SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report.
SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report.
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DOI：
10.1186/s12883-021-02087-x
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发表时间：
2021-02-11
期刊：
影响因子：
2.6
通讯作者：
Takiyama Y
中科院分区：
文献类型：
--
作者：
Koh K;Takaki R;Ishiura H;Tsuji S;Takiyama Y
ALDH18A1突变导致β-1-吡咯烷-5-羧酸合成酶(P5CS)缺乏，是一种与尿素循环相关的疾病，包括SPG9A、SPG9B、常染色体显性遗传皮肤松弛-3(ADCL3)和常染色体隐性遗传性皮肤松弛3A(ARCL3A)。这些疾病表现出广泛的临床谱，这使得P5CS缺乏症的诊断变得困难。我们在这里报告一个罕见的日本家庭，包括ALDH18A1突变(SPG9A)患者和CMT1A患者。一个日本家庭包括4代中5名CMT表型患者和5名HSP表型患者。HSP表型的患者表现为单纯或复杂的形式，并注意到家庭内的临床变异性。FISH分析显示，两名CMT患者存在PMP22重复(CMT1A)。外显子分析和Sanger测序显示，5例过敏性紫斑狼疮患者存在 >； A基因的杂合突变，导致SPG9A。单倍型分析表明，ALDH18A1突变可能是新发生的。到目前为止，尽管ALDH18A1的从头突变已经在ADCL3A中描述，但在早期的报告中没有在SPG9A中提到。因此，这是第一个发生ALDH18A1重新突变或性腺嵌合体新出现的SPG9A家族。血清氨基酸水平分析显示，两名SPG9A患者和两名未受影响的家庭成员瓜氨酸水平较低，一名患者的鸟氨酸水平较低。由于新发现的ALDH18A1突变c.755G >； A与先前报道的两个ADHSP家系和一名散发性SPG9A患者的突变相同，因此该基因组位置很容易发生突变。我们家系中携带c.755G >； A突变的患者表现出与先前报道的2个家系和1名散发性患者一样的临床症状变异。P5CS缺乏对ARCL3A、ADCL3、SPG9B和SPG9A等疾病表型的影响尚需进一步研究以阐明其与临床表现的关系。
ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A. A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine. Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.
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影响因子：
14.9
作者：
Tadaka S;Saigusa D;Motoike IN;Inoue J;Aoki Y;Shirota M;Koshiba S;Yamamoto M;Kinoshita K
通讯作者：
Kinoshita K
影响因子：
3.3
作者：
Koh K;Ishiura H;Tsuji S;Takiyama Y
通讯作者：
Takiyama Y
影响因子：
9.8
作者：
Fischer-Zirnsak, Bjoern;Escande-Beillard, Nathalie;Kornak, Uwe
通讯作者：
Kornak, Uwe
影响因子：
1.7
作者：
Nozaki, Fumihito;Kusunoki, Takashi;Fujii, Tatsuya
通讯作者：
Fujii, Tatsuya
DOI：
10.1136/jnnp-2018-318839
发表时间：
2019-03
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Yoshimura A;Yuan JH;Hashiguchi A;Ando M;Higuchi Y;Nakamura T;Okamoto Y;Nakagawa M;Takashima H
通讯作者：
Takashima H