Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency
Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency
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DOI：
10.1007/s10545-005-0533-8
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发表时间：
2005-08-01
影响因子：
4.2
通讯作者：
Pourfarzam, M
中科院分区：
文献类型：
--
作者：
Olpin, SE;Clark, S;Pourfarzam, M
一般性线粒体三功能蛋白（TFP）缺乏导致广泛的临床疾病谱，从严重的新生儿/婴儿心肌病和早期死亡到轻度慢性进行性感觉运动性多发性神经病伴发作性横纹肌溶解。由常见Glu 510 Gln突变引起的孤立性长链3-羟酰辅酶A脱氢酶（LCHAD）缺乏症通常会引起中度严重表型，伴有多器官受累，发病率和死亡率较高。然而，孤立的LCHAD缺乏症也可能与早期发现和治疗的患者的长期生存相一致。我们提供了9名患者的生化、临床和突变数据，涵盖了所有疾病谱。成纤维细胞酰基肉毒碱谱显示出与使用比率C-18（OH）/（C-14（OH）+C-12（OH））的临床表型的良好相关性。该比率显示了一个等级的值，从4例严重新生儿疾病患者的高值（2.5 +/- 0.8）到2例神经肌病患者的低值（0.35，0.2）。成纤维细胞脂肪酸氧化通量测定也显示出与患者表型的相关性，当表示为棕榈酸酯的残留活性百分比或肉豆蔻酸酯/油酸酯的活性百分比比率（M/O比率）时。4例严重新生儿疾病患者的成纤维细胞的M/O比值为4.0 +/- 0.6，而2例神经肌病患者的M/O比值为1.97和1.62。患者细胞中LCHAD和长链3-酮硫解酶活性的特异性酶测定显示与表型缺乏相关性。这些结果表明，完整细胞中的测量值（允许所有决定性和修饰性细胞因子存在）更好地反映了患者表型。突变分析揭示了许多α和β亚基突变。外周感觉运动性多发性神经病是轻度TFP蛋白缺乏的表现，通常作为最初的主要表现，但随后通常伴有发作性横纹肌溶解。轻微的临床表现和诊断的相对困难表明，这种形式的TFP可能是诊断不足。
General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C-18(OH)/(C-14(OH)+C-12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5 +/- 0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0 +/- 0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.