Abstract
Glycogen accumulation in the central nervous system of patients with classical infantile onset Pompe disease (IOPD) has been a consistent finding on the few post-mortems performed. While delays in myelination and a possible reduction in processing speed have previously been noted, it has only been recently that the potential for clinically significant progressive white matter disease has been noted. The limited reports thus far published infer that in some IOPD patients, this manifests as intellectual decline in the second decade of life. We present a CRIM negative patient, immunomodulated with rituximab and methotrexate at birth, who despite an initial good clinical response to ERT, at the age of just under 4 years, presented with evolving spasticity in the lower limbs. The investigation of which revealed progressive central nervous system involvement. Given both the earlier onset of the symptoms and consanguineous familial pedigree, extensive biochemical and genetic investigation was undertaken to ensure no alternative pathology was elucidated. In light of these findings, we review the radiology and post-mortems of previous cases and discuss the potential mechanisms that may underlie this presentation.
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Communicated by: Martina Huemer, MD
Appendices
Synopsis
Some patients with the classical variant of infantile onset Pompe disease run the risk of an early childhood onset progressive white matter involvement.
Details of the Contributions of Individual Authors
Dr. Broomfield conceived and was the main author of the manuscript.
Miss Fletcher: Helped collect data and has critically reviewed the manuscript.
Miss Hensman: Helped collect data and has critically reviewed the manuscript.
Mr. Wright: Both performed and analysed the data of the NGS investigations. He also critically reviewed the manuscript.
Miss Prunty performed the CSF HPLS tetrasaccharide assay and critically reviewed the manuscript.
Dr. Pavaine reviewed and selected the neuroimaging and critically reviewed the manuscript.
Dr. Jones helped collect data and conception of the manuscript and has reviewed the manuscript.
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Dr. A Broomfield
Competing Interest Statement
Dr. Broomfield and Dr. Jones have both received travel funding, teaching Honoria from and have done consultancy for Sanofi-Genzyme. The other authors have no conflict of interest of note.
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No funding was involved in this study and the authors confirm that the content of the article has not been influenced by the sponsors.
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Not applicable, given the nature of this case report.
A Patient Consent Statement
Parental consent for the use of the images has been granted.
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Not applicable given the nature of this case report.
Appendix
Genes examined by NGS targeted panel approach:
ABCD4, ACSF3, AMN, AUH, BCKDHA, BTD, CD320, CUBN, DBT, DHFR, DHFRL1, DNAJC19, FOLR1, FLOR2, FOLR3, FTCD, GIF, HCFC1, HLCS, IVD, LMBRD1, MCCC1, MCCC2, MCEE, MMAA, MMAB, MMACHC, MTHFD1, MTHFR, MTR, MTRR, MUT, OPA3, PCCA, PCCB, PPMIK, SERAC1, SLC19A3, SCL46A1, SLC52A1, SLC52A2, SLC5A3, SCULA2, SUCLG1, TAZ, TCN1, TCN2, TMEM70.
Unclassified variants identified through screening were the BCKDHD c.-4G>C heterozygote and PCCA C.1236A>G p.(Pro421Pro) het.
Genes examined using NGS targeted exome approach:
ACOX1, ACP5, AIMP1, ATN1, ATP7B, BCAP31, CGA, CLCN2, CLCN7, COL4A1, COL4A2, CSF1R, CTC1, DARS, DARS2, DCAF17, EARS2, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5,ERCC2, ERCC3, ERCC5, ERCC6, ERCC8, FA2H, FAM126A, FARS2, FHL1, FHL2, FKRP, FKTN, GAN, GBE1, GFAP, GJA1, GJC2, GPR56, GTF2H5, HSD17B4, HSPD1, HTRA1, JAM3, LAMA2, LARGE, LMNB1, MAGT1, MARS2, MLC1, MPLKIP, NDUFS1, NOTCH3, NPC1, NPC2, NUBPL, OCLN, OCRL, OSTM1, PEX1,PEX2,PEX3,PEX5,PEX6, PEX7, PEX10, PEX11B, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26, PLP1, PMM2, POLD1, POLR1C, POLR3A, POLR3B, POMGNT1, POMT1,POMT2.
RNASET2, SLC16A2, SLC17A5, SLC25A12, SLC7A2, SPG5A, SPG7, SPG11, SPG15, SPG18, SPG26, SPG35, PG53, TREM2, TUBB4A, TYROBP, ZFYVE26.
Unclassified variants identified using NGS targeted exome approach:
NM_025000.3 DCAF17 c.1030T>C p.(Trp344Arg) het
NM_004366.5 CLCN2 c.1930C>T p.(Arg644Cys) het
NM_003630.2 PEX3 c.161G>A p.(Arg54Gln) het
NM_001940.3 ATN1 c.1500_1508delGCAGCAGCA p.(Gln500_Gln502del) het
NM_000053.3 ATP7B c.442C>T p.(Arg148Trp) het
NM_013382.5 POMT2 c.2223A>G p.(=) het
NM_025137.3 SPG11 c.3146-4C>A het
NM_152415.2 SPG53 c.834A.G het
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Broomfield, A. et al. (2017). Rapidly Progressive White Matter Involvement in Early Childhood: The Expanding Phenotype of Infantile Onset Pompe?. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 39. JIMD Reports, vol 39. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_46
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DOI: https://doi.org/10.1007/8904_2017_46
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