Browsing by Author "Smith, Edward C"
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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 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 Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.(Genetics in medicine : official journal of the American College of Medical Genetics, 2018-04) Pena, Loren DM; Jiang, Yong-Hui; Schoch, Kelly; Spillmann, Rebecca C; Walley, Nicole; Stong, Nicholas; Rapisardo Horn, Sarah; Sullivan, Jennifer A; McConkie-Rosell, Allyn; Kansagra, Sujay; Smith, Edward C; El-Dairi, Mays; Bellet, Jane; Keels, Martha Ann; Jasien, Joan; Kranz, Peter G; Noel, Richard; Nagaraj, Shashi K; Lark, Robert K; Wechsler, Daniel SG; Del Gaudio, Daniela; Leung, Marco L; Hendon, Laura G; Parker, Collette C; Jones, Kelly L; Undiagnosed Diseases Network Members; Goldstein, David B; Shashi, VandanaPurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.