ObjectiveAlthough enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.MethodsWe evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.ResultsSeven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1–1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.ConclusionsThe ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.

Down syndrome is one of the most common conditions encountered in the genetics clinic. Due to improvements in healthcare, educational opportunities, and community inclusion over the past 30 years, the life expectancy and quality of life for individuals with Down syndrome have significantly improved. As prenatal screening and diagnostic techniques have become more enhanced and widely available, genetic counselors can expect to frequently provide information and support following a new diagnosis of Down syndrome. This guideline was written for genetic counselors and other healthcare providers regarding the communication of a diagnosis of Down syndrome to ensure that families are consistently given up-to-date and balanced information about the condition, delivered in a supportive and respectful manner.

Purpose Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN IPD patients receiving ERT monotherapy. Methods A chart review identified 20 CN IPD patients treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT) ≥51,200 at least twice; low titers (LT) <6,400 throughout treatment; or sustained intermediate titers (SIT) 6,400–25,600. Results Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, while the LT group exclusively carried splice site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. Conclusion Immunological responses are a significant risk in CN IPD; thus, immune tolerance induction in the naïve setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease.

The purpose of this study was to explore the perspectives of genetic counselors and parents of children with Down syndrome to define essential information for the initial discussion of a new diagnosis. We compared information given in both prenatal and postnatal settings, and also aimed to distinguish differences between the informational needs of parents and the information genetic counselors provide. Online surveys were distributed to members of the National Down Syndrome Congress, National Down Syndrome Society, and National Society of Genetic Counselors. Participants included 993 parents of children with Down syndrome and 389 genetic counselors. Participants rated 100 informational features about Down syndrome as Essential, Important, or Not Too Important for inclusion in the first discussion of the diagnosis. Responses identified 34 essential informational items for the initial discussion of Down syndrome, including clinical features, developmental abilities, a range of prognostications, and informational resources. Healthcare providers should consider incorporating these items in their initial discussion of a diagnosis in both prenatal and postnatal settings. Statistically significant differences between parent and genetic counselor responses illustrate that information is valued differently and that parents appreciate information about the abilities and potential of people with Down syndrome, as opposed to clinical details. Balancing clinical information with other aspects of the condition, as well as a better understanding of the information parents consider most important, may enable healthcare professionals to more effectively satisfy families' informational needs following a new diagnosis of Down syndrome.