Mordaunt Dylan A, Jolley Alexandra, Balasubramaniam Shanti, Thorburn David R, Mountford Hayley S, Compton Alison G, Nicholl Jillian, Manton Nicholas, Clark Damian, Bratkovic Drago, Friend Kathryn, Yu Sui
SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.
Department of Paediatrics, University of Adelaide, North Adelaide, Australia.
Am J Med Genet A. 2015 Jun;167(6):1330-6. doi: 10.1002/ajmg.a.36968. Epub 2015 Apr 21.
Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.
孤立性线粒体呼吸链复合物III缺乏症已在儿童和成人的一组异质性临床表现中被描述。它与MT-CYB（唯一由线粒体DNA编码的亚基）以及迄今为止描述的九个核基因中的突变有关：BCS1L、TTC19、UQCRB、UQCRQ、UQCRC2、CYC1、UQCC2、LYRM7和UQCC3。BCS1L、TTC19、UQCC2、LYRM7和UQCC3是复合物III组装因子。我们报告了一名8岁女孩，其父母为伊拉克近亲结婚，患儿表现为缓慢进展性脑病、严重发育不良、语言和沟通能力显著延迟，眼底镜检查可见双侧视网膜樱桃红斑。单核苷酸多态性阵列确定了涉及7.5%基因组的多个纯合区域。已知TTC19基因的突变会导致复合物III缺乏，且TTC19位于纯合区域内。TTC19测序显示外显子6存在纯合无义突变（c.937C>T；p.Q313X）。我们回顾了所有11例因TTC19突变导致复合物III缺乏的患者（包括我们的病例）的表型和基因型。观察到的一致特征是进行性神经变性伴Leigh样脑MRI异常。然而，在症状出现年龄和疾病进展速度方面观察到了显著差异。我们患者中观察到的双侧视网膜樱桃红斑和发育不良是独特的特征，在先前报道的TTC19突变患者中尚未描述。有趣的是，所有报道的TTC19突变都是无义突变。然而，临床表现的严重程度与残余复合物III酶活性并无特异性关联。
