BACKGROUND The ALDH18A1 gene is located at 10q24.1 and encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), a mitochondrial bifunctional enzyme that catalyzes the first two steps in de novo biosynthesis of proline, ornithine, citrulline, and arginine. ALDH18A1-related disorders have been classified into four groups, such as autosomal dominant and recessive hereditary spastic paraplegia (SPG9A and SPG9B, respectively), as well as autosomal dominant and recessive cutis laxa (ADCL3 and ARCL3A, respectively). Neurodegeneration is a characteristic feature of all groups. CASE REPORT Here, we report a girl with compound heterozygous disease-causing variants (c.-28-2A>G and c.383G>A, p.Arg128His) in the ALDH18A1 gene, revealed by whole exome sequencing. The c.-28-2A>G variant in intron 1, inherited from the mother, is a novel mutation, while the c.383G>A variant in exon 4, inherited from the father, has already been reported. The patient presented with vigorous infantile tremor preceding progressive spastic paraplegia. Dysmorphic features included elongated face, deep-set ears, upturned nose, long philtrum and pointed chin. Intrauterine and postnatal growth retardation, microcephaly, global developmental delay and profound intellectual disability were also noticed. Blood fasting ammonia level, plasma proline, ornithine and arginine levels were normal, while citrulline level was slightly decreased. Brain MRI revealed moderate hypoplasia of the corpus callosum and reduction of white matter volume. CONCLUSIONS The patient represents SPG9B, a rare form of autosomal recessive hereditary spastic paraplegias. The early onset tremor, preceding lower limb spasticity appears to be a unique early manifestation of neurodegeneration in this case.

中文翻译：

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震颤是 ALDH18A1 突变引起的遗传性痉挛性截瘫的早期征兆

背景 ALDH18A1 基因位于 10q24.1 并编码 delta-1-pyrroline-5-carboxylate synthetase (P5CS)，这是一种线粒体双功能酶，可催化脯氨酸、鸟氨酸、瓜氨酸和精氨酸从头生物合成的前两个步骤。ALDH18A1 相关疾病分为四组，例如常染色体显性和隐性遗传性痉挛性截瘫（分别为 SPG9A 和 SPG9B），以及常染色体显性和隐性皮肤松弛症（分别为 ADCL3 和 ARCL3A）。神经变性是所有群体的特征。病例报告 在此，我们报告了一名女孩，其 ALDH18A1 基因具有复合杂合致病变异（c.-28-2A>G 和 c.383G>A，p.Arg128His），通过全外显子组测序显示。遗传自母亲的内含子 1 中的 c.-28-2A>G 变异是一种新的突变，而遗传自父亲的外显子 4 中的 c.383G>A 变体已有报道。患者在进行性痉挛性截瘫之前出现剧烈的婴儿震颤。畸形特征包括拉长的脸、深陷的耳朵、上翘的鼻子、长人中和尖下巴。还注意到宫内和产后生长迟缓、小头畸形、全面发育迟缓和严重智力障碍。空腹血氨水平、血浆脯氨酸、鸟氨酸和精氨酸水平正常，而瓜氨酸水平略有下降。脑部 MRI 显示胼胝体中度发育不全和白质体积减少。结论 该患者代表 SPG9B，这是一种罕见的常染色体隐性遗传性痉挛性截瘫。早发性震颤，