Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany.
Division of Pediatric Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany.
J Inherit Metab Dis. 2021 Jul;44(4):857-870. doi: 10.1002/jimd.12364. Epub 2021 Feb 7.
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.
异戊酸血症（IVA）是一种代谢疾病，具有严重（经典 IVA）或轻度表型（轻度 IVA）。该疾病已被纳入全球新生儿筛查（NBS）计划。然而，通过 NBS 筛查的个体的长期临床获益却很少被研究。本研究是一项全国性的、前瞻性的、观察性的、多中心的研究，对 1998 年至 2018 年期间通过 NBS 确诊的 IVA 个体进行了研究。评估了 94 名 IVA 个体的长期临床结局，占德国 NBS 队列的 73.4%（经典 IVA：92.3%）。在经典 IVA（N=24）中，NBS 除了在一个患有致命新生儿败血症的个体中（3.8%）未能预防过早死亡外，但不能完全预防单次（N=10）或反复（N=7）的代谢失代偿，其中 13 例发生在新生儿期。智商（平均值±标准差，90.7±10.1）大多正常，但低于参考人群（P=0.0022），在严重新生儿失代偿的个体中更低（智商 78.8±7.1），而在没有危象的个体中更高（智商 94.7±7.5；P=0.01）。对于学校安置情况也得到了相似的结果。相比之下，轻度 IVA 个体的神经认知结局良好（智商 105.5±15.8；正常学校安置），疾病过程良性（无代谢失代偿，正常住院率），似乎不受代谢维持治疗的影响。总之，NBS 降低了经典 IVA 的死亡率，但不能可靠地预防严重的新生儿代谢失代偿，这对有利的神经认知结局至关重要。相比之下，无论是否接受代谢维持治疗，轻度 IVA 个体的临床结局都非常好，这使他们从 NBS 中获益的问题受到质疑。急需制定统一的分层治疗方案。
