Hashemi Seyyed-Saleh, Hajati Reza, Davarzani Atefeh, Rohani Mohammad, DanaeeFard Fardad, Rahimi Bidgoli Mohammad Masoud, Fatehi Farzad, Kariminejad Ariana, Najmabadi Hossein, Nafissi Shahriar, Alavi Afagh
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Department of Neurology, Iran University of Medical Sciences, Hazrat Rasool Hospital, Tehran, Iran.
Can J Neurol Sci. 2022 Sep;49(5):651-661. doi: 10.1017/cjn.2021.188. Epub 2021 Aug 6.
Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families.
Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation.
Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the , , and genes, while five families harbored mutations in the gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (-value <0.05).
It seems will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype-phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.
遗传性痉挛性截瘫（HSP）是一种具有下肢痉挛和无力症状的异质性神经退行性疾病。在HSP中已发现不同的遗传模式。大多数常染色体显性遗传性痉挛性截瘫（AD-HSP）与 基因（SPG4）突变相关，导致具有可变发病年龄（AAO）的纯合形式的HSP。疾病早发以及连续几代中症状加重的遗传早现现象可能与SPG4相关。在此，我们提出遗传早现现象在SPG4家族中可能是一个相对常见的发现。
对14名无亲缘关系的伊朗AD-HSP先证者的DNA进行全外显子组测序。分析数据，对候选变异进行PCR扩增并通过桑格法测序，随后在家庭成员中进行共分离分析。对7名先证者进行多重连接依赖探针扩增（MLPA）。记录先证者的临床特征，并在这些家族中检查可能的遗传早现现象。对其他先前报道的SPG4家族进行遗传早现现象调查。
我们的研究结果表明，SPG4是HSP的常见亚型；三个家族在 、 和 基因中携带变异，而五个家族在 基因中存在突变。仅SPG4家族的临床特征表明连续几代受影响个体的AAO降低，且这种差异具有统计学意义（-值<0.05）。
对于表现为纯合形式的AD-HSP和遗传早现现象的家族， 似乎将是第一个候选基因。因此，这可能是基因型-表型相关性的一个有力实例。然而，这些家族中遗传早现现象的潜在机制尚不清楚。
