Long-Term Outcome of Infantile Onset Pompe Disease Patients Treated with Enzyme Replacement Therapy - Data from a German-Austrian Cohort

BACKGROUND Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) was approved in Europe in 2006. Nevertheless, data on the long-term outcome of infantile onset Pompe disease (IOPD) patients at school age is still limited. OBJECTIVE We analyzed in detail cardiac, respiratory, motor, and cognitive function of 15 German-speaking patients aged 7 and older who started ERT at a median age of 5 months. RESULTS Starting dose was 20 mg/kg biweekly in 12 patients, 20 mg/kg weekly in 2, and 40 mg/kg weekly in one patient. CRIM-status was positive in 13 patients (86.7%) and negative or unknown in one patient each (6.7%). Three patients (20%) received immunomodulation. Median age at last assessment was 9.1 (7.0-19.5) years. At last follow-up 1 patient (6.7%) had mild cardiac hypertrophy, 6 (42.9%) had cardiac arrhythmias, and 7 (46.7%) required assisted ventilation. Seven patients (46.7%) achieved the ability to walk independently and 5 (33.3%) were still ambulatory at last follow-up. Six patients (40%) were able to sit without support, while the remaining 4 (26.7%) were tetraplegic. Eleven patients underwent cognitive testing (Culture Fair Intelligence Test), while 4 were unable to meet the requirements for cognitive testing. Intelligence quotients (IQs) ranged from normal (IQ 117, 102, 96, 94) in 4 patients (36.4%) to mild developmental delay (IQ 81) in one patient (9.1%) to intellectual disability (IQ 69, 63, 61, 3x <55) in 6 patients (54.5%). White matter abnormalities were present in 10 out of 12 cerebral MRIs from 7 patients. CONCLUSION Substantial motor, cardiac, respiratory, and cognitive deficits are frequent in IOPD long-term survivors who started ERT before 2016. The findings of this study can be valuable as comparative data when evaluating the impact of newer treatment strategies including higher enzyme dosage, immunomodulation, modified enzymes, or early start of treatment following newborn screening

P1–058: The Hsp90 co‐chaperone FKBP51 produces neurotoxic tau oligomers: Implication for aging and Alzheimer’s disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152589/1/alzjjalz201305279.pd

Crossover Scaling in Dendritic Evolution at Low Undercooling

We examine scaling in two-dimensional simulations of dendritic growth at low undercooling, as well as in three-dimensional pivalic acid dendrites grown on NASA's USMP-4 Isothermal Dendritic Growth Experiment. We report new results on self-similar evolution in both the experiments and simulations. We find that the time dependent scaling of our low undercooling simulations displays a cross-over scaling from a regime different than that characterizing Laplacian growth to steady-state growth

Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils

Formation of large protein fibrils with a characteristic cross β-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative amyloid diseases. Recent experiments have strongly implicated oligomeric intermediates, transiently formed during fibril assembly, as critical contributors to cellular toxicity in amyloid diseases. At the same time, amyloid fibril assembly can proceed along different assembly pathways that might or might not involve such oligomeric intermediates. Elucidating the mechanisms that determine whether fibril formation proceeds along non-oligomeric or oligomeric pathways, therefore, is important not just for understanding amyloid fibril assembly at the molecular level but also for developing new targets for intervening with fibril formation. We have investigated fibril formation by hen egg white lysozyme, an enzyme for which human variants underlie non-neuropathic amyloidosis. Using a combination of static and dynamic light scattering, atomic force microscopy and circular dichroism, we find that amyloidogenic lysozyme monomers switch between three different assembly pathways: from monomeric to oligomeric fibril assembly and, eventually, disordered precipitation as the ionic strength of the solution increases. Fibril assembly only occurred under conditions of net repulsion among the amyloidogenic monomers while net attraction caused precipitation. The transition from monomeric to oligomeric fibril assembly, in turn, occurred as salt-mediated charge screening reduced repulsion among individual charged residues on the same monomer. We suggest a model of amyloid fibril formation in which repulsive charge interactions are a prerequisite for ordered fibril assembly. Furthermore, the spatial extent of non-specific charge screening selects between monomeric and oligomeric assembly pathways by affecting which subset of denatured states can form suitable intermolecular bonds and by altering the energetic and entropic requirements for the initial intermediates emerging along the monomeric vs. oligomeric assembly path

Systems and methods for determining nanoparticle dimensions

In one embodiment, the dimensions of nanoparticles are determined by focusing light on a sample of nanoparticles suspended in a solution, collecting light scattered by the nanoparticles, measuring translational and rotational decay rates of the collected light, calculating a ratio of the rotational decay rate to translational decay rate, and estimating a first dimension of the nanoparticles based upon the decay rate ratio

Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils

Amyloid Diseases involve the growth of disease specific proteins into amyloid fibrils and their deposition in protein plaques. Amyloid fibril formation is typically preceded by oligomeric intermediates. Despite significant efforts, the specific role fibrils or oligomers play in the etiology of any given amyloid disease remains controversial. In neurodegenerative disease, though, amyloid oligomers are widely considered critical contributors to disease symptoms. Aside from oligomers as inevitable on-pathway precursors of fibril formation, there is significant evidence for off-pathway oligomer formation competing with fibril growth. The distinct mechanisms and pathways of oligomer formation directly affect our understanding under which conditions oligomers emerge in vivo, and whether their formation is directly coupled to, or distinct from, amyloid fibril formation. In this review, we will discuss the basic energy landscapes underlying the formation of on-pathway vs. off-pathway oligomers, their relation to the related amyloid aggregation kinetics, and their resulting implications for disease etiology. We will review evidence on how differences in the local environment of amyloid assembly can dramatically shift the relative preponderance of oligomers vs. fibrils. Finally, we will comment on gaps in our knowledge of oligomer assembly, of their structure, and on how to assess their relevance to disease etiology