Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy

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De ziekte van Fabry: op weg naar een behandeling

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Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy

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The Origins of Bagan: The archaeological landscape of Upper Burma to AD 1300.

The archaeological landscape of Upper Burma from the middle of the first millennium BC to the Bagan period in the 13th-14th century AD is a landscape of continuity. Finds of polished stone and bronze artifacts suggest the existence of early metal-using cultures in the Chindwin and Samon River Valleys, and along parts of the Ayeyarwady plain. Increasing technological and settlement complexity in the Samon Valley suggests that a distinctive culture whose agricultural and trade success can be read in the archaeological record of the Late Prehistoric period developed there. The appearance of the early urban "Pyu" system of walled central places during the early first millennium AD seems to have involved a spread of agricultural and management skills and population from the Samon. The leaders of the urban centres adopted Indic symbols and Sanskrit modes of kingship to enhance and extend their authority. The early urban system was subject over time to a range of stresses including siltation of water systems, external disruption and social changes as Buddhist notions of leadership eclipsed Brahmanical ones. The archaeological evidence indicates that a settlement was forming at Bagan during the last centuries of the first millennium AD. By the mid 11th century Bagan began to dominate Upper Burma, and the region began a transition from a system of largely autonomous city states to a centralised kingdom. Inscriptions of the 11th to 13th centuries indicate that as the Bagan Empire expanded it subsumed the agricultural lands that had been developed by the Pyu

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

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Behandeling van de ziekte van Gaucher in Nederland met enzymvervangingstherapie

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Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients

BACKGROUND We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT. METHODS Seventeen GD1 patients were included (n = 6 eliglustat, (two switched from ERT), n = 9 miglustat (seven switchers), n = 4 ERT (median dose 60U/kg/m). Plasma protein markers reflecting disease burden (chitotriosidase, CCL18) and lipids reflecting substrate accumulation (glucosylsphingosine, glucosylceramide) were determined. Also, liver and spleen volumes, hemoglobin, platelets, and fat fraction were measured. RESULTS In patients naïve to treatment, chitotriosidase, CCL18 and glucosylsphingosine decreased comparably upon eliglustat and ERT treatment, while the response to miglustat was less. After 2 years, median decrease of chitotriosidase was 89% (range 77-98), 88% (78-92) and 37% (29-46) for eliglustat, ERT and miglustat naïve patients respectively; decrease of CCL18 was 73% (63-78), 54% (43-86), and 10% (3-18); decrease of glucosylsphingosine was 86% (78-93), 78% (65-91), 48% (46-50). Plasma glucosylceramide in eliglustat treated patients (n = 4) reached values below the normal range (n = 20 healthy controls). Biochemical markers decreased or stabilized in switchers from ERT to eliglustat (n = 2), but less in miglustat switchers (n = 7). Clinical parameters responded comparably upon eliglustat and ERT treatment. CONCLUSIONS Our explorative study provides evidence that biochemical markers respond comparably in patients receiving eliglustat treatment and ERT, while the corresponding response to miglustat treatment is less.Medical Biochemistr

Gender- and Age-Associated Differences in Bone Marrow Adipose Tissue and Bone Marrow Fat Unsaturation Throughout the Skeleton, Quantified Using Chemical Shift Encoding-Based Water-Fat MRI

Bone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific variations and age- and gender-specific differences in BMAT and BMAT composition in healthy subjects. In this cross-sectional study, we included 40 healthy subjects (26 male: mean age 49 years, range 22-75 years; 14 female: mean age 50 years, range 29-71) and determined the bone marrow signal fat fraction and bone marrow unsaturation in the spine (C3-L5), pelvis, femora, and tibiae using chemical shift encoding-based water-fat imaging (WFI) with multiple gradient echoes (mGRE). Regions of interest covered the individual vertebral bodies, pelvis and proximal epimetaphysis, diaphysis, and distal epimetaphysis of the femur and tibia. The spinal fat fraction increased from cervical to lumbar vertebral bodies (mean fat fraction ( +/- SD or (IQR): cervical spine 0.37 +/- 0.1; thoracic spine 0.41 +/- 0.08. lumbar spine 0.46 +/- 0.01; p < 0.001). The femoral fat fraction increased from proximal to distal (proximal 0.78 +/- 0.09; diaphysis 0.86 (0.15); distal 0.93 +/- 0.02; p < 0.001), while within the tibia the fat fraction decreased from proximal to distal (proximal 0.92 +/- 0.01; diaphysis 0.91 (0.02); distal 0.90 +/- 0.01; p < 0.001). In female subjects, age was associated with fat fraction in the spine, pelvis, and proximal femur (rho = 0.88 p < 0.001; rho = 0.87 p < 0.001; rho = 0.63 p = 0.02; rho = 0.74 p = 0.002, respectively), while in male subjects age was only associated with spinal fat fraction (rho = 0.40 p = 0.04). Fat fraction and unsaturation were negatively associated within the spine (r = -0.40 p = 0.01), while in the extremities fat fraction and unsaturation were positively associated (distal femur: r = 0.42 p = 0.01; proximal tibia: r = 0.47, p = 0.002; distal tibia: r = 0.35 p = 0.03), both independent of age and gender. In conclusion, we confirm the distinct, age- and gender-dependent, distribution of BMAT throughout the human skeleton and we show that, contradicting previous animal studies, bone marrow unsaturation in human subjects is highest within the axial skeleton compared to the appendicular skeleton. Furthermore, we show that BMAT unsaturation was negatively correlated with BMAT within the spine, while in the appendicular skeleton, BMAT and BMAT unsaturation were positively associated

Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start

OBJECTIVE: To evaluate the effect of chenodeoxycholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX). METHODS: In this retrospective cohort study, we report the clinical long-term follow-up characteristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical characteristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up. RESULTS: Median follow-up time was 8 years (6 months-31.5 years). Patients diagnosed and treated before the age of 24 years had a significantly better outcome at follow-up. When considering only patients with a good treatment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms during follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature. There was an improvement or stabilization in favor of patients diagnosed and treated before the age of 24 compared to those treated after the age of 24: 100% vs 58% for mRS scores and 100% vs 50% for EDSS scores, respectively. CONCLUSIONS: Treatment start at an early age can reverse and even prevent the development of neurologic symptoms in CTX. This study emphasizes the importance of early diagnosis in CTX and provides a rationale to include CTX in newborn screening programs

Gray and white matter are both affected in classical galactosemia: An explorative study on the association between neuroimaging and clinical outcome

Contains fulltext : 229605.pdf (Publisher’s version ) (Open Access)BACKGROUND: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome. METHODS: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated. RESULTS: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM. CONCLUSION: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease