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The lysosomal storage diseases chronic visceral acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are both macrophage storage disorders with overlapping clinical manifestations. We compared cross-sectional data on visceral, hematological, and biochemical manifestations of untreated adult patients with chronic visceral ASMD ( n  = 19) and GD1 ( n  = 85). Spleen volume, liver volume, and bone marrow fat fraction did not significantly differ between the two disease groups ( p >0.05 for all). Chitotriosidase activity was higher in GD1 (GD1: median 30 940 nmol/(mL.h), range 513-201 352, ASMD: median 1693 nmol/(mL.h), range 326-6620, p <0.001), whereas platelet levels were lower (GD1: median 102 10 9 /L, range 16-726, ASMD: median 154 10 9 /L, range 86-484, p <0.010), as were hemoglobin levels (GD1: median 7.8 mmol/L, range 5.0-10.4, ASMD: median 9.0 mmol/L, range 7.0-10.4, p <0.001). No bone complications were reported for ASMD, compared to 33% in GD1 ( p <0.005). In ASMD pulmonary disease was more severe as evidenced by a median diffusion capacity of the lungs for carbon monoxide of 73% of predicted (range 26-104), compared to 85% (range 53-126) in GD1 ( p  = 0.029). In conclusion, bone complications, hematological abnormalities, chitotriosidase activity, and CCL18 levels were more prominent in GD1, while pulmonary manifestations were more common in AMSD. Different secondary pathophysiological processes surrounding sphingomyelin and glucosylceramide accumulation might explain these differences., Competing Interests: LvD, JA, MvdL, MM, EA, and AvK have no competing interests to declare. EE is involved in a pre‐marketing study with Sanofi Genzyme as a sub‐investigator. BS was involved in premarketing studies with Chiesi and Reneo Pharmaceuticals. CH is involved in premarketing studies with Sanofi Genzyme, Protalix, and Idorsia., (© 2024 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Bone marrow fat, an unique component of the bone marrow cavity increases with aging and menopause and is inversely related to bone mass. Sex steroids may be involved in the regulation of bone marrow fat, because men have higher bone marrow fat than women and clinical observations have suggested that the variation in bone marrow fat fraction is greater in premenopausal compared to postmenopausal women and men. We hypothesized that the menstrual cycle and/or estrogen affects the bone marrow fat fraction. First, we measured vertebral bone marrow fat fraction with Dixon Quantitative Chemical Shift MRI (QCSI) twice a week during 1 month in 10 regularly ovulating women. The vertebral bone marrow fat fraction increased 0.02 (95% CI, 0.00 to 0.03) during the follicular phase (p = 0.033), and showed a nonsignificant decrease of 0.02 (95% CI, -0.01 to 0.04) during the luteal phase (p = 0.091). To determine the effect of estrogen on bone marrow fat, we measured vertebral bone marrow fat fraction every week for 6 consecutive weeks in 6 postmenopausal women before, during, and after 2 weeks of oral 17-β estradiol treatment (2 mg/day). Bone marrow fat fraction decreased by 0.05 (95% CI, 0.01 to 0.09) from 0.48 (95% CI, 0.42 to 0.53) to 0.43 (95% CI, 0.34 to 0.51) during 17-β estradiol administration (p < 0.001) and increased again after cessation. During 17-β estradiol administration the bone formation marker procollagen type I N propeptide (P1NP) increased (p = 0.034) and the bone resorption marker C-terminal crosslinking telopeptides of collagen type I (CTx) decreased (p < 0.001). In conclusion, we described the variation in vertebral bone marrow fat fraction among ovulating premenopausal women. And among postmenopausal women, we demonstrated that 17-β estradiol rapidly reduces the marrow fat fraction, suggesting that 17-β estradiol regulates bone marrow fat independent of bone mass., (© 2015 American Society for Bone and Mineral Research.)

This paper describes the effects of a switch to velaglucerase alfa in a group of adult patients with type 1 Gaucher disease, all of whom had previously had their dose reduced as a consequence of the worldwide imiglucerase shortage. Thirty-two patients from two large European Gaucher centers switched to treatment with velaglucerase alfa after 1-8.5 months of dose reduction. The course of important Gaucher disease parameters was studied at four time points: one year before the shortage, just before the shortage, before a switch to velaglucerase and after up to one year of treatment with velaglucerase. These parameters included hemoglobin concentration, platelet count, plasma chitotriosidase activity in all patients, and spleen and liver volumes (as well as bone marrow fat fraction images) in 10 patients. Decreases in platelet counts as a result of reduced treatment with imiglucerase were quickly restored on treatment with velaglucerase alfa. Chitotriosidase activity declined overall after switching. Five out of 10 patients had an increase in liver volume of at least 10% after six months of velaglucerase treatment, which was reversible in 3. Most patients received infusions at home and no important side effects were observed. Velaglucerase alfa appears to be a safe and effective alternative for imiglucerase.

Background and Objectives: Gaucher disease type I can be successfully treated with enzyme replacement therapy (ERT). In order to reduce the burden of the intravenously administered enzyme, a low frequency of administration was prospectively studied in patients with stable and minor disease following ERT., Design and Methods: Eleven patients were randomly assigned either to continue their original regimen of a dose of ERT once every week or fortnight (five patients) or to lower the frequency of administration to once every 4 weeks, at the same cumulative dose (six patients). The primary end-point was change in liver ratio (mL/kg body weight). Secondary end-points were spleen volume, hemoglobin level, platelet count, lumbar bone marrow fat content measured with quantitative chemical shift imaging (QCSI), white cell count, and plasma levels of ferritin, chitotriosidase, liver enzymes and angiotensin-converting enzyme (ACE)., Results: There were no significant mean differences between the two treatment arms in liver ratio or any of the other end-points. However, there were two treatment failures in the low frequency of administration group. These patients showed progression of disease as evidenced by a reduction of QCSI in one patient and an increase in liver ratio as well as a slow decrease in QCSI in the other. Both patients already had relatively low baseline QCSI values. One patient switched back to the original regimen at 6 months because of subjective complaints., Interpretation and Conclusions: Low frequency ERT in adult Gaucher type I patients maintains stable disease in most, but not all patients with stable and minimal disease. Close monitoring of all disease parameters remains mandatory.

In Diffusion Tensor Imaging (DTI), differently oriented fiber bundles inside one voxel are incorrectly modeled by a single tensor. High Angular Resolution Diffusion Imaging (HARDI) aims at using more complex models, such as a two-tensor model, for estimating two fiber bundles. We propose a new method for creating experimental phantom data of fiber crossings, by mixing the DWI-signals from high FA-regions with different orientation. The properties of these experimental phantoms approach the conditions of real data. These phantoms can thus serve as a 'ground truth' in validating crossing reconstruction algorithms. The angular resolution of a dual tensor model is determined using series of crossings, generated under different angles. An angular resolution of 0.67pi was found in data scanned with a diffusion weighting parameter b = 1000 s/mm2. This resolution did not change significantly in experiments with b = 3000 and 5000 s/mm2, keeping the scanning time constant.

Objective: The purpose of this study was to evaluate the role of contrast-enhanced dynamic MRI in predicting the disease activity of Crohn's disease., Materials and Methods: Forty-eight patients in two hospitals who had clinically suspected exacerbation of Crohn's disease were included in this study. In three levels of thickened small-bowel wall, axial dynamic T1-weighted sequences were performed every 4-6 sec for a total duration of 2-3 min after contrast administration; static T1-weighted turbo spin-echo sequences were acquired both before and after contrast administration. The slope of enhancement, enhancement ratio, time to enhancement, enhancement time, and thickness of the small-bowel wall were determined. These MRI results were compared with overall clinical grade, Crohn's disease activity index (CDAI), and Van Hees activity index. Clinical grade was based on clinical information, physical findings, laboratory studies, endoscopy, surgery, and other imaging studies. Spearman's correlation coefficient and p values were determined per hospital. Fisher's z-transformation was applied before pooling the correlation coefficients from both hospitals., Results: The enhancement ratio based on the static series showed significant correlation with the clinical grade (r = 0.29, p = 0.045), CDAI (r =0.31, p = 0.033), and Van Hees activity index (r = 0.36, p = 0.016). The enhancement ratio based on the dynamic series correlated significantly with the CDAI (r = 0.38, p = 0.016). Wall thickness correlated significantly with clinical grade (r = 0.47, p = 0.003) and Van Hees activity index (r = 0.41, p = 0.007)., Conclusion: These data suggest that the enhancement ratio of bowel wall after IV administration of gadodiamide and bowel wall thickness are weak to moderate indicators of the severity of Crohn's disease.

Introduction: Cardiovascular response to fast posture change can be used to model individual orthostatic response under normal circumstances and after spaceflight. We set out to construct a computer-controlled tilt table suitable for repeated sinusoidal tilt motion as well as fast, single head-up tilt (HUT). The movement profile of the table was designed to prevent muscle tensing and limit vestibular stimulation., Methods: On the new table, 20 healthy subjects underwent a protocol of fast HUT and sinusoidal tilt motion at 2.5 tilts per minute. BP was measured non-invasively (Finapres). Time domain dynamic response to HUT and frequency domain response to sinusoidal tilts were derived from the beat-to-beat BP and from interbeat-interval (IBI) series., Results: Tilt motion did not induce dizziness and was experienced by all subjects as smooth. The systolic BP response to fast HUT correlated mildly with the systolic BP spectral power at the sinusoidal tilt frequency (R = 0.47). The IBI response to fast HUT correlated well with the IBI power at the sinusoidal tilt frequency (R = 0.74)., Discussion: In this study we presented a computer controlled tilt table capable of fast posture change and sinusoidal tilts. An exploratory protocol demonstrated that the table is suitable for obtaining cardiovascular response to posture change for modeling purposes.

Background and Purpose: Peroxisomal biogenesis disorders (PBDs) refer to a group of disorders of peroxisomal biogenesis causing neuronal migration disorder, delayed myelination, and demyelination. The aim of this study was to evaluate the added value of diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) compared with that of conventional T2-weighted imaging in assessing the extent of white matter damage in patients with PBDs., Methods: Three patients (aged 12, 16, and 80 months) with PBD (type 1 protein targeting sequence [PTS1]) and three age-matched control subjects underwent MR imaging on a 1.5-T system. The protocol included axial T2-weighted, DWI, and DTI sequences. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) changes were calculated using regions of interest at several predefined white matter areas and compared with those of age-matched control subjects. Color-coded maps were obtained to visualize the range of FA values., Results: On the T2-weighted images, one patient revealed severe hypomyelination throughout the brain; the two other patients showed focal abnormal high-signal-intensity areas. All patients had significantly decreased FA values in white matter areas that appeared abnormal on the T2-weighted images. In two of the three patients, significant FA reduction was also found in normal-appearing white matter. The ADC values of the patients were significantly increased compared with those of the age-matched controls., Conclusion: Although based on a small number of patients, our data suggest that DWI and DTI can be used to characterize and quantify white matter tract injury in patients with PBD-PTS1. Furthermore, our data suggest that these techniques have the potential to identify neurodegenerative changes not yet visible on T2-weighted images.

Conventional MR, diffusion-weighted, and diffusion tensor imaging were performed in an 8-day-old girl with citrullinemia. She had severe hyperammonemia for several days. On conventional T2-weighted MR images, symmetric, confluent high signal intensity was found in the bilateral thalami, basal ganglia, cortex, and subcortical white matter. Diffusion-weighted imaging demonstrated decreased apparent diffusion coefficient in these areas, reflecting cytotoxic edema. Follow-up MR imaging at the age of 4 months revealed subcortical cysts, ulegyric changes, and atrophy, which were most prominent in the occipital lobes. Diffusion tensor imaging revealed decreased anisotropy throughout the brain, consistent with diffuse injury to the oligodendro-axonal unit. Diffusion-weighted and diffusion tensor imaging are valuable techniques for the detection of irreversible brain damage and for the characterization of hyperintense lesions on T2-weighted MR images in patients with the neonatal form of citrullinemia.

Objective: The objective of our study was to determine the merit of the fat fraction of axial bone marrow measured by Dixon quantitative chemical shift imaging (Dixon QCSI) as a clinical parameter to quantitatively assess the extent of skeletal involvement in type 1 Gaucher's disease., Materials and Methods: Dixon QCSI was performed in 30 adult patients (age range, 18-69 years; mean, 39 years) with type 1 Gaucher's disease who were untreated. The relationship between the mean value of the fat fraction in vertebrae L3, L4, and L5 and the presence, absence, and severity of clinical bone complications (chronic bone pain, bone crisis, fracture, avascular necrosis, and joint replacement) as well as the conventional MR imaging of bone marrow involvement were studied. Also the relationship of fat fraction to sex, age, and other disease parameters (history of splenectomy, liver and spleen volume, plasma chitotriosidase, hemoglobin level, and platelet count) was evaluated. Our results were compared with the fat fraction of healthy volunteers., Results: The fat fraction measured in patients with Gaucher's disease ranged from 0.08 to 0.40 (mean, 0.20). Bone complications occurred primarily in patients with a fat fraction of less than 0.23. Univariate logistic regression analysis indicated that for every decrease of 0.1 of the fat fraction, the risk of bone complications increased 85% (p < 0.05). The fat fraction was correlated with liver size, but no correlation with other disease parameters was found. In the patient population, the fat fraction was significantly lower than in the healthy population (range, 0.27-0.55; mean, 0.37; p < 0.001)., Conclusion: The fat fraction of the lumbar spine when measured with Dixon QCSI is associated with the occurrence of bone complications. It may, therefore, be a clinically useful parameter.

This study was undertaken to analyze MRI findings in leprosy patients with neuropathic feet, which are suspected of having osteomyelitis. As far as we know, there is no literature concerning osteomyelitis and MRI in neuropathic leprosy feet at present. Therefore, we have included MRI examination of 18 events of suspected osteomyelitis in 12 leprosy patients. All patients with long-standing neuropathic foot problems were clinically suspected of having osteomyelitis. All patients underwent the MRI protocol with the inclusion of Two Point Dixon Chemical Shift Imaging as a fat-suppression sequence. For the MRI evaluation, we used signs that are described in literature for detecting osteomyelitis in diabetic feet. The primary MRI signs were positive in 17 of 18 patients. The secondary MRI signs were positive in 100% of the patients. Our results show that MRI with the use of Two Point Dixon Chemical Shift Imaging is a promising diagnostic modality to detect osteomyelitis in the presence of neurosteoarthropathic changes in patients with leprosy. Whenever available, MRI could play an important role in detecting osteomyelitis in leprosy patients with long-standing neuropathic feet.

Summary: Conventional MR imaging, MR spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging were performed in a 5-month-old male patient with mitochondrial encephalomyopathy. On conventional T2-weighted MR images, symmetric, confluent high signal intensity was found in the temporoparietal white matter. A large lactate peak and decreased N-acetylaspartate were found in this region on proton MR spectroscopic images. Diffusion-weighted imaging showed increased apparent diffusion coefficient, representing vasogenic edema. Diffusion tensor imaging revealed decreased anisotropy, consistent with injury to the oligodendro-axonal unit. A muscle biopsy specimen revealed an isolated complex III enzyme respiratory chain deficiency. Diffusion-weighted and diffusion tensor imaging are valuable techniques for the characterization of hyperintense lesions on T2-weighted MR images in cases of mitochondrial encephalomyopathy.