Early clinical phenotype of late onset Pompe disease: Lessons learned from newborn screening

Huggins, Erin; Holland, Maggie; Case, Laura E.; Blount, Janet; Landstrom, Andrew P.; Jones, Hilary; Kishnani, Priya S.

doi:10.1016/j.ymgme.2022.01.003

Cited by 19 publications

(26 citation statements)

References 29 publications

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“…The presence of cardiomyopathy or cardiomegaly within the first year of life is a clear distinguishing feature between IOPD and LOPD. The latter represents the majority of cases identified via NBS and over time, some of these infants have developed features of Pompe disease and have been initiated on ERT (Burton et al, 2017b;Huggins et al, 2022). Unclear diagnoses lead to uncertainty regarding disease management.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike patients with IOPD or clinically ascertained LOPD for whom diagnoses can be confirmed clinically and biochemically and treatment can be initiated in a timely manner, diagnosis of LOPD in the setting of NBS is more difficult. Infants with LOPD do not have cardiomyopathy, muscle weakness may be subtle, if present, and biomarkers such as urine glucose tetrasaccharide (Glc 4 ), creatine kinase (CK), and aspartate aminotransferase (AST) are often normal in the pre-symptomatic phase of LOPD (Huggins et al, 2022). Thus, confirmation of a diagnosis of LOPD often relies heavily on GAA sequencing in the absence of a clear clinical phenotype.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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.

Self Cite

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“…Huggins et al followed 20 infants and children (aged 6–21 months) newly diagnosed with late-onset Pompe disease (LOPD) to determine a clinical phenotype for this group ( 41 ). While most LOPD infants had average or above-average scores on the AIMS, participants' scores were extremely variable and ranged between the 5th and 90th percentiles ( 41 ). The authors suggest that in further research on specific groups of patients, a detailed assessment of the musculoskeletal system should accompany the AIMS.…”

Section: Genetic Disordersmentioning

confidence: 99%

The Alberta Infant Motor Scale: A tool for the assessment of motor aspects of neurodevelopment in infancy and early childhood

Eliks

Gajewska

2022

Front. Neurol.

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According to the recommendations of the American Academy of Pediatrics, the surveillance of motor development should accompany systematic appointments with medical professionals in infancy and early childhood. One of the standardized tools for evaluating motor development is the Alberta Infant Motor Scale (AIMS). This paper aims to present assumptions and psychometric properties of the AIMS, the methodology of assessment of an infant's performance with the AIMS, and research on the validation and standardization of the AIMS as well as the use of the scale as an outcome measure. We conducted a non-systematic literature review using three electronic databases: PubMed, Scopus, and Embase (from June 1992 to February 2022). We included original research with a full-text manuscript in English. No geographical restrictions were applied. The search terms “alberta infant motor scale” AND “reliability” OR “validity” and “alberta infant motor scale” AND “norms” OR “reference” OR “standardization” were used for literature review on the validation and standardization of the AIMS in other non-Canadian populations. This narrative review also focuses on how the AIMS is applied as an outcome measure in research by presenting studies on the AIMS conducted over the last decade. Our review found that the AIMS is widely used for both research and clinical purposes. The AIMS has been used as an outcome measure in both interventional and observational studies conducted on both neurotypical infants and those with conditions affecting motor development. The advantages of the scale are its infant-friendliness, time duration of the examination, and relative ease of application for an examiner. The scale has been validated and standardized in many countries.

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“…In IOPD, treatment should be initiated as soon as possible; delays of even days can influence outcomes [ [15] , [16] , [17] , [18] , [19] , [20] ]. In patients with LOPD, ERT is associated with better outcome when started before irreversible muscle damage occurs [ [21] , [22] , [23] ]. In the absence of a family history, early (presymptomatic) diagnosis can only be achieved through newborn screening (NBS).…”

Section: Introductionmentioning

confidence: 99%

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Gragnaniello¹,

Pijnappel²,

Groen³

et al. 2022

Molecular Genetics and Metabolism Reports

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Early clinical phenotype of late onset Pompe disease: Lessons learned from newborn screening

Cited by 19 publications

References 29 publications

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

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

The Alberta Infant Motor Scale: A tool for the assessment of motor aspects of neurodevelopment in infancy and early childhood

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

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