Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.

A Delphi Survey Study to Formulate Statements on the Treatability of Inherited Metabolic Disorders to Decide on Eligibility for Newborn Screening.

The Wilson and Jungner (W&J) and Andermann criteria are meant to help select diseases eligible for population-based screening. With the introduction of next-generation sequencing (NGS) methods for newborn screening (NBS), more inherited metabolic diseases (IMDs) can technically be included, and a revision of the criteria was attempted. This study aimed to formulate statements and investigate whether those statements could elaborate on the criterion of treatability for IMDs to decide on eligibility for NBS. An online Delphi study was started among a panel of Dutch IMD experts (EPs). EPs evaluated, amended, and approved statements on treatability that were subsequently applied to 10 IMDs. After two rounds of Delphi, consensus was reached on 10 statements. Application of these statements selected 5 out of 10 IMDs proposed for this study as eligible for NBS, including 3 IMDs in the current Dutch NBS. The statement: 'The expected benefit/burden ratio of early treatment is positive and results in a significant health outcome' contributed most to decision-making. Our Delphi study resulted in 10 statements that can help to decide on eligibility for inclusion in NBS based on treatability, also showing that other criteria could be handled in a comparable way. Validation of the statements is required before these can be applied as guidance to authorities.

Are Anti-rhGAA Antibodies a Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease? A Systematic Review.

BACKGROUND: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres on treatment response in adults with late-onset Pompe disease (LOPD) remains unclear but may contribute to interpatient variation. We therefore conducted a systematic review on this subject. METHODS: A systematic search was performed in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Articles were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titres. In addition, articles mentioning dosages different from the standard recommended dosage were included. RESULTS: Our literature search retrieved 2562 publications, and 17 fulfilled our selection criteria, describing 443 cases. Seven publications reported on anti-rhGAA antibody titres on a group level, with the percentage of patients with a high titre as defined in the included articles ranging from 0-33%. Six publications reported on the effect of anti-rhGAA antibody titre on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in Medical Research Council (MRC) score in patients with no detectable antibody titre. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titres. Seven publications reported on 17 individual patients with a high antibody titre (range 1:12,800-1:3,906,250). In only two cases were high-sustained neutralising antibodies reported to interfere with treatment efficacy. CONCLUSIONS: No clear effect of anti-rhGAA IgG antibodies on treatment response could be established for the majority of LOPD patients with a high antibody titre. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described.

Neurofilament Light and Its Association With CNS Involvement in Patients With Classic Infantile Pompe Disease.

BACKGROUND AND OBJECTIVES: Enzyme replacement therapy (ERT) has substantially improved the outcome of classic infantile Pompe disease, an inheritable muscle disease previously fatal at infancy. However, under treatment, patients develop white matter abnormalities and neurocognitive problems. Therefore, upcoming therapies also target the brain. Currently, biomarkers reflecting CNS involvement are lacking. We aimed to study the association of neurofilament light (NfL) and CNS involvement. METHODS: To investigate the potential of NfL, we analyzed serum samples of patients with classic infantile Pompe disease who were treated with ERT. The samples were collected at ages of <1, 5, and 10 years, as well as around MRI scans. We compared the outcomes with levels in age- and sex-matched peers. Control samples were originally collected as part of routine blood work in children who underwent small surgeries and stored in the biobank of the Erasmus MC/Sophia Children's Hospital. RESULTS: We analyzed 74 serum samples of 17 patients collected at ages ranging from 22 days to 21.2 years (1-8 samples per patient) and compared these with outcomes of 71 matched peers. In the first year of age, NfL levels in patients and controls were similar (10.3 vs 11.0 pg/mL), but mixed linear model analysis showed a yearly increase of NfL of 6.0% in patients, compared with a decrease of 8.8% in controls (p < 0.001). Higher NfL was associated with lower IQ scores (p = 0.009) and lower processing speed scores (p = 0.001). DISCUSSION: We found significant differences in NfL levels between patients and controls and a good association between NfL and cognition. NfL deserves further exploration as a biomarker for CNS involvement in patients with classic infantile Pompe disease.

Home-Based Infusion of Alglucosidase Alfa Can Safely be Implemented in Adults with Late-Onset Pompe Disease: Lessons Learned from 18,380 Infusions.

BACKGROUND: Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. OBJECTIVES: This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. METHOD: We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. RESULTS: We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. CONCLUSION: Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present.

Home-based enzyme replacement therapy in children and adults with Pompe disease; a prospective study.

BACKGROUND: Pompe disease is a lysosomal storage disease treated with life-long enzyme replacement therapy (ERT). Home-based ERT has been provided in the Netherlands since 2008 because it diminishes the burden of treatment, increases patient flexibility and autonomy, and is thus a more patient-centred approach to ERT. METHODS: All Dutch Pompe patients receiving alglucosidase alfa infusions at home were approached to participate in a questionnaire to validate the safety of home-based ERT. Prospective data on symptoms occurring during or within 48 h after infusion and retrospective data on infusion associated reactions (IARs) in the last three months were collected four times during one year. RESULTS: In total, 116 out of 120 eligible patients (17 classic infantile, 2 atypical infantile, 15 childhood onset and 82 adult) filled out 423 questionnaires (response rate: 88.1%). Symptoms during or after infusion were reported 27 times in 17 patients. Fatigue was the most commonly reported health complaint (in 9.5% of patients). Four health complaints were judged to be IARs and reported to the Erasmus MC University Medical Center. None of the IARs reported in this study warranted emergency clinical care. CONCLUSIONS: Our data demonstrate that home-based ERT in Pompe disease can be safely implemented as few, mostly mild, symptoms were reported during or after infusion. Insights from this study can be used as a base for implementing home-based ERT in other countries and to further optimize patient care, as unreported mild symptoms do not pose a health risk but may still be relevant to the patient.

Analysis of urinary oligosaccharide excretion patterns by UHPLC/HRAM mass spectrometry for screening of lysosomal storage disorders.

Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins and glycolipids leads to the accumulation of incompletely degraded oligosaccharides within lysosomes. In metabolic laboratories, these disorders are commonly diagnosed by thin-layer chromatography (TLC) but more recently also mass spectrometry-based approaches have been published. To expand the possibilities to screen for these diseases, we developed an ultra-high-performance liquid chromatography (UHPLC) with a high-resolution accurate mass (HRAM) mass spectrometry (MS) screening platform, together with an open-source iterative bioinformatics pipeline. This pipeline generates comprehensive biomarker profiles and allows for extensive quality control (QC) monitoring. Using this platform, we were able to identify α-mannosidosis, ß-mannosidosis, α-N-acetylgalactosaminidase deficiency, sialidosis, galactosialidosis, fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, GM2 gangliosidosis (M. Sandhoff) and mucolipidosis II/III in patient samples. Aberrant urinary oligosaccharide excretions were also detected for other disorders, including NGLY1 congenital disorder of deglycosylation, sialic acid storage disease, MPS type IV B and GSD II (Pompe disease). For the latter disorder, we identified heptahexose (Hex7), as a potential urinary biomarker, in addition to glucose tetrasaccharide (Glc4), for the diagnosis and monitoring of young onset cases of Pompe disease. Occasionally, so-called "neonate" biomarker profiles were observed in young patients, which were probably due to nutrition. Our UHPLC/HRAM-MS screening platform can easily be adopted in biochemical laboratories and allows for simple and robust screening and straightforward interpretation of the screening results to detect disorders in which aberrant oligosaccharides accumulate.

Diffusion tensor imaging of the brain in Pompe disease.

Enzyme replacement therapy has drastically changed prospects of patients with Pompe disease, a progressive metabolic myopathy. As classic infantile patients survive due to treatment, they exhibit progressive white matter abnormalities, while brain involvement in late-onset patients is not fully elucidated. To study the underlying microstructure of white matter, we acquired structural (T1, T2, FLAIR) and diffusion tensor imaging (DTI) of the brain in 12 classic infantile patients (age 5-20 years) and 18 late-onset Pompe patients (age 11-56 years). Structural images were scored according to a rating scale for classic infantile patients. Fractional anisotropy (FA) and mean diffusivity (MD) from classic infantile patients were compared to a reference population, using a Wilcoxon signed-rank, one sample test. Effect sizes (Hedges' G) were used to compare DTI metrics across different tracts. For late-onset patients, results were compared to (reported) tractography data on normal aging. In classic infantile patients, we found a significant lower FA and higher MD (p < 0.01) compared to the reference population. Large-association fibers were most severely affected. Classic infantile patients with advanced white matter abnormalities on structural MRI showed the largest deviations from the reference population. FA and MD were similar for younger and older late-onset patients in large WM-association fibers. We conclude that, while no deviations from typical neurodevelopment were found in late-onset patients, classic infantile Pompe patients showed quantifiable, substantially altered white matter microstructure, which corresponded with disease stage on structural MRI. DTI holds promise to monitor therapy response in future therapies targeting the brain.

Antibodies against recombinant human alpha-glucosidase do not seem to affect clinical outcome in childhood onset Pompe disease.

BACKGROUND: Enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA, alglucosidase alfa) has improved survival, motor outcomes, daily life activity and quality of life in Pompe patients. However, ERT in Pompe disease often induces formation of antibodies, which may reduce the efficacy of treatment and can lead to adverse events. In this study antibody formation and their effect on clinical outcome in patients with childhood onset Pompe disease treated with enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) are analyzed. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to determine anti-rhGAA antibody titers at predefined time points. The effect of antibodies on rhGAA activity (neutralizing effects) was measured in vitro. Clinical effects were evaluated by assessing muscle strength (MRC score) and function (QMFT-score), pulmonary function and infusion associated reactions (IARs). RESULTS: Twenty-two patients were included (age at start ERT 1.1-16.4 years, median treatment duration 12.4 years). Peak antibody titers were low (< 1:1250) in 9%, intermediate (1:1250-1:31,250) in 68% and high (≥ 1:31250) in 23% of patients; three patients (14%) had more than one titer of ≥ 1:31,250. Four patients (18%) experienced IARs; two patients from the high titer group had 86% of all IARs. Inhibition of intracellular GAA activity (58%) in vitro was found in one sample. The clinical course did not appear to be influenced by antibody titers. CONCLUSIONS: Ninety-one percent of childhood onset Pompe patients developed anti-rhGAA antibodies (above background level), a minority of whom had high antibody titers at repeated time points, which do not seem to interfere with clinical outcome. High antibody titers may be associated with the occurrence of IARs. Although the majority of patients does not develop high titers; antibody titers should be determined in case of clinical deterioration.

Is the brain involved in patients with late-onset Pompe disease?

Our objective was to investigate brain structure, cerebral vasculature, and cognitive function in a cohort of patients with late-onset Pompe disease, with particular reference to the differences from those with the classic infantile phenotype, where extensive white-matter abnormalities (WMA) and impaired cognition on long-term enzyme treatment are reported in a subset of patients. Brain imaging (T1, T2, T2 fluid-attenuated inversion recovery, susceptibility-weighted images, and magnetic resonance angiography-time of flight) was combined with extensive cognitive testing of general intelligence (Wechsler IQ Test, Montreal Cognitive Assessment [MoCA]) and specific neuropsychological domains (verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities). We included 19 patients with late-onset Pompe disease (age range 11-56 years). Two patients showed mild punctate WMA within normal range for age, with a Fazekas score (FS) of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients yet did not show any aneurysms or vascular dissections. Most patients had age-adjusted scores within the normal range for the Wechsler index scores (verbal comprehension, perceptual reasoning, working memory, and processing speed) and combined total intelligence (IQ) score (median 101, interquartile range 91-111; one patient had a below-average score for total IQ) as well as for the specific domains verbal fluency, attention, and memory. A subset of patients performed suboptimally on the Rey Complex Figure Test (9/14 patients) or cube-copying/clock-drawing test of the MoCA (8/10 patients). We therefore concluded that our study showed no brain abnormalities, other than minor microvascular lesions considered within normal range for age, nor general cognitive impairment in late-onset Pompe patients. These findings are in sharp contrast with the widespread WMA and cognitive problems found in some classic infantile patients.

Can serial cerebral MRIs predict the neuronopathic phenotype of MPS II?

OBJECTIVE: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. METHODS: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease-specific protocol. MRI sumscores were calculated for atrophy, white-matter abnormalities (WMA) and Virchow-Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. RESULTS: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non-neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). White-matter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = -.90 for atrophy and -.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the Virchow-Robin spaces (VRS) on MRI were minimal. CONCLUSION: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophy-scores were higher in young neuronopathic patients than in non-neuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with white-matter abnormalities.

Effects of higher and more frequent dosing of alglucosidase alfa and immunomodulation on long-term clinical outcome of classic infantile Pompe patients.

The aim of this study was to compare the long-term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross-reactive immunologic material (CRIM)-negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator-free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)-naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator-free survival was 50% and 92%. Both CRIM-negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk. Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM-negative also received immunomodulation. B-cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B-cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250-1:800 000 and 1:250-1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator-free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis.

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5' UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

Craniosynostosis affects the majority of mucopolysaccharidosis patients and can contribute to increased intracranial pressure.

BACKGROUND: The mucopolysaccharidoses are multisystem lysosomal storage diseases characterized by extensive skeletal deformities, including skull abnormalities. The objective of this study was to determine the incidence of craniosynostosis in the different mucopolysaccharidosis (MPS) types and its clinical consequences. METHODS: In a prospective cohort study spanning 10 years, skull imaging and clinical evaluations were performed in 47 MPS patients (type I, II, VI, and VII). A total of 215 radiographs of the skull were analyzed. The presence and type of craniosynostosis, the sutures involved, progression over time, skull shape, head circumference, fundoscopy, and ventriculoperitoneal shunt (VPS) placement data were evaluated. RESULTS: Craniosynostosis of at least one suture was present in 77% of all 47 MPS patients (≤ 6 years of age in 40% of all patients). In 32% of all MPS patients, premature closure of all sutures was seen (≤ 6 years of age in 13% of all patients). All patients with early closure had a more severe MPS phenotype, both in the neuronopathic (MPS I, II) and non-neuronopathic (MPS VI) patient groups. Because of symptomatic increased intracranial pressure (ICP), a VPS was placed in six patients, with craniosynostosis as a likely or certain causative factor for the increased pressure in four patients. One patient underwent cranial vault expansion because of severe craniosynostosis. CONCLUSIONS: Craniosynostosis occurs in the majority of MPS patients. Since the clinical consequences can be severe and surgical intervention is possible, skull growth and signs and symptoms of increased ICP should be monitored in both neuronopathic and non-neuronopathic patients with MPS.

Cardiac outcome in classic infantile Pompe disease after 13 years of treatment with recombinant human acid alpha-glucosidase.

BACKGROUND: Cardiac failure is the main cause of death in untreated classic infantile Pompe disease, an inheritable metabolic myopathy characterized by progressive hypertrophic cardiomyopathy. Since the introduction of enzyme replacement therapy (ERT), survival has increased significantly due to reduced cardiac hypertrophy and improved cardiac function. However, little is known about ERT's long-term effects on the heart. METHODS: Fourteen patients were included in this prospective study. Cardiac dimensions, function, conduction and rhythm disturbances were evaluated at baseline and at regular intervals thereafter. RESULTS: Treatment duration ranged from 1.1 to 13.9 years (median 4.8 years). At baseline, all patients had increased left ventricular mass index (LVMI) (median LVMI 226 g/m2, range 98 to 599 g/m2, Z-score median 7, range 2.4-12.4). During the first four weeks, LVMI continued to increase in six patients. Normalization of LVMI was observed in 13 patients (median 30 weeks; range 3 to 660 weeks). After clinical deterioration, LVMI increased again slightly in one patient. At baseline, PR interval was shortened in all patients; it normalized in only three. A delta-wave pattern on ECG was seen in six patients and resulted in documented periods of supraventricular tachycardias (SVTs) in three patients, two of whom required medication and/or ablation. One patient had severe bradycardia (35 beats/min). CONCLUSION: This study shows that ERT significantly reduced LVMI, and sustained this effect over a period of 13.9 years. The risk for rhythm disturbances remains. Regular cardiac evaluations should be continued, also after initially good response to ERT.

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain.

AIM: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. METHOD: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. RESULTS: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. INTERPRETATION: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. WHAT THIS PAPER ADDS: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities.

High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy.

OBJECTIVE: To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha-glucosidase (rhGAA) in patients with classic infantile Pompe disease. STUDY DESIGN: Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme-linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator-free) survival, reduction in left ventricular mass index, and improvement of motor function. RESULTS: Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. CONCLUSIONS: Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.

Long-term cognitive follow-up in children treated for Maroteaux-Lamy syndrome.

BACKGROUND: It remains unclear to what extent the brain is affected by Maroteaux-Lamy syndrome (MPS VI), a progressive lysosomal storage disorder. While enzyme replacement therapy (ERT) elicits positive effects, the drug cannot cross the blood-brain barrier. We therefore studied cognitive development and brain abnormalities in the Dutch MPS VI patient population treated with ERT. METHODS: In a series of 11 children with MPS VI (age 2 to 20 years), we assessed cognitive functioning and brain magnetic resonance imaging prospectively at the start of ERT and at regular times thereafter up to 4.8 years. We also assessed the children's clinical characteristics, their siblings' cognitive development, and their parents' educational levels. RESULTS: The patients' intelligence scores ranged from normal to mentally delayed (range test scores 52-131). In 90%, their scores remained fairly stable during follow-up, generally lying in the same range as their siblings' test scores (median for patients = 104, median for siblings = 88) and comparing well with the parental educational levels. Native-speaking patients had higher intelligence test scores than non-native-speaking patients. Two patients, both with high baseline glycosaminoglycan levels in their urine and severe mutations in the arylsulfatase B gene, scored clearly lower than expected. Patients with pY210C performed best. Brain abnormalities were aspecific, occurring more in patients with severe symptoms. CONCLUSION: Our study shows that cognitive development in MPS VI patients is determined not only by familial and social-background factors, but, in patients with a severe form of the disease, also by the disease itself. Therefore in patients with severe disease presentation cognition should be monitored carefully.

Pain: a prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey.

BACKGROUND: While clinical observations suggest that many patients with mucopolysaccharidosis (MPS) experience chronic pain, few studies have assessed its extent and impact. We therefore investigated its prevalence in patients with all types of MPS in the Netherlands. We also examined the association between pain and health related quality of life (HRQoL) and other clinical variables. METHODS: We conducted a nationwide MPS survey that used questionnaires on MPS and disease-related symptoms (MPS-specific questionnaire), developmental level (Vineland Screener 0-6 years), quality of life (PedsQl and SF-36), and disability (Childhood Health Assessment Questionnaire). Depending on their age and developmental level, patients or their parents were asked to assess pain by keeping a pain diary for five consecutive days: either the Non-communicating Children's Pain Checklist - Revised (3-18 years intellectually disabled and children <8 years), the VAS-score (> 18 years), or the Faces Pain Scale - Revised (8-18 years). RESULTS: Eighty-nine MPS patients were invited, 55 of whom agreed to participate (response rate 62 %; median age 10.9 years, range 2.9-47.2 years). They covered a wide spectrum in all age groups, ranging from no pain to severe pain. Forty percent scored above the cut-off value for pain. Most reported pain sites were the back and hips. While the MPS III group experienced the highest frequency of pain (52.9 %), 50 % of patients with an intellectual disability seemed to experience pain, versus 30 % of patients with a normal intelligence. MPS patients scored much lower (i.e., more pain) than a random sample of the Dutch population on the bodily pain domain of the SF-36 scale and the PedsQl. CONCLUSION: With or without intellectual disabilities, many MPS patients experience pain. We recommend that standardized pain assessments are included in the regular follow-up program of patients with MPS.