Pediatric Endocrinology and Inherited Metabolic Department, Guangdong Women and Children Hospital, Guangzhou 511442, China.
Department of Clinical Laboratory, Guangdong Women and Children Hospital, Guangzhou 511442, China.
Int J Mol Sci. 2023 Jun 16;24(12):10239. doi: 10.3390/ijms241210239.
Biotinidase (BTD) deficiency (OMIM 253260) is an autosomal recessively inherited metabolic disorder resulting from deficient activity of the BTD enzyme, which can cleave and release biotin from a variety of biotin-dependent carboxylases, and is therefore recognized as a tool to recycle biotin. Being a condition caused by variations on gene with a consequence of free biotin shortage, BTD deficiency may impair the activity of biotin-dependent carboxylases, and thus bring about a buildup of potentially toxic compounds in the body, primarily 3-hydroxyisovaleryl-carnitine in plasma as well as 3-hydroxyisovaleric acid in urine. The phenotype of BTD deficiency may vary dramatically, from asymptomatic adults to severe neurological anomalies, even death in infancy. In the present study, we reported on a 5-month-old boy, whose parents sought for medical consultation in our clinic for their son due to his loss of consciousness, repeated tetany, and motor retardation. Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive. The brain MRI at 12 months showed cerebellar hypoplasia and multiple foci of leukodystrophy. The result of antiepileptic therapy was not satisfying. During hospitalization, BTD deficiency was suggested by elevated concentration of 3-hydroxyisovaleryl-carnitine in the blood spots and 3-hydroxyisovaleric acid in the urine. The child was then diagnosed with profound BTD deficiency based on the above findings and low BTD enzyme activity. Subsequent mutational analysis revealed a novel homozygous variant, c.637_637delC (p.H213Tfs*51) in exon 4 of gene in the proband, which was recognized as a further support to the diagnosis. Therefore, biotin treatment was started immediately, eventually with satisfactory outcomes achieved in terms of prevention of epileptic seizure, performance in deep tendon reflexes, and improvement of muscular hypotonia, but unfortunately, the therapy failed to show any evident effects on poor feeding and intellectual disability. This painful lesson suggests that newborn screening for inherited metabolic diseases is essential for early identification and treatment, which should have been performed in this case to avoid this tragedy.
生物素酶（BTD）缺乏症（OMIM 253260）是一种常染色体隐性遗传代谢疾病，由 BTD 酶活性缺乏引起，该酶可以切割并从多种生物素依赖性羧化酶中释放生物素，因此被认为是一种回收生物素的工具。由于基因变异导致游离生物素缺乏，BTD 缺乏症可能会损害生物素依赖性羧化酶的活性，从而导致体内潜在毒性化合物的积累，主要是血浆中的 3-羟基异戊酰基辅酶 A 和尿液中的 3-羟基异戊酸。BTD 缺乏症的表型可能差异很大，从无症状的成年人到严重的神经异常，甚至在婴儿期死亡。在本研究中，我们报告了一例 5 个月大的男孩，其父母因儿子意识丧失、反复抽搐和运动发育迟缓而到我们的诊所就诊。详细的临床特征包括严重的精神运动发育迟缓、肌张力低下和生长发育不良。12 个月时的脑 MRI 显示小脑发育不良和多处白质营养不良。抗癫痫治疗效果不理想。住院期间，通过血斑中 3-羟基异戊酰基辅酶 A 和尿液中 3-羟基异戊酸浓度升高，提示存在 BTD 缺乏症。随后根据上述发现和低 BTD 酶活性诊断为严重 BTD 缺乏症。随后的突变分析显示，先证者基因第 4 外显子中的 c.637_637delC（p.H213Tfs*51）为纯合突变，进一步支持了该诊断。因此，立即开始进行生物素治疗，最终在预防癫痫发作、深腱反射表现和改善肌肉张力低下方面取得了满意的结果，但不幸的是，治疗对喂养不良和智力残疾没有明显效果。这个惨痛的教训表明，遗传性代谢疾病的新生儿筛查对于早期识别和治疗至关重要，本病例就应该进行筛查，以避免这种悲剧。
