Frits A. Wijburg

Plasma chitotriosidase and CCL18: Early biochemical surrogate markers in type B Niemann-Pick disease

SummaryType B Niemann-Pick disease (NPD) is a nonneuronopathic lysosomal storage disorder which is characterized by accumulation of sphingomyelin-laden macrophages. The availability of plasma markers for storage cells may be of great value in facilitating therapeutic decisions. Given the similarity of the storage cells in NPD and Gaucher disease, we studied Gaucher plasma markers (chitotriosidase and CCL18) in two siblings homozygous for the R228C mutation in acid sphingomyelinase (ASM) and a type B course of NPD. The older sibling, first examined at the age of 9 months, showed marked hepatosplenomegaly and pulmonary involvement. The younger sibling has mild asymptomatic hepatosplenomgaly at the age of 5 months. Analysis of plasma specimens revealed markedly increased levels of chitotriosidase and CCL18 in the older sibling. In the younger child also, plasma chitotriosidase and CCL18 were clearly elevated above normal values almost immediately after birth and rapidly increased further. Histochemistry confirmed production of CCL18 by foam cells. In conclusion, plasma chitotriosidase and CCL18 may also serve as markers for the formation of pathological lipid-laden macrophages in type B NPD, in analogy to Gaucher disease. The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of enzyme supplementation therapy that is currently being developed.

Treatment of lysosomal storage disorders: successes and challenges

Treatment options for a number of lysosomal storage disorders have rapidly expanded and currently include enzyme replacement therapy, substrate reduction, chaperone treatment, hematopoietic stem cell transplantation, and gene-therapy. Combination treatments are also explored. Most therapies are not curative but change the phenotypic expression of the disease. The effectiveness of treatment varies considerably between the different diseases, but also between sub-groups of patients with a specific lysosomal storage disorder. The heterogeneity of the patient populations complicates the prediction of benefits of therapy, specifically in patients with milder disease manifestations. In addition, there is a lack of data on the natural history of diseases and disease phenotypes. Initial trial data show benefits on relevant short-term endpoints, but the real world situation may reveal different outcomes. Collaborative international studies are much needed to study the long-term clinical efficacy of treatments, and to detect new complications or associated conditions of the diseases. This review summarizes the available treatment modalities for lysosomal storage disorders and the challenges associated with long term clinical care for these patients.

Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement therapy (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans

IntroductionMucopolysaccharidosis type I (MPS I) results in a defective breakdown of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, which leads to a progressive disease. Enzyme replacement therapy (ERT) results in clearance of these GAGs from a range of tissues and can significantly ameliorate several symptoms. The biochemical efficacy of ERT is generally assessed by the determination of the total urinary excretion of GAGs. However, this has limitations. We studied the concentrations of heparan sulfate and dermatan sulfate derived disaccharides (HS and DS, respectively) in the plasma and urine of seven patients and compared these levels with total urinary GAGs (uGAGs) levels.MethodsPlasma and urine samples were collected at different time points relative to the weekly ERT for three non-consecutive weeks in seven MPS I patients who had been treated with ERT for at least 2.5xa0years. Heparan and dermatan sulfate in plasma and urine were enzymatically digested into disaccharides, and HS and DS levels were determined by HPLC-MS/MS analysis. uGAGs were measured by the DMB test.ResultsThe levels of HS and DS were markedly decreased compared with the levels before the initiation of ERT. However, the concentrations of DS in plasma and of both HS and DS in urine remained significantly elevated in all studied patients, while in six patients the level of total uGAGs had normalized. The concentrations of plasma and urinary HS during the weekly ERT followed a U-shaped curve. However, the effect size is small. The concentrations of plasma and urinary DS and uGAGs appeared to be in a steady state.ConclusionsHS and DS are sensitive biomarkers for monitoring the biochemical treatment efficacy of ERT and remain elevated despite long-term treatment. This finding may be related to the labeled dose or antibody status of the patient. The timing of the sample collection is not relevant, at least at the current dose of 100xa0IU/kg/weekly.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

SummaryWe report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

Fatty acid oxidation in the human fetus : Implications for fetal and adult disease

SummaryStudies in the last few years have shown a remarkably high activity of fatty acid oxidation (FAO) enzymes in human placenta. We have recently shown mRNA expression as well as enzymatic activity of long-chain FAO enzymes in the human embryo and fetus. In this study we show activity of the FAO enzymes carnitine palmitoyltranferase 1, medium-chain acyl-CoA dehydrogenase and short-chain hydroxyacyl-CoA dehydrogenase in embryonic and fetal tissues. In addition, we show the presence of different acylcarnitines in fetal liver and kidney, which substantiates the notion that the mitochondrial FAO enzymes are not only present in human fetal tissues but also metabolically active. In a glucose-rich environment FAO might be necessary for additional ATP production from fatty acids, but also for the breakdown of fatty acids that are products of the turnover of membranes in the growing fetus. The importance of FAO in the human embryo and fetus is further stressed by the fact that a higher frequency of prematurity, intrauterine growth retardation, fetal morbidity and intrauterine death is noted in long-chain FAO defects. Furthermore, in animal studies, gestational loss during early embryonic development has been observed as a consequence of disturbed FAO. Finally, there are indications that regulation of activity of FAO during fetal development might not only be important for fetal life but may also have implications for health and disease in adulthood.

Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests

BackgroundFabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.MethodsForty-eight Fabry patients (15 male, 30 treated with enzyme replacement therapy) and 48 sex- and age-matched controls completed a questionnaire on autonomic symptoms (the Autonomic Symptom Profile). Thirty-six Fabry patients underwent cardiovascular function tests.ResultsThe Autonomic Symptom Profile revealed a significantly higher sum score in Fabry patients than in healthy control subjects (22 versus 12), but a relatively low score compared to patients with proven autonomic neuropathy. Fabry patients scored worse than healthy controls in the orthostatic intolerance domain. Scores in the male sexual dysfunction domain were comparable between healthy controls and male Fabry patients. The cardiovascular autonomic function tests revealed only mild abnormalities in seven patients. None of these seven patients showed more than one abnormal test result. Enzyme replacement therapy was not associated with less severe disease, lower ASP scores or less frequent abnormal cardiovascular function test results.ConclusionsMale sexual function and autonomic control of the cardiovascular system are nearly normal in Fabry patients, which cast doubt on the general accepted assumption that autonomic neuropathy is the main cause of symptoms and signs compatible with autonomic dysfunction in Fabry disease. Possibly, end-organ damage plays a key role in the development of symptoms and signs in Fabry patients. An exceptional kind of autonomic neuropathy is another but less likely explanation.

Restricted upper extremity range of motion in mucopolysaccharidosis type I: no response to one year of enzyme replacement therapy

SummaryBackground: Mucopolysaccharidosis type I (MPS I) results from deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Glycosaminoglycans (GAGs) accumulate in multiple organs and the storage in connective tissues results in restricted mobility. Previous studies provided evidence of an improvement in range of motion (ROM), as measured by goniometry, after supplementation of recombinant enzyme (ERT). Aim: The aim of the study was to evaluate the efficacy of ERT in improving ROM in patients with MPS I, using a blinded three-dimensional (3D) video analysis of unrestricted movements of the upper extremities. Methods: In 6 patients with the attenuated phenotype of MPS I, the longitudinal changes in the upper extremity ROM were analysed by 3D video analysis during one year of ERT. Results: At baseline, all studied movements except for elbow flexion were restricted. No significant improvement of the restricted upper extremity ROM was observed after one year of ERT. Conclusion: Long-standing restrictions in ROM probably cannot be reversed by ERT. Early initiation of treatment might be essential to prevent irreversible functional defects.

Long-term statin treatment in children with familial hypercholesterolemia: more insight into tolerability and adherence.

BackgroundStatins are currently the preferred pharmacological therapy in individuals with familial hypercholesterolemia (FH) with the aim to prevent premature atherosclerosis. In adults, these agents have been proven to be safe and well tolerated; however, non-adherence is a significant clinical issue.ObjectivesIn this study, we evaluated tolerability and adherence to statin therapy in young adult FH patients 10xa0years after this was initiated in their childhood.MethodsA questionnaire including items on medical history, adherence and reasons for discontinuation was sent to 214 young adult FH patients that initiated statin therapy at least 10xa0years ago. Tolerability was defined as 100xa0% minus the percentage of patients that discontinued statin therapy due to side effects. Adherence was defined as the extent to which patients took their medication as prescribed by their physician. We labelled patients adherent if they took 80xa0% or more of their pills in the month preceding our assessment.ResultsFollow-up was successful in 205 (95.8xa0%) subjects (age 18–30xa0years). A history of side effects was reported by 40 (19.5xa0%) of the patients, and mainly consisted of muscle complaints and gastrointestinal symptoms. Three patients (1.5xa0%) discontinued statin therapy because of side effects. Rhadbomyolysis or other serious adverse events were not reported. In fact, 169 (82.4xa0%) of 205 patients remained on statin treatment and 78.7xa0% (148 out of 188) were adherent. None of the patient characteristics were significantly associated with adherence.ConclusionsIndividuals with FH who started statin therapy in childhood demonstrated good adherence during ten years of treatment. Furthermore, statin therapy was well tolerated; only a small minority discontinued therapy because of side effects and the side effects that were reported were mild in nature.

Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome

BackgroundThe lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB). The success of current therapies, including haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) may be influenced by a number of factors and monitored using biomarkers of metabolic correction. We describe the pattern of SDB seen in the largest MPS I cohort described to date and determine therapies and biomarkers influencing the severity of long-term airway disease.MethodsTherapeutic, clinical and biomarker data, including longitudinal outcome parameters from 150 sleep oximetry studies were collected in 61 MPS I (44 Hurler, 17 attenuated) patients between 6xa0months pre to 16xa0years post-treatment (median follow-up 22xa0months). The presence and functional nature of an immune response to ERT was determined using ELISA and a cellular uptake inhibition assay. Multivariate analysis was performed to determine significant correlators of airway disease.ResultsThe incidence of SDB in our cohort is 68%, while 16% require therapeutic intervention for airway obstruction. A greater rate of progression (73%) and requirement for intervention is seen amongst ERT patients in contrast to HSCT treated individuals (24%). Multivariate analysis identifies poorer metabolic clearance, as measured by a rise in the biomarker urinary dermatan sulphate: chondroitin sulphate (DS:CS) ratio, as a significant correlator of increased presence and severity of SDB in MPS I patients (pu2009=u20090.0017, 0.008). Amongst transplanted Hurler patients, delivered enzyme (leukocyte iduronidase) at one year is significantly raised in those without SDB (pu2009=u20090.004). Cellular uptake inhibitory antibodies in ERT treated patients correlate with reduced substrate clearance and occurrence of severe SDB (pu2009=u20090.001).ConclusionWe have identified biochemical and therapeutic factors modifying airway disease across the phenotypic spectrum in MPS I. Interventions maximising substrate reduction correlate with improved long-term SDB, while inhibitory antibodies impact on biochemical and clinical outcomes. Monitoring and tolerisation strategies should be re-evaluated to improve detection and minimise the inhibitory antibody response to ERT in MPS I and other lysosomal storage diseases. Future studies should consider the use of sleep disordered breathing as an objective parameter of clinical and metabolic improvement.

Prevalence of symptoms in female Fabry disease patients: a case-control survey

BackgroundFabry disease (FD) is an X-linked lysosomal storage disorder, caused by a deficiency of α-galactosidase A. Several studies demonstrated that heterozygotes have symptoms such as acroparesthesia, abdominal pain and chronic fatigue. However, as these symptoms are aspecific and relatively common in the general population, it is important to compare the prevalence of these symptoms with an appropriate control group. The aim of this study was to explore the prevalence of signs and symptoms in FD females in comparison to a control group.MethodsFD females and age-matched controls were approached to complete a questionnaire. This questionnaire was developed by the Dutch Fabry patient organisation (Fabry Support en Informatie Groep Nederland, FSIGN) with input from Fabry expert-physicians from the AMC. We compared the prevalence symptoms using Pearson’s chi-square test. Bonferroni correction was used to correct for multiple comparisons.ResultsA total of 63 heterozygotes and 52 controls completed the questionnaire. Many symptoms were also common in controls. Yet, fatigue, palpitations, pains in hands and feet, joint pain, dizziness, loss of libido and proteinuria during pregnancy were more common in Fabry females (all pu2009<u20090.001).ConclusionIn addition to acroparesthesia - fatigue, palpitations, dizziness, proteinuria during pregnancy, libido loss and joint pain are more prevalent in FD females as compared to a control group. Although, these symptoms are present in a significant proportion of normal controls they deserve further attention by treating physicians to better understand their significance, treatment and relationship with FD.