Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction

Li, Cindy; Desai, Ankit K.; Gupta, Punita; Dempsey, Katherine; Bhambhani, Vikas; Hopkin, Robert J.; Fıçıcıoğlu, Can; Tanpaiboon, Pranoot; Craigen, William J.; Rosenberg, Amy S.; Kishnani, Priya S.

doi:10.1038/s41436-020-01080-y

Cited by 37 publications

(34 citation statements)

References 40 publications

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“…Surprisingly, within the cohort treated with ERT + ITI, although early treated patients (≤4 weeks) showed a better outcome than late treated, the number of immunotolerant patients (titre ≤6400) did not differ significantly between these groups. However, early treated patients were significantly more likely to remain seronegative than late treated patients [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel

et al. 2022

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Background Classic infantile onset of Pompe disease (c-IOPD) leads to hypotonia and hypertrophic cardiomyopathy within the first days to weeks of life and, without treatment, patients die of cardiorespiratory failure in their first 1–2 years of life. Enzymatic replacement therapy (ERT) with alglucosidase alfa is the only available treatment, but adverse immune reactions can reduce ERT’s effectiveness and safety. It is therefore very important to identify strategies to prevent and manage these complications. Several articles have been written on this disease over the last 10 years, but no univocal indications have been established. Methods Our study presents a review of the current literature on management of immune responses to ERT in c-IOPD as considered by an Italian study group of pediatric metabolists and immunologists in light of our shared patient experience. Results We summarize the protocols for the management of adverse reactions to ERT, analyzing their advantages and disadvantages, and provide expert recommendations for their optimal management, to the best of current knowledge. However, further studies are needed to improve actual management protocols, which still have several limitations.

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Section: Resultsmentioning

confidence: 99%

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel

et al. 2022

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“…However, ERT did not produce the expected effects in this patient. Very recently, Li et al reported that in CRIM-negative IOPD patients treated with ITI + ERT, the clinical outcomes of the early group (treatment initiation at age ≤4 weeks) were much better than those of the intermediate group (treatment initiation at age >4 and ≤15 weeks) and late group (treatment initiation at age >15 weeks) ( Li et al, 2021 ). In the intermediate group and late group, 66% (10/15) of the patients needed a breathing device during the treatment.…”

Section: Discussionmentioning

confidence: 99%

A Multi-Centre Prospective Study of the Efficacy and Safety of Alglucosidase Alfa in Chinese Patients With Infantile-Onset Pompe Disease

Zhu

Qiu

et al. 2022

Front. Pharmacol.

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Background: A high prevalence of infantile-onset Pompe disease (IOPD) in the Chinese population has been noted, but there are currently no reported clinical trials of enzyme replacement therapy (ERT) for IOPD in this population. The purpose of this study was to evaluate the efficacy and safety of alglucosidase alfa in Chinese patients with IOPD.Materials and Methods: A multicentre, single-arm, prospective, open-label clinical trial was performed at 4 sites in China. Eligible Chinese subjects with IOPD received an infusion of alglucosidase alfa at a dose of 20 mg/kg every 2 weeks for up to 52 weeks. The primary endpoints of clinical efficacy were the survival rate and changes in the left ventricular mass index (LVMI). The safety assessment was based on the incidence of adverse events (AEs).Results: A total of 10 eligible subjects were enrolled in the study. The mean age at the start of ERT was 5.36 ± 1.56 months. Nine subjects had survived after 52 weeks of treatment. One subject discontinued the study and died after mechanical ventilation was withdrawn. The intent-to-treat analysis demonstrated that the survival rate was 90.0% (95% confidence interval: 55.5–99.7%). The mean LVMI at week 52 was 70.59 ± 39.93 g/m2 compared to that of 298.02 ± 178.43 g/m2 at baseline, with a difference of -227.60 ± 155.99 g/m2. All subjects had left ventricular mass (LVM) Z scores >10 at baseline, and eight subjects (80%) achieved Z scores <5 at week 52. No treatment-related AEs were observed, and no AEs led to the discontinuation of treatment.Conclusions: This clinical trial is the first study of ERT for IOPD in China, indicating that alglucosidase alfa has favourable efficacy and safety for the treatment of Chinese patients with IOPD (ClinicalTrials.gov number, NCT03687333).

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“…The utility of NBS for Pompe disease in the US has been demonstrated with the development of successful screening programs in many states resulting in significant improvements in clinical outcomes for IOPD (Li et al, 2021), yet there remains a challenge in appropriately diagnosing and managing patients with LOPD. This challenge is critically important to address because of the high number of patients with suspected LOPD ascertained via NBS (the vast majority of which do not have a phenotype in the neonatal period) and the large number of these infants with a genotype that includes a VUS or novel variant (Burton et al, 2017b;Klug et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Development of a clinically validated in vitro functional assay to assess pathogenicity of novel GAA variants in patients with Pompe disease identified via newborn screening

Goomber

Huggins²,

Rehder³

et al. 2022

Front. Genet.

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Purpose: The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain significance (VUS) and novel variants identified in the GAA gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of GAA variants. Methods: We developed an in vitro mammalian cell expression and functional analysis system based on guidelines established by the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group for PS3/BS3. We validated the assay with 12 control variants and subsequently analyzed eight VUS or novel variants in GAA identified in patients with a positive newborn screen for Pompe disease without phenotypic evidence of infantile-onset disease.Results: The control variants were analyzed in our expression system and an activity range was established. The pathogenic controls had GAA activity between 0% and 11% of normal. The benign or likely benign controls had an activity range of 54%–100%. The pseudodeficiency variant had activity of 17%. These ranges were then applied to the variants selected for functional studies. Using the threshold of <11%, we were able to apply PS3_ supporting to classify two variants as likely pathogenic (c.316C > T and c.1103G > A) and provide further evidence to support the classification of likely pathogenic for two variants (c.1721T > C and c.1048G > A). One variant (c.1123C > T) was able to be reclassified based on other supporting evidence. We were unable to reclassify three variants (c.664G > A, c.2450A > G, and c.1378G > A) due to insufficient or conflicting evidence.Conclusion: We investigated eight GAA variants as proof of concept using our validated and reproducible in vitro expression and functional analysis system. While additional work is needed to further refine our system with additional controls and different variant types in order to apply the PS3/BS3 criteria at a higher level, this tool can be utilized for variant classification to meet the growing need for novel GAA variant classification in the era of newborn screening for Pompe disease.

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Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction

Cited by 37 publications

References 40 publications

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel

A Multi-Centre Prospective Study of the Efficacy and Safety of Alglucosidase Alfa in Chinese Patients With Infantile-Onset Pompe Disease

Development of a clinically validated in vitro functional assay to assess pathogenicity of novel GAA variants in patients with Pompe disease identified via newborn screening

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