Attenuated osteoarticular phenotype of type VI mucopolysaccharidosis: a report of four patients and a review of the literature

One of the first descriptions of mucopolysaccharidosis type VI was probably by the neurologist Nonne [12]. After several investigators indicated heterogeneity of MPS VI based on radiological findings, the patients’ size, and longevity [13, 14], McKusick suggested separating a severe form (mucopolysaccharidosis type VIA) from a mild variant (type VIB) [15]. Based on McKusick’s classification, the longevity, size, lack of cardiac insufficiency in association with mild cardiac murmurs, lack of abnormality of sella turcica, and the absence of umbilical or inguinal hernia, marked hepatosplenomegaly, and marked corneal opacities warranted the diagnosis of the mild B variant of MPS VI [15]. Apart from severe and attenuated phenotypes, descriptive classification systems have also described an intermediate disease form. Other authors suggested other classification systems based on height and urinary glycosaminoglycan (uGAG) levels, the age at the onset of symptoms, patient’s height, and the age of death [16, 17]. In reality, there are no fixed parameters to ascribe a particular patient to a single category, and the decision is subjective depending on physician’s experience and knowledge. The relatively attenuated disease form is generally characterized by later onset of symptoms which may not at first appear in a recognized pattern, but when apparent, the milder symptoms may be observed by an alert physician and lead ultimately to diagnosis usually after 5 years of age, but it may be delayed until the second or third decades.

Results from our study and review of the literature allow for distinguishing two types of attenuated MPS VI phenotypes: osteoarticular and cardiac. It is likely that patients with osteoarticular symptoms will be found in either rheumatology or orthopedic clinics. The similarity of attenuated MPS VI to the more commonly seen rheumatological conditions means that patients are often misdiagnosed and there is a delay before the patient’s symptoms are attributed to MPS. Patients with a cardiac variant of MPS VI are much more probable to be found in cardiology clinics [18, 19]. In these patients, cardiac disease progresses silently and ultimately leading to heart failure and does not correspond with the other typical MPS features which are very mild or absent [8]. An advanced valve defect is an indication for valve surgery, which may be beneficial in these patients at an earlier stage of the disease. In both phenotypes, the pathological process seems to be restricted at first to one system only, either osteoarticular or cardiovascular. In the cardiac phenotype, however, it tends to have more serious complications leading to fast disease progression and abrupt death [7].

Despite the utility of communicating with these descriptive categories, it is important to recognize that the symptoms of the disease manifested along a continuum. Using a descriptive classification is very helpful for clinicians; however, it is important to bear in mind its implications. The term attenuated (or used by some slowly progressing) implies a slower disease progression, and it may be perceived that these patients do not require treatment as urgently as severe patients. The truth is that these patients may remain asymptomatic for years with silently (but not necessarily slowly) progressing disease and be recognized in an advanced disease stage when it is too late for any intervention [7]. For this reason, we previously suggested using a term cardiac MPS VI variant to add a sense of urgency as these patients require treatment to be administered prior to the onset of valve disease [8].

The awareness among cardiologists and rheumatologists should be raised so they can play an important role, not only in the management but also in the diagnosis of these patients [18]. The extent of cardiac involvement may be underestimated in patients with mucopolysaccharidosis because of restrictive pulmonary disease and skeletal abnormalities that limit patients’ activities [19]. We have previously presented a diagnostic algorithm, suggesting uGAG analysis in any patient with valve disease even in the presence of very mild or untypical disease symptoms [18]. In cases with a high index of suspicion such as those with a positive family history or those with other characteristic features of MPS VI, enzymatic activity should be determined even if uGAG excretion is low. As attenuated patients may still be very difficult to recognize, the delay in diagnosis may make it difficult to influence valve disease with available treatment. Apart from this, we have to bear in mind that the usefulness of enzyme replacement therapy is limited due to the fact that a given enzyme preparation does not have beneficial effects on all aspects of a disorder in the same degree. The effect of ERT alone on cardiac structure and function in MPS patients has been documented in only a few studies [20‐23] and larger studies with longer follow-up are still needed. Additionally, clinical studies have shown that many symptoms of mucopolysaccharidoses even after long-term treatment are not anymore reversible. It seems probable that in the future, a tailored combination therapy using ERT with novel therapeutic options such as application of small molecules that either inhibit a key enzyme which is responsible for substrate synthesis (substrate deprivation) or act as a chaperone to increase the residual activity of the lysosomal enzyme (enzyme-enhancing therapy) will be the most effective [24].

By identifying patient’s genotype, it may be possible to predict the course of the disease and establish more tailored treatment plan. Patients with the p.Y210C mutation should be covered by a special care team of orthopedists, physiotherapists, and rheumatologists with a plan of rehabilitation, proper early use of orthoses and other support devices, the best determination of time for bone and joint surgery, and application of drug treatments. Patients with the p.R152W should be referred to a cardiologist before the appearance of symptoms from the circulatory system. The mechanism why the p.R152W mutation seems to have a special affinity for the heart valves remains unknown. Perhaps this stems from the specific structure of the valves, and each of these mutations causes different residual enzyme activity. Detecting these differences would explain the process of affecting different organs dependent on the flow dynamics of the substrate.