t.p.19
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available for disease treatment. It is effective in most infantile patients,
whereas the improvement is quite variable in adults. We analyzed
muscle biopsies from 14 late-onset patients at molecular, biochemical,
and histopathological level before and after ERT. We evaluated the
following morphological parameters: CSA, number of vacuolated fibers,
degree of glycogen accumulation, percentage of vacuolization in type I
and II fibers. Pre-treatment muscle biopsies showed marked
histopathological variability ranging from almost normal morphology to
severe vacuolar myopathy. Post-treatment muscle biopsies
morphologically improved in seven patients, worsened in two patients
and were unchanged in all the other subjects. Immunohistochemical
analysis of the autophagic/lysosomal markers EEA1 (early endosome
antigen 1), LC3 (microtubule-associated protein 1 light chain 3), and
LAMP2 (lysosome associated membrane protein 2) showed a variable
binding in both the first and the second biopsies. GAA enzymatic
activity, tested by a fluorimetric assay in both lymphocytes and muscle
tissue from 5 patients after ERT, was mildly increased in skeletal muscle
compared with pre-treatment levels. Also, GAA expression assessed by
immunoblotting slightly increased in a few patients. All patients
clinically improved or remained stable after ERT.
http://dx.doi:10.1016/j.nmd.2014.06.254
T.P.19
Effects of antibody formation during enzyme replacement therapy in 73 adult
patients with Pompe disease
J.M. de Vries, E. Kuperus, M. Hoogeveen-Westerveld, S.C.A. Wens,
M.A. Kroos, M.E. Kruijshaar, P.A. van Doorn, A.T. van der Ploeg,
W.W.M. Pijnappel
Center for Lysosomal and Metabolic Diseases, Erasmus MC University
Medical Center, Rotterdam, The Netherlands
High sustained antibody titers against enzyme replacement therapy
(ERT) with alglucosidase alfa adversely affect clinical outcome in
classic-infantile Pompe disease. The long-term effects of antibody
formation on therapeutic efficacy in non-classic Pompe disease are yet
unknown. We studied whether the presence of anti-alglucosidase alfa
antibodies has an impact on treatment outcome and occurrence of
infusion-associated reactions (IARs) in a large cohort of adult patients.
This prospective single-centre cohort study included 73 adult patients
who were treated with 20 mg/kg alglucosidase alfa every other week and
started to receive ERT at least 3 years ago. Antibody titers were
measured at approximately 6, 12 and 36 months of ERT using ELISA
and their effects on enzyme activity were measured in the medium and
in cultured fibroblasts in vitro. Clinical parameters included muscle
strength (MRC sumscore), pulmonary function (FVC in upright and
supine positions), and IARs. 71 of the 73 (97%) patients developed
antibodies against alglucosidase alfa. The mean titer peaked at 6 months
to 1:1259 and thereafter declined to 1:270 at 36 months of treatment.
Individual titers and titer courses varied, but in the majority (93%) of
patients titers decreased or stabilized with continued ERT. Patients with
high peak titers showed moderate to high levels of in vitro enzyme
inhibition. An increased risk for IARs was found in patients with higher
antibody peak titers as 7 (44%) of 16 patients with high titers
(P1:31,250) experienced IARs, 5 (19%) of 27 patients with intermediate
titers (1:1250 to <1:31,250), and only 1 (3%) of 30 patients with a low
or no titer (0 to <1250) (p = 0.001). No relation was found with
antibody titer and poorer clinical outcome for MRC sumscore and FVC
in upright and supine positions after a 36 months treatment period.
Antibody formation to alglucosidase alfa in non-classic Pompe patients
increases the risk for infusion-associated reactions, but is not associated
with unfavorable clinical outcome during 3 years of treatment.
http://dx.doi:10.1016/j.nmd.2014.06.255
T.P.20
Effect of enzyme replacement therapy in late onset Pompe disease: Open
pilot study of 60 weeks follow up
J.S. Park 1, Y.E. Park 2, Y.C. Choi 3, J.H. Shin 4, J.M. Lee 4, D.S. Kim 4
1 Kyungpook National University School of Medicine, Daegu, Republic
of Korea; 2 Pusan National Univerisity Hospital, Pusan, Republic of
Korea; 3 College of Medicine, Yonsei University, Seoul, Republic of
Korea; 4 Pusan National Univerisity Yangsan Hospital, Yangsan,
Republic of Korea
Late-onset Pompe disease (LOPD) is an autosomal recessive disorder
caused by deficiency of the enzyme acid glucosidase alfa (GAA),
Recently, enzyme replacement therapy (ERT) using recombinant human
GAA (rhGAA) became clinically available, and is expected to modify
clinical course of LOPD. In this study, we have evaluated the efficacy
and adverse events of ERT for 60 weeks in Korean LOPD patients.
Five Korean LOPD patients were included in the study. At baseline,
clinical and laboratory features including motor and pulmonary
function was assessed, and rhGAA was infused every two weeks. Then,
patients were examined at every 12 weeks interval to evaluate their
changes in motor and pulmonary function for 48 weeks along with
adverse reactions of ERT. The motor and pulmonary function of the
patients demonstrated mild improvement or stabilization after 60 weeks
of ERT. And none of them showed deterioration in their ambulatory or
respiratory status. One of our patients developed a serious anaphylactic
reaction which necessitated the cessation of further ERT. This is the
first report of clinical study on the ERT of Korean LOPD patients. Our
study showed ERT for 48 weeks produced only mild improvement or
stabilization of motor and pulmonary function in LOPD patients,
suggesting that advanced pathological change is responsible for the
limited efficacy of ERT.
http://dx.doi:10.1016/j.nmd.2014.06.256
T.P.21
Assessing immunogenicity of rhGAA in adult Pompe disease subjects
E. Masat 1, P. Laforet 2, D. Amelin 1, P. Veron 3, K. Laloui 4,
O. Benveniste 5, F. Mingozzi 6
1 University Pierre and Marie Curie, Paris, France; 2 AP-HP,
Pitie-Salpetriere University Hospital, Paris-Est Neuromuscular Center,
Paris, France; 3 Genethon, Evry, France; 4 AP-HP, Pitie-Salpetriere
University Hospital, Institute of Myology, Paris, France; 5 AP-HP,
Pitie-Salpetriere University Hospital, Department of Internal Medicine 1,
Paris, France; 6 University Pierre and Marie Curie, Genethon, Paris, France
Pompe disease (PD) is an inherited metabolic myopathy caused by a
deficiency of the lysosomal enzyme acid a-glucosidase (GAA). Enzyme
replacement therapy (ERT) has improved the outcome of PD,
unfortunately the immune responses against GAA are not uncommon
and in some cases prevent therapeutic efficacy. The aim of this study
was to investigate the mechanisms of the immune responses against
recombinant human GAA (rhGAA) in adult patients undergoing ERT.
About one-third of all subjects screened (n = 35) showed significant
levels of anti-rhGAA binding antibodies, mainly IgG4. After dendritic
cell maturation in the presence of rhGAA a positive IFN-gamma
ELISpot signal was detectable in some of the subject’s peripheral blood
870 Abstracts / Neuromuscular Disorders 24 (2014) 791–924