Inoue K, Tanaka H, Scaglia F, Araki A, Shaffer L G, Lupski J R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ann Neurol. 2001 Dec;50(6):747-54. doi: 10.1002/ana.10036.
A submicroscopic duplication that contains the entire proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that carrier females for the duplication are usually asymptomatic. We describe 2 unrelated female patients who present with mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, has also shown clinical improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in both patients. Interphase fluorescent in situ hybridization analyses of the family members indicated that the duplication in both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocytes nor proteolipid protein gene coding alterations were identified in either patient. These findings indicate that, occasionally, females with a proteolipid protein gene duplication can manifest an early-onset neurological phenotype. We hypothesize that the remarkable clinical improvement is a result of myelin compensation by oligodendrocytes expressing one copy of proteolipid protein gene secondary to selection for a favorable X inactivation pattern. These findings indicate plasticity of oligodendrocytes in the formation of central nervous system myelin and suggest a potential role for stem cell transplantation therapies.
一个包含整个蛋白脂蛋白基因的亚显微重复是佩利措伊斯-梅茨巴赫病的主要病因，这是一种X连锁的中枢神经系统脱髓鞘疾病。先前的研究表明，携带该重复的女性通常无症状。我们描述了2例无关的女性患者，她们表现为轻度佩利措伊斯-梅茨巴赫病或痉挛性截瘫。在1例患者中，临床特征以及头颅磁共振成像和脑干听觉诱发电位结果在10年期间有显著改善。另1例表现为痉挛性双瘫且最初被诊断为脑瘫的患者也有临床改善。间期荧光原位杂交在2例患者中均检测到蛋白脂蛋白基因重复。对家庭成员的间期荧光原位杂交分析表明，2例患者的重复均为新发事件。2例患者外周淋巴细胞中均未发现X染色体失活偏斜，也未发现蛋白脂蛋白基因编码改变。这些发现表明，偶尔，携带蛋白脂蛋白基因重复的女性可表现出早发性神经表型。我们推测，显著的临床改善是由于少突胶质细胞对蛋白脂蛋白基因一个拷贝的表达进行髓鞘补偿，这继发于对有利的X染色体失活模式的选择。这些发现表明少突胶质细胞在中枢神经系统髓鞘形成中具有可塑性，并提示干细胞移植治疗的潜在作用。
