Masliah-Planchon Julien, Dupont Céline, Vartzelis George, Trimouille Aurélien, Eymard-Pierre Eléonore, Gay-Bellile Mathilde, Renaldo Florence, Dorboz Imen, Pagan Cécile, Quentin Samuel, Elmaleh Monique, Kotsogianni Christina, Konstantelou Elissavet, Drunat Séverine, Tabet Anne-Claude, Boespflug-Tanguy Odile
UF de Génétique moléculaire, Hôpital Robert Debré, AP-HP, Paris, France.
Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France.
BMC Med Genet. 2015 Sep 2;16:77. doi: 10.1186/s12881-015-0226-6.
Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia, progressive spasticity, and cognitive decline. PMD classically results from a duplication of a genomic segment encompassing the entire PLP1 gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys.
Here we report the case of a girl with typical PMD. Copy number analysis of the PLP1 locus revealed a duplication of the entire gene and FISH analysis showed that the extra copy of the PLP1 gene was actually inserted in chromosome 1p36. This insertion of an additional copy of PLP1 in an autosome led to a functional duplication irrespective of the X-inactivation pattern. Subsequent overexpression of PLP1 was the cause of the PMD phenotype observed in this girl. Further sequencing of the breakpoint junction revealed a microhomology and thus suggested a replication based mechanism (such as FoSTeS or MMBIR).
This case emphasizes the susceptibility of the PLP1 locus to complex rearrangement likely driven by the Xq22 local genomic architecture. In addition, careful consideration should be given to girls with classical PMD clinical features since they usually experience complex PLP1 genomic alteration with a distinct risk of inheritance.
佩利措伊斯-梅茨巴赫病（PMD）是一种X连锁性脱髓鞘疾病，其特征为眼球震颤、肌张力减退、共济失调、进行性痉挛和认知功能下降。经典的PMD是由包含整个PLP1基因的基因组片段重复所致。由于PLP1基因位于Xq22，PMD主要影响男性。
我们在此报告一例典型PMD女童病例。对PLP1基因座进行拷贝数分析发现整个基因存在重复，荧光原位杂交（FISH）分析显示PLP1基因的额外拷贝实际上插入到了1号染色体的1p36区域。PLP1基因在常染色体上的这种额外拷贝插入导致了功能重复，而与X染色体失活模式无关。随后PLP1的过表达是该女童出现PMD表型的原因。对断点连接区的进一步测序发现了微同源性，因此提示了一种基于复制的机制（如FoSTeS或MMBIR）。
该病例强调了PLP1基因座对可能由Xq22局部基因组结构驱动的复杂重排的易感性。此外，对于具有典型PMD临床特征的女童应予以仔细考虑，因为她们通常经历复杂的PLP1基因组改变且具有独特的遗传风险。
