A genetic modifier of symptom onset in Pompe disease

Bergsma, Atze J.; Groen, Stijn L.M. in ‘t; Dorpel, Jan J A van den; Hout, Hannerieke J.M.P. van den; Beek, Nadine A.M.E. van der; Schöser, Benedikt; Toscano, Antonio; Musumeci, Olimpia; Bembi, Bruno; Dardis, Andrea; Morrone, Amelia; Tummolo, Albina; Pasquini, Elisabetta; Ploeg, Ans T. van der; Pijnappel, W.W.M. Pim

doi:10.1016/j.ebiom.2019.03.048

Cited by 37 publications

(45 citation statements)

References 35 publications

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“…Recent findings indicate that analysis of the modifier c.510C> T variant, which is silent but modulates splicing in patients carrying the common c.-32-13T>G (IVS1) variants, is also important. 11 Previously, we described an exon-flanking RT-PCR that can be used to detect novel disease-associated variants that affect pre-mRNA splicing, irrespective of their location. 9,12 This assay is important for diagnosis but also to allow the design of antisense oligonucleotides that can restore splicing.…”

Section: Introductionmentioning

confidence: 99%

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Groen

Faria

Iuliano

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid a-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5 0 UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

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Section: Introductionmentioning

confidence: 99%

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Groen

Faria

Iuliano

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Consistent with the original intent of NBS, PD must be considered a time critical condition, for which all PD NBS results including second tier should be provided as early as possible. Given the ever-increasing population-based variation outcome data for PD [30], implementation of tNGS second tier testing of PD from a DBS [16], is both feasible and sufficient in the required time frame for NBS and follow up.…”

Section: Discussionmentioning

confidence: 99%

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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“…22 The likely cause of this condition is considered to be the modifying effect of in-gene or out-gene variants. 23,24 Besides the severity of the mutation, the course of PD is variable due to CRIM status and residual GAA enzymatic activity in muscles. 5,25 Different disease phenotypes are related to the levels of residual GAA enzymatic activity in muscles; less than 3% of normal enzymatic activity is found in severe infantile cases, and residual levels ranging 3 to 30% of normal are found in less severe late-onset forms.…”

Section: Discussionmentioning

confidence: 99%

A Newborn with Infantile-Onset Pompe Disease Improving after Administration of Enzyme Replacement Therapy: Case Report

Bor

İlhan

Gümüş

et al. 2020

J Pediatr Intensive Care

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Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid α-1,4-glucosidase enzyme (GAA). PD has two forms, namely the infantile-onset and the late-onset form. In untreated cases, infantile-onset form usually leads to cardio-respiratory failure and death in the first year of life. Herein, we report a newborn with infantile-onset PD characterized by muscular hypotonia, respiratory distress, hypertrophic cardiomyopathy, hepatomegaly, elevated serum enzyme levels of aspartate aminotransferase of 117 IU/L (three times the normal value), alanine aminotransferase of 66 IU/L (1.8 times the normal value), lactate dehydrogenase of 558 IU/L (1.2 times the normal value), and creatine kinase >5,000 IU/L (16 times the normal value). Dried blood spot testing was performed and revealed decreased GAA enzymatic activity (0.07 nmol/mL/h, normal 0.93–7.33 nmol/mL/h). GAA gene analysis performed for confirming the diagnosis showed homozygous mutation c.896T >C (p.Leu299Pro). Initiation of enzyme replacement therapy (ERT) (ERT; 20 mg/kg, once every week) at 28 days of age resulted in weaning off from respiratory support within 1 week after treatment, normalization of cardiac abnormalities, and normal neuromotor development in the 16th month of age. Early diagnosis and early treatment with ERT, especially in the neonatal period, is of great importance to improve cardiac function and motor development in infantile-onset PD.

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A genetic modifier of symptom onset in Pompe disease

Cited by 37 publications

References 35 publications

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

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

A Newborn with Infantile-Onset Pompe Disease Improving after Administration of Enzyme Replacement Therapy: Case Report

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