Lohmann Ebba, Periquet Magali, Bonifati Vincenzo, Wood Nick W, De Michele Giuseppe, Bonnet Anne-Marie, Fraix Valérie, Broussolle Emmanuel, Horstink Martin W I M, Vidailhet Marie, Verpillat Patrice, Gasser Thomas, Nicholl David, Teive Hélio, Raskin Salmo, Rascol Olivier, Destée Alain, Ruberg Merle, Gasparini Francesca, Meco Giuseppe, Agid Yves, Durr Alexandra, Brice Alexis
INSERM U289, Hôpital de la Salpêtrière, Paris, France.
Ann Neurol. 2003 Aug;54(2):176-85. doi: 10.1002/ana.10613.
To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.
为了建立早发性帕金森病的表型-基因型相关性，我们比较了146例携带帕金基因突变的患者和250例未携带该突变的患者的表型。虽然没有单一症状能区分这两组患者，但携带突变的患者发病明显更早且更对称，发病时更常出现肌张力障碍和反射亢进，疾病进展较慢，并且尽管左旋多巴剂量较低，但对其反应有增强的趋势。经过向前逐步多因素逻辑回归分析，发病时的肌张力障碍和活跃的反射不再有显著差异，但与发病年龄相关，而非与帕金基因突变的存在相关。帕金基因突变携带者的发病年龄各不相同，疾病进展速度也各异：发病年龄越小，病情进展越慢。基因型影响表型：至少携带一个错义突变的携带者比携带两个截短突变的携带者帕金森病统一评分量表运动评分更高。突变的定位也很重要，因为帕金基因功能域中的错义突变会导致发病更早。与携带两个突变的患者相比，携带单一杂合突变的患者发病更晚且更不对称，左旋多巴诱发的波动和肌张力障碍更频繁。
