We gathered data from 33 adult patients with MPS IVA. As the questionnaire return rate was 100%, this number of patients is probably very close to the whole population of MPS IVA adult patients in Spain, although there may be a number of patients who are undiagnosed.
The median age at diagnosis was 5 years, which concurs with data in the International Morquio A Registry in 2007 . More than one-third of our patients had affected siblings, possibly because genetic counselling and prenatal testing were more difficult to obtain years ago than nowadays, or even unavailable.
More than 50% of our patients had the classical phenotype. We did not examine the relationship between phenotype and GALNS mutations, and genetic analysis was available for only 16 patients. However, we found two GALNS mutations that have been associated with classical phenotype (c.1156C > T and c.901G > T) . It would be interesting to assess such relationship in a future study with more complete genetic data available.
With regard to the clinical manifestations of MPS IVA, height was under the third percentile in most patients—short stature is common in MPS IVA patients . As expected, length and weight were normal at birth.
Another common clinical manifestation was ligamentous laxity, which can complicate personal care and activities such as getting dressed. It can also make writing difficult, which can be a problem for work or study.
Other non-skeletal manifestations, such as corneal clouding and respiratory compromise, were frequent in our patient population, correlating with findings in other studies [4, 15]. We found that up to one-third of patients needed non-invasive ventilation. This finding highlights the relevance of periodic respiratory check-ups in patients with MPS IVA.
Hearing loss is also common in MPS IVA. Patients suffer frequent otitis and middle and inner ear abnormalities, which cause mixed hypoacusis at around 5 years of age . More than 75% of patients with MPS IVA in our study had hearing loss, a percentage similar to that found in the Morquio A Clinical Assessment Program study .
In our study, five of the seven patients who began ERT did so before the age of 18 years under an early access programme . Two patients left the country and were lost to follow-up, meaning we had data from only five patients treated with elosulfase alfa. This small number of patients meant that it was not possible to perform an in-depth analysis of the potential effects of ERT. However, in one study of 37 adult patients with MPS IVA treated for 120 weeks with elosulfase alfa, endurance increased and performance of ADL improved, without changes in pulmonary function . However, in 10 patients with more severe disease and limited mobility treated with elosulfase alfa for 48 weeks, results were inconsistent because of clinical heterogeneity of patients, severe deformities, and the small sample size . Nevertheless, in a study with 5-year follow-up, elosulfase alfa prevented disease progression . Moreover, performance of ADL improved after 120 weeks of ERT in 170 patients .
The percentages of surgical intervention were similar to those found in the International Morquio A Registry in 2007, in which 50% of patients underwent cervical surgery, 30% ear surgery, 26% limb surgery and 25% hip surgery . Orthopaedic surgery in patients with MPS IVA should be considered individually, assessing risk, timing, pain, and patient preferences .
Burden of disease
Patients with MPS IVA had reduced mobility [4, 15, 21]. In our study, almost 80% of patients had problems for walking, and more than 65% needed a wheelchair some or all the time. It should be noted that wheelchair use has been related to worse HRQoL . Furthermore, as shown in our study, patients with MPS IVA need help with self-care and performing ADL .
Another common symptom in patients with MPS IVA is pain, which is related to musculoskeletal problems. Pain can affect the spine, the upper and lower extremities, and the head and neck, and can interfere with mobility and ADL. In our study, almost 80% of patients reported some degree of pain. Similarly, in a patient-reported outcomes survey, 74% of adults reported joint pain . Pain was more severe in wheelchair users than in non-users and was worse in patients who used a wheelchair all the time compared with those who used a wheelchair intermittently, in contrast with other published results .
Psychological symptoms can go unnoticed because of the severity of physical symptoms. However, many patients with MPS have some degree of psychological disturbance , with more than 50% of patients with MPS IVA having psychological symptoms in one study . We found that 20% of patients symptoms of anxiety, but we did not use a specific questionnaire for mental health. Therefore, this percentage is not conclusive.
The high burden of disease in our study could be partly because 60% of our patients had not been cared for at paediatric reference units when they were children/teenagers, being managed instead at trauma and orthopaedic clinics because of the bone dysplasia, but without specific follow-up of the other disease features. In addition, the transition from paediatric to adult units is not always well managed in Spain.
Various factors relating to surgery are also probably implicated in the high disease burden. First, the number of surgical procedures was insufficient. Second, surgical outcomes were not as good as expected or desired, perhaps because some procedures were performed at non-specialist centres. In general terms, these patients may not have received optimal healthcare because of the severity of their disease and the absence of referral to specialist centres. This, together with a lack of co-operation from some patients not happy with the multiple examinations, may also be the reason for the large amount of data missing.
Finally, earlier onset of ERT probably leads to a better disease course. However, the beneficial effect of elosulfase alfa has still to be confirmed in long-term studies inpatients treated from early age .
Disease progression impairs HRQoL in patients with MPS IVA. The median score of HAQ in the present study was 2.12; as HAQ scores can range between 0 (no disability) and 3 (maximum disability) , this result shows that patients with MPS IVA had an important disability. Moreover, as we confirmed in our study, HRQoL is worse in patients with the intermediate or classical phenotypes. Many factors contribute to a poor HRQoL: mobility, endurance, problems performing ADL, dependence on caregivers, frequent surgical interventions, fatigue and pain. Maintaining functionality and mobility, as well as pain control, will probably improve HRQoL in patients with MPS IVA .
Unemployment is related to a poorer HRQoL. Only 15% of our patients had a job, and only one patient worked full-time. In an international study in patients with MPS IVA, HRQoL was statistically significantly better in employed patients . This difference could be due not only to higher psychological wellness, but also to a better physical state.
In this study, HRQoL, as measured by the HAQ score, was higher in patients treated with elosulfase alfa than in those not treated with ERT. Because of the small number of patients, we did not perform any statistical analysis, but we could hypothesise that ERT improved mobility, and thence HRQoL. A further comparison of 6MWT results in a larger number of ERT treated and untreated patients would be necessary.
It is recommended that the disease burden be assessed each year. At the annual visit, the physician in charge should evaluate HRQoL, fatigue, ADL, pain severity, and use of wheelchair or walking aids . In addition, psychological health deserves more attention and should be assessed regularly .
It was a multicentre retrospective study and some data were missing. Especially in older patients, some data were not recorded or were lost. Regarding diagnosis test, urinary GAGs, enzyme activity and GALNS mutations were not assessed in all patients. The reasons were that these test were not available or easily accessed when middle age or old patients were diagnosed. In addition, urinary GAGs were measured in different laboratories with different references values. Furthermore, available tests were not the same for all laboratories and hospitals.
Classification of patients as classical, intermediate and non-classical phenotypes is not current practice. However, as it is stated above, the disease should be considered as a continuum . Moreover, this classification allowed a better comparison between patients. In addition, although height is not the only abnormality that could be assessed, it is an objective measure that reflects the severity of bone dysplasia. Other authors have also categorized patients in these three groups by height [3, 7, 9].
We did not analyse GAG levels because measurements were performed at different laboratories with different cut-off points and different measurement units. However, all laboratories were specialized centres that were validated for the study of the MPS IVA.
As for ERT, elosulfase alfa has been approved by the Spanish Agency of Medicines and Medical Devices for the treatment of MPS IVA, but it is not yet on the market in Spain. Therefore, access to ERT is limited and only seven patients in the study received elosulfase alfa, all them on compassionate use.