DDC Clinic for Special Needs Children, Middlefield, OH 44062, USA.
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5372-7. doi: 10.1073/pnas.1014265108. Epub 2011 Mar 14.
We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.
我们描述了一种常染色体隐性遗传病，其特征为脑血管病和 14 名旧秩序阿米什人中风的早期发病。该病的表型高度异质，从严重的发育障碍到正常的学校教育都有。脑血管病是该病的主要标志，其共同特征是大动脉的多发性狭窄和动脉瘤，伴有慢性缺血性改变、烟雾病形态以及先前急性梗死和出血的证据。疾病的早期迹象包括宫内生长受限、婴儿性低张力和易激惹，随后是生长不良和身材矮小。发绀、雷诺现象、冻疮样病变、低调嘶哑的声音、青光眼、偏头痛和关节炎经常观察到。继发于脑血管病的中风的早期发病或复发似乎总是与不良结局相关。这些患者中发现的红细胞沉降率 (ESR)、IgG、新蝶呤和 TNF-α 升高表明存在免疫紊乱。通过全基因组 homozygosity 映射，我们将疾病基因定位到染色体 (Chr) 20q11.22-q12。候选基因测序在 SAMHD1 基因中发现了一个纯合突变，c.1411-2A > G，与该疾病相关。该突变出现在内含子 12 的剪接受体位点，导致外显子 13 的跳跃，并产生一种异常蛋白，其框架内缺失 31 个氨基酸。免疫印迹分析显示受影响的细胞系中缺乏突变的 SAMHD1 蛋白表达。SAMHD1 的功能尚不清楚，但在 SAMHD1 突变患者中发现的炎症性脑血管病表明其在免疫调节和脑血管血红素平衡中具有重要作用。
