J J Verschuuren

Leiden University, Leyden, South Holland, Netherlands

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Publications (110)583.17 Total impact

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    ABSTRACT: Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness, with a large variation of disease progression. To investigate possible causes for this diversity it is necessary to compare the disease course between different BMD patients. Due to the rarity of the disease, it is difficult to compose and study large groups of patients of the same age. Therefore we have developed a model to enable comparison of disease severity in BMD patients of different ages. For this purpose, Dutch and Flemish DNA-confirmed BMD patients were interviewed using a standardized questionnaire focusing on the age at reaching five disease milestones: first motor symptoms, difficulty walking stairs, use of a walking aid, wheelchair dependence and mechanical home ventilation. Each patient received 10 points for the age at which a specific milestone was reached and an individual composite score was calculated for each age. Combining the results of all participants, a population mean score was calculated at each age individually. Information was gathered from 113 BMD patients, ranging in age from 6 to 66 (median 39) years. Estimated mean survival for reaching the individual disease milestones was: first motor symptoms 11 years (SE 0.92; n = 109), difficulties walking stairs 25 years (SE 1.5; n = 90), use of a walking aid 37 years (SE 1.8; n = 71), wheelchair dependence 50 years (SE 2.0; n = 35) and mechanical home ventilation 63 years (SE 1.2; n = 5). Out of all individual data a model for disease severity was calculated. The maximum score in this model was 50 points. Mean population scores at age 10, 20, 30, 40, 50 and 60 years respectively were 8.4, 16.7, 20.2, 23.7, 26.8 and 30. When combining these mean scores with their SD, individual Z-scores can be calculated, enabling comparison of disease severity in BMD patients of different ages. As long as no prospectively collected long-term follow-up data are available, this scale could form a useful tool for clinical research in BMD.
    Neuromuscular Disorders 10/2014; 24(s 9–10):795. · 3.46 Impact Factor
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    ABSTRACT: Becker muscular dystrophy (BMD) presents with limb-girdle distribution of muscle weakness similar to limb girdle muscular dystrophies (LGMDs). To facilitate the differential diagnosis and direct genetic testing clinical markers indicating towards BMD could be helpful in the diagnostic process. We investigated if a combination of muscle testing and MRI could provide a diagnostic marker. Quantitative muscle testing of hip-flexors and extensors, knee-flexors and extensors was performed. To minimize confounding effects of age and weight, mean z-scores for muscle strength of the individual groups was calculated. On 3T MRI the gluteus maximus, iliopsoas, vastus lateralis, medialis and intermedius, rectus femoris, biceps femoris long and short head, semimembranosus, semitendinosus and sartorius were scored for fatty infiltration: 1 = normal, 2 = fatty streaks, 3 = <30%, 4 = 30–60% and 5 = >60%. Eleven patients (mean age 39 years, range 20–63) with variable symptoms ranging from no motor symptoms (n = 3) to wheelchair dependence (n = 1) were tested. Ten patients had negative z-scores and all had fatty infiltration on MRI. Overall knee extension showed the lowest z-score followed by knee flexion, hip extension, while hip flexion was relatively spared. In terms of fatty infiltration the biceps femoris long head was most severely affected and the iliopsoas least. Evaluation of the mean fatty infiltration score of the tested groups showed the highest mean fat score for hip extension muscles followed by knee flexion, knee extension, while hip flexion again appeared relatively spared. We show that in BMD patients hip flexion is spared compared to the other investigated muscles, which is mirrored by the MRI. This could be a valuable clue in the clinical setting as in LGMDs like type 2L and 2A, relatively common in the Netherlands, hip flexion is usually clearly affected. Thus, spared hip flexion on muscle testing or MRI in males with LGMD patters of weakness points to a diagnosis of BMD.
    Neuromuscular Disorders 10/2014; 24(s 9–10):795. · 3.46 Impact Factor
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    ABSTRACT: Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and 31P MRS. MRI and 31P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher (P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls (P ≤ 0.05). The Pi/ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions (P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions (P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls (P < 0.05). These findings suggest that 31P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration. Copyright © 2014 John Wiley & Sons, Ltd.
    NMR in Biomedicine 09/2014; · 3.45 Impact Factor
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    ABSTRACT: Objective Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioural disabilities which are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. We used quantitative MRI to study brain microstructure in DMD.MethodsT1-weighted and diffusion tensor images (DTI) were obtained on a 3 tesla MR scanner from 30 patients and 22 age-matched controls (ages 8-18 years). All subjects underwent neuropsychological examination. Group comparisons on tissue volume and DTI parameters were made between DMD and controls, and between two DMD subgroups that were classified according to predicted Dp140 isoform expression (DMD_Dp140+ and DMD_Dp140-).ResultsDMD patients had smaller total brain volume, smaller grey matter volume, lower white matter fractional anisotropy, and higher white matter mean and radial diffusivity than healthy controls. DMD patients also performed worse on neuropsychological examination. Subgroup analyses showed that DMD_Dp140- contributed most to the grey matter volume differences and performed worse on information processing.InterpretationBoth grey and white matter is affected in boys with DMD at a whole-brain level. Differences between subgroup DMD_Dp140- and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 07/2014; · 11.19 Impact Factor
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    ABSTRACT: Introduction: Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. Antibody-mediated functional loss of voltage-gated calcium channels (VGCCs) on the presynaptic surface results in reduced neurotransmitter release. Muscle weakness starts in the proximal limbs and is accompanied by autonomic failure and areflexia. About 50 – 60% of the patients have small-cell lung cancer (SCLC), with antibodies produced in reaction to VGCC on tumor cells. In non-tumor LEMS, an autoimmune reaction causes antibody production. Knowledge of the pathophysiology of antibody production in SCLC-LEMS and non-tumor LEMS and a detailed understanding of the neuromuscular junction and its dysfunction in LEMS is needed for drug development. Areas covered: This review gives an overview of the clinical symptoms, diagnosis and pathophysiology of LEMS. Current treatment options and results of recent research on newly developed symptomatic treatment are described. Expert opinion: Extensive search for SCLC is needed in LEMS patients. Appropriate tumor treatment should be started in SCLC-LEMS. In both SCLC-LEMS and non-tumor LEMS, symptomatic treatment consists of 3,4-diaminopyridine. If insufficient, pyridostigmine can be added, although a small trial failed to prove its benefit in LEMS and it is probably only efficient in a subset of patients. In moderate-to-severe disease, immunosuppressive treatment with prednisolone and azathioprine should be started. Research on drugs in LEMS is complicated by the infrequency of the disorder. Future developments are mainly expected in the field of symptomatic treatment. Possibly, further studies on immunosuppression in myasthenia gravis will be meaningful for the therapeutic strategy in LEMS as well.
    Expert Opinion on Orphan Drugs. 01/2014; 2(2).
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    ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5,2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggest an underlying autoimmune mechanism, supporting the use of immune therapy.
    Autoimmunity Reviews. 01/2014;
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    ABSTRACT: The purpose of this study was to assess leg muscle quality and give a detailed description of leg muscle involvement in of Duchenne muscular dystrophy patients using quantitative MRI and strength measurements. Fatty infiltration, as well as total and contractile (not fatty infiltrated) cross sectional areas of various leg muscles were determined in 16 Duchenne patients and 11 controls (aged 8 to 15). To determine specific muscle strength, four leg muscle groups (quadriceps femoris, hamstrings, anterior tibialis and triceps surae) were measured and related to the amount of contractile tissue. In patients, the quadriceps femoris showed decreased total and contractile cross sectional area, attributable to muscle atrophy. The total, but not the contractile, cross sectional area of the triceps surae was increased in patients, corresponding to hypertrophy. Specific strength decreased in all four muscle groups of Duchenne patients, indicating reduced muscle quality. This suggests that muscle hypertrophy and fatty infiltration are two distinct pathological processes, differing between muscle groups. Additionally, the quality of remaining muscle fibers is severely reduced in the legs of Duchenne patients. The combination of quantitative MRI and quantitative muscle testing could be a valuable outcome parameter in longitudinal studies and in the follow-up of therapeutic effects.
    Neuromuscular Disorders 01/2014; · 3.46 Impact Factor
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    ABSTRACT: Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii) low-density lipoprotein receptor-related protein 4 (Lrp4), which responds to neural Agrin by binding and stimulating MuSK. Passive transfer studies in mice have shown that IgG4 antibodies from MuSK MG patients cause disease without requiring complement or other immune components, suggesting that these MuSK antibodies cause disease by directly interfering with MuSK function. Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. In contrast, these IgG4 antibodies have no direct effect on MuSK dimerization or MuSK internalization. These results provide insight into the unique pathogenesis of MuSK MG and provide clues toward development of specific treatment options.
    Proceedings of the National Academy of Sciences 12/2013; · 9.81 Impact Factor
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    ABSTRACT: Becker muscular dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne muscular dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45-47 deletion. Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration. 33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%-78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45-47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45-47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients' age. Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45-47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced.
    Journal of neurology, neurosurgery, and psychiatry 11/2013; · 4.87 Impact Factor
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    ABSTRACT: Autoantibodies against three different postsynaptic antigens and one presynaptic antigen at the neuromuscular junction are known to cause myasthenic syndromes. The mechanisms by which these antibodies cause muscle weakness varies from antigenic modulation and complement-mediated membrane damage to inhibition of endogenous ligand binding and blocking of essential protein-protein interactions. These mechanisms are related to the autoantibody titre, specific epitopes on the target proteins and IgG autoantibody subclass. We here review the role of specific autoantibody-binding epitopes in myasthenia gravis, their possible relevance to the pathophysiology of the disease, and potential implications of epitope mapping knowledge for new therapeutic strategies. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 11/2013; · 6.46 Impact Factor
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    ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.
    Journal of Neurology 10/2013; · 3.58 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. While many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence < 5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately, global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardised patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organisations and industry. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2013; · 5.21 Impact Factor
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    ABSTRACT: OBJECTIVE: Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. METHODS: Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. RESULTS: Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. CONCLUSIONS: This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.
    Journal of neurology, neurosurgery, and psychiatry 05/2013; · 4.87 Impact Factor
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    ABSTRACT: Lambert-Eaton myasthenic syndrome (LEMS) is characterized by fluctuating muscle weakness and autonomic dysfunction. In 90% of the LEMS patients the disease is associated with auto-antibodies against the voltage-gated calcium channels (VGCC). Several auto-immune responses against other antigenic targets have been described to (co)-occur in LEMS patients. To identify new LEMS associated small cell lung cancer (SCLC) markers immunoprecipitation with a SCLC cell line was performed. We discovered strong immunoreactivity against the 120 kDa large ERC1 protein in one tumor-negative VGCC-positive LEMS patient. A recombinant ELISA assay and a cellular assay expressing GFP-tagged full length ERC1 were used to confirm the presence of auto-antibodies against ERC1 in this patient. Additional testing of 58 LEMS patients including 9 VGCC auto-antibody negative LEMS patients, 48 myasthenia gravis patients, 84 control patients with other diseases and 12 healthy controls revealed no other cases. ERC1 is therefore a new, but rare, antigen in LEMS.
    Human immunology 04/2013; · 2.55 Impact Factor
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    ABSTRACT: PURPOSE: To compare different lipid multipeak spectral models to the single-peak model in Dixon-based fat-water separation and to evaluate differences between visually scored magnetic resonance (MR) images and quantitatively assessed fat fractions in muscle of Duchenne muscular dystrophy patients. MATERIALS AND METHODS: T1-weighted and 3-point Dixon imaging of the upper and lower leg was performed in 13 Duchenne patients and six healthy controls. Three-, four-, and five-peak lipid spectrum models were compared to a single-peak model and to each other. T1-weighted images were visually scored by two radiologists and quantitative fat fractions were obtained from Dixon images. RESULTS: Differences between the multipeak spectral models were minimal. The three-peak model was used for subsequent comparisons. Although there was high correlation between quantitative and visual scores, visual scores were consistently higher than quantitative values of the same muscles. CONCLUSION: There are minor differences between the various lipid spectral models in terms of quantifying fat fraction in a large number of skeletal muscles in the legs of Duchenne patients and healthy controls. Quantitative 3-point Dixon MRI is more precise and reliable than visual radiological methods for evaluation of fat fractions for potential longitudinal follow-up or therapy evaluation of Duchenne patients. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 01/2013; · 2.57 Impact Factor
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    ABSTRACT: Autoantibodies against muscle-specific kinase (MuSK), a protein essential for clustering of acetylcholine receptors at the neuromuscular junction (NMJ), are detected in the serum of a proportion of myasthenia gravis (MG) patients. In most MuSK MG patients the anti-MuSK activity resides in the IgG4 subclass, a minor IgG component without very well-defined, but presumably anti-inflammatory, roles in immunity. In recent years, several animal model studies showed that anti-MuSK autoantibodies can cause muscle weakness by directly affecting NMJ function and, therefore, are likely not simply bystander disease markers in MuSK MG patients. In passive transfer mice, we recently provided proof that MuSK MG patient IgG4 is severely myasthenogenic, causing functional defects at NMJs. Against the clinical, serological, and pharmacological background of MuSK MG, here we discuss the MuSK MG animal models generated by our laboratory and others that have been instrumental in elucidating the etiological and pathophysiological roles of anti-MuSK antibodies.
    Annals of the New York Academy of Sciences 12/2012; 1275(1):114-22. · 4.38 Impact Factor
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    ABSTRACT: BACKGROUND: Due partly to physicians' unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. METHODS: We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3--6 months and analyzed using repeated-measures ANOVA. RESULTS: Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of -1.3% point/year for manual muscle testing and of -2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast. CONCLUSIONS: Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.
    Orphanet Journal of Rare Diseases 11/2012; 7(1):88. · 4.32 Impact Factor

Publication Stats

2k Citations
583.17 Total Impact Points

Institutions

  • 2014
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1997–2014
    • Leiden University Medical Centre
      • • Department of Human Genetics
      • • Department of Neurology
      Leyden, South Holland, Netherlands
  • 2013
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • Institute of Genetic Medicine
      Newcastle upon Tyne, ENG, United Kingdom
  • 2010
    • HagaZiekenhuis van Den Haag
      's-Gravenhage, South Holland, Netherlands
  • 2008
    • Universitair Ziekenhuis Leuven
      • Department of Neurology
      Louvain, Flanders, Belgium
  • 1996–1998
    • Memorial Sloan-Kettering Cancer Center
      • Department of Neurology
      New York City, New York, United States
  • 1990–1997
    • Maastricht University
      • • Neurologie
      • • MHeNS School for Mental Health and Neuroscience
      Maestricht, Limburg, Netherlands