Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
J Inherit Metab Dis. 2022 Nov;45(6):1028-1038. doi: 10.1002/jimd.12541. Epub 2022 Aug 7.
The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX. Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients. As more patients are identified, distinct clinical features are emerging depending on the location of the pathogenic variant. In this review, we carefully catalogued the clinical features of all published NAXD deficiency patients and found distinct patterns in clinical presentations depending on which subcellular compartment is affected by the enzymatic deficiency. Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions. Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration. This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage. A deeper understanding of the clinical phenotype may facilitate rapid identification of new cases and allow earlier therapeutic intervention. Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments. In this review, we found distinct patterns in the clinical presentations of NAXD deficiency patients based on the location of the pathogenic variant, which determines the subcellular compartment that is affected by the enzymatic deficiency.
中心辅助因子 NAD(P)H 容易受到水合作用的损伤，导致形成氧化还原非活性衍生物，命名为 NAD(P)HX。高度保守的酶 NAD(P)HX 脱水酶 (NAXD) 和 NAD(P)HX 差向异构酶 (NAXE) 可修复细胞内的 NAD(P)HX。最近，在年轻患者中，NAXD 和 NAXE 基因的致病性变异与看似微不足道的发热、感染或疾病后迅速恶化和死亡有关。随着越来越多的患者被发现，根据致病性变异的位置，出现了不同的临床特征。在这篇综述中，我们仔细记录了所有已发表的 NAXD 缺乏症患者的临床特征，并发现根据受酶缺乏影响的亚细胞区室，临床表现存在明显的模式。NAXD 的外显子 1 包含一个线粒体前肽，而一个独特的细胞质同工型从外显子 2 的一个替代起始密码子起始。受影响细胞质和线粒体同工型的 NAXD 缺乏症患者表现出神经缺陷、癫痫发作和皮肤损伤。有趣的是，仅受影响线粒体同工型的 NAXD 变异患者表现出肌病、中度神经病和心脏表现，没有特征性皮肤损伤、癫痫发作或神经退行性变。这表明细胞质 NAD(P)HX 的修复可能会防止神经损伤，而肌肉纤维可能对线粒体 NAD(P)HX 的损伤更为敏感。对临床表型的深入了解可能有助于快速识别新病例并允许更早的治疗干预。烟酸为基础的治疗方法很有前景，但 NAXD 和 NAXE 缺乏症的疾病建模方面的进展可能会确定更具体的化合物作为靶向治疗。在这篇综述中，我们根据致病性变异的位置发现了 NAXD 缺乏症患者的临床表现存在明显的模式，这决定了受酶缺乏影响的亚细胞区室。
