Browsing by Subject "Enzyme Replacement Therapy"
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Item Open Access Adjunctive albuterol enhances the response to enzyme replacement therapy in late-onset Pompe disease.(FASEB J, 2014-05) Koeberl, Dwight D; Austin, Stephanie; Case, Laura E; Smith, Edward C; Buckley, Anne F; Young, Sarah P; Bali, Deeksha; Kishnani, Priya SEffective dosages for enzyme replacement therapy (ERT) in Pompe disease are much higher than for other lysosomal storage disorders, which has been attributed to low cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle. We have previously demonstrated the benefit of increased CI-MPR-mediated uptake of recombinant human acid-α-glucosidase during ERT in mice with Pompe disease following addition of albuterol therapy. Currently we have completed a pilot study of albuterol in patients with late-onset Pompe disease already on ERT for >2 yr, who were not improving further. The 6-min walk test (6MWT) distance increased in all 7 subjects at wk 6 (30±13 m; P=0.002), wk 12 (34±14 m; P=0.004), and wk 24 (42±37 m; P=0.02), in comparison with baseline. Grip strength was improved significantly for both hands at wk 12. Furthermore, individual subjects reported benefits; e.g., a female patient could stand up from sitting on the floor much more easily (time for supine to standing position decreased from 30 to 11 s), and a male patient could readily swing his legs out of his van seat (hip abduction increased from 1 to 2+ on manual muscle testing). Finally, analysis of the quadriceps biopsies suggested increased CI-MPR at wk 12 (P=0.08), compared with baseline. With the exception of 1 patient who succumbed to respiratory complications of Pompe disease in the first week, only mild adverse events have been reported, including tremor, transient difficulty falling asleep, and mild urinary retention (requiring early morning voiding). Therefore, this pilot study revealed initial safety and efficacy in an open label study of adjunctive albuterol therapy in patients with late-onset Pompe disease who had been stable on ERT with no improvements noted over the previous several years.Item Open Access Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III.(Mol Genet Metab, 2013-02) Sun, Baodong; Fredrickson, Keri; Austin, Stephanie; Tolun, Adviye A; Thurberg, Beth L; Kraus, William E; Bali, Deeksha; Chen, Yuan-Tsong; Kishnani, Priya SWe investigated the feasibility of using recombinant human acid-α glucosidase (rhGAA, Alglucosidase alfa), an FDA approved therapy for Pompe disease, as a treatment approach for glycogen storage disease type III (GSD III). An in vitro disease model was established by isolating primary myoblasts from skeletal muscle biopsies of patients with GSD IIIa. We demonstrated that rhGAA significantly reduced glycogen levels in the two GSD IIIa patients' muscle cells (by 17% and 48%, respectively) suggesting that rhGAA could be a novel therapy for GSD III. This conclusion needs to be confirmed in other in vivo models.Item Open Access Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.(PLoS One, 2013) Banugaria, Suhrad G; Prater, Sean N; Patel, Trusha T; Dearmey, Stephanie M; Milleson, Christie; Sheets, Kathryn B; Bali, Deeksha S; Rehder, Catherine W; Raiman, Julian AJ; Wang, Raymond A; Labarthe, Francois; Charrow, Joel; Harmatz, Paul; Chakraborty, Pranesh; Rosenberg, Amy S; Kishnani, Priya SOBJECTIVE: Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy. METHODS: We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy. RESULTS: Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients. CONCLUSIONS: The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.Item Open Access Early cognitive development in children with infantile Pompe disease.(Molecular genetics and metabolism, 2012-03) Spiridigliozzi, Gail A; Heller, James H; Case, Laura E; Jones, Harrison N; Kishnani, Priya SThis report describes the cognitive development of 17 children with infantile Pompe disease who participated in a 52-week clinical trial of enzyme replacement therapy (ERT) via biweekly infusion of Myozyme® (alglucosidase alfa). Subjects were six months of age or younger (adjusted for gestational age) upon initiation of ERT. The Mental Scale of the Bayley Scales of Infant Development-Second Edition (BSID-II) was administered to obtain a Mental Development Index (MDI) at baseline and weeks 12, 26, 38, and 52 of ERT to assess cognitive development in this treated cohort. Data regarding motor development were also obtained at the same visits and these were used to determine correlations between cognitive and motor development. Over the course of the study, two subgroups of subjects emerged: high responders who were sitting independently and/or ambulating by week 52 (n=13) and limited responders who showed minimal motor gains throughout the first year of ERT (n=4). In the high responder group, MDI scores on the BSID-II remained stable throughout the study and were within normal limits. Positive correlations between cognitive and motor development were also present. These data suggest that the cognitive function of infants up to 18 months of age with Pompe disease is unaffected by the possible presence of glycogen in the central nervous system. Continued investigation of the cognitive development of older survivors is warranted.Item Open Access Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.(Mol Genet Metab, 2011-06) Koeberl, Dwight D; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li, Songtao; Banugaria, Suhrad G; Chen, Y-T; Bali, Deeksha SEnzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA.Item Open Access Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with Pompe disease.(Molecular genetics and metabolism, 2020-02) Han, Sang-Oh; Haynes, Alexina C; Li, Songtao; Abraham, Dennis M; Kishnani, Priya S; Steet, Richard; Koeberl, Dwight DPompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA) leading to progressive myopathy. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA has limitations, including inefficient uptake of rhGAA in skeletal muscle linked to low cation-independent mannose-6-phosphate receptor (CI-MPR) expression.Purpose
To test the hypothesis that antihypertensive agents causing muscle hypertrophy by increasing insulin-like growth factor 1 expression can increase CI-MPR-mediated uptake of recombinant enzyme with therapeutic effects in skeletal muscle.Methods
Three such agents were evaluated in mice with Pompe disease (carvedilol, losartan, and propranolol), either with or without concurrent ERT.Results
Carvedilol, a selective β-blocker, increased muscle strength but reduced biochemical correction from ERT. Administration of drugs alone had minimal effect, with the exception of losartan that increased glycogen storage and mortality either by itself or in combination with ERT.Conclusion
The β-blocker carvedilol had beneficial effects during ERT in mice with Pompe disease, in comparison with propranolol or losartan. Caution is warranted when prescribing antihypertensive drugs in Pompe disease.Item Open Access Glucosylsphingosine (Lyso-Gb1): An Informative Biomarker in the Clinical Monitoring of Patients with Gaucher Disease.(International journal of molecular sciences, 2022-11) Gayed, Matthew M; Jung, Seung-Hye; Huggins, Erin; Rodriguez-Rassi, Eleanor; DeArmey, Stephanie; Kishnani, Priya Sunil; Stiles, Ashlee RHistorically, disease burden and treatment responses in patients with Gaucher disease (GD) was assessed by monitoring clinical data, laboratory, imaging, chitotriosidase (CHITO), and other biomarkers; however, these biomarkers lack specificity and CHITO is uninformative in patients heterozygous or homozygous for the CHIT1 c.1049_1072dup24 variant. Recently, glucosylsphingosine (lyso-Gb1), a sensitive and specific GD biomarker, has been recommended for patient monitoring. Furthermore, studies measuring lyso-Gb1 and CHITO in patients on long-term treatment with enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT) reported as group data show a reduction in both analytes, yet individualized patient data are generally unavailable. We describe seven patients on long-term treatment with longitudinal clinical data with monitoring based on current treatment guidelines. We present four patients who exhibit stable disease with normalized CHITO despite elevated lyso-Gb1. We present one patient who transitioned from ERT to SRT due to lack of a clinical response with life-threatening thrombocytopenia who responded with marked improvement in platelets, and normalized levels of both CHITO and lyso-Gb1. Finally, we present two ERT to SRT switch patients with stable disease on ERT who exhibited non-compliance on SRT, one with mirrored marked elevations of CHITO and lyso-Gb1; and another with normal CHITO and platelets, but increasing lyso-Gb1 levels and enlarged spleen. These clinical vignettes highlight the role of lyso-Gb1 as a sensitive biomarker in management of patients with GD, and its further value when CHITO is normal and thus uninformative. We highlight the personalized medicine approach needed to optimize treatment outcomes and recommendations for these patients.Item Open Access Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.(Genetics in medicine : official journal of the American College of Medical Genetics, 2020-05) Khan, Aleena A; Case, Laura E; Herbert, Mrudu; DeArmey, Stephanie; Jones, Harrison; Crisp, Kelly; Zimmerman, Kanecia; ElMallah, Mai K; Young, Sarah P; Kishnani, Priya SPurpose
Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease.Methods
We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated.Results
Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses.Conclusion
Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.Item Open Access Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.(Hum Gene Ther, 2012-05) Zhang, P; Sun, B; Osada, T; Rodriguiz, R; Yang, XY; Luo, X; Kemper, AR; Clay, TM; Koeberl, DDPompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses.Item Open Access Improved muscle function in a phase I/II clinical trial of albuterol in Pompe disease.(Molecular genetics and metabolism, 2020-02) Koeberl, Dwight D; Case, Laura E; Desai, Ankit; Smith, Edward C; Walters, Crista; Han, Sang-Oh; Thurberg, Beth L; Young, Sarah P; Bali, Deeksha; Kishnani, Priya SThis 24-week, Phase I/II, double-blind, randomized, placebo-controlled study investigated the safety and efficacy of extended-release albuterol in late-onset Pompe disease stably treated with enzyme replacement therapy at the standard dose for 4.9 (1.0-9.4) years and with no contraindications to intake of albuterol. Twelve of 13 participants completed the study. No serious adverse events were related to albuterol, and transient minor drug-related adverse events included muscle spasms and tremors. For the albuterol group, forced vital capacity in the supine position increased by 10% (p < .005), and forced expiratory volume in one second increased by 8% (p < .05); the six-minute walk test increased 25 m (p < .05; excluding one participant unable to complete muscle function testing); the Gross Motor Function Measure increased by 8% (p < .005) with the greatest increases in the Standing (18%; p < .05) and Walking, Running, and Jumping (11%; p < .005) subtests. No significant improvements would be expected in patients with late-onset Pompe disease who were stably treated with enzyme replacement therapy. The placebo group demonstrated no significant increases in performance on any measure. These data support a potential benefit of extended-release albuterol as adjunctive therapy in carefully selected patients with late-onset Pompe disease based on ability to take albuterol on enzyme replacement therapy (NCT01885936).Item Open Access Oropharyngeal Dysphagia in Infants and Children with Infantile Pompe Disease.(Dysphagia, 2009-09) Jones, HN; Muller, CW; Lin, M; Banugaria, SG; Case, LE; Li, JS; O'Grady, G; Heller, JH; Kishnani, PSPompe disease is a rare genetic progressive neuromuscular disorder. The most severe form, infantile Pompe disease, has historically resulted in early mortality, most commonly due to cardiorespiratory failure. Treatment with enzyme replacement therapy (ERT) using alglucosidase alfa (Myozyme((R))) has extended the lifespan of individuals with this disease. With the introduction of ERT and the resultant improved survival, dysphagia is being encountered clinically with increasing regularity though systematic data remain unavailable. We retrospectively studied the oropharyngeal swallowing of 13 infants and children with Pompe disease using videofluoroscopy before initiation of ERT, allowing for baseline swallow function to be established in an untreated cohort. Dysphagia was present in all 13 subjects, even in a participant only 15 days old. Oral stage signs were present in 77%, most frequently a weak suck in 69%. Pharyngeal stage signs were present in 100%, including a pharyngeal swallow delay in 92% and pharyngeal residue in 77%. Airway invasion was present in 76.9% of subjects, including penetration in five (38.46%) and silent aspiration in an additional five (38.46%). No relationship in the relative involvement of swallowing, gross motor function, and cardiac disease appeared to be present.Item Open Access Salmeterol enhances the cardiac response to gene therapy in Pompe disease.(Mol Genet Metab, 2016-05) Han, Sang-Oh; Li, Songtao; Koeberl, Dwight DEnzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.Item Open Access Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy.(Orphanet J Rare Dis, 2013-06-20) Prater, Sean N; Patel, Trusha T; Buckley, Anne F; Mandel, Hanna; Vlodavski, Eugene; Banugaria, Suhrad G; Feeney, Erin J; Raben, Nina; Kishnani, Priya SBACKGROUND: Pompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD). METHODS: Muscle biopsies from 8 [4 female, 4 male; 6 cross-reactive immunologic material (CRIM)-positive, 2 CRIM-negative] patients with a confirmed diagnosis of classic IPD were examined using standard histopathological approaches. In addition, muscle biopsies were evaluated by immunostaining for lysosomal marker (lysosomal-associated membrane protein-2; LAMP2), autophagosomal marker (microtubule-associated protein 1 light chain 3; LC3), and acid and alkaline ATPases. All patients received rhGAA by infusion at cumulative biweekly doses of 20-40 mg/kg. RESULTS: Median age at diagnosis of classic IPD was 3.4 months (range: 0 to 6.5 months; n = 8). At the time of muscle biopsy, the patients' ages ranged from 1 to 103 months and ERT duration ranged from 0 (i.e., baseline, pre-ERT) to 96 months. The response to therapy varied considerably among the patients: some patients demonstrated motor gains while others experienced deterioration of motor function, either with or without a period of initial clinical benefit. Skeletal muscle pathology included fiber destruction, lysosomal vacuolation, and autophagic abnormalities (i.e., buildup), particularly in fibers with minimal lysosomal enlargement. Overall, the pathology reflected clinical status. CONCLUSIONS: This is the first study to investigate the impact of rhGAA ERT on lysosomal glycogen accumulation and autophagic buildup in patients with classic IPD beyond 18 months of treatment. Our findings indicate that ERT does not fully halt or reverse the underlying skeletal muscle pathology in IPD. The best outcomes were observed in the two patients who began therapy early, namely at 0.5 and 1.1 months of age.Item Open Access The emerging phenotype of late-onset Pompe disease: A systematic literature review.(Molecular genetics and metabolism, 2017-03) Chan, Justin; Desai, Ankit K; Kazi, Zoheb B; Corey, Kaitlyn; Austin, Stephanie; Hobson-Webb, Lisa D; Case, Laura E; Jones, Harrison N; Kishnani, Priya SBackground
Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype.Purpose
To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006.Methods
All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review.Results
We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease.Conclusions
With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.Item Open Access The emerging phenotype of long-term survivors with infantile Pompe disease.(Genetics in medicine : official journal of the American College of Medical Genetics, 2012-09) Prater, Sean N; Banugaria, Suhrad G; DeArmey, Stephanie M; Botha, Eleanor G; Stege, Erin M; Case, Laura E; Jones, Harrison N; Phornphutkul, Chanika; Wang, Raymond Y; Young, Sarah P; Kishnani, Priya SPurpose
Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors.Methods
Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor, and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status.Results
Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4-12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers.Conclusion
Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.