The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype.
The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype.
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DOI：
10.1007/s00401-014-1251-9
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发表时间：
2014-03
影响因子：
12.7
通讯作者：
Kirby J
中科院分区：
文献类型：
--
作者：
Cooper-Knock J;Shaw PJ;Kirby J
C9ORF72的GGGGCC(G4C2)重复扩增是家族性肌萎缩侧索硬化症(ALS)、额颞叶痴呆(FTLD)和ALS-FTLD的最常见原因，也是这些疾病的散发性形式之一。对大量ALS和FTLD队列的筛选发现，C9ORF72-ALS在ALS表型的临床谱系中都有表达，尽管与其他遗传亚型相比，C9ORF72携带者有更高的球部起病发生率。相比之下，C9ORF72-FTLD主要与行为变异型FTD有关，后者通常表现为精神病，最常见的形式是幻觉和妄想。然而，C9ORF72的扩展并不局限于这些临床表型。在C9ORF72扩张型ALS患者中，帕金森综合征的发生率高于预期，G4C2重复序列在其他运动表型中也有报道，如原发性侧索硬化症、进行性肌肉萎缩、皮质基底膜综合征和亨廷顿样疾病。此外，在包括阿尔茨海默病和路易体痴呆在内的非运动表型中也发现了这种扩张。目前尚不清楚G4C2重复扩增的临床变异的基础是什么。一个可能的解释是重复长度。Southern blotting对扩张的大小进行了测定，证明存在体细胞的异质性，在不同的组织中扩张的长度不同，甚至在大脑内也是如此。到目前为止，在ALS中还没有建立与扩张大小和临床表型相关的关系，而在FTLD中，只有小脑中的重复大小与病程相关。体细胞的异质性表明，在重复中存在一定程度的不稳定性，并且有证据表明，随着后续世代发病年龄的降低，预期会出现。这种扩展长度的可变性/不稳定性，以及它与环境和遗传修饰物(如TMEM106B)的相互作用，可能是该突变引起的不同临床表型的基础。
The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS–FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer’s disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.
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影响因子：
3.7
作者：
Dobson-Stone C;Hallupp M;Loy CT;Thompson EM;Haan E;Sue CM;Panegyres PK;Razquin C;Seijo-Martínez M;Rene R;Gascon J;Campdelacreu J;Schmoll B;Volk AE;Brooks WS;Schofield PR;Pastor P;Kwok JB
通讯作者：
Kwok JB
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
3.5
作者：
Dols-Icardo, Oriol;Garcia-Redondo, Alberto;Clarimon, Jordi
通讯作者：
Clarimon, Jordi
影响因子：
14.5
作者：
Chio, Adriano;Borghero, Giuseppe;Sabatelli, Mario
通讯作者：
Sabatelli, Mario
影响因子：
4
作者：
Galimberti, Daniela;Arosio, Beatrice;Scarpini, Elio
通讯作者：
Scarpini, Elio