Abstract
Phosphoglucomutase 1 (PGM1) deficiency is a recently defined disease characterized by glycogenosis and a congenital glycosylation disorder caused by recessive mutations in the PGM1 gene. We report a case of a 12-year-old boy with first-cousin parents who was diagnosed with a PGM1 deficiency due to significantly decreased PGM1 activity in his muscle. However, Sanger sequencing revealed no pathogenic mutation in the PGM1 gene in this patient. As this case presented with a cleft palate in addition to hypoglycemia and elevated transaminases and creatine kinase, karyotyping was performed and identified homozygous inv(1)(p31.1p32.3). Based on the chromosomal location of the PGM1 gene at 1p31, we analyzed the breakpoint of the inversion. Fluorescence in situ hybridization (FISH) combined with long PCR analysis revealed that the inversion disrupts the PGM1 gene within intron 1. Since the initiation codon in the PGM1 gene is located within exon 1, we speculated that this inversion inactivates the PGM1 gene and was therefore responsible for the patient’s phenotype. When standard molecular testing fails to reveal a mutation despite a positive clinical and biochemical diagnosis, the presence of a gross structural variant that requires karyotypic examination must be considered.
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Acknowledgments
We thank the patient and his family for their participation in this study. We also thank past and present members of our laboratory. This research was partly supported by the intramural research grant (29-4) for Neurological and Psychiatric Disorders of NCNP (H. Sugie).
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Communicated by: Eva Morava, MD PhD
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Synopsis Sentence
Karyotypic examination must be considered when standard molecular testing fails to reveal a mutation despite a positive clinical and biochemical diagnosis.
Conflict of Interest
Katsuyuki Yokoi, Yoko Nakajima, Ohye Tamae, Hidehito Inagaki, Yoshinao Wada, Tokiko Fukuda, Hideo Sugie, Isao Yuasa, Tetsuya Ito, and Hiroki Kurahashi declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2005(5). Informed consent was obtained from all patients for inclusion in the study.
Author Contributions
Katsuyuki Yokoi retrieved the data and drafted and revised the manuscript.
Yoko Nakajima and Tetsuya Ito discovered the patients and provided many data.
Tamae Ohye did cytogenetic analysis and sequence analysis.
Hidehito Inagaki supported and supervised experiments.
Yoshinao Wada did mass spectrometry.
Tokiko Fukuda and Hideo Sugie estimated enzyme activity.
Isao Yuasa did IEF of serum transferrin.
Hiroki Kurahashi: conception and design, analysis and interpretation, and revising the article critically for important intellectual content.
All authors contributed to and reviewed the manuscript.
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Yokoi, K. et al. (2018). Disruption of the Responsible Gene in a Phosphoglucomutase 1 Deficiency Patient by Homozygous Chromosomal Inversion. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_108
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DOI: https://doi.org/10.1007/8904_2018_108
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