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Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant.
Mol Genet Metab 2017; 122(3):99-107MG

Abstract

OBJECTIVE

Newborn screening (NBS) has led to early diagnosis and early initiation of treatment for infantile onset Pompe Disease (IOPD). However, guidelines for management of late onset Pompe disease (LOPD) via NBS, especially with the IVS c.-32-13T>G are not clear. This IVS variant is noted in 68-90% cases with LOPD and has been presumed to result in "adult" disease in compound heterozygosity, with a few cases with earlier onset and a mild to no phenotype in homozygosity. Our study evaluates newborns with LOPD having IVS variant with a diligent multidisciplinary approach to determine if they have an early presentation.

METHODS

Seven children with LOPD identified by NBS with IVS variant (3 compound heterozygous, and 4 homozygous) were evaluated with clinical, biochemical (CK, AST, ALT, and urinary Glc4), cardiac evaluation, physical therapy (PT), occupational, and speech/language therapy.

RESULTS

All seven patients demonstrated motor involvement by age 6months; the three patients with c.-32-13 T>G variant in compound heterozygosity had symptoms as neonates. Patients with c.-32-13 T>G variant in compound heterozygosity had more involvement with persistent hyperCKemia, elevated AST and ALT, swallowing difficulties, limb-girdle weakness, delayed motor milestones, and were initiated on ERT. The patients with c.-32-13T>G variant in homozygosity had normal laboratory parameters, and presented with very subtle yet LOPD specific signs, identified only by meticulous assessments.

CONCLUSION

This patient cohort represents the first carefully phenotyped cohort of infants with LOPD with the "late-onset" GAA variant c.-32-13T>G detected by NBS in the USA. It emphasizes not only the opportunity for early detection of skeletal and other muscle involvement in infants with c.-32-13T>G variant but also a high probability of overlooking or underestimating the significance of clinically present and detectable features. It can thus serve as a valuable contribution in the development of evaluation and treatment algorithms for infants with LOPD.

Authors+Show Affiliations

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.Department of Orthopedics, Duke University School of Medicine, Durham, NC, USA.Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.Department of Physical Therapy and Occupational Therapy, Duke Health, Durham, NC, USA.Department of Physical Therapy and Occupational Therapy, Duke Health, Durham, NC, USA.Department of Physical Therapy and Occupational Therapy, Duke Health, Durham, NC, USA.Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. Electronic address: priya.kishnani@duke.edu.

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28951071

Citation

Rairikar, Mugdha V., et al. "Insight Into the Phenotype of Infants With Pompe Disease Identified By Newborn Screening With the Common c.-32-13T>G "late-onset" GAA Variant." Molecular Genetics and Metabolism, vol. 122, no. 3, 2017, pp. 99-107.
Rairikar MV, Case LE, Bailey LA, et al. Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant. Mol Genet Metab. 2017;122(3):99-107.
Rairikar, M. V., Case, L. E., Bailey, L. A., Kazi, Z. B., Desai, A. K., Berrier, K. L., ... Kishnani, P. S. (2017). Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant. Molecular Genetics and Metabolism, 122(3), pp. 99-107. doi:10.1016/j.ymgme.2017.09.008.
Rairikar MV, et al. Insight Into the Phenotype of Infants With Pompe Disease Identified By Newborn Screening With the Common c.-32-13T>G "late-onset" GAA Variant. Mol Genet Metab. 2017;122(3):99-107. PubMed PMID: 28951071.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant. AU - Rairikar,Mugdha V, AU - Case,Laura E, AU - Bailey,Lauren A, AU - Kazi,Zoheb B, AU - Desai,Ankit K, AU - Berrier,Kathryn L, AU - Coats,Julie, AU - Gandy,Rachel, AU - Quinones,Rebecca, AU - Kishnani,Priya S, Y1 - 2017/09/19/ PY - 2017/08/06/received PY - 2017/09/14/revised PY - 2017/09/14/accepted PY - 2017/9/28/pubmed PY - 2018/8/2/medline PY - 2017/9/28/entrez KW - Enzyme replacement therapy KW - Glycogen storage disease type II KW - IVS variant KW - Late onset Pompe disease KW - Newborn screening KW - c.-32-13T>G SP - 99 EP - 107 JF - Molecular genetics and metabolism JO - Mol. Genet. Metab. VL - 122 IS - 3 N2 - OBJECTIVE: Newborn screening (NBS) has led to early diagnosis and early initiation of treatment for infantile onset Pompe Disease (IOPD). However, guidelines for management of late onset Pompe disease (LOPD) via NBS, especially with the IVS c.-32-13T>G are not clear. This IVS variant is noted in 68-90% cases with LOPD and has been presumed to result in "adult" disease in compound heterozygosity, with a few cases with earlier onset and a mild to no phenotype in homozygosity. Our study evaluates newborns with LOPD having IVS variant with a diligent multidisciplinary approach to determine if they have an early presentation. METHODS: Seven children with LOPD identified by NBS with IVS variant (3 compound heterozygous, and 4 homozygous) were evaluated with clinical, biochemical (CK, AST, ALT, and urinary Glc4), cardiac evaluation, physical therapy (PT), occupational, and speech/language therapy. RESULTS: All seven patients demonstrated motor involvement by age 6months; the three patients with c.-32-13 T>G variant in compound heterozygosity had symptoms as neonates. Patients with c.-32-13 T>G variant in compound heterozygosity had more involvement with persistent hyperCKemia, elevated AST and ALT, swallowing difficulties, limb-girdle weakness, delayed motor milestones, and were initiated on ERT. The patients with c.-32-13T>G variant in homozygosity had normal laboratory parameters, and presented with very subtle yet LOPD specific signs, identified only by meticulous assessments. CONCLUSION: This patient cohort represents the first carefully phenotyped cohort of infants with LOPD with the "late-onset" GAA variant c.-32-13T>G detected by NBS in the USA. It emphasizes not only the opportunity for early detection of skeletal and other muscle involvement in infants with c.-32-13T>G variant but also a high probability of overlooking or underestimating the significance of clinically present and detectable features. It can thus serve as a valuable contribution in the development of evaluation and treatment algorithms for infants with LOPD. SN - 1096-7206 UR - https://www.unboundmedicine.com/medline/citation/28951071/Insight_into_the_phenotype_of_infants_with_Pompe_disease_identified_by_newborn_screening_with_the_common_c__32_13T>G_"late_onset"_GAA_variant_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(17)30501-2 DB - PRIME DP - Unbound Medicine ER -