Publications by authors named "Timothy M Cox"

99 Publications

Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics.

Metabolites 2020 Dec 30;11(1). Epub 2020 Dec 30.

Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK.

Sandhoff disease (SD) is a lysosomal disease caused by mutations in the gene coding for the β subunit of β-hexosaminidase, leading to deficiency in the enzymes β-hexosaminidase (HEX) A and B. SD is characterised by an accumulation of gangliosides and related glycolipids, mainly in the central nervous system, and progressive neurodegeneration. The underlying cellular mechanisms leading to neurodegeneration and the contribution of inflammation in SD remain undefined. The aim of the present study was to measure global changes in metabolism over time that might reveal novel molecular pathways of disease. We used liquid chromatography-mass spectrometry and H Nuclear Magnetic Resonance spectroscopy to profile intact lipids and aqueous metabolites, respectively. We examined spinal cord and cerebrum from healthy and mice, a mouse model of SD, at ages one, two, three and four months. We report decreased concentrations in lipids typical of the myelin sheath, galactosylceramides and plasmalogen-phosphatidylethanolamines, suggesting that reduced synthesis of myelin lipids is an early event in the development of disease pathology. Reduction in neuronal density is progressive, as demonstrated by decreased concentrations of -acetylaspartate and amino acid neurotransmitters. Finally, microglial activation, indicated by increased amounts of myo-inositol correlates closely with the late symptomatic phases of the disease.
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http://dx.doi.org/10.3390/metabo11010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823728PMC
December 2020

Human glucocerebrosidase mediates formation of xylosyl-cholesterol by β-xylosidase and transxylosidase reactions.

J Lipid Res 2021 Jan 6;62:100018. Epub 2021 Jan 6.

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands. Electronic address:

Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as an acceptor for the subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase, and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from patients with Gaucher disease. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyze the formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.
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http://dx.doi.org/10.1194/jlr.RA120001043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903134PMC
January 2021

Lysosomal Diseases and Neuropsychiatry: Opportunities to Rebalance the Mind.

Authors:
Timothy M Cox

Front Mol Biosci 2020 26;7:177. Epub 2020 Aug 26.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

The brain is the physical organ of the mind but efforts to understand mental illness within a neurobiological context have hitherto been unavailing. Mental disorders (anxiety, depression, bipolar disorder, and schizophrenia) affect about one fifth of the population and present an almost endless societal challenge at the frontier of human sciences. Prodigious technological advances in functional neuroimaging and large-scale genetics have not yet delivered the prospect of refined molecular understanding of mental illness beyond early anatomical descriptions of brain metabolism. However, intensive clinical phenotyping and quantitative metabolic studies using sophisticated radio-ligands in positron-emission tomography, persistently favor the neurobiological approach. This pursues a familiar maxim in Medicine, aptly summarized in the words of Arthur Koestler: "Nature is generous in her senseless experiments on mankind." Hitherto, studies in neuropsychiatry have largely ignored rare genetic disorders but derangements of specific components within the cerebral laboratory offer rich opportunities for mechanistic exploration. Aberrant psychic behavior is characteristic of many inborn errors of metabolism and although each disorder represents a universe of its own, we are at a threshold for understanding, since contemporary genetics and cell biology furnish abundant materials to take on the perturbing enigma of mental derangement. A further development relates to orphan drugs with actions on defined molecular targets: these represent new ways to study the pathogenesis of psychiatric phenomena associated with rare diseases and in a manner not formerly possible. Here we introduce the frontier of schizophrenia and its strong association with late-onset Tay-Sachs disease as a paradigm to explore.
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http://dx.doi.org/10.3389/fmolb.2020.00177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479189PMC
August 2020

Improving the quantitative classification of Erlenmeyer flask deformities.

Skeletal Radiol 2021 Feb 30;50(2):361-369. Epub 2020 Jul 30.

Department of Radiology, University of Cambridge School of Clinical Medicine, Box 218, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

The Erlenmeyer flask deformity is a common skeletal modeling deformity, but current classification systems are binary and may restrict its utility as a predictor of associated skeletal conditions. A quantifiable 3-point system of severity classification could improve its predictive potential in disease. Ratios were derived from volumes of regions of interests drawn in 50 Gaucher's disease patients. ROIs were drawn from the distal physis to 2 cm proximal, 2 cm to 4 cm, and 4 cm to 6 cm. Width was also measured at each of these boundaries. Two readers rated these 100 femurs using a 3-point scale of severity classification. Weighted kappa indicated reliability and one-way analysis of variance characterized ratio differences across the severity scale. Accuracy analyses allowed determination of clinical cutoffs for each ratio. Pearson's correlations assessed the associations of volume and width with a shape-based concavity metric of the femur. The volume ratio incorporating the metaphyseal region from 0 to 2 cm and the diametaphyseal region at 4-6 cm was most accurate at distinguishing femurs on the 3-point scale. Receiver operating characteristic curves for this ratio indicated areas of 0.95 to distinguish normal and mild femurs and 0.93 to distinguish mild and severe femurs. Volume was moderately associated with the degree of femur concavity. The proposed volume ratio method is an objective, proficient method at distinguishing severities of the Erlenmeyer flask deformity with the potential for automation. This may have application across diseases associated with the deformity and deficient osteoclast-mediated modeling of growing bone.
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http://dx.doi.org/10.1007/s00256-020-03561-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736022PMC
February 2021

Comment: Why are females with Fabry disease affected?

Mol Genet Metab Rep 2019 Dec 22;21:100529. Epub 2019 Oct 22.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

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http://dx.doi.org/10.1016/j.ymgmr.2019.100529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819736PMC
December 2019

The lysosomal disease caused by mutant VPS33A.

Hum Mol Genet 2019 08;28(15):2514-2530

Department of Medicine, University of Cambridge, Cambridge, UK.

A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments and-common to sphingolipid diseases-abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate. Lipidomic screening showed elevated β-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding. We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes. Treatment of HeLa cells stably expressing the mutant VPS33A with a proteasome inhibitor rescued the mutant protein from degradation. We propose that the disease is due to diminished intracellular abundance of intact VPS33A. Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease.
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http://dx.doi.org/10.1093/hmg/ddz077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644154PMC
August 2019

Splenic Artery Aneurysms, A Rare Complication of Type 1 Gaucher Disease: Report of Five Cases.

J Clin Med 2019 Feb 8;8(2). Epub 2019 Feb 8.

Reference Centre of Lysosomal Diseases, University Hospital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy, France.

Type 1 Gaucher disease is a rare genetic lysosomal disorder due to acid betaglucosidase deficiency. The main features are thrombocytopenia, anemia, hepatosplenomegaly and complex skeletal disease. Complications include pulmonary hypertension, cirrhosis and splenic infarction; comorbidities, such as autoimmune phenomena, B-cell malignancies and Parkinson disease also occur. Visceral aneurysms have been only rarely noted in Gaucher disease. We report the retrospective data from patients with Gaucher disease type 1 and splenic arterial aneurysm We describe the different outcomes of a giant splenic arterial aneurysm in five patients with type 1 Gaucher disease and discuss the main possible pathophysiological explanations. Aneurysms of the splenic artery are rare in Gaucher disease but are probably greatly under-reported.
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http://dx.doi.org/10.3390/jcm8020219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406779PMC
February 2019

The Lysosomal Protein Arylsulfatase B Is a Key Enzyme Involved in Skeletal Turnover.

J Bone Miner Res 2018 12 24;33(12):2186-2201. Epub 2018 Aug 24.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Skeletal pathologies are frequently observed in lysosomal storage disorders, yet the relevance of specific lysosomal enzymes in bone remodeling cell types is poorly defined. Two lysosomal enzymes, ie, cathepsin K (Ctsk) and Acp5 (also known as tartrate-resistant acid phosphatase), have long been known as molecular marker proteins of differentiated osteoclasts. However, whereas the cysteine protease Ctsk is directly involved in the degradation of bone matrix proteins, the molecular function of Acp5 in osteoclasts is still unknown. Here we show that Acp5, in concert with Acp2 (lysosomal acid phosphatase), is required for dephosphorylation of the lysosomal mannose 6-phosphate targeting signal to promote the activity of specific lysosomal enzymes. Using an unbiased approach we identified the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), mutated in mucopolysaccharidosis type VI (MPS-VI), as an osteoclast marker, whose activity depends on dephosphorylation by Acp2 and Acp5. Similar to Acp2/Acp5 mice, Arsb-deficient mice display lysosomal storage accumulation in osteoclasts, impaired osteoclast activity, and high trabecular bone mass. Of note, the most prominent lysosomal storage accumulation was observed in osteocytes from Arsb-deficient mice, yet this pathology did not impair production of sclerostin (Sost) and Fgf23. Because the influence of enzyme replacement therapy (ERT) on bone remodeling in MPS-VI is still unknown, we additionally treated Arsb-deficient mice by weekly injection of recombinant human ARSB from 12 to 24 weeks of age. We found that the high bone mass phenotype of Arsb-deficient mice and the underlying bone cell deficits were fully corrected by ERT in the trabecular compartment. Taken together, our results do not only show that the function of Acp5 in osteoclasts is linked to dephosphorylation and activation of lysosomal enzymes, they also provide an important proof-of-principle for the feasibility of ERT to correct bone cell pathologies in lysosomal storage disorders. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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http://dx.doi.org/10.1002/jbmr.3563DOI Listing
December 2018

The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

J Neurol 2018 Aug 29;265(8):1789-1794. Epub 2018 May 29.

John Van Geest Centre for Brain Repair, Cambridge, UK.

We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.
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http://dx.doi.org/10.1007/s00415-018-8908-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060775PMC
August 2018

Therapeutic position of eliglustat.

Blood Cells Mol Dis 2018 03 22;69:117-118. Epub 2017 Nov 22.

Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

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http://dx.doi.org/10.1016/j.bcmd.2017.11.001DOI Listing
March 2018

Reduced cerebral vascularization in experimental neuronopathic Gaucher disease.

J Pathol 2018 01;244(1):120-128

Department of Medicine, University of Cambridge, Cambridge, UK.

The glycosphingolipidosis, Gaucher disease, in which a range of neurological manifestations occur, results from a deficiency of acid β-glucocerebrosidase, with subsequent accumulation of β-glucocerebroside, its upstream substrates, and the non-acylated congener β-glucosylsphingosine. However, the mechanisms by which end-organ dysfunction arise are poorly understood. Here, we report strikingly diminished cerebral microvascular density in a murine model of disease, and provide a detailed analysis of the accompanying cerebral glycosphingolipidome in these animals, with marked elevations of β-glucosylsphingosine. Further in vitro studies confirmed a concentration-dependent impairment of endothelial cytokinesis upon exposure to quasi-pathological concentrations of β-glucosylsphingosine. These findings support a premise for pathogenic disruption of cerebral angiogenesis as an end-organ effect, with potential for therapeutic modulation in neuronopathic Gaucher disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4992DOI Listing
January 2018

Heterogeneity in a large pedigree with Danon disease: Implications for pathogenesis and management.

Mol Genet Metab 2018 02 21;123(2):177-183. Epub 2017 Jun 21.

Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address:

Background: Danon disease is an X-linked disturbance of autophagy manifesting with cognitive impairment and disordered heart and skeletal muscle. After a period of relative stability, patients deteriorate rapidly and may quickly become ineligible for elective heart transplantation - the only life-saving therapy.

Methods: We report a large pedigree with diverse manifestations of Danon disease in hemizygotes and female heterozygotes.

Results: Malignant cardiac arrhythmias requiring amiodarone treatment induced thyroid disease in two patients; intractable thyrotoxicosis, which enhances autophagy, caused the death of a 21year-old man. Our patients also had striking elevation of serum troponin I during the accelerated phase of their illness (p<0.01) and rising concentrations heralded cardiac decompensation. We argue for changes to cardiac transplantation eligibility criteria.

Conclusion: Danon disease causes hypertrophic cardiomyopathy - here we propose a common pathophysiological basis for the metabolic and structural effects of this descriptive class of heart disorders. We also contend that troponin I may have prognostic value and merits exploration for clinical decision-making including health warning bracelets. Rapamycin (Sirolimus®), an approved immunosuppressant which also influences autophagy, may prove beneficial. In the interim, while new treatments are developed, a revaluation of cardiac transplantation eligibility criteria is warranted.
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http://dx.doi.org/10.1016/j.ymgme.2017.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588538PMC
February 2018

Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease.

J Lipid Res 2017 07 4;58(7):1306-1314. Epub 2017 Apr 4.

Department of Biochemistry, Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders.
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http://dx.doi.org/10.1194/jlr.M073395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496029PMC
July 2017

Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy.

Blood 2017 04 6;129(17):2375-2383. Epub 2017 Feb 6.

Sanofi Genzyme, Cambridge, MA; and.

In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was noninferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in ≥85% of patients as well as individually in ≥92%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as #NCT00943111.
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http://dx.doi.org/10.1182/blood-2016-12-758409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409450PMC
April 2017

Roscoe O. Brady: Physician whose pioneering discoveries in lipid biochemistry revolutionized treatment and understanding of lysosomal diseases.

Blood Cells Mol Dis 2018 02 12;68:4-8. Epub 2017 Jan 12.

Department of Medicine, Addenbrooke's Hospital, University of Cambridge, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.bcmd.2016.10.030DOI Listing
February 2018

Brexit and rare diseases: big risk, bigger opportunity?

Curr Med Res Opin 2017 04 9;33(4):783-784. Epub 2017 Mar 9.

a Department of Medicine , University of Cambridge , Cambridge , UK.

The UK's planned exit from the EU will leave its national health sector in a very dangerous position. It will also have profound consequences for domestic UK law. The impact may be particularly drastic for patients for whom EU law protects the right to treatment. At a particular risk are patients with rare, 'orphan', diseases whose treatments are uniquely enabled at the EU level. We examine the potential effects of Brexit on the orphan sector and identify an opportunity to solve long-standing and intensifying difficulties, especially the pricing of orphan drugs.
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http://dx.doi.org/10.1080/03007995.2017.1284053DOI Listing
April 2017

A Specific Activity-Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease.

Chembiochem 2017 02 31;18(4):402-412. Epub 2017 Jan 31.

Department of Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.

Galactosylceramidase (GALC) is the lysosomal β-galactosidase responsible for the hydrolysis of galactosylceramide. Inherited deficiency in GALC causes Krabbe disease, a devastating neurological disorder characterized by accumulation of galactosylceramide and its deacylated counterpart, the toxic sphingoid base galactosylsphingosine (psychosine). We report the design and application of a fluorescently tagged activity-based probe (ABP) for the sensitive and specific labeling of active GALC molecules from various species. The probe consists of a β-galactopyranose-configured cyclophellitol-epoxide core, conferring specificity for GALC, equipped with a BODIPY fluorophore at C6 that allows visualization of active enzyme in cells and tissues. Detection of residual GALC in patient fibroblasts holds great promise for laboratory diagnosis of Krabbe disease. We further describe a procedure for in situ imaging of active GALC in murine brain by intra-cerebroventricular infusion of the ABP. In conclusion, this GALC-specific ABP should find broad applications in diagnosis, drug development, and evaluation of therapy for Krabbe disease.
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http://dx.doi.org/10.1002/cbic.201600561DOI Listing
February 2017

Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients.

Blood Cells Mol Dis 2018 02 21;68:86-92. Epub 2016 Oct 21.

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden. Electronic address:

Background: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1.

Methods: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken.

Results: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations.

Conclusions: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD.
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http://dx.doi.org/10.1016/j.bcmd.2016.10.011DOI Listing
February 2018

Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: A sub-analysis of the eliglustat ENCORE trial.

Mol Genet Metab Rep 2016 Dec 30;9:25-28. Epub 2016 Sep 30.

Sanofi Genzyme, Cambridge, MA, USA.

Gaucher disease type 1 is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid β-glucosidase resulting in accumulation of glucosylceramide and clinical manifestations of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. The historic standard of care is intravenous recombinant enzyme therapy with imiglucerase. Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 who have a compatible CYP2D6-metabolizer phenotype (≈ 95% of patients). The 12-month ENCORE trial (NCT00943111) found eliglustat non-inferior to imiglucerase in maintaining stability in adult Gaucher patients previously stabilized after ≥ 3 years of enzyme therapy (imiglucerase or velaglucerase alfa). This post-hoc analysis examined safety and efficacy in the 30 ENCORE patients who were receiving velaglucerase alfa at study entry and were randomized to eliglustat (n = 22) or imiglucerase (n = 8). Efficacy and safety in velaglucerase alfa-transitioned patients were consistent with the full ENCORE trial population; 90% of patients switched to eliglustat and 88% of patients switched to imiglucerase met the composite endpoint (stable hemoglobin concentration, platelet count, spleen volume, and liver volume). Clinical stability was maintained for 12 months in Gaucher disease type 1 patients in the ENCORE trial who switched from velaglucerase alfa to either eliglustat or imiglucerase.
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http://dx.doi.org/10.1016/j.ymgmr.2016.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050260PMC
December 2016

Identification of Modifier Genes in a Mouse Model of Gaucher Disease.

Cell Rep 2016 09 25;16(10):2546-2553. Epub 2016 Aug 25.

Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Diseases caused by single-gene mutations can display substantial phenotypic variability, which may be due to genetic, environmental, or epigenetic modifiers. Here, we induce Gaucher disease (GD), a rare inherited metabolic disorder, by injecting 15 inbred mouse strains with a low dose of a chemical inhibitor of acid β-glucosidase, the enzyme defective in GD. Different mouse strains exhibit widely different lifespans, which is unrelated to levels of acid β-glucosidase's substrate accumulation. Genome-wide association reveals a number of candidate risk loci, including a marker within Grin2b, which in combination with another marker allows us to predict the lifespan of additional mouse strains. An antagonist of the NMDA receptor (encoded by Grin2b) significantly increases the lifespan of GD mice that would otherwise have lived for a short time. Our data identify putative modifier genes that may be involved in determining GD severity, which might help elucidate phenotypic variability between patients with similar GD mutations.
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http://dx.doi.org/10.1016/j.celrep.2016.07.085DOI Listing
September 2016

Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe.

Eur J Intern Med 2017 Jan 10;37:25-32. Epub 2016 Aug 10.

Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom. Electronic address:

Purpose: In Gaucher disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher disease management.

Results: Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided.

Conclusions: As a first-line therapy for type 1 Gaucher disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring.
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http://dx.doi.org/10.1016/j.ejim.2016.07.011DOI Listing
January 2017

Metachromatic Leukodystrophy: An Assessment of Disease Burden.

J Child Neurol 2016 11 7;31(13):1457-1463. Epub 2016 Jul 7.

Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Metachromatic leukodystrophy is accompanied by severe motor and cognitive dysfunction. This is the first survey of metachromatic leukodystrophy caregiver perspectives to identify relevant clinical/quality-of-life outcomes for patients/caregivers. Interviews and 1 focus group were conducted with 30 caregivers representing 23 patients. Caregivers were asked about their experiences, including diagnostic process, signs/symptoms, symptoms affecting caregivers' and patients' lives, and treatment priorities. Caregivers reported loss of physical autonomy, weight loss, limited social relationships, frequent crying, and challenging sibling relationships. Most troublesome symptoms were immobility (9/30) and respiratory difficulties (6/30). Health care visits were frequent: 8/22 patients had experienced ≥11 hospitalizations since diagnosis, and 14/22 caregivers reported that these lasted ≥4 days. Caregivers also experienced work problems, feelings of fear/sadness, and loss of social relationships. Caregivers/physicians consider a therapy that could improve decline in mobility, pain, cognitive ability, communication, or food intake as conferring the greatest benefit. In conclusion, a so-far-unreported physical/economic burden in these families is presented.
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http://dx.doi.org/10.1177/0883073816656401DOI Listing
November 2016

Editorial.

Expert Rev Mol Med 2016 May 10;18:e10. Epub 2016 May 10.

Department of Medicine,University of Cambridge,UK.

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http://dx.doi.org/10.1017/erm.2016.10DOI Listing
May 2016

Saving orphan drug legislations: misconceptions and clarifications.

Expert Rev Pharmacoecon Outcomes Res 2016 ;16(1):111-7

a Department of Medicine , University of Cambridge , Cambridge , United Kingdom.

Orphan-drug sales are rocketing, with revenue expected to total $176 billion annually by 2020. As a share of the industry, orphan drugs now account for close to 15% of all prescription revenue globally (excluding generics) and the sector is set to grow at more than twice the rate (10.5%) of the overall prescription market (4.3%). But this success also equates to costs--borne by individual patients and cash-strapped health systems. Prices for orphan drugs can be 19 times higher than for other medications, hampering access for patients, many of whom are children. With ever more such expensive drugs reaching the market, the situation is becoming unsustainable and putting the survival of the orphan drug legislation itself at risk. Here the authors consider why there has been an increase in orphan drug designations, how orphan drug prices are set and regulated, before discussing proposals for how changes which could save the legislation.
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http://dx.doi.org/10.1586/14737167.2016.1141052DOI Listing
October 2016

Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.

J Lipid Res 2016 Mar 2;57(3):451-63. Epub 2016 Jan 2.

Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands Departments of Medical Biochemistry Leiden Institute of Chemistry, Leiden, The Netherlands

The membrane lipid glucosylceramide (GlcCer) is continuously formed and degraded. Cells express two GlcCer-degrading β-glucosidases, glucocerebrosidase (GBA) and GBA2, located in and outside the lysosome, respectively. Here we demonstrate that through transglucosylation both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol, and vice versa. Furthermore, the natural occurrence of 1-O-cholesteryl-β-D-glucopyranoside (GlcChol) in mouse tissues and human plasma is demonstrated using LC-MS/MS and (13)C6-labeled GlcChol as internal standard. In cells, the inhibition of GBA increases GlcChol, whereas inhibition of GBA2 decreases glucosylated sterol. Similarly, in GBA2-deficient mice, GlcChol is reduced. Depletion of GlcCer by inhibition of GlcCer synthase decreases GlcChol in cells and likewise in plasma of inhibitor-treated Gaucher disease patients. In tissues of mice with Niemann-Pick type C disease, a condition characterized by intralysosomal accumulation of cholesterol, marked elevations in GlcChol occur as well. When lysosomal accumulation of cholesterol is induced in cultured cells, GlcChol is formed via lysosomal GBA. This illustrates that reversible transglucosylation reactions are highly dependent on local availability of suitable acceptors. In conclusion, mammalian tissues contain GlcChol formed by transglucosylation through β-glucosidases using GlcCer as donor. Our findings reveal a novel metabolic function for GlcCer.
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http://dx.doi.org/10.1194/jlr.M064923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766994PMC
March 2016

Clinician-scientist MB/PhD training in the UK: a nationwide survey of medical school policy.

BMJ Open 2015 Dec 30;5(12):e009852. Epub 2015 Dec 30.

Department of Medicine, University of Cambridge, Cambridge, UK.

Objective: This study surveyed all UK medical schools regarding their Bachelor of Medicine (MB), Doctor of Philosophy (PhD) (MB/PhD) training policy in order to map the current training landscape and to provide evidence for further research and policy development.

Setting: Deans of all UK medical schools registered with the Medical Schools Council were invited to participate in this survey electronically.

Primary: The number of medical schools that operate institutional MB/PhD programmes or permit self-directed student PhD intercalation.

Secondary: Medical school recruitment procedures and attitudes to policy guidance.

Findings: 27 of 33 (81%) registered UK medical schools responded. Four (14%) offer an institutional MB/PhD programme. However, of those without institutional programmes, 17 (73%) permit study interruption and PhD intercalation: two do not (one of whom had discontinued their programme in 2013), three were unsure and one failed to answer the question. Regarding student eligibility, respondents cited high academic achievement in medical studies and a bachelor's or master's degree. Of the Medical schools without institutional MB/PhD programmes, 5 (21%) have intentions to establish a programme, 8 (34%) do not and 3 were unsure, seven did not answer. 19 medical schools (70%) considered national guidelines are needed for future MB/PhD programme development.

Conclusions: We report the first national survey of MB/PhD training in the UK. Four medical schools have operational institutional MB/PhD programmes, with a further five intending to establish one. Most medical schools permit study interruption and PhD intercalation. The total number MB/PhD students yet to graduate from medical school could exceed 150, with 30 graduating per year. A majority of medical school respondents to this survey believe national guidelines are required for MB/PhD programme development and implementation. Further research should focus on the MB/PhD student experience. Discussion regarding local and national MB/PhD policies between medical schools and academic stakeholders are needed.
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http://dx.doi.org/10.1136/bmjopen-2015-009852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710833PMC
December 2015

Compassionate use of orphan drugs.

Orphanet J Rare Dis 2015 Aug 21;10:100. Epub 2015 Aug 21.

Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.

Background: EU regulation 726/2004 authorises manufacturers to provide drugs to patients on a temporary basis when marketing authorisation sought centrally for the entire EU is still pending. Individual Member States retain the right to approve and implement such 'compassionate use' programmes which companies will usually provide for free. Nevertheless some companies have opted not to partake in such programmes, in effect restricting access to drugs for patients in need. Here we survey the state of compassionate use programmes in the EU with particular reference to the rare disease field, and provide legal and ethical arguments to encourage their increased compassionate use in the EU and beyond. We contend that if enacted, these recommendations will be mutually beneficial to companies as well as patients.

Methods: Requests for information from the European Medicines Agency were made under the UK Freedom of Information Act 2000. Legal, ethical and economic/pragmatic analysis identified means by which provision of therapy in compassionate use programmes might be increased.

Results: More than 50 notifications of compassionate use programmes have been submitted to the EMA by Member States since 2006. About 40 % relate to orphan drugs. As there is a compulsory register of programmes but not of outcomes, their success is difficult to evaluate but, for example, the French programme expedited treatment for more than 20,000 (orphan and non-orphan) patients over a period of three years.

Conclusion: Compelling self-interested, legal and ethical arguments can be mounted to encourage manufacturers to offer therapies on a compassionate use basis and these are often equally applicable to provision on a humanitarian aid basis. The EU's compassionate use programmes are instrumental in ensuring continuity of access to drugs until approval and reimbursement decisions are finalised. We propose the creation of a registry of drugs offered on a compassionate use basis; further transparency would allow such programmes to be evaluated and direct patients to sources of treatment.
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http://dx.doi.org/10.1186/s13023-015-0306-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546220PMC
August 2015

Gaucher disease and comorbidities: B-cell malignancy and parkinsonism.

Am J Hematol 2015 Jul;90 Suppl 1:S25-8

Department of Clinical Neurosciences, University of Cambridge, United Kingdom.

Data emerging from the International Collaborative Gaucher Group (ICGG) Gaucher Registry together with other contemporary clinical surveys have revealed a close association between Gaucher disease and non-Hodgkin's B-cell lymphoma and myeloma and Gaucher disease and Parkinson's disease. Several possible explanations for increased B-cell proliferation and neoplasia in Gaucher disease have been proposed, including the possible influence of sphingosine (derived from the extra lysosomal metabolism of glucosylceramide), gene modifiers, splenectomy and immune system deregulation induced by cytokines, chemokines, and hydrolases released from Gaucher cells. Parkinson's disease is frequently seen in the otherwise-healthy relatives of Gaucher disease patients leading to the finding that GBA mutations represent a genetic risk factor for Parkinson's disease. The mechanism of the association between GBA mutations and Parkinson's disease has yet to be elucidated but the pathogenesis appears distinct from that of Gaucher disease. Several pathogenic pathways have been proposed including lysosomal and/or mitochondrial dysfunction. The effect of Gaucher disease specific therapies on the incidence of cancer or Parkinson's disease are not clear and will likely be evaluated in future ICGG Gaucher Registry studies.
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http://dx.doi.org/10.1002/ajh.24057DOI Listing
July 2015