Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations
Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations
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DOI：
10.1007/s10545-015-9836-6
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发表时间：
2015-09-01
影响因子：
4.2
通讯作者：
McFarland, Robert
中科院分区：
文献类型：
--
作者：
Huemer, Martina;Karall, Daniela;McFarland, Robert
FBXL4缺乏症是最近发现的一种线粒体维持障碍，与细胞中线粒体DNA的缺失有关。迄今为止，FBXL4缺乏症的遗传诊断已在28个人中确立。本文回顾性回顾了21例患者的临床和生化结果，并评估了脑成像、形态学和遗传学数据。新生儿/早发性严重乳酸酸中毒，肌肉张力减退，喂养问题和发育不良是首次出现的特征性模式。67%的病例存在面部畸形特征。7名儿童死亡（平均年龄37个月）；11例患儿存活（随访时平均年龄46个月），3例患儿失访。所有幸存者都出现了严重的精神运动迟缓。脑成像对新生儿无特异性，但发现晚发性、快速进行性脑萎缩。所有个体均出现血乳酸升高和代谢性酸中毒；在45%的测量中肌酸激酶升高。患者组织和细胞的诊断检查显示严重的合并呼吸链缺陷，与线粒体能量代谢相关的酶普遍减少，线粒体DNA含量相对减少。在整个FBXL4基因中检测到突变，尽管没有明确描述基因型-表型相关性。用“线粒体药物”治疗并没有被证明有效。总之，早发性脑病、持续性乳酸酸中毒、深度肌张力低下和典型面部畸形的临床模式应促使对FBXL4进行分子遗传分析。诊断的建立允许遗传咨询，防止患者进行无用的诊断程序，并允许准确的预后。
FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.