Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway.
European Reference Network for Hereditary Metabolic Diseases (MetabERN).
Brain. 2023 Jul 3;146(7):3003-3013. doi: 10.1093/brain/awad010.
There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.
目前已发现的可治疗神经发育疾病的病因较少。支链酮酸脱氢酶激酶（BCKDK）缺乏导致支链氨基酸（BCAA）耗竭，并与以自闭症、智力障碍和小头畸形为特征的神经发育障碍相关。我们报告了迄今为止最大的患者队列，拓宽了表型和基因型谱。此外，这是第一项报告新生儿筛查结果和中期临床结果的研究。在这项横断面研究中，通过代谢性疾病欧洲网络（MetabERN）倡议，通过研究人员的实践招募了诊断为 BCKDK 缺乏症的患者。收集了临床、生化和遗传数据。从合作中心检索了支链氨基酸脱氢酶激酶缺乏症患者的干血斑（DBS）新生儿筛查（NBS）氨基酸谱，并与健康新生儿参考人群进行了比较。从 13 个家庭中纳入了 21 名 BCKDK 突变患者。患者的诊断时间为 8 个月至 16 岁（平均 5.8 岁，43%为女性）。在诊断时，血浆和 CSF 中的 BCAA 水平（亮氨酸、缬氨酸和异亮氨酸）低于参考值。所有患者均有全面的神经发育迟缓；18/21 名患者有粗大运动功能（GMF）障碍，其中 5/18 名患者 GMF 为 III 级或更差，16/16 名患者智力障碍，17/16 名患者语言障碍，12/17 名患者自闭症谱系障碍，9/21 名患者癫痫，12/15 名患者动作笨拙，3/21 名患者感音神经性听力损失，4/20 名患者喂养困难。出生时未见小头畸形，但 17/20 名患者在随访期间出现小头畸形。6 名患者出现退行性变化。21 名患者中有 3 名（15%）出现运动障碍：多动（1 名）、躯干共济失调（1 名）和肌张力障碍（2 名）。接受高蛋白饮食（≥2g/kg/天）和 BCAA 补充（100-250mg/kg/天）治疗后，血浆 BCAA 显著增加（P<0.001），13/13 名患者的运动功能和头围稳定/改善，11/15 名患者分别稳定/改善。在有随访数据的病例中，在 2 岁之前开始治疗的 3 名患者中，没有 1 名在随访时出现自闭症。开始治疗年龄最小的（8 个月）患者在 3 岁时发育正常。DBS 的 NBS 发现 BCAA 水平明显低于正常人群。这项工作强调了饮食治疗的潜在益处，特别是早期补充 BCAA。因此，提高对这种可治疗疾病的认识并将其视为早期检测的候选者非常重要。
