Tse Jonathan, Abu-Qamar Asem, Youssef Omar, Pejka Sherry L
Western Michigan University Homer Stryker School of Meidcine, Kalamazoo, MI, USA.
Department of Pediatrics and Adolescent Medicine, Bronson Methodist Hospital, Kalamazoo, MI, USA.
Case Rep Neurol. 2024 Dec 3;17(1):1-8. doi: 10.1159/000542886. eCollection 2025 Jan-Dec.
Biotin-thiamine responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder characterized by diverse and variable phenotypic features, which can make diagnosis challenging. However, prompt treatment with thiamine and biotin can effectively manage the condition. Diagnosis relies on the identification of biallelic pathogenic variants in the gene. This case report describes two novel variants of uncertain significance in the gene, which may be correlated with the phenotypic manifestations of BTBGD.
Our case is a 7-month-old female infant who presented with a 3-week history of irritability, altered behavior, and refusal of newly introduced solid foods. Symptoms started with an upper respiratory tract infection, followed by lethargy, floppiness, and abnormal movements. The patient was admitted to the pediatric ward with a broad differential diagnosis. Extensive laboratory evaluations revealed lactic acidosis. MRI brain showed symmetric restricted diffusion affecting the bilateral basal ganglia, thalami, and cortical regions. Whole genome sequencing identified biallelic variants of the SLC19A3: a c.1364T>G p.Met455Arg missense variant in the maternal allele and a 2.3 kb deletion of intron 3 of the paternal allele. Both variants were identified as variants of uncertain significance. However, given the clinical picture, MRI brain findings, resolution of symptoms with empiric biotin and thiamine supplementation, and biallelic SLC19A3 variants of unknown significance, the patient most likely suffers from BTBGD. Patient continues to show sustained developmental progress on biotin and thiamine supplementation.
This case highlights the fact that genetic testing remains a vital but improvable tool for the diagnosis of BTBGD. As of yet, genetic testing and diagnosis of BTBGD continues to be limited by the knowledge of which SLC19A3 variants are established to be pathogenic variants. Thus, further research is required to study other SCL19A3 variants of unknown significance to further improve genetic testing and diagnosis of BTBGD in the future.
生物素 - 硫胺素反应性基底节疾病（BTBGD）是一种罕见的常染色体隐性神经代谢障碍，其特征为多样且可变的表型特征，这可能使诊断具有挑战性。然而，硫胺素和生物素的及时治疗可有效控制病情。诊断依赖于在该基因中鉴定双等位基因致病性变异。本病例报告描述了该基因中两个意义未明的新变异，它们可能与BTBGD的表型表现相关。
我们的病例是一名7个月大的女婴，有3周的烦躁、行为改变及拒绝新引入固体食物的病史。症状始于上呼吸道感染，随后出现嗜睡、肢体松软和异常运动。该患者因广泛的鉴别诊断被收入儿科病房。广泛的实验室评估显示乳酸酸中毒。脑部MRI显示双侧基底节、丘脑和皮质区域对称的扩散受限。全基因组测序鉴定出SLC19A3的双等位基因变异：母本等位基因中的c.1364T>G p.Met455Arg错义变异和父本等位基因中第3内含子的2.3 kb缺失。这两个变异均被鉴定为意义未明的变异。然而，鉴于临床表现、脑部MRI结果、经验性补充生物素和硫胺素后症状缓解以及意义未明的双等位基因SLC19A3变异，该患者很可能患有BTBGD。患者在补充生物素和硫胺素后持续显示出发育进展。
本病例突出了基因检测仍然是诊断BTBGD的重要但有待改进的工具这一事实。截至目前，BTBGD的基因检测和诊断仍受到对哪些SLC19A3变异被确定为致病性变异的认识的限制。因此，需要进一步研究其他意义未明的SCL19A3变异，以在未来进一步改善BTBGD的基因检测和诊断。
