Department of Neurology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Mov Disord. 2020 Dec;35(12):2343-2347. doi: 10.1002/mds.28244. Epub 2020 Sep 19.
In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction.
To demonstrate linkage and to identify the underlying genetic cause of disease.
Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed.
Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS.
Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.
在一个丹麦家族中，五代中有多人出现早发性阵发性颅部运动障碍、肌肉骨骼异常和肾功能障碍。
展示连锁关系并确定疾病的潜在遗传原因。
进行了全基因组单核苷酸多态性分析、序列标记位点分析、外显子组测序和 Sanger 测序。
连锁分析确定了 9 号染色体上的一个候选位点。外显子组测序揭示了所有受影响个体中存在的 LMX1B 中的一种新型变异，对数几率 (LOD) 得分 z = 6.54，预测为有害。指甲髌骨综合征 (NPS) 是由 LMX1B 编码的转录因子的致病变异引起的，该转录因子对细胞骨架和肾脏生长以及多巴胺能和 5-羟色胺能网络发育至关重要。NPS 的特征是肌肉骨骼异常和肾功能障碍。运动障碍以前与 NPS 无关。
阵发性运动障碍是 NPS 谱中以前未被认识到的特征。致病机制可能与异常的多巴胺能回路有关。
