Gomal Center of Biochemistry and Biotechnology, Gomal University, D.I.Khan, Pakistan.
Diagnostic and Research Institute of Human Genetics, Medical University of Graz, 8010, Graz, Austria.
Metab Brain Dis. 2022 Jan;37(1):243-252. doi: 10.1007/s11011-021-00832-2. Epub 2021 Nov 1.
L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly.
In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools.
Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH.
L-2-羟戊二酸尿症（L2HGA）是一种罕见的神经代谢疾病，由于 L-2-羟戊二酸在脑脊液（CSF）、血浆和尿液中的积累而发生。L2HGA 的临床表现包括智力障碍、小脑共济失调、癫痫、言语问题和大头畸形。
在本研究中，我们确定了一个有 5 名受影响个体的多代近亲巴基斯坦家庭。通过生化测试和脑部 CT 扫描进行临床研究。通过全基因组 SNP 基因分型、全外显子组测序和 Sanger 测序进行基因座作图。对于计算机研究，使用 I-TASSER、Cluspro 和 AutoDock VINA 工具进行蛋白质结构建模和对接。
受影响的个体表现出认知障碍、步态障碍、言语困难和精神运动迟缓。对一名男性患者的放射学分析显示白质脑白质呈脱髓鞘样低衰减，提示为少突胶质细胞发育不良。该家系的纯合子作图显示染色体 14 上标记 rs2039791 和 rs781354 之间存在连锁区域。随后的全外显子组分析确定了 L2HGDH 第二个外显子中的一个新的移码突变 NM_024884.3:c.180delG，p.(Ala62Profs*24)。Sanger 测序证实该突变与疾病表型的分离。该突变是迄今为止发表的最 N 端功能丧失突变的鉴定进一步扩展了 L2HGDH 的突变谱。
