Autosomal‐recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood‐onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile‐onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next‐generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2‐related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N‐terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2‐related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well‐characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.

中文翻译：

---

七个具有新型ALS2突变的运动神经元疾病家族的基因型与表型相关性

Alsin Rho鸟嘌呤核苷酸交换因子（ALS2）的常染色体隐性突变该基因可能导致儿童期进行性神经退行性运动神经元疾病（MND）的特定亚型。这些疾病可表现为从婴儿升性遗传性痉挛性截瘫（IAHSP）到伴或不伴有较低运动神经元的少年发作形式，少年原发性侧索硬化症（JPLS）和少年肌萎缩性侧索硬化症（JALS）的临床连续性。我们报告了来自七个不相关的土耳其和也门家庭的11名患者的IAHSP或JPLS的临床体征。我们进行了单倍型分析或下一代面板测序，然后进行了Sanger测序，以阐明遗传疾病的原因。我们描述了他们的临床表型，并使用生物信息学工具分析了检测到的变异的致病性。我们进一步审查了所有先前报告的ALS2病例相关的MND。我们确定了五个新的纯合致病变种中ALS2在各种位置：c.275_276delAT（p.Tyr92CysfsTer11），c.1044C> G（p.Tyr348Ter），c.1718C> A（p.Ala573Glu），c.3161T> C（ p.Leu1054Pro）和c.1471 + 1G> A（NM_020919.3，NP_065970.2）。在我们的队列中，疾病发作是在婴儿期或儿童早期，运动神经元体征迅速发作。肌肉无力，痉挛，严重的构音困难，吞咽困难和面部无力是生命的头十年。聚集在N末端Alsin域中的移码和无意义突变最为普遍。我们用五个新的致病变体丰富了ALS2相关疾病的突变谱。我们的研究表明ALS2的检出率很高具有临床特征明确的早期MND的患者体内的突变。具有相同致病变异的患者的家族内甚至家族间的多样性表明，表型表达的修饰子还未知。