The Morquio A Clinical Assessment Program: Baseline results illustrating progressive,
multisystemic clinical impairments in Morquio A subjects
Paul Harmatz
a, Karl Eugen Mengel
b, Roberto Giugliani
c, Vassili Valayannopoulos
d, Shuan-Pei Lin
e,
Rossella Parini
f, Nathalie Guffon
g, Barbara K. Burton
h, Christian J. Hendriksz
i, John Mitchell
j, Ana Martins
k,
Simon Jones
l, Norberto Guelbert
m, Ashok Vellodi
n, Carla Hollak
o, Peter Slasor
p, Celeste Decker
p,⁎
aChildren's Hospital & Research Center Oakland, Oakland, USA
bVilla Metabolica, Centre for Pediatric and Adolescent Medicine, MC University of Mainz, Mainz, Germany cMedical Genetics Service/HCPA, Department of Genetics/UFRGS and INAGEMP, Porto Alegre, Brazil dHôpital Necker-Enfants Malades, Paris, France
eMackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan fAz. Ospedaliera S. Gerardo, Monza, Italy
gHôpital Femme Mère Enfant, Lyon, France
hAnn and Robert H. Lurie Children's Hospital and Northwestern University Feinberg School of Medicine, Chicago, USA iBirmingham Children's Hospital NHS Foundation Trust, Birmingham, UK
jMcGill University Health Centre, Montreal, Canada kUniversidade Federal de São Paulo, São Paulo, Brazil
lCentral Manchester University Hospital, University of Manchester, Manchester, UK mHospital de Niños de Cordoba, Cordoba, Argentina
nGreat Ormond Street Hospital, London, UK oAcademic Medical Center, Amsterdam, Netherlands pBioMarin Pharmaceutical Inc., Novato, USA
a b s t r a c t
a r t i c l e
i n f o
Article history:
Received 20 December 2012
Received in revised form 30 January 2013 Accepted 30 January 2013
Available online 9 February 2013
Keywords: MPS Morquio GALNS
Lysosomal storage disorder Endurance
Respiratory function
Objectives:The objectives of this study are to quantify endurance and respiratory function and better characterize spectrum of symptoms and biochemical abnormalities in mucopolysaccharidosis IVA subjects.
Methods:MorCAP was a multicenter, multinational, cross sectional study amended to be longitudinal in 2011. Each study visit required collection of medical history, clinical assessments, and keratan sulfate (KS) levels.
Results:Data from thefirst visit of 325 subjects (53% female) were available. Mean age was 14.5 years. Mean±SD height z-scores were−5.6±3.1 as determined by the CDC growth charts. Mean±SD from the 6-minute-walk-test was 212.6±152.2 m, revealing limitations in functional endurance testing, and 30.0±24.0 stairs/min for the 3-minute-stair-climb test. Respiratory function showed limitations comparable to MPS VI patients; mean±SD was 1.2±0.9 l based on forced vital capacity and 34.8±25.5 l/min based on maximum voluntary ventilation. Mean urinary keratan sulfate (uKS) was elevated for all ages, and negatively correlated with age. Higher uKS cor-related with greater clinical impairment based on height z-scores, endurance and respiratory function tests. The MPS Health Assessment Questionnaire reveals impairments in mobility and activities of daily living in comparison to an age-matched control population.
Conclusions:MPS IVA is a multisystem disorder with a continuum of clinical presentation. All affected individuals experience significant functional limitations and reduced quality of life. Older patients have more severe exercise and respiratory capacity limitations, and more frequent cardiac pathology illustrating the progressive nature of disease.
© 2013 Elsevier Inc.
1. Introduction
The mucopolysaccharidosis are a group of lysosomal storage disorders (LSDs) in which deficient enzyme activity results in impairment of the degradation of glycosaminoglycans (GAGs) which, in turn, accumulate
in various tissues and organs. Morquio syndrome, including both MPS IVA (Morquio A syndrome; OMIM 253000) and MPS IVB (Morquio B syndrome; OMIM 253010), wasfirst described in 1929 [1]. Although MPS IVB was originally thought to be the milder form of MPS IVA, these were later demonstrated to be genetically distinct disorders each with a different deficient enzyme[2]. MPS IVA is characterized by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), resulting in accumulation of the GAGs keratan sulfate (KS) and chondroitin-6-sulfate (CS) in various ⁎ Corresponding author at: 105 Digital Drive, Novato, CA 94949, USA.
E-mail address:cdecker@bmrn.com(C. Decker).
1096-7192 © 2013 Elsevier Inc.
http://dx.doi.org/10.1016/j.ymgme.2013.01.021
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Molecular Genetics and Metabolism
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tissues and organs[3–5]. Accumulation of KS leads to multi-systemic im-pairments[5].
Information characterizing disease progression in MPS IVA is limited. The progression of symptoms is variable, likely due to known genetic het-erogeneity[5–8]with over 175 identified mutations in the GALNS gene [9]. Life expectancy in patients with the rapidly progressing phenotype ranges from the second to the third decade[10,11]. Rarely patients with a more slowly progressing phenotype survive beyond 60 years. Mortality is commonly due to cardiorespiratory or neurologic complications [10,12–16]. To date, the management of MPS IVA has focused primarily on palliative care to manage pain, infection and respiratory disease[14], as well as on corrective orthopedic surgeries[17].
The wide phenotypic spectrum of MPS IVA[7,18,19]and limitations in current urinary GAG (uGAG) testing make it a challenging disorder to diagnose[9,20]. Clinical suspicion is usually based on skeletal radio-graphs revealing characteristic platyspondyly often with associated thoracolumbar gibbus, cox valga withflaring of the iliac wings, genu valgum and dysplastic capital femoral epiphyses, failure to ossify the lateral side of the upper tibial epiphysis and proximal pointing of the metacarpals[6]. Suspicion of MPS IVA may be supported by quantitative and/or qualitative testing of uGAG levels demonstrating increased levels and presence of KS, but diagnosis requires confirmation of GALNS deficiency in WBC orfibroblasts, or mutation analysis showing the presence of pathogenic mutations in both alleles[9,21]. However, patients with more slowly progressing disease may not present with these obvious physical or radiologic manifestations and diagnosis may not occur until later in life[4,6,22–25].
The Morquio A Clinical Assessment Program (MorCAP) is thefirst lon-gitudinal study involving direct assessments of MPS IVA patients. This multicenter, multinational, prospective study was initiated in 2008 to as-sess and describe the spectrum of symptoms in this disorder including growth, endurance, respiratory function, cardiac function, medical and surgical history, as well as to measure select biochemical abnormalities such as GAG levels, and inflammatory markers in MPS IVA patients. This first report will describe the design and methodology of this clinical study as well as the cross-sectional baseline results of thefirst 325 pa-tients enrolled.
2. Methods
Originally, MorCAP was a single visit, cross sectional study of MPS IVA patients without limitations on age or symptom severity with thefirst patient enrolling in 2008. To gain more detailed insight into the natural history of MPS IVA, the study was amended to be longitudinal and was approved as such at all sites in 2011. For inclusion to the study, individuals had a confirmed diagnosis of MPS IVA as documented by either molecular genetic testing or reduced GALNS activity as compared to the laboratory-reported normal enzyme activity range for GALNS. Not all individuals provided genetic diagnosis and consequently, this information is not reported or analyzed. Exclusion criteria included previous HSCT or a con-current disease or condition that would interfere with participation in the study. Subjects remain in the study for up to 10 years unless the subject enrolls in an interventional trial or the study is discontinued for clinical or administrative reasons.
At the time of publication, baseline data from 325 patients were available. At each study visit, a detailed medical history, selected clinical assessments, and physical examination are completed. The 6-minute walk test (6-MWT)[26], 3-minute-stair-climb-test (3-MSCT)[27]and respiratory function tests are performed according to published guide-lines. Sites were provided with scheduling recommendations to allow for adequate rest between effort-based procedures. The investigator may opt to forgo assessments if clinically contraindicated. Additional details of the schedule of assessments for the MorCAP study are avail-able online in Supplemental Tavail-able 1.
The MPS Health Assessment Questionnaire (MPS HAQ) is a compre-hensive clinical assessment instrument originally developed for MPS I
patients, adapted for use in MPS VI patients[28]and now used to evaluate MPS IVA patients. Caregivers of patientsb14 years of age complete the
MPS HAQ patient questions until the patient reaches 14 years; at 14 years of age, the patient completes the questionnaire independently. Translations of the questionnaire have been provided to patients/ caregivers in their native language.
Urine KS and creatinine are measured from afirst morning void and uKS values are normalized to creatinine levels. Measurements of uKS are determined by a validated LC–MS/MS assay in which uKS measure-ments are a measure of the sum of mono- and di-sulfated galactoseβ1 N-acetyl-D-glucosamine disaccharides (Galβ1–4GlcNAc(6S) and Gal(6S) β1–4GlcNAc(6S)) generated after keratanase II digestion of KS in urine with values normalized to creatinine excretion [29–32]. Biochemical markers of bone and cartilage metabolism are collected from all subjects, and will be measured in a random subset with other samples stored for future analysis.
2.1. Statistical analysis
Baseline data from study visit 1 collected from clinical assessments were summarized descriptively and graphically, including demo-graphics, medical history, growth history, medications, vital signs and findings from physical examinations. For 6-MWT, 3-MSCT, FVC and MVV, p-values were calculated using an analysis of variance (ANOVA) to compare low uKS versus high uKS groups, controlled for age group. For each age group, p-values were also calculated to test equality of low versus high uKS group.
Continuous variables were summarized using descriptive statistics for mean, median, standard deviation, minimum, and maximum. For subjects who were physically unable to perform the 6-MWT or the 3-MSCT, a value of zero was assigned. Count and percent were used to summarize categorical variables.
3. Results
3.1. Demographics
Complete baseline results are currently available from 325 subjects with MPS IVA representing a global sample including 10 countries. Genders were nearly evenly distributed. The majority (79%) of subjects were in the pediatric age group (18 years and younger); mean and medi-an ages were 14.5 years medi-and 11.6 years (Table 1). Short stature was ap-parent in the study population and affected male and female patients to approximately an equal degree (Figs. 1A and B) with mean±SD (median; min, max) height z-score for≤18 years population of−5.10 ± 2.85 (−5.23; −11.75, 1.93) and −7.59 ± 3.04 (−8.94; −11.37, 0.50) for >18 years population. The mean±SD (median; min, max) for height is 101.2±15.8 (97.4; 77.8, 163.0)cm and length is 104.2±15.7 (101.0; 53.2, 156.5)cm (Table 1). Relative to previously reported height data in MPS IVA patients[11], the range of subject heights in the current study was generally similar, with the exception that many female subjects had heights>90th percentile when measured against curves derived from previously published data[11](Figs. 1A and B).
universal physical feature with 97% of subjects reported with this condition.
In their medical history, the majority of MPS IVA patients (71%) reported surgical procedures; in patients≥5 years, >70% experienced at least one surgical procedure in each age group. Surgical interventions reported in >10% of patients included ear ventilation tube insertion (26%), adenoidectomy (22%), osteotomy (19%), spinal fusion (18%), spinal decompression (14%) and tonsillectomy (11%) (Fig. 2). Just over half (51%) of the subjects were reported to have nervous system disor-ders, including 30% with cervical myelopathy, 14% with cervical cord compression, and 13% with thoracolumbar cord compression. These dis-orders were reported in 36% (16/45) of the 0–4 years old group, 48% (61/ 127) of 5–11 year olds, 58% (49/84) of 12–18 year olds, and 55% (38/69) of the >18 years old group.
Concomitant medications were used by 211 (65%) subjects, with a greater proportion of patients >18 years of age (71%) requiring concom-itant medications as compared to those in the≤18 years old group (63%). Most commonly reported were medications used to treat pain and in-flammation; 79 (24%) of subjects used analgesics and of those 12 (4%) used natural opium alkaloids, and 69 (21%), used anti-inflammatory medications. Antibacterial medication, for treatment of infections such as otitis media and pneumonia, was the next most common with 62 (19%); followed by medications used to treat obstructive airway disease consisting of 44 (14%) of subjects. Additional details from patient medical histories are available online in Supplementary Table 2.
3.2. Clinical assessments
Limitations in endurance and respiratory function are presented in Table 3. The 6-MWT was assessed in 316 patients; though the range was wide (0–864 m), the mean and median were similar at 212.6 ± 152.2 and 224.0 m. Mean walk distance was 251.6 ± 121.5 in 0–4 year olds (n = 37), 232.5 ± 140.1 in 5–11 year olds (n = 127), 181.2 ± 177.3 in 12–18 year olds (n = 84), and 193.1 ± 148.5 in
>18 year olds (n = 68). The 3-MSCT, performed by 274 evaluable subjects, also showed a wide range of 0.0–115.0 stairs/min, with a similar mean and median of 30.0 ± 24.0 and 29.0 stairs/min. Most patients had limited lung volumes, with a mean (median; min, max) FVC in 261 patients of 1.2± 0.9 (0.9, 0.2, 5.0)l; MVV in 237 evaluable patients was 34.8± 25.5 (26.6, 1.3–160.0)liters per minute.
The most common results from ECGs included the presence of sinus tachycardia (n=14), sinus arrhythmias (n=11), and right or left bun-dle branch block (n=11). Subjects were also reported with T wave ab-normalities (n=7), right or left atrial enlargement (n=7), right or left axis deviation (n=5), and right or left ventricular hypertrophy (n=4). Echocardiograms showed cardiac valve regurgitation as a common finding, with tricuspid regurgitation in 111 (34%), mitral regurgitation in 82 (25%), aortic regurgitation in 63 (19%), and pulmonary regurgita-tion in 46 (14%) subjects overall; incidence of cardiac valve stenosis was not as prevalent but still present in each age group. While aortic valve stenosis was relatively uncommon in the younger study population, in-cidence increased with age, being reported in 16% of the patients >18 years of age but in only 4% of patients≤18 years of age. Mitral ste-nosis was reported in 15 (5%) subjects, 3 (1%) were reported with pul-monary stenosis and 3 (1%) with tricuspid stenosis (Fig. 3).
3.3. Patient-reported outcomes
Mobility impairment was demonstrated by reported use of wheel-chairs and walking aids in all age groups, with 45% reporting the use of a wheelchair and 24% of a walking aid. Of these, 27% and 28% always required their wheelchair or walking aid, respectively. Impairment in activities of daily living such as grooming, use offingernail clippers and ability to brush hair and independently wash was also reported (online Supplementary Table 3).
3.4. Levels of keratan sulfate
Keratan sulfate concentrations were measured in patient samples of urine and plasma. As measurable plasma KS concentrations may overlap between Morquio A and unaffected individuals[32,33], urine KS levels more consistently distinguish MPS IVA from unaffected individuals; hence, uKS levels are reported for the MorCAP population.
Urine KS levels were available from 310 individuals with values miss-ing for the other 15 individuals; mean±SD (median; min, max) uKS (expressed asμg/mg creatinine) was 36.4±28.4 (31.2; 0.9, 222.7), and was higher in patients ≤18 years when compared to patients >18 years (Table 2). This decrease in uKS may reflect the expected de-crease in cartilage formation as patients reach puberty and bone growth centers close[33]. In order to account for age-related decrease, uKS cut-off levels were identified based on correlation between uKS and 6-MWT with locally weighted scatterplot smoothing. Low uKS was de-fined as≤20μg/mg for subjects≤18 years old and≤10μg/mg for sub-jects >18 years old. On average, subsub-jects with high uKS demonstrated greater clinical impairment, as measured by height and length z-scores, and endurance and respiratory function tests, than those with low uKS levels (Table 3).Fig. 4demonstrates that pediatric patients with the low-est uKS levels have the talllow-est average height, those with mid-range uKS have mid-range height and those patients with the highest uKS have the shortest or lowest heights. Both pediatric and adult subjects with low uKS on average had closer to normal height, longer walk distance, great-er stair climb result, and greatgreat-er FVC and MVV volumes (Table 3).
3.5. Discussion/conclusion
This study is thefirst to define the natural history of MPS IVA through direct clinical observation and testing in a large number of affected indi-viduals, although patient-reported outcomes describing disease mani-festations have been previously reported by the International Morquio Organization (IMO)[34]. Study data will assist in evaluation of clinical Table 1
Demographics and baseline characteristics of MPS IVA patients.
Demographic
Number of patients 325
0–4 years 45
5–11 years 127
12–18 years 84
>18 years 69
Female N (%) 172 (52.9%)
Years of age mean (median; min, max) 14.5 (11.6; 1.1, 65.6) Race
White 240 (73.8%)
Asian 51 (15.7%)
Black or African American 7 (2.2%)
Other 27 (8.3%)
Height by years mean (median; min, max) cm
0–4 (n = 45) 88.5 (89.1; 77.8, 102.8)
5–11 (n = 116) 102.0 (98.8; 81.9, 152.5)
12–18 (n = 67) 108.1 (101.1; 86.0, 163.0)
>18 (n = 58) 116.0 (104.9; 87.5, 180.2) All subjects (n = 286) 104.2 (98.9; 77.8, 180.2) Length by years mean (median; min, max) cm
0–4 (n = 32) 90.1 (90.8; 77.9, 98.8)
5–11 (n = 90) 104.5 (102.2; 86.5, 153.0)
12–18 (n = 72) 110.0 (103.7; 53.2, 156.5)
>18 (n = 56) 114.8 (105.8; 85.2, 183.0) All subjects (n = 250) 106.6 (102.4; 53.2, 183.0) Height z-score by age vs normal mean
(median; min, max) cm
0–4 (n = 45) −2.09 (−2.28;−4.94, 1.93)
5–11 (n = 116) −5.00 (−5.32;−9.51, 0.94) 12–18 (n = 67) −7.27 (−7.41;−11.75, 0.26) >18 (n = 58)a −7.59 (−8.94;−11.37, 0.50)
All subjects (n = 286) −5.60 (−5.60;−11.75, 1.93)
and biomarker endpoints that may be used to measure disease progres-sion and efficacy of potential treatments. With 325 patients enrolled from 10 countries, MorCAP is estimated to represent approximately 10% of the global MPS IVA patient population based on an estimated average incidence of 1:250,000 births[35]and world birth rates in developing countries, providing the ability to identify general conclusions about symptoms and disease progression in this patient population.
While the heterogeneity of MPS IVA is reflected by the varied clinical presentation of study subjects, on average and consistent with reports in the literature, data demonstrates significant impairment across mul-tiple domains including growth[5,6,11–14,34], endurance and mobility
[12–14,17,34,36], respiratory function[5,10,14–16,34], and the impact of burden of illness on quality of life[14,34]. In addition, clinical impair-ments are more severe in older age groups in general, suggesting pro-gression of clinical symptoms with age[14,34,36].
with age in both genders with a high correlation between uKS and height (Figs. 1A and B). The significantly impacted height in the MorCAP study population (Table 1) reinforces the assertion of the severe skeletal impli-cations of MPS IVA in all clinical phenotypes[5,6,11,17,34]. These severe skeletal manifestations may impact the accuracy of measuring growth in MPS IVA patients as progressively worsening muscle weakness or bone abnormalities can negatively impact patient ability to be measured in a standing position, thus requiring measurement by length. Although a high correlation exists between height and length measurements, change in measurement may cause a 1–2 centimeter variance[37].
Plasma KS and uKS levels are hypothesized to be reflective of the total body storage of KS[29]. Urine KS levels of 36.4 (0.9, 222.7)μg/mg (Table 2) in the MorCAP study population were elevated as compared to reported norms of approximately 1.94 (0.47, 3.90)μg/mg in the unaf-fected population[38]. No gender differences in uKS levels were ob-served. Higher uKS levels were found to be associated with a greater degree of impairment in several clinical outcome measures (6-MWT, 3-MSCT, height, FVC and MVV) across age groups (Table 3), in spite of expected age-related decrease in uKS levels associated with closure of growth plates. This suggests that higher uKS levels may be indicative of a more rapidly progressive end of the disease spectrum; however, it is difficult to classify patients only on baseline uKS levels. Additional longitudinal data will provide a more definitive prognosis for the study population.
Endurance measures are important indicators of functional im-pairment in individuals with progressive diseases[39]. The 6-MWT,
a submaximal exercise test widely used to measure endurance andfl ex-ibility in a range of patients[39–41]including those with MPS disorders [39,42], and the 3-MSCT evaluate the effort required by the cardiovas-cular, pulmonary and/or musculoskeletal systems to perform an activity [39,43]. The results of the 6-MWT and 3-MSCT reveal impairment in the MPS IVA population regardless of age group, suggesting that these mea-sures are appropriate to assess changes across the entire study popula-tion. The overall mean (SD) 6-MWT distance of 212 (152) meters (m) is significantly reduced when compared to the lower limit of normal, reported as ranging from 470–664 m for healthy individuals aged 4–16 years[44,45]and approximately 500–580 m for healthy adults [26]. Although no normative data is available for the 3-MSCT, the stair climb rate of 29 (24)stairs/min reported in MPS IVA patients here shows more significant impairment when compared to the baseline stair climb rate of 50± 29.5 in the MPS VI population[42]. Although dif-ferences in stair height and stairwell configuration prohibit standardi-zation, the 3-MSCT was adapted from the 3-minute step test, which is a validated measure of respiratory function for children with cystic fibrosis, and takes the severe physical limitations of children with MPS VI into account[27].
Impairments in both the 6-MWT and 3-MSCT correlate with uKS levels, although less impairment was observed with the older age group in the results of the 6-MWT in the low uKS group (Table 3). How-ever, even the low uKS adult subjects who showed the least impairment in the 6-MWT at 265.7 m reveal significant impairment (Table 3) when compared to the unaffected adult population[38], reinforcing the value Fig. 2.Incidence of selected surgical procedures for all subjects.
of this test as a prognostic measure for MPS IVA patients. As well as being associated with uKS levels, changes in endurance measures corre-late with respiratory function (Table 3) and disease severity[39], and have been associated with increased severity of exertional dyspnea, tachycardia, tachypnea and orthopenia[28]. Firm conclusions regarding the prognostic value of uKS will require longitudinal data collection to definitively determine associations between this biomarker and clinical outcomes.
In the absence of a standard curve to evaluate respiratory function for patients with MPS diseases that reflects height, weight and thoracic malformations, comparisons of FVC measures to standard norms are rel-atively meaningless[28]. However, FVC and MVV impairments were comparable tofindings with other MPS diseases[28,46]. Respiratory function impairment was demonstrated in all age groups by severely limited volumes in FVC and MVV (Table 3) and was correlated with uKS levels (Table 3). The limitation in MVV in this study population not only indicates reduced lung volumes, but also suggests a reduced ability to carry out the work of breathing. This may reflect limitations in strength of the diaphragm and/or intercostal muscles as well as limit-ed chest wall compliance[47]and airway obstruction[14,15,47-49]. It is likely that the low FVC volumes are related to reduced height[14,28], malformed thorax, and reduced patency of the upper airway that is
characteristic of MPS IVA disease[14]; there is no evidence in the liter-ature that GAG accumulation in the lungs interferes directly with respi-ratory function. A significant proportion of morbidity and mortality in MPS IVA is related to the respiratory system[14]; this is reflected by the number of subjects reporting respiratory system complications in medical history and the common use of medications to treat respiratory disorders.
Cardiac involvement was frequently found in the MorCAP popula-tion (Fig. 3), despite the lack of literature to suggest that this condition is commonly associated with MPS IVA [5,50]. The assertion of the underreporting of cardiac involvement in MPS IVA[14]is reinforced by the results of the ECGfindings coupled with the reported incidence of regurgitation and stenosis in all ages of the MorCAP study population. Regurgitation was more commonly found than stenosis[14,50–53], with tricuspid regurgitation most commonly reported in the MorCAP population, consistent with the literature[50–52]. Although further re-search and longitudinal data are needed to further elucidate the cause of thisfinding, as cardiac disease is always progressive[50]this baseline data reinforces recommendations for frequent cardiac assessments [14].
Quality of life for MPS IVA patients is significantly impacted by disease progression and manifestations regardless of clinical phenotype[14] (online Supplementary Table 3). Patients had frequent infections as compared to unaffected individuals. Vision and hearing impairments were also reported. The use of pain medications in all age categories is in-dicative of the pain associated with tasks of daily living for all individuals with MPS IVA; the increased use of pain medication with age suggests increased pain with age. More than half of the MorCAP study population required a wheelchair or walking aid for mobility. Almost 75% of patients
b12 years of age and more than 95% of patients in the≥12 years age groups required surgical or medical interventions, which carry a high risk for surgical and anesthetic complications due to GAG accumulation obstructing airways as well as skeletal abnormalities, risk of spinal cord injury, frequent lung infections and restrictive lung and cardiac diseases Table 2
Urine KS (μg/mg creatinine) by age group in MPS IVA subjects.
uKS group 0–4 (n = 45)
5–11 (n = 127)
12–18 (n = 84)
Over 18 (n = 69)
n 39 124 82 65
Mean (SD) 56.9 (25.1) 46.8 (30.6) 30.5 (20.4) 11.9 (8.1)
Median 52.7 43.3 28.1 10.1
Min, max 19.9, 112.0 4.8, 222.7 1.7, 110.3 0.9, 41.6
p-Valuesb0.0001 for all pairwise comparisons of mean uKS by age groups, except p-value = 0.0230 for 0–4 years vs. 5–11 year old groups.
p-Value for overall comparisonb0.0001.
Table 3
Endurance and pulmonary function in MPS IVA subjects by uKS (μg/mg creatinine) and age group. Low uKS is≤20μg/mg for subjects≤18 years old and≤10μg/mg for subjects >18 years old.
Age≤18 years Age > 18 years
Low uKS group (n = 44)
High uKS group (n = 201)
Missing uKS (n = 1)
All (n = 256)
Low uKS group (n = 32)
High uKS group (n = 33)
Missing uKS (n = 4)
All (n = 69)
6-MWT (m) p= 0.0013a
p = 0.1215b p= 0.0002b
N 45 195 8 248 32 33 3 68
Mean (SD) 255.4 (183.7) 216.5 (143.1) 45.1 (68.6) 218.0 (153.2) 265.7 (140.9) 136.6 (125.9) 40.0 (69.3) 193.1 (148.5)
Median 264.0 234.9 18.5 234.0 311.2 100.0 0.0 206.0
Min, max 0.0, 801.3 0.0, 864.0 0.0, 200.6 0.0, 864.0 0.0, 510.0 0.0, 418.6 0.0, 120.0 0.0, 510.0
3-MSCT (steps/min) p= 0.0085a
p = 0.1948b p= 0.0016b
N 42 165 8 215 26 31 2 59
Mean (SD) 36.6 (28.0) 31.1 (23.5) 15.5 (16.4) 31.6 (24.5) 34.0 (20.6) 16.4 (19.3) 15.0 (21.2) 24.1 (21.5)
Median 34.2 31.0 12.7 31.0 34.9 6.3 15.0 23.3
Min, max 0.0, 115.0 0.0, 112.4 0.0, 43.5 0.0, 115.0 0.0, 89.6 0.0, 63.2 0.0, 30.0 0.0, 89.6
FVC (L) pb0.0001a
pb0.0001b p
b0.0001b
N 43 148 4 195 32 33 1 66
Mean (SD) 1.9 (1.0) 0.9 (0.4) 0.6 (0.1) 1.1 (0.7) 2.1 (1.3) 0.8 (0.4) 3.0 (NA) 1.5 (1.1)
Median 1.7 0.8 0.5 0.9 1.80 0.80 3.00 1.00
Min, max 0.5, 4.5 0.2, 2.7 0.5, 0.7 0.2, 4.5 0.5, 5.0 0.3, 2.5 3.0, 3.0 0.3, 5.0
MVV (L/min) pb0.0001a
pb0.0001b p
b0.0001b
N 40 134 4 178 28 30 1 59
Mean (SD) 56.1 (29.6) 25.7 (13.1) 19.4 (4.9) 32.4 (22.1) 59.2 (37.5) 24.2 (10.9) 98.7 (NA) 42.1 (32.8)
Median 51.8 24.0 18.6 25.5 44.0 22.1 98.7 31.5
Min, max 9.7, 119.0 1.3, 90.0 14.5, 25.8 1.3,119.0 13.7, 160.0 6.3, 56.7 98.7, 98.7 6.3, 160.0
[15,34]. Spinal fusion and decompression surgeries were both reported in >10% of the MorCAP study population while instability of the spinal region places patients at risk for spinal injury[10]. Combined, these findings suggest significant burden of the disease across all ages and phenotypes of MPS IVA.
The Morquio A Clinical Assessment Program (MorCAP) is thefirst lon-gitudinal study involving direct assessments of MPS IVA patients. Baseline data provides insight into the clinical presentation and significant burden of illness associated with MPS IVA regardless of age and clinical pheno-type. All individuals with MPS IVA develop progressively severe clinical manifestations, although potentially later in life for those individuals with more slowly progressive disease. Characterization of clinical impair-ments across a large subject population is expected to improve under-standing of the disease and to potentially facilitate better management. While further analyses of patients returning for longitudinal annual as-sessments will provide insight into the natural history of MPS IVA, the current cross-sectional data reported here demonstrates the progressive worsening of the disorder with age and offers guidance for clinical trial outcomes, the diagnostic process, and the ongoing management of MPS IVA patients.
Supplementary data to this article can be found online athttp://dx. doi.org/10.1016/j.ymgme.2013.01.021.
Conflict of interest statements
Paul Harmatz has provided consulting services, received research grants, participated in advisory board meetings and received speaker honoraria and travel support from BioMarin Pharmaceutical Inc. Carla Hollak is an investigator of BioMarin Pharmaceutical Inc. Peter Slasor and Celeste Decker are employees and stockholders of BioMarin Phar-maceutical Inc. All other authors are investigators and/or consultants of BioMarin Pharmaceutical Inc., have received research grants from BioMarin Pharmaceutical Inc. in accordance to clinical trials hospital contracts and travel support from BioMarin Pharmaceutical Inc.
Acknowledgments
The authors would like to acknowledge the patients and families who participated in this investigation and all MorCAP investigators and clinic coordinators. This study was supported, in part, with funds
provided by the National Center for Research Resources, 5 M01 RR-01271 (Dr. Harmatz). Dr. Parini would like to thank Fondazione Pierfranco and Luisa Mariani of Milano for providingfinancial support for clinical assistance to metabolic patients. Brad Glasscock, Monica Miller, Ken Martin, Elaina Jurecki, Gina Park and Dan DiPrimeo of BioMarin Pharmaceutical Inc. provided assistance with preparing this manuscript. Medical writing was provided by Judy Wiles and layout assistance by Selma Tse both of Facet Communications with funding from BioMarin Pharmaceutical Inc.
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