periods of time.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06332.xDOI Listing
November 2006