Heparin cofactor II-thrombin complex: a biomarker of MPS disease

The mucopolysaccharidoses are a group of lysosomal storage disorders caused by defects in the degradation of glycosaminoglycans. Each disorder is characterized by progressive multi-system disease with considerable clinical heterogeneity. The clinical heterogeneity of these disorders is thought to be related to the degree of the metabolic block in glycosaminoglycan degradation which in turn is related to the underlying mutation at the respective locus. There are currently no objective means other than longitudinal clinical observation, or the detection of a recurrent genetic mutation to accurately predict the clinical course for an individual patient, particularly when diagnosed early. In addition, there are no specific disease biomarkers that reflect the total body burden of disease. The lack of specific biomarkers has made monitoring treatment responses and predicting disease course difficult in these disorders. The recent introduction of enzyme replacement therapy for MPS I, II, and VI highlights the need for objective measures of disease burden and disease responsiveness. We show that serum levels of heparin cofactor II–thrombin complex is a reliable biomarker of the mucopolysaccharidoses. Untreated patients have serum levels that range from 3- to 112-fold above control values. In a series of patients with varying severity of mucopolysaccharidosis I, the serum complex concentration was reflective of disease severity. In addition, serum heparin cofactor II–thrombin levels showed responsiveness to various treatment regimens. We propose that serum levels of heparin cofactor II–thrombin complex may provide an important assessment and monitoring tool for patients with mucopolysaccharidosis.     

Histomorphometric Analysis of the Tibial Growth Plate in a Feline Model of Mucopolysaccharidosis Type VI

Mucopolysaccharidosis type VI (MPS VI) is a genetically inherited lysosomal storage disorder. Severely affected children exhibit a range of skeletal abnormalities including short stature, facial dysmorphia, and dysostosis multiplex. Naturally occurring and transgenic animal models of MPS VI are also found which exhibit pathology similar to the human disorder. In this paper we have characterized the formation of trabecular bone from growth plate cartilage in a feline model of MPS VI. Tibial trabecular bone was shown to be osteopenic in MPS VI animals with a bone mineral volume (BV/TV) of 4.51% compared with a BV/TV of 15.64% in normal animals. In addition to osteopenia, a rearrangement of trabecular bone architecture was also observed in MPS VI tibiae, with fewer, thinner trabeculae noted; bone formation rate was also decreased. These observations support those previously made in the L5 vertebrae of MPS VI animals. When the sequential formation of growth plate cartilage structural elements, their transition into primary bone spongiosa, and remodeling into secondary bone spongiosa was characterized, no difference between normal and MPS VI could be detected in the number of cartilage septae and their arrangement in the proliferative and hypertrophic regions of the growth plate or trabecular elements in the primary spongiosa. However, a deviation from normal was observed in the resting zone of the growth plate and in the secondary spongiosa of bone. Thus, the osteopenia observed in MPS VI bone appears to arise primarily from a defect in bone production within the metaphysis and diaphysis rather than the creation of an abnormal template in the preceding growth plate cartilage. Received: 29 March 1998 / Accepted: 21 November 1998     

Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients

PurposeMain symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before.Material and methodsMRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS.ResultsThe deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132 ± 24 vs. 177 ± 6, BA/VA transition 113 ± 21 vs. 152 ± 13, right VA 108 ± 23 vs. 156 ± 13, left VA 110± 22 vs. 157 ± 14 (all p < 0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27 ± 4 vs. 21 ± 2, right VA 20 ± 6 vs. 10 ± 1, left VA 18 ± 5 vs. 11 ± 2 (all p < 0.005).ConclusionMPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.     

MRI in the mild type of mucopolysaccharidosis II (Hunter's syndrome)

We report imaging findings in a 3-year-old boy with the typical mild type of Hunter's disease. MRI revealed multifocal large cyst- or spindle-like areas of increased and decreased signal in the white matter, including the corpus callosum on T1- and T2-weighted images. The white matter showed high signal on T2-weighted images, isointense with cerebrospinal fluid on all other pulse sequences. To our knowledge, these appearances have not been reported in this disorder. Deposition of mucopolysaccharide and/or glycolipid and increase in fluid content seem to be responsible.     

The value of computed tomography in patients with mucopolysaccharidosis

Summary Cranial computed tomography (CT) was performed on 11 cases of mucopolysaccharidosis (MPS) IVA (Morquio syndrome). Our results suggest that although the patients may have normal intelligence CT changes may be seen with increasing age. In two cases white matter low density was found and in a third there was gross dilatation of the ventricles, basal cisterns and subarachnoid space. Nine other patients with various types of mucopolysaccharidosis also had cranial CT performed and in general those types associated with mental retardation showed changes although there was an interesting exception involving a case of MPS IIIA who had a normal CT scan.     

血样低温放置时间对黏多糖贮积症酶学检测的影响

目的探讨4 ℃条件下血样放置时间对黏多糖贮积症(MPS)酶学检测的影响。 方法选择2020年1月5日至9日，采集自5例健康志愿者(男性为2例，女性为3例，年龄为24~30岁)的血样各6管为研究对象。将其依次命名为血样1、2、3、4、5(研究组)。将采集的5×6管血样，置于4 ℃条件保存，于不同放置时间点(0、24、48、72、96、120 h)对其进行MPS酶学检测。同时收集本院医学遗传科20例健康受试者进行外周血细胞染色体检查后的剩余血样，将其混合与研究组同批次检测作为MPS酶活性正常值(对照组)。①观察研究组血样放置不同时间点，血浆颜色变化，并进行血浆游离血红蛋白(f-Hb)检测，评估血样溶血情况。②进行白细胞分离，并检测放置不同时间点白细胞中α-硫酸艾杜糖醛酸酶(IDUA)、α-N-乙酰葡萄糖胺酶(NAGLU)和β-葡萄糖醛酸酶(GUSB)活性水平，比较各种酶活性水平在不同检测时间点的差异。所有受试者均签署临床研究知情同意书，本研究遵循的程序符合四川大学华西第二医院伦理委员会制定的伦理学批准，并得到该委员会批准(审批文号：20180094)。 结果①血样在放置72 h时血浆颜色开始逐渐变红，放置时间越长，变红的程度越深；血浆f-Hb水平提示放置72 h呈增高趋势，并且随着放置时间延长，溶血程度也越来越严重。②血样1~5放置24、48、72、96、120 h时，IDUA、NAGLU活性水平分别与自身未放置血样比较，差异均无统计学意义(P>0.05)。③血样1~5在放置24、48、72、96 h的GUSB活性水平分别与未放置血样比较，差异亦均无统计学意义(P>0.05)；但是，放置120 h时GUSB活性水平明显低于未放置血样，2组比较，差异有统计学意义(t＝4.601、P＝0.002)。 结论综合溶血情况和酶活性水平等多种因素，建议进行MPS酶学检测的外周血血样于采集后72 h(3 d)内送达检测实验室，72~120 h(3~5 d)送达实验室的血样，需取决于血样自身质量和待检测溶酶体酶类型，于120 h(5 d)时送达的检测失败可能性极大。     

Synchrotron X-ray diffraction to understand crystallographic texture of enamel affected by Hunter syndrome

ObjectiveTo determine whether Hunter syndrome (MPS II) affects the crystallographic texture (preferred orientation) of enamel.DesignSynchrotron X-ray diffraction, being a state of the art technique, has been used to determine the enamel crystallite orientation in enamel affected by Hunter syndrome (MPS II). The incisal, lingual and cervical regions of the MPS II affected tooth were observed and compared to healthy tooth.ResultsIt was observed that there is a loss of organization of crystallites in deciduous incisal enamel affected by Hunter syndrome (MPS II) as compared to healthy deciduous enamel tissue. Generally it was observed that, in contrast to the healthy enamel, the enamel affected by MPS II possessed a lower crystallographic preferred orientation, with a more uniform spatial distribution; however, the enamel at the incisal tip was relatively unaffected.ConclusionHunter syndrome affects the enamel texture in the lingual and cervical regions of the tooth.     

Does enzyme replacement therapy influence the ocular changes in type VI mucopolysaccharidosis?

Background  To describe the ocular changes noted in seven patients with type VI mucopolysaccharidosis (MPS VI) during 44 months of follow-up while on enzyme replacement therapy (ERT). Methods  One male and six female patients with MPS VI were followed-up for a mean period of 44 months while undergoing enzyme replacement therapy (ERT) with recombinant arylsulfatase B (Naglazyme™). They were examined annually for visual acuity, corneal clouding, intraocular pressure (IOP), optic nerve head and fundus morphology. Corneal clouding was documented by photography. We acknowledge that our methodology may not have been sensitive enough to detect extremely mild ocular changes, including minimal increases in corneal thickness or clouding. Nevertheless, this limitation has been considered in the interpretation of our findings. Results  Ophthalmological findings remained stable in 5/7 patients. One patient experienced a modest improvement in visual acuity of more than 2 Snellen lines in one eye, while another patient suffered a deterioration in visual acuity of more than 2 Snellen lines in both eyes. Five out of seven patients showed optic nerve pathology: two of these exhibited optic nerve head swelling, while the other three showed variable degrees of optic nerve atrophy. All seven patients suffered from the typical corneal stromal opacities, however, to variable extents. Conclusion  Visual function and ocular findings did not deteriorate in six out of seven MPS VI patients during a mean follow-up period of 3 and a half years on ERT.     

Craniosynostosis and metabolic bone disorder. A review

IntroductionSome metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder.Material and methodsA review of the literature on metabolic forms of craniosynostosis was performed.ResultsThe most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe.ConclusionThe impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.