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Léa El Haddad,1 Mainur Khan,1 Rania Soufny,1 David Mummy,2 Bastiaan Driehuys,2 Wissam Mansour,3 Priya S Kishnani,4 Mai K ElMallah1 1Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; 2Department of Radiology, Duke University Medical Center, Durham, NC, USA; 3Division of Pulmonary and Sleep Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA; 4Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USACorrespondence: Mai K ElMallah, Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Duke University Medical Center, Box 2644, Durham, NC, 27710, USA, Tel +1-919-684-3577, Email mai.elmallah@duke.eduAbstract: Pompe disease (PD) is a neuromuscular disorder caused by a deficiency of acid alpha-glucosidase (GAA) – a lysosomal enzyme responsible for hydrolyzing glycogen. GAA deficiency leads to accumulation of glycogen in lysosomes, causing cellular disruption. The severity of PD is directly related to the extent of GAA deficiency – if no or minimal GAA is produced, symptoms are severe and manifest in infancy, known as infantile onset PD (IOPD). If left untreated, infants with IOPD experience muscle hypotonia and cardio-respiratory failure leading to significant morbidity and mortality in the first year of life. In contrast, late-onset PD (LOPD) patients have more GAA activity and present later in life, but also have significant respiratory function decline. Despite FDA-approved enzyme replacement therapy, respiratory insufficiency remains a major cause of morbidity and mortality, emphasizing the importance of early detection and management of respiratory complications. These complications include impaired cough and airway clearance, respiratory muscle weakness, sleep-related breathing issues, and pulmonary infections. This review aims to provide an overview of the respiratory pathology, monitoring, and management of PD patients. In addition, we discuss the impact of novel approaches and therapies on respiratory function in PD.Keywords: Pompe disease, respiratory complications, respiratory monitoring, respiratory therapy

Objective: To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.Study Design: We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function.Result: After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related.Conclusion: rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment. [ABSTRACT FROM AUTHOR]

Purpose: Oxidative stress has been implicated in Down syndrome (DS) pathology. This study compares DS individuals and controls on their urinary levels of allantoin and 2,3-dinor-iPF2α-III; these biomarkers have been previously validated in a clinical model of oxidative stress.Methods: Urine samples were collected from 48 individuals with DS and 130 controls. Biomarkers were assayed by ultraperformance liquid chromatography-tandem mass spectrometry, normalized by urinary creatinine concentration.Results: After adjusting for age and gender, mean allantoin levels were lower among DS individuals versus controls (P = .04). The adjusted mean levels of 2,3-dinor-iPF2α-III were similar in DS individuals and controls (P = .7).Conclusions: Our results do not support the hypothesis that DS individuals have chronic systemic oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients' day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52 weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL., Methods: PROs evaluated included the Subject's Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Rasch-built Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher's exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis)., Results: At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P = 0.0005; and LS mean difference 0.385; P = 0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P = 0.37; and LS mean difference 3.1; P = 0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P = 0.95; and LS mean difference -0.8; P = 0.48). Self-care, usual activities, and depression/anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P = 0.54; and LS mean difference -0.108; P = 0.52)., Conclusions: Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL., Trial Registration: NCT03729362; Registration date: November 1, 2018; https://clinicaltrials.gov/study/NCT03729362., Competing Interests: Declarations Ethics approval and consent to participate PROPEL was approved by the appropriate independent ethics committees and institutional review boards at each study site and was conducted according to international guidelines for clinical studies, such as the Declaration of Helsinki and Good Clinical Practice Guidelines. All participants provided written informed consent before participating in the study. Consent for publication Not applicable. Competing interests KGC received research funding from Alnylam, Biogen, Pfizer, Roche, Sanofi Genzyme; advisory board member honoraria from Alexion, Alnylam, Amicus Therapeutics, Inc., argenx, Biogen, Ipsen, Janssen Pharmaceutics, Lupin, Pfizer, Roche, Sanofi Genzyme and UCB; and is Chairholder of the Emil von Behring Chair for Neuromuscular and Neurodegenerative Disorders by CSL Behring. BJB reports consultant/advisory board membership for Pfizer, Amicus Therapeutics, Inc., and Sanofi; and owns stocks in Lacerta Therapeutics. JD-M reports consulting fees/honoraria from Sarepta, Sanofi, Audentes; has received grant support from Sanofi, Spark and Boehringer Ingelheim; and payment for speaking from Sanofi, Sarepta and Lupin. MMD serves or recently served as a consultant for Abata/Third Rock, Abcuro, Amicus Therapeutics, Inc., argenx, Astellas, Cabaletta Bio, Catalyst, CNSA, Covance/Labcorp, CSL Behring, Dianthus, Horizon, EMD Serono/Merck, Ig Society, Inc, Janssen Pharmaceuticals, Medlink, Octapharma, Priovant, Sanofi Genzyme, Shire Takeda, TACT/Treat NMD, UCB Biopharma, Valenza Bio and Wolters Kluwer Health/UpToDate; and has received research grants or contracts, or educational grants from Alexion/AstraZeneca, Alnylam Pharmaceuticals, Amicus Therapeutics, Inc., argenx, Bristol-Myers Squibb, Catalyst, CSL Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, and UCB Biopharma/RaPharma. PSK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics, Inc., and has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Inc., JCR Pharmaceuticals, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio). She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, Inc., and Advisory Board for Baebies. She has held equity in Asklepios Biopharmaceuticals and may receive milestone payments related to that equity in the future. HK served as a consultant for Alexion AstraZeneca Rare disease, argenx, UCB, Immunovant, Sanofi, and has received research grants or educational grants from Sanofi, MDA, and Healey ALS platform trial. TM has participated in an advisory capacity for Abbvie, Alexion, Amicus Therapeutics, Inc., Annji, argenx, Arvinas, Audentes, Cabaletta, Maze Therapeutics, Momenta, Ra Pharmaceuticals, Sanofi Genzyme, Sarepta, Spark Therapeutics, and UCB. He is a member of the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California and Myasthenia Gravis Foundation of America. He has received research funding from the Myositis Association, the Muscular Dystrophy Association, the NIH and from the following sponsors: Alexion, Amicus Therapeutics, Inc., Annji, argenx, Audentes, Bristol-Myers Squib, Cabaletta, Cartesian Therapeutics, Grifols, Momenta, Ra Pharmaceuticals, Sanofi Genzyme, Spark Therapeutics, UCB, and Valerion. He is a member of the data safety monitoring board for Acceleron, Applied Therapeutics, Sarepta, and the NIH. MR has received honoraria for educational symposia from Sanofi Genzyme and Amicus Therapeutics, Inc., and for participation on advisory boards for Sanofi, and Amicus Therapeutics, Inc. BS has received unrestricted research grants from Amicus Therapeutics, Inc., Astellas, Roche, Marigold Foundation, AMDA Foundation and speaker’s honoraria from Amicus Therapeutics, Inc., Alexion, Kedrion, and Sanofi. He has participated as a scientific adviser for Amicus Therapeutics, Inc., argenx, Astellas, Bayer, Maze, Pepgen, Sanofi, and Spark. He declares no stocks or shares. NH and AK are employees of Certara, which is a paid consultant to Amicus Therapeutics, Inc. FH and SS are employees of and hold stock in Amicus Therapeutics, Inc. AT has received honorarium for educational talks from Sanofi Genzyme and Amicus Therapeutics, Inc. and for participation on advisory boards for Sanofi, Amicus Therapeutics, Inc., Aro and Spark. He is a member of the European Reference Network for Neuromuscular Disorders (EU-NMD)– Project ID 739543., (© 2024. The Author(s).)

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the Phkg2 -/- mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers - the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications., Competing Interests: Declaration of competing interest RG, AA, JL, and PSK have patents pending. PSK has received research/grant support from Kriya Therapeutics. AA is a cofounder and Board Director at TorqueBio and serves as advisor to Atsena Therapeutics, Ring Therapeutics, Ginkgo Bioworks and Mammoth Biosciences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Infantile-onset Pompe disease (IOPD) is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). It is characterized by severe and progressive hypertrophic cardiomyopathy and muscle weakness with death in the first 2 years of life if left untreated. Enzyme replacement therapy (ERT) with alglucosidase-alfa is lifesaving, but its effectiveness is influenced by the patient's cross-reactive immunologic material (CRIM) status, dose of ERT, and the development of high antibody titers, which can reduce the therapy's efficacy. The inability of CRIM-negative IOPD patients to produce native GAA exposes them to a high risk of development of anti-rhGAA IgG antibody titers, leading to treatment failure. We present the case of CRIM-negative dizygotic twins treated with high-dose alglucosidase-alfa (40 mg/kg/week), initiated at 28 days (Twin A) and 44 days (Twin B). Both twins received immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG to mitigate antibody response. Initial evaluations revealed elevated left ventricular mass index (LVMI) and elevated biomarkers (urine glucose tetrasaccharide (Glc 4 ), creatine kinase (CK), and aspartate aminotransferase (AST)) in both twins. Following treatment, cardiac function and biomarkers normalized within several months, with a slight delay in Twin B compared to Twin A, likely attributed to the later initiation of ERT. Both twins safely tolerated ITI, achieving immune tolerance with low antibody titers. At 28 months, the twins transitioned to avalglucosidase-alfa (40 mg/kg every other week (EOW)), which was well tolerated without an increase in antibody titers. At 39 months, both twins exhibited normal cardiac function, LVMI, and biomarkers. Motor skills continued to improve, though some kinematic concerns persisted. These cases underscore the importance of early, high-dose ERT combined with ITI in managing CRIM-negative IOPD. While transitioning to avalglucosidase-alfa at 40 mg/kg/EOW was beneficial and well-tolerated in our patients, further studies are needed to confirm its long-term efficacy compared to the high-dose weekly 40 mg/kg alglucosidase-alfa., Competing Interests: Priya S. Kishnani reports a relationship with Sanofi Genzyme that includes: board membership, consulting or advisory, and funding grants. Priya S. Kishnani reports a relationship with Amicus Therapeutics Inc. Research & Gene Therapy Center of Excellence that includes: board membership, consulting or advisory, and funding grants. Priya S. Kishnani reports a relationship with Maze Therapeutics Inc. that includes: consulting or advisory and equity or stocks. Priya S. Kishnani reports a relationship with Asklepios BioPharmaceutical Inc. that includes: consulting or advisory and equity or stocks. Priya S. Kishnani reports a relationship with Babies that includes: board membership. Ankit K. Desai reports a relationship with Sanofi Genzyme that includes: funding grants. Ankit K. Desai reports a relationship with Lysosomal Storage Network that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Years of research into the structure, processing, and function of acid alpha-glucosidase led to the development and 2006 approval of alglucosidase alfa (recombinant human acid alpha-glucosidase, Myozyme®/Lumizyme®), an enzyme replacement therapy and the first approved treatment for Pompe disease. Alglucosidase alfa has been a lifesaving treatment for patients with infantile-onset Pompe disease and radically improved daily life for patients with late-onset Pompe disease; however, long-term experience with alglucosidase alfa unraveled key unmet needs in these populations. Despite treatment, Pompe disease continues to progress, especially from a skeletal muscle perspective, resulting in a multitude of functional limitations. Strong collaboration between the scientific and patient communities led to increased awareness of Pompe disease, a better understanding of disease pathophysiology, knowledge of the clinical course of the disease as patients surpassed the first decade of life, and the strengths and limitations of enzyme replacement therapy. Taken together, these advancements spurred the need for development of a next generation of enzyme replacement therapy and provided a framework for progress toward other novel treatments. This review provides an overview of the development of avalglucosidase alfa as a model to highlight the interaction between clinical experience with existing treatments, the role of the clinician scientist, translational research at both system and cellular levels, and the iterative and collaborative process that optimizes the development of therapeutics., Competing Interests: Declaration of competing interest, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gaucher disease (GD) type 3 is an autosomal recessive lysosomal disease caused by deficiency of β-glucocerebrosidase (GCase) and encompasses a spectrum of cardiac, neurological, and ophthalmological abnormalities. Although the clinical presentations can be diverse, a recognized clinical trajectory points to an early onset, predominantly before 18 years. GD type 3c is primarily caused by homozygosity for GBA pathogenic variant c.1342G>C (p.Asp448His; historically referred to as D409H) and includes visceral, hematological, skeletal, and cardiac abnormalities. Notably, GD type 3c is distinct from other GD types because it is primarily characterized by valvular heart disease. Yet, with less than 50 patients with GD type 3c reported to date, the phenotypic spectrum and extent of cardiac involvement remains ill-defined. We present a 20-year-old female with an atypical presentation of GD type 3c consisting of chronic intermediate uveitis as the presenting feature and the presence of extensive polyneuropathy starting in adolescence which has been previously unreported in GD type 3c. Distinctively, she has maintained normal cardiac function. Moreover, we compare our case with those reported in the literature to broaden awareness of the varied initial presentations of this disease. The diverse presentations seen in GD type 3c, underscored by our case and those previously reported, demonstrate the need for standardized evaluation and management protocols., Competing Interests: John S. Wang, Rebecca L. Koch, Daniel Kenney‐Jung, Erin Huggins, Sirajbir S. Sodhi, Andrew P. Landstrom, Dilraj S. Grewal, and Priya S. Kishnani declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Priya S. Kishnani has received honoraria and grant support from Sanofi and Takeda Pharmaceuticals., (© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Gaucher disease type 1 (GD1) is known for phenotypic heterogeneity and varied natural history. Registrational clinical trials enrolled narrowly defined phenotypes, but greater diversity is encountered in clinical practice. We report real-world outcomes with long-term eliglustat treatment in adults with GD1 in the International Collaborative Gaucher Group Gaucher Registry. Among 5985 GD1 patients in the Registry as of January 6, 2023, 872 started eliglustat at ≥18 years old; of these, 469 met inclusion criteria. We compared clinical parameters at eliglustat initiation (i.e., baseline) and follow-up in treatment-naïve patients and used linear mixed models to estimate annual change from baseline in parameters among patients who switched to eliglustat after ≥1 year on enzyme replacement therapy. Over 4 years of follow-up in non-splenectomized treatment-naïve patients, hemoglobin and platelet count increased, liver and spleen volume decreased, and total lumbar spine bone mineral density (BMD) Z-score decreased slightly. Among non-splenectomized switch patients, on average, hemoglobin decreased -0.030 (95% CI: -0.053, -0.008) g/dL (N = 272) and platelet count increased 2.229 (95% CI: 0.751, 3.706) × 10 3 /mm 3 (N = 262) annually up to 10 years; liver volume decreased (-0.009 [95% CI: -0.015, -0.003] MN) (N = 102) and spleen volume remained stable (-0.070 [95% CI: -0.150, 0.010] MN) (N = 106) annually up to 7 years; and total lumbar spine BMD Z-score increased 0.041 (95% CI: 0.015, 0.066) (N = 183) annually up to 8 years. Among splenectomized switch patients, clinical parameters were stable over time. These long-term, real-world outcomes are consistent with the eliglustat clinical trials and emerging real-world experience across the GD phenotypic spectrum., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted., Methods: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation., Findings: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (P difference  = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively., Conclusion: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined., Trial Registration: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered., (© 2024. The Author(s).)

Background: Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey., Case Presentation: A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31- related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant., Conclusions: GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31 -related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses., Competing Interests: The authors have no competing interests as defined by MGM, or other interests that might be perceived to influence the results and/or discussion reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Background: Hypophosphatasia (HPP) is an inborn error of metabolism with a variable presentation. We conducted a modified Delphi panel to obtain expert consensus on knowledge gaps regarding disease severity and progression in adult patients with HPP., Methods: Healthcare professionals (HCPs) with experience managing adult patients with HPP were recruited to participate in a 3-round Delphi panel (round 1: paper survey and 1:1 interview; rounds 2-3: email survey). Panelists rated the extent of their agreement with statements about disease severity and progression in adult patients with HPP. Consensus was defined as ≥ 80% agreement., Results: Ten HCPs completed round 1; nine completed rounds 2 and 3. Consensus was reached on 46/120 statements derived from steering committee input. Disease severity markers in adult patients with HPP can be bone-related (recurrent/poorly healing fractures, pseudo-fractures, metatarsal fractures, osteomalacia) or involve dentition or physiologic/functional manifestations (use of mobility devices/home modifications, abnormal gait, pain). Disease progression markers can include recurrent/poorly healing low-trauma fractures, development of ectopic calcifications, and/or impairment of functional activity. Panelists supported the development of a tool to help assess disease severity in the clinic and track changes in severity over time. Panelists also highlighted the role of a multidisciplinary team, centers with expertise, and the need to refer patients when disease severity is not clear., Conclusions: These statements regarding disease severity, progression, and assessment methods address some knowledge gaps in adult patients with HPP and may be helpful for treating HCPs, although the small sample size affects the ability to generalize the healthcare provider experience., (© 2024. The Author(s).)

BackgroundGlycogen storage disease type IV (GSD IV) is an ultrarare autosomal recessive disorder that causes deficiency of functional glycogen branching enzyme and formation of abnormally structured glycogen termed polyglucosan. GSD IV has traditionally been categorized based on primary hepatic or neuromuscular involvement, with hepatic GSD IV subclassified as discrete subtypes: classic (progressive) and nonprogressive.MethodsTo better understand the progression of liver disease in GSD IV, we present clinical and histopathology data from 23 patients from around the world and characterized the liver involvement in the Gbe1ys/ys knockin mouse model.ResultsWe propose an alternative to the established subtype-based terminology for characterizing liver disease in GSD IV and recognize 3 tiers of disease severity: (i) "severe progressive" liver disease, (ii) "intermediate progressive" liver disease, and (iii) "attenuated" liver disease. Analysis of liver pathology revealed that risk for liver failure cannot be predicted from liver biopsy findings alone in individuals affected by GSD IV. Moreover, analysis of postmortem liver pathology from an individual who died over 40 years after being diagnosed with nonprogressive hepatic GSD IV in childhood verified that liver fibrosis did not regress. Last, characterization of the liver involvement in a mouse model known to recapitulate the adult-onset neurodegenerative form of GSD IV (Gbe1ys/ys mouse model) demonstrated hepatic disease.ConclusionOur findings challenge the established subtype-based view of GSD IV and suggest that liver disease severity among patients with GSD IV represents a disease continuum.Trial registrationClinicalTrials.gov NCT02683512FundingNone.

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019., (© 2024. The Author(s).)

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels., Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI., Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea., Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chen, Hsu, Fang, Desai, Lee, Hwu, Tsai, Kishnani and Chien.)

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016., (© 2023. The Author(s).)

Background: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry., Methods: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points., Results: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60-632 m) at baseline (n = 31) to 484 m at Month 12 (range 240-739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from - 0.72 (95% CI: - 1.23, - 0.21; n = 38) to - 1.13 (95% CI: - 1.76, - 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions., Conclusions: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up., Registration: NCT02306720; EUPAS13514., (© 2024. The Author(s).)

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT., Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment., Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week., Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted., Competing Interests: AD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. AD has received honoraria from Sanofi Genzyme. CG has received Honoraria from Sanofi, Amicus Therapeutics, and RegenX Bio. RW serves on the Scientific Advisory Board for and owns equity in M6P Therapeutics. PK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer, and Asklepios Biopharmaceutical, Inc. (AskBio). PK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Babies. PK has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals and may receive milestone payments related to that equity in the future. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Desai, Shrivastava, Grant, Wang, Burt and Kishnani.)

Background: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures., Methods: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement)., Results: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05)., Conclusions: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD., Competing Interests: Declaration of Competing Interest KAH: is an employee and may hold stock and/or stock options in Sanofi. KIB: has served as a consultant to Sanofi, Amicus Therapeutics, Takeda, Valerion, and has participated in advisory boards for Sanofi, AskBio, Spark Therapeutics and Takeda; he is currently an employee of Sanofi. PD: is an employee and may hold stock and/or stock options in Sanofi. MMD: serves or recently served as a consultant for Abcuro, Amazentis/Vandria, ArgenX, Astellas, Catalyst, Cello, CNSA, Covance/Labcorp, CSL-Behring, Dianthus, EcoR1, EMD Serono/Merck, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc., Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, TACT, Abata/Third Rock, UCB Biopharma, and UpToDate. MMD received research grants, contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith & TMA. AH: is an employee and may hold stock and/or stock options in Sanofi. PSK: has received research/grant support from Sanofi Genzyme and Amicus Therapeutics; has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio); is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies; and has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. JM: is an employee and may hold stock and/or stock options in Sanofi. LP: is an employee and may hold stock and/or stock options in Sanofi. BS: Unrestricted research grants from Amicus, Astellas, Marigold Foundation, AMDA Foundation. Speaker honoraria from Kedrion, Alexion. Scientific advisor for Amicus, Argenx, Astellas, Maze, Pepgen, Sanofi, Spark, and Taysha. No stocks or shares. NT: is an employee and may hold stock and/or stock options in Sanofi. AT: has received honorarium as a scientific board component (Sanofi, Amicus, and Aro) and as a speaker for Sanofi, Spark, and Amicus. NvdB: received speaker honoraria from Sanofi and Amicus Therapeutics, and has served as scientific advisor for Sanofi under agreements with Erasmus MC University Medical Center and the relevant industry. TZ: is an employee and may hold stock and/or stock options in Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD., Method: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children., Results: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing., Discussion: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline., Competing Interests: Declaration of Competing Interest D. Kenney-Jung, A. Korlimarla, G. A. Spiridigliozzi, M. Malinzak, G. Nichting, S.-H. Jung, C. Phornphutkul and J. Owen report no disclosures. W. F. Wiggins is a Strategic Advisor to Qure.ai. He has served on the Medical Advisory Board of the University of Wisconsin-GE CT Protocols Partnership. A. Sun receives research funding and clinical trial support from Ultragenyx, LogicBio, BioMarin, Aeglea, and Takeda. R. Wang receives research/grant support from Biomarin Pharmaceuticals and Ultragenyx, has received consulting fees / honoraria from Biomarin Pharmaceuticals, Takeda, and Regenxbio Inc., and owns equity in Biomarin Pharmaceuticals and Regenxbio, Inc. J. M. Provenzale receives research funding from Bayer, Inc. P. S. Kishnani has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. She has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio). She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies. P. S. Kishnani has equity in Asklepios Biopharmaceutical, Inc. (AskBio) and Maze Therapeutics., (Copyright © 2023. Published by Elsevier Inc.)

Background: Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important for diagnosis, the frequency of and factors associated with clinically relevant assessment changes are unclear., Objectives: The authors aimed to characterize pathogenicity assignment change in cardiomyopathy-associated genes and to identify factors associated with this change., Methods: We identified 10 sarcomeric and 6 desmosomal genetic cardiomyopathy-associated genes along with comparison gene sets. We analyzed clinically meaningful changes in pathogenicity assignment between any of the following: pathogenic/likely pathogenic (P/LP), conflicting interpretations of pathogenicity or variant of unknown significance (C/VUS), and benign/likely benign. We explored association of minor allele frequency (MAF) differences between well, and traditionally poorly, represented ancestries in genetic studies with assessment stability. Analyses were performed using ClinVar and GnomAD data., Results: Of the 30,975 cardiomyopathy-associated gene variants in ClinVar, 2,276 of them (7.3%) had a clinically meaningful change in pathogenicity assignment over the study period, 2011 to 2021. Sixty-seven percent of variants that underwent a clinically significant change moved from P/LP or benign/likely benign to C/VUS. Among cardiomyopathy variants downgraded from P/LP, 35% had a MAF above 1 × 10 -4 in non-Europeans and below 1 × 10 -4 in Europeans., Conclusions: Over the past 10 years, 7.3% of cardiomyopathy gene variants underwent a clinically meaningful change in pathogenicity assignment. Over 30% of downgrades from P/LP may be attributable to higher MAF in Non-Europeans than Europeans. This finding suggests that low ancestral diversity in genetic studies has increased diagnostic uncertainty in cardiomyopathy gene variants.

Background: The construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS ® ) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT)., Methods: In the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers' maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients' age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods., Results: 123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively., Conclusions: PROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD., Trial Registration: ClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www., Clinicaltrials: gov/search?term=NCT03729362 ., (© 2024. The Author(s).)

Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800)., Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800)., Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers., Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies., Competing Interests: AD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. AD has received honoraria from Sanofi Genzyme. PK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer, and Asklepios Biopharmaceutical, Inc. AskBio. PK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies. PK has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. AR is on the Medical Advisory Board of Sonoma Biotherapeutics, and the Scientific Advisory Boards of 4DMT and the Alice and YT Chen Genetics and Genomics Center and is a Consultant for EpiVax, Inc. AR is employed by Epivax, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Desai, Smith, Yi, Rosenberg, Burt and Kishnani.)

Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions., (© 2023 SSIEM.)

Background: Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Variants of uncertain significance (VUS) cause diagnostic delay and uncertainty amongst patients and health care providers., Results: The ALPL gene variant database (https://alplmutationdatabase.jku.at/) is an open-access archive for interpretation of the clinical significance of variants reported in ALPL. The database contains coding and non-coding variants, including single nucleotide variants, insertions/deletions and structural variants affecting coding or non-coding sequences of ALPL. Each variant in the database is displayed with details explaining the corresponding pathogenicity, and all reported genotypes and phenotypes, including references. In 2021, the ALPL gene variant classification project was established to reclassify VUS and continuously assess and update genetic, phenotypic, and functional variant information in the database. For this purpose, the database provides a unique submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the stringent ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature research including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing of variants in a co-transfection model to measure ALP residual activity., Conclusion: This classification project and the ALPL gene variant database will serve the global medical community, widen the genotypic and phenotypic HPP spectrum by reporting and characterizing new ALPL variants based on ACMG/AMP criteria and thus facilitate improved genetic counseling and medical decision-making for affected patients and families. The project may also serve as a gold standard framework for multidisciplinary collaboration for variant interpretation in other rare diseases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The objective of this study was to better understand the clinical profiles of children with hypophosphatasia (HPP) prior to treatment with enzyme replacement therapy (ERT)., Methods: Pretreatment demographics and medical histories of ERT-treated children (aged &lt;18 years) enrolled in the Global HPP Registry (2015-2020) were analyzed overall, by age at first HPP manifestation (&lt;6 months vs. 6 months to 18 years), and by geographic region (USA/Canada, Europe, and Japan)., Results: Data from 151 children with HPP were analyzed. Sex distribution was balanced overall (52.3% female; 47.7% male) but differed in Japan (63.0% female; 37.0% male). Prior to ERT initiation, common manifestations were skeletal (67.5%) and extraskeletal, with the foremost types being muscular (48.3%), constitutional/metabolic (47.0%), and neurologic (39.7%). A high proportion of children who first presented at &lt;6 months of age (perinatal/infantile period) had a history of bone deformity (59.3%) and respiratory failure (38.3%), while those aged 6 months to 18 years at first manifestation had a predominance of early loss of primary teeth (62.3%) and gross motor delay (41.0%). Those from Japan were reported to have a younger median age overall, the highest proportion of skeletal manifestations (80.4%) and growth impairment, while European data reported the highest proportion of muscular manifestations (70.7%). In the USA/Canada, skeletal and muscular manifestations were reported at the same frequency (57.4%)., Conclusion: Prior to ERT, skeletal and extraskeletal manifestations were commonly reported in children with HPP, with differences by age at first HPP manifestation and geographical region. Comprehensive assessments of children with HPP are warranted prior to ERT initiation., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD., Results: We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age < 1 year. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between ALGLU as a time-varying exposure and survival, adjusting for age at first treatment, sex, and cross-reactive immunologic material (CRIM)/immune tolerance induction (ITI) status. Dose was measured as average relative dose received over time (in multiples of label dose, range > 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22-0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28-0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose., Conclusions: Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses., (© 2023. The Author(s).)

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies., (© 2023 John Wiley & Sons Ltd.)

Individuals with Down syndrome (DS) have been particularly impacted by respiratory conditions, such as pneumonia. However, the description of co-occurring recurrent infections, the response to pneumococcal immunization, and the association of these was previously unknown. We screened individuals with DS using an 11-item screener and prospectively collected pneumococcal titers and laboratory results. We found that the screener did not successfully predict which individuals with DS who would have inadequate pneumococcal titers. Thirty four of the 55 individuals with DS (62%) had abnormal pneumococcal titers demonstrating an inadequate response to routine immunization. In the absence of a valid screener, clinicians should consider screening all individuals with DS through the use of pneumococcal titers to 23 serotypes to assess vaccine response., (© 2023 Wiley Periodicals LLC.)

Background and Objectives: The Pompe Disease Symptom Scale (PDSS) and Impact Scale (PDIS) were created to measure the severity of symptoms and functional limitations experienced by patients with late-onset Pompe disease (LOPD). The objectives of this analysis were to establish a scoring algorithm and to examine the reliability, validity, and responsiveness of the measures using data from the COMET clinical trial., Methods: The COMET trial was a randomized, double-blind study comparing the efficacy and safety of avalglucosidase alfa and alglucosidase alfa in patients with LOPD aged 16-78 years at baseline. Adult participants (18 years or older) completed the PDSS and PDIS daily for 14 days at baseline and for 2 weeks before quarterly clinic visits for 1 year after randomization using an electronic diary. Data were pooled across treatment groups for the current analyses. Factor analysis and inter-item correlations were used to derive a scoring algorithm. Test-retest and internal consistency analyses examined the reliability of the measures. Correlations with criterion measures were used to evaluate validity and sensitivity to change. Anchor and distribution-based analyses were conducted to estimate thresholds for meaningful change., Results: Five multi-item domain scores were derived from the PDSS (Shortness of Breath, Overall Fatigue, Fatigue/Pain, Upper Extremity Weakness, Pain) and 2 from the PDIS (Mood, Difficulty Performing Activities). Internal consistency (Cronbach α > 0.90) and test-retest reliability (intraclass correlation >0.60) of the scores were supported. Cross-sectional and longitudinal correlations with the criterion measures generally supported the validity of the scores ( r > 0.40). Within-patient meaningful change estimates ranging from 1.0 to 1.5 points were generated for the PDSS and PDIS domain scores., Discussion: The PDSS and PDIS are reliable and valid measures of LOPD symptoms and functional impacts. The measures can be used to evaluate burden of LOPD and effects of treatments in clinical trials, observational research, and clinical practice., Trial Registration Information: ClinicalTrials.gov identifier: NCT02782741., Competing Interests: M.M. Dimachkie has received consulting fees from Abata/Third Rock, Abcuro, Amazentis, ArgenX, Astellas, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc, Sanofi, Scholar Rock, Shire Takeda, Spark Therapeutics, TACT, UCB Biopharma, and UpToDate. M.M. Dimachkie has undertaken contracted research for or received unrestricted educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, TMA, UCB Biopharma/RaPharma, and Viromed/Healixmith. P.S. Kishnani has received research/grant support from Sanofi and Amicus Therapeutics and has received consulting fees and honoraria from Sanofi, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical, and Asklepios Biopharmaceutical, Inc. (AskBio). P.S. Kishnani is a member of the Pompe and Gaucher Disease Registry Advisory Boards for Sanofi, Amicus Therapeutics, and Baebies. P.S. Kishnani has equity in Asklepios Biopharmaceutical, Inc. (AskBio), and Maze Therapeutics. C. Ivanescu is an employee of IQVIA. G. Flore was an employee of IQVIA at the time of study participation. C. Gwaltney has received consulting fees from Sanofi. N.A.M.E. van der Beek has received consulting fees and travel reimbursement from Sanofi and Amicus Therapeutics. A. Hamed is an employee of Sanofi. K. An Haack and her spouse are employees of Sanofi. L. Pollissard is an employee of Sanofi. E. Baranowski was an employee of Sanofi at the time of study participation. S.E. Sparks is an employee of Sanofi. P. DasMahapatra is an employee of Sanofi. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, diagnosis, management, quality of life and future research directions. Some GSDs have available guidelines for diagnosis and management. Diagnostic considerations include phenotypic characterization, biomarkers, imaging, genetic testing, enzyme activity analysis and histology. Management includes surveillance for development of characteristic disease sequelae, avoidance of fasting in several hepatic GSDs, medically prescribed diets, appropriate exercise regimens and emergency letters. Specific therapeutic interventions are available for some diseases, such as enzyme replacement therapy to correct enzyme deficiency in Pompe disease and SGLT2 inhibitors for neutropenia and neutrophil dysfunction in GSD Ib. Progress in diagnosis, management and definitive therapies affects the natural course and hence morbidity and mortality. The natural history of GSDs is still being described. The quality of life of patients with these conditions varies, and standard sets of patient-centred outcomes have not yet been developed. The landscape of novel therapeutics and GSD clinical trials is vast, and emerging research is discussed herein., (© 2023. Springer Nature Limited.)

Plasma ceramide levels (henceforth, "ceramides") are biomarkers of some diseases that are comorbidities of Down syndrome (DS). We sought to determine if comorbidities in DS were associated with ceramides, studying a convenience cohort of 35 study participants, all ≥12 months old. To identify comorbidities, we reviewed the problem lists in electronic health records that were concurrent with sample collection. We placed clinically related comorbidities into one of five categories of comorbidities, henceforth, categories: obesity/overweight; autoimmune disease; congenital heart disease; bacterial infection; and central nervous system (CNS) condition. We measured the eight ceramides most frequently associated with disease using liquid chromatography-tandem mass spectrometry. We calculated a ceramide composite outcome score (CCOS) for each participant by normalizing each ceramide level to the mean for that level in the study population and then summing the normalized levels, to be proxy variable for all eight ceramides in aggregate. We used multivariable linear regression models adjusted for age and sex to test associations of categories with ceramides and with CCOSs. Post hoc, we realized that co-occurring comorbidities might interfere with establishing associations between predictor categories and ceramides and that stratified analyses might eliminate their influence on associations. We posited that CCOSs could be used to screen for associations of categories with multiple ceramides, since most diseases have been associated with more than one ceramide. We chose to omit in the stratified analyses the two categories that were the most different from one another in their associations with their CCOSs, having the most divergent regression coefficients (the highest positive and lowest negative coefficients). We first omitted one of these two divergent categories in a stratified analysis and tested in the remaining participants (those without a comorbidity in the interfering category) for associations of the other four categories with their CCOSs and then did the same for the other divergent category. In each of these two screening stratified analyses, we found one category was significantly associated with its CCOS. In the two identified categories, we then tested for associations with each of the eight ceramides, using the appropriate stratified analysis. Next, we sought to determine if the associations of the two categories with ceramides we found by omitting participants in the interfering categories held in our small sample for participants in the omitted categories as well. For each of the two categories, we therefore omitted participants without the interfering category and determined associations between the predictor category and individual ceramides in the remaining participants (those with a comorbidity in the interfering category). In the a priori analyses, autoimmune disease was inversely associated with C16 and CNS condition was inversely associated with C23. Obesity/overweight and CNS condition were the two categories with the most divergent regression coefficients (0.037 vs. -0.048). In post hoc stratified analyses, after omitting participants with obesity/overweight, thereby leaving participants without obesity/overweight, bacterial infection was associated with its CCOS and then with C14, C20, and C22. However, in the companion stratified analyses, omitting participants without obesity/overweight, thereby leaving participants with obesity/overweight, bacterial infection was not associated with any of the eight ceramides. Similarly, in post hoc stratified analyses after omitting participants with a CNS condition, thereby leaving participants without a CNS condition, obesity/overweight was associated with its CCOS and then with C14, C23, and C24. In the companion analyses, omitting participants without a CNS condition, thereby leaving participants with a CNS condition, obesity/overweight was inversely associated with C24.1. In conclusion, CNS and autoimmune disease were inversely associated with one ceramide each in a priori analyses. In post hoc analyses, we serendipitously omitted categories that interfered with associations of other categories with ceramides in stratified analyses. We found that bacterial infection was associated with three ceramides in participants without obesity/overweight and that obesity/overweight was associated with three ceramides in participants without a CNS condition. We therefore identified obesity/overweight and CNS conditions as potential confounders or effect modifiers for these associations. This is the first report of ceramides in DS and in human bacterial infection. Further study of ceramides in comorbidities of DS is justified., (© 2023 Wiley Periodicals LLC.)

Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno-associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8-LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti-recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six-minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.-32-13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector-mediated gene therapy., Competing Interests: Dr. Dwight D. Koeberl and Dr. Priya S. Kishnani have developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. Dr. Dwight D. Koeberl has served as a consultant for Sangamo Therapeutics and for Genzyme Sanofi, Amicus, and Vertex; has received grant support from Viking Therapeutics, Genzyme Sanofi, Roivant Rare Diseases, and Amicus; and has equity in Askbio, which is developing gene therapy for Pompe disease. Dr. William B. Hannah has received consulting fees from PTC Therapeutics and ReCode Therapeutics. Dr. Edward C. Smith received salary support for his role as PI on this study. Dr. Laura E. Case has received honoraria from Genzyme Sanofi and Amicus, has participated in research supported by Genzyme Sanofi, Amicus, AskBio, Valerion, Biomarin, and by Roivant Sciences; and is a member of the Pompe Registry North American Board of Advisors Genzyme Sanofi. Dr. Deeksha Bali has received research grant support and travel funds from Genzyme Sanofi, Baebies Inc., Biomarin, Alexion Inc., SOBI biopharma, and JCR biopharma. Dr. Priya S. Kishnani has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. She received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical, and Asklepios Biopharmaceutical, Inc. (AskBio). She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Gezyme, Amicus Therapeutics, and Baebies. Dr. Priya S. Kishnani has equity in Asklepios Biopharmaceutical, Inc. (AskBio) which is developing gene therapy for Pompe disease and has equity in Maze Therapeutics which is developing a small molecule therapy for Pompe disease., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse-specific CD20 monoclonal antibody to suppress anti-AAV NAbs and enable readministration of AAV vectors of the same capsid in mice., Methods: An AAV8 vector (AAV8-CB-hGAA) that ubiquitously expresses human α-glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8-LSP-hSEAP) that contains a liver-specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti-AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B-cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood., Results: In näive mice, an 8-week IS treatment along with AAV8-CB-hGAA injection effectively depleted CD19 + B220 + B cells from blood, spleen, and bone marrow and prevented the formation of anti-AAV8 NAbs. Following administration of AAV8-LSP-hSEAP, increasing levels of hSEAP were detected in blood for up to 6 weeks, indicating successful AAV readministration. In mice pre-immunized with AAV8-CB-hGAA, comparison of IS treatment for 8, 12, 16, and 20 weeks revealed that the 16-week IS treatment demonstrated the highest plasma hSEAP level following AAV8-LSP-hSEAP readministration., Conclusions: Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV-mediated gene therapy. A combination IS treatment with bortezomib and a mouse-specific CD20 monoclonal antibody effectively suppressed anti-AAV NAbs in naïve mice and in mice with pre-existing antibodies, allowing successful readministration of the same AAV capsid vector., (© 2023 John Wiley & Sons Ltd.)

Purpose: Children with Pompe disease, a rare genetic metabolic myopathy, often have speech impairments. In this study, we provide a comprehensive description of articulation, resonance, and voice in children with Pompe disease., Method: Fifteen children with Pompe disease (11 with infantile-onset Pompe disease [IOPD], four with late-onset Pompe disease [LOPD]) ranging from 6 to 18 years of age participated in standard speech assessments. Measures included maximum tongue pressure; nasalance; cepstral peak prominence (CPP); low/high ratio (L/H ratio); diadochokinetic (DDK) rates; percent consonants correct (PCC); and visual analog scale (VAS) ratings of articulation, resonance, voice quality, and overall speech severity. Maximum tongue pressures, nasalance, CPP, L/H ratio, DDK rates, and PCC were compared to normative data from typically developing (TD) children. Correlation analyses and multiple regression models of speech measure predictors were conducted., Results: Children with IOPD had greater speech impairment than those with LOPD. The IOPD group had lower maximum tongue pressures, slower articulation rates, lower PCC scores, higher nasalance, and higher L/H voice ratios than TD children. VAS ratings confirmed the presence of impaired articulatory precision, hypernasality, and dysphonia for most of the children with IOPD, with severity of impairment ratings ranging from mild to severe. The LOPD group had mildly elevated nasalance and L/H ratio values relative to TD children, and auditory-perceptual ratings suggested mild to no speech impairment., Conclusions: Speech disorders involving articulatory precision, resonance balance, and voice quality are common in children with Pompe disease, especially in those with IOPD. With improvements in the detection and treatment of Pompe disease, clinicians should be aware of the associated speech deficits.