Is Newborn Screening the Ultimate Strategy to Reduce Diagnostic Delays in Pompe Disease? The Parent and Patient Perspective

Saich, Raymond; Brown, Renée F; Collicoat, Maddy; Jenner, Catherine; Primmer, Jenna; Clancy, Beverley; Holland, Tarryn; Krinks, Steven

doi:10.3390/ijns6010001

Cited by 9 publications

(11 citation statements)

References 42 publications

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“…A family history of negative PD screens without carrier information gives families a false sense of security, as reported in the Australian PD cases [7]. A significant fraction of FPs will be due to recurrent carriers or pseudodeficiencies with low enzyme values, and a likely source of anxiety or rightful concern in future newborn births in those families.…”

Section: Genome Scale Data and Its Impact On Pd Screeningmentioning

confidence: 99%

“…However, for suspected IOPD cases, time to treatment initiation within two weeks is critical. Therefore, timely second tier tNGS reporting in IOPD may be the only option for avoiding diagnostic and treatment delays and avoiding a negative impact on quality of life and potentially on lifespan [7,13]. The treating clinician, in the case of classic IOPD, would need DNA sequencing data in the diagnostic-phase to determine treatment-associated predictive sequence information (CRIM status and phenotype onset predictions) prior to initiating enzyme replacement therapy [2,6].…”

Section: Timelinessmentioning

confidence: 99%

“…If NBS programs routinely perform tNGS on premises, or use DNA sequencing services that return results within 7 days, then overall reporting and treatment initiation may occur within 10 days, benefiting classic IOPD or CRIM-negative IOPD cases. Starting ERT within this timeframe for CRIM-negative IOPD, and before the immune system has matured, might also enable natural immune tolerance [7]. Omitting the tNGS assay as the second tier PD NBS test and putting the burden on the follow-up referral centers to obtain a molecular diagnostic result, while providing a faster NBS turn-around time may delay treatment initiation.…”

Section: Timelinessmentioning

confidence: 99%

“…If an infant is found to have any form of disease, follow-up with appropriate treatment is necessary and should start early. Recent reports on IOPD continue to shed light on some of the unique challenges care providers face in diagnosing and managing this genetic disease [2,7]. While delays in PD symptom onset and diagnosis are less common in IOPD (under 3-4 months) compared to LOPD, based on the Pompe Registry data [8], the IOPD cases with cross-reactive immunological material (CRIM), negative statuses almost invariably develop high antibody titers to enzyme replacement therapy (ERT).…”

Section: Introductionmentioning

confidence: 99%

“…If CRIM negative IOPDs are not identified in the newborn period, and if immune modulation therapy and ERT treatment are not initiated within days of birth, 100% ventilator free-survival is unlikely, and death may occur within the first two years of life [2,9]. Several Australian IOPD cases that were not identified by NBS, but identified by clinical examination alone have responded poorly to ERT and developed high antibody titres [7]. CRIM-positive IOPDs can also show high antibody titres, which may be predicted based on genotype [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Smith

Bainbridge

Parad

et al. 2020

IJNS

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Pompe disease (PD) is screened by a two tier newborn screening (NBS) algorithm, the first tier of which is an enzymatic assay performed on newborn dried blood spots (DBS). As first tier enzymatic screening tests have false positive results, an immediate second tier test on the same sample is critical in resolving newborn health status. Two methodologies have been proposed for second tier testing: (a) measurement of enzymatic activities such as of Creatine/Creatinine over alpha-glucosidase ratio, and (b) DNA sequencing (a molecular genetics approach), such as targeted next generation sequencing. (tNGS). In this review, we discuss the tNGS approach, as well as the challenges in providing second tier screening and follow-up care. While tNGS can predict genotype-phenotype effects when known, these advantages may be diminished when the variants are novel, of unknown significance or not discoverable by current test methodologies. Due to the fact that criticisms of screening algorithms that utilize tNGS are based on perceived complexities, including variant detection and interpretation, we clarify the actual limitations and present the rationale that supports optimizing a molecular genetic testing approach with tNGS. Second tier tNGS can benefit clinical decision-making through the use of the initial NBS DBS punch and rapid turn-around time methodology for tNGS, that includes copy number variant analysis, variant effect prediction, and variant ‘cut-off’ tools for the reduction of false positive results. The availability of DNA sequence data will contribute to the improved understanding of genotype-phenotype associations and application of treatment. The ultimate goal of second tier testing should enable the earliest possible diagnosis for the earliest initiation of the most effective clinical interventions in infants with PD.

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Section: Genome Scale Data and Its Impact On Pd Screeningmentioning

confidence: 99%

Section: Timelinessmentioning

confidence: 99%

Section: Timelinessmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Smith

Bainbridge

Parad

et al. 2020

IJNS

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Newborn screening for Pompe disease: Parental experiences and follow‐up care for a late‐onset diagnosis

Prakash

Penn

Jackson

et al. 2022

Journal of Genetic Counseling

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Pompe disease (PD) is a type of lysosomal storage disorder, in which the glycogen stored in lysosomes begins to accumulate due to deficiency of the enzyme acid alpha-glucosidase (GAA) (Barba-Romero et al., 2012). Deficiency of GAA causes accumulation of glycogen in skeletal, cardiac and smooth muscles leading to a clinical spectrum of PD. There is a high degree of variability among individuals affected with PD seen in age of onset, rate of disease progression and clinical phenotype (Chan et al., 2017). This condition is inherited in an autosomal recessive manner with incidences ranging from 1:14,000 in African Americans to 1:100,000 in individuals of European descent (Kishnani et al., 2012).Two broad subtypes have been classified clinically, depending on age of onset (before or after 1 year of age of the patient) and the residual GAA activity (Chan et al., 2017;Dasouki et al., 2014).Classic infantile-onset Pompe disease (IOPD) is a rapidly progressing form that can present shortly after birth with cardiomyopathy, cardiorespiratory failure, and death within the first year of life due to a lower concentration of GAA (Chan et al., 2017). Late-onset Pompe

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Neonatal and carrier screening for rare diseases: how innovation challenges screening criteria worldwide

et al. 2020

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Screening for rare diseases first began more than 50 years ago with neonatal bloodspot screening (NBS) for phenylketonuria, and carrier screening for Tay-Sachs disease, sickle cell anaemia and β-thalassaemia. NBS’s primary aim is health gain for children, while carrier screening enables autonomous reproductive choice. While screening can be beneficial, it also has the potential to cause harm and thus decisions are needed on whether a specific screening is worthwhile. These decisions are usually based on screening principles and criteria. Technological developments, both treatment driven and test driven, have led to expansions in neonatal screening and carrier screening. This article demonstrates how the dynamics and expansions in NBS and carrier screening have challenged four well-known screening criteria (treatment, test, target population and programme evaluation), and the decision-making based on them. We show that shifting perspectives on screening criteria for NBS as well as carrier screening lead to converging debates in these separate fields. For example, the child is traditionally considered to be the beneficiary in NBS, but the family and society can also benefit. Vice versa, carrier screening may be driven by disease prevention, rather than reproductive autonomy, raising cross-disciplinary questions regarding potential beneficiaries and which diseases to include. In addition, the stakeholders from these separate fields vary: Globally NBS is often governed as a public health programme while carrier screening is usually available via medical professionals. The article concludes with a call for an exchange of vision and knowledge among all stakeholders of both fields to attune the dynamics of screening.

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Is Newborn Screening the Ultimate Strategy to Reduce Diagnostic Delays in Pompe Disease? The Parent and Patient Perspective

Cited by 9 publications

References 42 publications

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Newborn screening for Pompe disease: Parental experiences and follow‐up care for a late‐onset diagnosis

Neonatal and carrier screening for rare diseases: how innovation challenges screening criteria worldwide

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