Natural history of craniovertebral abnormalities in a single-center study in 54 patients with Hurler syndrome.

OBJECTIVE: Craniovertebral junction (CVJ) abnormalities are common and well documented in mucopolysaccharidosis type I-Hurler syndrome (MPS IH), often causing severe spinal canal narrowing. However, the requirement for surgical decompression and/or fusion is uncommon. Although hematopoietic cell transplant (HCT) has been shown to prolong the lives of patients with MPS IH, its effect in halting or reversing musculoskeletal abnormalities is less clear. Unfortunately, there are currently no universal guidelines for imaging or indication for surgical interventions in these patients. The goal of this study was to track the progression of the CVJ anatomy in patients with MPS IH following HCT, and to examine radiographic features in patients who needed surgical intervention. METHODS: Patients with MPS IH treated at the University of Minnesota with allogeneic HCT between 2008 and 2020 were retrospectively reviewed. Patients who underwent CVJ surgery were identified with chart review. All MPS IH cervical scans were examined, and the odontoid retroflexion angle, clivoaxial angle (CXA), canal width, and Grabb-Oakes distance (pB-C2) were measured yearly for up to 7 years after HCT. Longitudinal models based on the measurements were made. An intraclass correlation coefficient was used to measure interrater reliability. Nine children without MPS IH were examined for control CVJ measurements. RESULTS: A total of 253 cervical spine MRI scans were reviewed in 54 patients with MPS IH. Only 4 (7.4%) patients in the study cohort required surgery. Three of them had posterior fossa and C1 decompression, and 1 had a C1-2 fusion. There was no statistically significant difference in the spinal parameters that were examined between surgery and nonsurgery groups. Among the measurements, canal width and CXA varied drastically in patients with different neck positions. Odontoid retroflexion angle and CXA tended to decrease with age. Canal width and pB-C2 tended to increase with age. CONCLUSIONS: Based on the data, the authors observed an increase in canal width and pB-C2, whereas the CXA and odontoid retroflexion angle became more acute as the patients aged after HCT. The longitudinal models derived from these data mirrored the development in children without MPS IH. Spinal measurements obtained on MR images alone are not sufficient in identifying patients who require surgical intervention. Symptom monitoring and clinical examination, as well as pathological spinal cord changes on MRI, are more crucial in assessing the need for surgery than is obtaining serial imaging.

Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.

Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.

OBJECTIVE: Previous research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I. METHODS: Volumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls. RESULTS: The MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT. CONCLUSIONS: We found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

Cathepsin B inhibition attenuates cardiovascular pathology in mucopolysaccharidosis I mice.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder with multisystemic features, including heart enlargement, heart valve dysfunction, and aortic stiffness and dilatation. Previous studies have shown that MPS I mice overexpress cathepsin B (CtsB) in multiple tissues, including those from the cardiovascular system. Here, we hypothesized that inhibition of CtsB could ameliorate cardiac function parameters, as well as aorta and valve abnormalities found in MPS I. First, we found that total elastase activity in an MPS I aorta is elevated. Following that, we demonstrated that CtsB leaks from the lysosome in MPS I human fibroblasts, possibly acting as a degradative agent of extracellular matrix components from the aorta, cardiac muscle, and heart valves. We then used a CtsB inhibitor in vivo in the MPS I mouse model. After 4 months of treatment, partial inhibition of CtsB activity in treated mice reduced aortic dilatation, as well as heart valve thickening, and led to improvements in cardiac function parameters, although none of these were completely normalized. Based on these results, we conclude that lysosomal alterations in this disease promote leakage of CtsB to outside the organelle, where this protein can have multiple pathological roles. CtsB inhibition improved cardiovascular parameters in MPS I mice and can have a potential benefit in this disease.

Characterization of Hip Morphology in Children With Mucopolysaccharidosis Types I and II.

BACKGROUND: The purpose of this study is to describe the natural history of hip morphology in patients with mucopolysaccharidoses (MPS) I and MPS II. METHODOLOGY: This is a retrospective radiographic analysis of 88 hips in 44 children with MPS I and II. Radiographs were examined to determine hip migration, femoral head sphericity, and acetabular dysplasia at different ages throughout childhood. In individual hips, change in morphology and rate of change were analyzed. RESULTS: There was a high rate of hip migration and femoral head dysplasia in both MPS I and MPS II. Progressive migration was seen in three quarters of hips and progressive femoral head deformity in over half of hips. Acetabular dysplasia was variable, ranging from normal to severely dysplastic, but did not change with time. Overall, hips were more dysplastic in MPS I than MPS II. CONCLUSIONS: Hip morphology is variable in MPS I and MPS II ranging from almost normal to severely dysplastic. Some hips do not deteriorate with time and thus surgical intervention may not be necessary in all cases. Deterioration is slow allowing time to plan a holistic approach to treatment. LEVEL OF EVIDENCE: Level IV-case series.

Hurler syndrome: orofacial, dental, and skeletal findings of a case.

Hurler syndrome is a disorder of mucopolysaccharide metabolism caused due to inherited deficiencies of lysosomal α-l-iduronidase activity. We present a case of a 15-year-old male patient presenting with clinical and laboratory characteristics of the syndrome. A rare combination of skeletal, ophthalmologic, and dental findings was observed in this patient. Mucopolysaccharides excretion spot test of urine was positive and an assay of alpha-l-iduronidase enzyme was deficient, confirming the clinical diagnosis of Hurler syndrome.

Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness.

BACKGROUND: Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients. OBJECTIVES: The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls. METHODS: MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory. RESULTS: A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (± SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p<0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm(2)/mmHg versus 0.16 ± 0.05 mm(2)/mmHg; adjusted p=0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p<0.001). cCSD in MPS patients was lower than that of controls (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients. CONCLUSIONS: Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.

Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs.

INTRODUCTION: Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder characterized by deficient α-l-iduronidase activity leading to accumulation of poorly degraded dermatan and heparan sulfate glycosaminoglycans (GAGs). MPS I is associated with significant cervical spine disease, including vertebral dysplasia, odontoid hypoplasia, and accelerated disk degeneration, leading to spinal cord compression and kypho-scoliosis. The objective of this study was to establish the nature and rate of progression of cervical vertebral bone disease in MPS I using a canine model. METHODS: C2 vertebrae were obtained post-mortem from normal and MPS I dogs at 3, 6 and 12 months-of-age. Morphometric parameters and mineral density for the vertebral trabecular bone and odontoid process were determined using micro-computed tomography. Vertebrae were then processed for paraffin histology, and cartilage area in both the vertebral epiphyses and odontoid process were quantified. RESULTS: Vertebral bodies of MPS I dogs had lower trabecular bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) than normals at all ages. For MPS I dogs, BV/TV, Tb.Th and BMD plateaued after 6 months-of-age. The odontoid process appeared morphologically abnormal for MPS I dogs at 6 and 12 months-of-age, although BV/TV and BMD were not significantly different from normals. MPS I dogs had significantly more cartilage in the vertebral epiphyses at both 3 and 6 months-of-age. At 12 months-of-age, epiphyseal growth plates in normal dogs were absent, but in MPS I dogs they persisted. CONCLUSIONS: In this study we report reduced trabecular bone content and mineralization, and delayed cartilage to bone conversion in MPS I dogs from 3 months-of-age, which may increase vertebral fracture risk and contribute to progressive deformity. The abnormalities of the odontoid process we describe likely contribute to increased incidence of atlanto-axial subluxation observed clinically. Therapeutic strategies that enhance bone formation may decrease incidence of spine disease in MPS I patients.

The craniocervical junction following successful haematopoietic stem cell transplantation for mucopolysaccharidosis type I H (Hurler syndrome).

Mucopolysaccharidosis I Hurler (MPS IH) is a progressive multisystemic disorder caused by alpha-L-iduronidase deficiency. First choice of treatment in MPS IH children is haematopoietic stem cell transplantation (HSCT). The effect of HSCT has been shown to have limited influence on skeletal manifestations by poor penetration of musculoskeletal tissues by the enzyme derived from donor leucocytes. Aim of this study was to investigate the effect of HSCT on the craniocervical junction (CCJ) in Hurler patients. We analysed retrospectively sequential magnetic resonance imaging (MRI) scans of 30 patients with Hurler disease treated by HSCT since 1982 at the Royal Manchester Children's Hospital, UK, in order to determine whether the patients suffer from dens hypoplasia. Results were compared with biochemical and clinical characteristics: Enzyme activity (EA), chimerism, urinary glycosaminoglycan (GAG) excretion and neurological status. Investigations were part of standard clinical procedures. Results are descriptive in presentation. In 26/30 patients a determination of odontoid hypoplasia was feasible. The majority showed a normal dens length and an increase with age. Only 3/26 revealed a dens hypoplasia. One of them had only partial donor engraftment (DE) with reduced EA, one of them suffered from chronic graft versus host disease (GVHD). One patient with only partial DE and reduced EA presented with initial dens hypoplasia until preadolescence but normalized later on. There may be a trend towards lower EA and the occurrence of DH in transplanted MPS patients - perhaps the dosage of enzyme plays a role in the correction of skeletal complications in this patient group. HSCT patients with incomplete DE and therefore lower EAs may require special attention and care.

[Hurler's syndrome--early clinical suspicion]. / Hurlers syndrom--tidlig klinisk mistanke.

BACKGROUND: Hurler's syndrome is a rare congenital metabolic disorder and is inevitably lethal when untreated. The presenting symptoms are usually vague, resembling those found in otherwise healthy children. MATERIAL AND METHODS: We present a patient with Hurler's syndrome and discuss the unspecific clinical signs and symptoms seen in these patients based on a review of relevant literature. RESULTS: A two-months-old infant boy was operated for a rightsided inguinal hernia. The anaesthesiologist had difficulty intubating the patient. During the following months the patient had a severe allergic reaction to vaccination, chronic rhinitis with recurrent upper airway infections, and diarrhoea and vomiting. Eventually, failure to gain weight, and psychomotoric delay led to a thorough clinical investigation. Extensive X-ray diagnostics and analysis of urine and serum concluded with Hurler's syndrome. INTERPRETATION: Clinical vigilance is needed in the diagnosis of Hurler's syndrome. Early symptoms, such as rhinitis and hernia, are vague and unspecific. Radiological features, such as broad costae or gibbus, are helpful in obtaining the diagnosis. Decreased level of alpha-L-iduronidase in serum confirms the diagnosis of Hurler's syndrome. Patients tend to be treated symptomatically before the eventual diagnosis of this syndrome.

Combined aortic and mitral stenosis in mucopolysaccharidosis type I-S (Ullrich-Scheie syndrome).

The genetic mucopolysaccharidosis syndromes (MPS) are autosomal recessive inborn errors of metabolism. Heart valve involvement in MPS is not uncommon but only a few case reports of successful cardiac surgery are available. In particular, reports of combined aortic and mitral stenosis associated with MPS type I-S are very rare. Both type I and type VI MPS are associated with significant left sided valvar heart disease that requires surgical valve replacement because of irregular valve thickening, fibrosis, and calcification. A 35 year old man had severe mitral valve stenosis after successful surgical replacement of a stenotic aortic valve. Valvar heart disease was investigated by cardiac ultrasound and left heart catheterisation. Histomorphological characterisation of the affected mitral valve was performed. The case illustrates typically associated clinical features of cardiac and extracardiac abnormalities found in MPS type I-S.

Diagnosis from single-digit radiography.

This pictorial assay illustrates the value of plain radiographs of the digit in diagnosing disease in children. Although the hand is regarded as a mirror of disease, the finger often points to the correct diagnosis. The authors present a series of cases for which a coned-down view of a single digit is given. In some cases the findings indicate a specific diagnosis, whereas in others only a differential diagnosis is possible. The radiographic findings and a brief differential diagnosis, as well as the definitive diagnosis, are presented for each case.

Mucopolysaccharidosis: thickening of dura mater at the craniocervical junction and other CT/MRI findings.

Cranial CT and/or MRI imaging of 8 patients with mucopolysaccharidosis (MPS) was retrospectively evaluated. Two patients had MPS IH, 1 had MPS IS, 1 had MPS IVA and 4 had MPS IV. CT and MRI showed thickening of dura mater at the cranio-cervical junction, causing narrowing of the subarachnoid space, in all the patients examined. Spinal cord compression was detected in 4 patients. Other findings were: white matter alterations, mild to severe hydrocephalus, skull dysplasia and odontoid dysplasia. White matter alterations were evident as large areas and as multiple dispersed spots of prolonged T1 and T2 value. Reduced gray/white matter contrast was demonstrated on T2-weighted MRI images. It is important to examine the cranio-cervical junction carefully for thickening of dura mater in all patients with mucopolysaccharidosis examined by CT or MRI, because of the generally progressive clinical course of MPS. In patients with symptomatic cord compression, surgical intervention should be considered.

Articular manifestations of Scheie's syndrome.

A patient with the clinical and biochemical features of Scheie's syndrome is reported. Radiological investigation has shown severe progressive juxta-articular cystic lesions, which have not, to our knowledge, previously been described in Scheie's syndrome.

Hypertrophic cardiomyopathy in mucopolysaccharidoses: regression after bone marrow transplantation.

Mucopolysaccharide storage disease (MPS) presents clinically with a broad spectrum of abnormalities, among which cardiovascular involvement has been described. The echocardiographic findings have recently been reported for the various types of MPS. Among these, asymmetric septal hypertrophy (ASH) has been documented. We present a case of a 9-year-old girl suffering from type I MPS, atypical variant, with echocardiographic signs of ASH. She was given a bone marrow transplant after which the hypertrophic cardiomyopathy regressed.

Radiographic findings in a canine model of mucopolysaccharidosis I. Changes associated with bone marrow transplantation.

Eight dogs with mucopolysaccharidosis I (MPS I) were studied and their radiographic lesions compared with those reported in human MPS I. Three of the dogs received bone marrow transplants from unaffected littermates at 5 months of age. These dogs, and two affected control littermates were radiographed at 3, 6, 9, 12, 15, 18 and 20 months post-transplantation to evaluate the effects in chondro-osseous tissues. Although bone marrow transplantation did not alleviate all radiographically detectable changes, there was delayed onset of some lesions and reduced severity of most lesions in the dogs receiving transplants. Those lesions most closely associated with clinical lameness or gait abnormalities in untreated canine MPS I were most improved (or eliminated), and this was reflected in marked clinical improvement.

Radiological findings in patients with mucopolysaccharidosis I H/S (Hurler-Scheie syndrome).

The development of radiological changes in two patients with mucopolysaccharidosis (MPS) Type I H/S is described. Radiological findings reveal enlargement of the sella in one patient, impression of the basilar skull in the other patient. Sclerosis and thickening of the base of skull was observed in both patients. The mandibular necks were short with striking flattening of the superior surfaces of the condyles, when the patients reached adult age. At the age of 12, hypertelorism and spaced teeth were already present in both patients. In addition, they showed early costal, clavicular and scapular changes, irregularities of the acromial joints and acetabulae, hypoplasia of the inferior portion of the iliac bones and flared iliac wings. The flat femurs had short metaphyses and were held in valgus position. Development of dentigerous cysts as well as mandibular changes seem to be rather specific for this variant of alpha-L-iduronidase deficiency. In contrast to the classical form of MPS I, skeletal changes of the spine and hands are minimal.

The stylohyoid ligament in Hurler syndrome and related conditions: comparison with normal children.

The stylohyoid ligament is seen on lateral radiographs of the neck to be normally calcified to some extent in approximately 25% of all children between ages 1 1/2 and 15. When it appears, the ossification pattern is a relatively thin configuration in 90% of children. In 8 out of 9 children with Hurler syndrome, the stylohyoid was calcified, and was thicker than in normal children. This finding illustrates the nature of the stylohyoid ligament as a bone analogue, and its participation in the skeletal deformation pattern of dysostosis multiplex.