Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: Lack of correlation with genotype
Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: Lack of correlation with genotype
复制标题
DOI：
10.1016/j.ymgme.2012.09.001
复制
发表时间：
2012-11-01
影响因子：
3.8
通讯作者：
Kerr, Douglas S.
中科院分区：
文献类型：
--
作者：
DeBrosse, Suzanne D.;Okajima, Kazuki;Kerr, Douglas S.
丙酮酸脱氢酶复合物（PDC）缺乏症是一种相对常见的线粒体疾病，主要表现为神经系统表现和乳酸血症。我们分析了59名同意的有症状受试者的临床结局和神经学特征（27名男性，32名女性），他们被证实患有PDC缺陷症，其中一个PDC基因发生了明确的突变（PDHA 1，n = 53; PDHB，n = 4; DIAT，n=2），包括47个不同的突变，其中22个是新的，并获得其临床记录和/或结构化访谈。39%的受试者（23/59）已经死亡。其中，91%（21/23）在4岁前死亡，61%（14/23）在1岁前死亡，43%（10/23）在3个月内死亡。男性死亡率为56%，女性为25%。死亡原因包括严重乳酸酸中毒、呼吸衰竭和感染。在存活超过6个月的受试者中，观察到广泛的智力结果。在42名接受专业智力评估的受试者中，19%的受试者智力正常或处于边缘水平（CQ/IQ >= 70）。10%有轻度智力残疾（ID）（CQ/IQ 55-69），17%有中度ID（CQ/IQ 40-54），24%有重度ID（CQ/IQ 25-39），33%有重度ID（CQ/IQ= 70）（这4人中只有2人在12岁后进行了评估）。女性的平均结局为重度至极重度ID，而男性为轻度至中度ID。在可获得特定神经学数据的受试者中，大多数存在肌张力减退（89%），肌张力亢进或混合性肌张力亢进/肌张力减退（49%）很常见。癫痫（57%），小头畸形（49%）。脑结构异常包括心室扩大（67%）和胼胝体发育不全、发育不全或发育不全（55%）是常见的。Leigh综合征仅占35%。脑结构异常在女性中更常见，Leigh综合征在男性中更常见。在一个由16名年龄大于3.5岁的非卧床受试者组成的亚组中，评估了平衡性，在13名受试者中发现了共济失调。周围神经病变记录在2例，但没有客观地评价在大多数subject. The遗传证实PDC缺乏症的结果是异质性和不独特的。特定基因型和结果之间的相关性尚未建立。虽然更多的女性存活，与X连锁PDHA 1突变的患病率相关，但有症状的存活女性通常在认知方面受损更严重，并且与男性相比具有不同的神经功能障碍模式。新生儿或婴儿出现症状与不良结局相关。具有PDHA 1突变和低成纤维细胞PDC活性的男性不太可能存活超过婴儿期。携带PDHA 1突变的受试者的兄弟姐妹的复发率低于5%。奇怪的是，在这项回顾性审查中，被认为可能与发育相关的潜在因素，如体外PDC活性、特定突变、生酮饮食、补充剂或药物的使用，通常未被证实与生存或神经认知功能的客观结局显著相关。因此，这些结果的可变性的基础在很大程度上仍然没有确定。(C)2012 Elsevier Inc. All rights reserved.
Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DIAT, n=2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained.39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ >= 70). 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ= 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID.Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%). and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more common in males. In a subgroup of 16 ambulatory subjects >3.5 years in whom balance was evaluated, ataxia was found in 13. Peripheral neuropathy was documented in 2 cases but not objectively evaluated in most subjects.Outcomes of this population with genetically confirmed PDC deficiency are heterogeneous and not distinctive. Correlations between specific genotypes and outcomes were not established. Although more females survive, related to the prevalence of X-linked PDHA1 mutations, symptomatic surviving females are generally more severely impaired cognitively and have a different pattern of neurological impairment compared to males. Neonatal or infant onset of symptoms was associated with poor outcomes. Males with PDHA1 mutations and low fibroblast PDC activity were less likely to survive beyond infancy. Recurrence rate in siblings of subjects with PDHA1 mutation was less than 5%. Paradoxically, in this retrospective review, potential factors considered possibly relevant to development, such as in vitro PDC activity, specific mutations, use of ketogenic diets, supplements, or medications, were generally not confirmed to be significantly correlated with objective outcomes of survival or neuro-cognitive function. Therefore, the basis of variability of these outcomes remains largely undetermined. (C) 2012 Elsevier Inc. All rights reserved.