Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light

Neurogenetics - Tập 24 Số 4 - Trang 291-301
Edouard Palu1, Julius Järvilehto2, Jana Pennonen2, Nadine Huber3, Sanna‐Kaisa Herukka4, Annakaisa Haapasalo3, Pirjo Isohanni2, Henna Tyynismaa2, Mari Auranen5, Emil Ylikallio5
1Department of Clinical Neurophysiology, Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
2Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
3A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
4Department of Neurology, Kuopio University Hospital, Kuopio, Finland
5Clinical Neurosciences, Neurology, Helsinki University Hospital, Biomedicum Room 525B, Haartmaninkatu 8, 00290, Helsinki, Finland

Tóm tắt

AbstractCharcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers’ growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.

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Neurogenetics

Tập 24 Số 4

291-301

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