Children with Pompe disease: clinical characteristics, peculiar features and effects of enzyme replacement therapy

Pompe disease is a metabolic myopathy. Since the first description of the disease in 1932 by J.C. Pompe,1 tremendous progress has been made from discovering the biochemical and genetic basis of the disease to developing enzyme replacement therapy (ERT). With this therapy, the management of Pompe disease has moved from supportive care alone, to a disease-specific intervention aimed at correcting the underlying enzymatic defect. While in the past research mainly concentrated on elucidating the biochemical pathways and pathophysiology of Pompe disease, nowadays focus has shifted towards documenting the natural history of the disease and studying the effect of the new treatment. A structured follow-up of a large number of patients is difficult in a rare disorder like Pompe disease. The establishment of an expert center for Pompe disease at the Erasmus MC University Medical Center has helped us to systematically study all Pompe patients living in the Netherlands. At present, we follow 149 patients, of which 18 patients are diagnosed with classic-infantile Pompe disease; and 20 children and 111 adults with less progressive forms of the disease. The studies in this thesis have focused on children with Pompe disease. Our aim was to delineate the first presentation and clinical characteristics of the disease and to study the long-term effects of enzyme replacement therapy with recombinant human alpha-glucosidase

Analisis Pentingnya Penilaian Prestasi Kerja dalam Hubungannya dengan Peningkatan Motivasi Karyawan

Performance appraisal is one of many aspects that are very important in Human resource management. On the other hand, motivation is also vital for a Manager because it drives and directs all human behavior, including an employees performance. This short essay tries to analyze the relationship Between performance appraisal and motivation, and how performance appraisal system can enhance motivation of employees. The motivation itself is seen in the light of content and Process theorie

Critical Roles for Anterior Insula and Dorsal Striatum in Punishment-Based Avoidance Learning

SummaryThe division of human learning systems into reward and punishment opponent modules is still a debated issue. While the implication of ventral prefrontostriatal circuits in reward-based learning is well established, the neural underpinnings of punishment-based learning remain unclear. To elucidate the causal implication of brain regions that were related to punishment learning in a previous functional neuroimaging study, we tested the effects of brain damage on behavioral performance, using the same task contrasting monetary gains and losses. Cortical and subcortical candidate regions, the anterior insula and dorsal striatum, were assessed in patients presenting brain tumor and Huntington disease, respectively. Both groups exhibited selective impairment of punishment-based learning. Computational modeling suggested complementary roles for these structures: the anterior insula might be involved in learning the negative value of loss-predicting cues, whereas the dorsal striatum might be involved in choosing between those cues so as to avoid the worst

QTLs and candidate genes for desiccation and abscisic acid content in maize kernels

<p>Abstract</p> <p>Background</p> <p>Kernel moisture at harvest is an important trait since a low value is required to prevent unexpected early germination and ensure seed preservation. It is also well known that early germination occurs in viviparous mutants, which are impaired in abscisic acid (ABA) biosynthesis. To provide some insight into the genetic determinism of kernel desiccation in maize, quantitative trait loci (QTLs) were detected for traits related to kernel moisture and ABA content in both embryo and endosperm during kernel desiccation. In parallel, the expression and mapping of genes involved in kernel desiccation and ABA biosynthesis, were examined to detect candidate genes.</p> <p>Results</p> <p>The use of an intermated recombinant inbred line population allowed for precise QTL mapping. For 29 traits examined in an unreplicated time course trial of days after pollination, a total of 78 QTLs were detected, 43 being related to kernel desiccation, 15 to kernel weight and 20 to ABA content. Multi QTL models explained 35 to 50% of the phenotypic variation for traits related to water status, indicating a large genetic control amenable to breeding. Ten of the 20 loci controlling ABA content colocated with previously detected QTLs controlling water status and ABA content in water stressed leaves. Mapping of candidate genes associated with kernel desiccation and ABA biosynthesis revealed several colocations between genes with putative functions and QTLs. Parallel investigation via RT-PCR experiments showed that the expression patterns of the ABA-responsive <it>Rab17 </it>and <it>Rab28 </it>genes as well as the late embryogenesis abundant <it>Emb5 </it>and aquaporin genes were related to desiccation rate and parental allele effect. Database searches led to the identification and mapping of two <it>zeaxanthin epoxidase </it>(<it>ZEP</it>) and five novel <it>9-cis-epoxycarotenoid dioxygenase </it>(<it>NCED</it>) related genes, both gene families being involved in ABA biosynthesis. The expression of these genes appeared independent in the embryo and endosperm and not correlated with ABA content in either tissue.</p> <p>Conclusions</p> <p>A high resolution QTL map for kernel desiccation and ABA content in embryo and endosperm showed several precise colocations between desiccation and ABA traits. Five new members of the maize <it>NCED </it>gene family and another maize <it>ZEP </it>gene were identified and mapped. Among all the identified candidates, aquaporins and members of the <it>Responsive to ABA </it>gene family appeared better candidates than <it>NCEDs </it>and <it>ZEPs</it>.</p

Cardiac outcome in classic infantile Pompe disease after 13\xe2\x80\xafyears 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\xe2\x80\x9312.4). 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

Hearing loss in Pompe disease revisited: results from a study of 24 children

Little information is available regarding the auditory function in Pompe patients. Hearing loss has been reported in classic infantile patients, but it is still unknown whether central nervous system involvement interferes with auditory function and whether enzyme replacement therapy can improve hearing. Audi

PAS-positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease

Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters

The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients

Pompe disease is a lysosomal storage disorder characterized by progressive muscle weakness. With the emergence of new treatment options, psychometrically robust outcome measures are needed to monitor patients’ clinical status. We constructed a motor function test that is easy and quick to use. The Quick Motor Function Test (QMFT) was constructed on the basis of the clinical expertise of several physicians involved in the care of Pompe patients; the Gross Motor Function Measure and the IPA/Erasmus MC Pompe survey. The test comprises 16 items. Validity and test reliability were determined in a cohort of 91 Pompe patients (5 to 76 years of age). In addition, responsiveness of the scale to changes in clinical condition over time was examined in a subgroup of 18 patients receiving treatment and 23 untreated patients. Interrater and intrarater reliabilities were good (intraclass correlation coefficients: 0.78 to 0.98 and 0.76 to 0.98). The test correlated strongly with proximal muscle strength assessed by hand held dynamometry and manual muscle testing (rs= 0.81, rs=0.89), and showed significant differences between patient groups with different disease severities. A clinical-empirical exploration to assess responsiveness showed promising results, albeit it should be repeated in a larger group of patients. In conclusion, the Quick Motor Function Test can reliably rate clinical severity and motor function in children and adults with Pompe disease