Rudenskaya G E, Guseva D M, Mironovich O L, Kadnikova V A, Dadali E L, Komar'kov I F, Novoselova O G, Ryzhkova O P
Research Centre for Medical Genetics, Moscow, Russia.
Genomed Ltd, Moscow, Russia.
Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(2):71-78. doi: 10.17116/jnevro202112102171.
In the course of studies of spastic paraplegias in Russian patients to detect AP4-associated forms, estimate their proportion in the total SPG group and analyze clinical and molecular characteristics.
Five families of Russian ethnicity: four with SPG47, one with SPG51 (4 girls and a boy aged 2.5-9 years) were studied. Clinical and genealogical methods, whole-exome sequencing (WES) and verification by familial Sanger sequencing were used.
In our total group, including 118 families with 21 different forms, SPG AP4-associated forms accounted for 4.2% owing mainly to SPG47 (3.4%, 5 place in SPG structure; 20% and 2 place in AE subgroup.) In non-consanguineous, unrelated SPG47 families three patients had identical genotypes: homozygosity for an earlier reported mutation c.1160_1161 delCA (p.Thr387ArgfsTer30) in AP4B1 exon 6; the 4 patient was compound-heterozygous for the same mutation and novel c.1240C>T (p.Gln414Ter) in exon 7. Frequency of c.1160_1161 delCA may be caused by founder effect in Slavic populations though the idea needs additional studies. The SPG51 patient was compound heterozygous for novel AP4E1 mutations c.2604delA (p.Ser868fs) and c.3346A>G (p.Arg1116Gly). Parent's heterozygosity in all cases was confirmed by Sanger sequencing. Phenotypes were typical: early development delay, muscle hypotony transforming into sever spasticity, mental deficiency, microceplaly (in all SPG47 cases), epilepsy (in 3 SPG47 and SPG51 cases), MRI changes, mainly hydrocephalus and/or hypoplasia of corpus callosum (in 3 SPG47 cases) and few extraneural signs.
AP4-associated SPG should be taken into consideration in patients with early-onset severe nervous diseases mimicking non-genetic organic CNS disorders and massive exome sequencing (WES or other variants) should be performed.
在对俄罗斯患者痉挛性截瘫的研究过程中，检测与AP4相关的类型，评估其在痉挛性截瘫（SPG）总群体中的比例，并分析临床和分子特征。
研究了五个俄罗斯族裔家庭：四个患有SPG47，一个患有SPG51（4名女孩和1名2.5至9岁男孩）。采用了临床和系谱学方法、全外显子组测序（WES）以及家族性桑格测序进行验证。
在我们的总群体中，包括118个家庭、21种不同类型，与SPG AP4相关的类型占4.2%，主要归因于SPG47（3.4%，在SPG结构中排第5位；在AE亚组中占20%且排第2位）。在非近亲、无血缘关系的SPG47家庭中，3例患者具有相同的基因型：AP4B1外显子6中一个先前报道的突变c.1160_1161delCA（p.Thr387ArgfsTer30）的纯合子；第4例患者为该相同突变与外显子7中新型c.1240C>T（p.Gln414Ter）的复合杂合子。c.1160_1161delCA的频率可能是由斯拉夫人群中的奠基者效应引起的，不过这一观点需要进一步研究。SPG51患者为新型AP4E1突变c.2604delA（p.Ser868fs）和c.3346A>G（p.Arg1116Gly）的复合杂合子。所有病例中父母的杂合性均通过桑格测序得以证实。表型具有典型性：早期发育迟缓、肌张力减退转变为严重痉挛、智力缺陷、小头畸形（所有SPG47病例）、癫痫（3例SPG47和SPG51病例）、MRI改变，主要为脑积水和/或胼胝体发育不全（3例SPG47病例）以及少数神经外体征。
对于表现出类似非遗传性器质性中枢神经系统疾病的早发性严重神经疾病患者，应考虑与AP4相关的痉挛性截瘫，并应进行大规模外显子组测序（WES或其他变体）。
