一个反复出现的纯合错义变体,c.160G>C;p.(Val54Leu)在HIKESHI,在Ashkenazi犹太人口中被发现引起高频率的骨髓过盈性脑白质营养不良。我们根据另外7名受影响个体的临床病史提供了这种疾病的扩展表型分类。评估阿什肯纳齐犹太人口的载波频率,并提供神经病理学研究。
临床信息,神经影像学,并收集生物样本。对1例患者进行脑部尸检。
患有HIKESHI相关疾病的个体具有共同的临床特征:早期轴向张力减退演变为肌张力障碍或进行性痉挛,反射亢进和阵风,生长困难的喂养困难,和眼球震颤.在9个受影响的个体中,有5个发生了高热疾病期间的严重发病率或死亡。分析了7例患者的磁共振图像,并显示了弥漫性骨髓增生和call体薄。超过125,000名Ashkenazi犹太人的基因分型数据显示,载波频率为216中的1。1例大体病理检查提示脑白质异常。微观上,髓鞘几乎完全缺失,轴突相对保留.脑白质显示几个反应性星形胶质细胞和小胶质细胞。
我们提供了HIKESHI相关脑白质营养不良的髓鞘原发疾病的病理证据。这些发现与在脑磁共振成像中看到的骨髓增生异常以及早发性痉挛/肌张力障碍四肢瘫痪和眼震的临床特征一致。在Ashkenazi犹太人口中发现的复发性变异的高携带率需要更多地关注这种疾病的筛查和诊断,尤其是在这个群体中。
A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study.
Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case.
Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia.
We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.