少见基因位点突变Alpers综合征的临床特征
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摘要
目的探讨POLG基因突变导致的Alpers综合征的临床特征。方法回顾性分析1例幼儿期起病Alpers综合征的临床特征和基因突变位点的临床资料。结果男性幼儿,4岁3个月,以反复抽搐持续状态入院。既往有运动不耐受、下肢乏力现象、生长发育落后和体格消瘦。四肢肌力0～1级,肌张力明显降低,肌容积减少。双侧膝反射未引出。辅助检查提示高乳酸血症,脑脊液蛋白增高。双侧脑干中枢性听路传导时间延长;肌电图提示多发性周围神经源性损害肌电改变(主要累及感觉、运动神经轴索)。头颅MRI示脑沟深,脑外间隙增宽;两侧侧脑室及第三脑室饱满;右侧额叶、双侧基底节区异常信号。视频脑电图结果为背景活动减慢,发作间期左侧枕区棘慢波散发,监测到局灶性癫痫持续状态(EPC)。线粒体病核基因和线粒体基因二代测序结果显示POLG基因的复合杂合变异,一个c.2890C>T(p.Arg964Cys)错义变异来源于父亲,另一个c.2584G>A(p.Ala862Thr)错义变异来源于母亲。结合临床诊断为Alpers综合征。结论 POLG基因突变所致的Alpers综合征是引起EPC的重要原因,进行性病程,药物难治,需要及早识别和诊断。
Objective To investigate clinical characteristics of Alpers syndrome induced by POLG gene mutations.Methods Tata of a case with Alpers syndrome induced by POLG gene mutations were reviewed retrospectively and clinical features were analyzed.Results The patient was a 4 years and 3 months old boy,who was with developmental delay,short stature and myopathy and administrated because of recurrent seizures and epilepsia partialis continua(EPC).Physical examination revealed lessen muscle bulk,strength and tone in bilateral upper and lower extremities.Bilateral knee reflex was not drawn out.Lumbar puncture revealed an elevated protein level of above 1.0 g/L.A comprehensive metabolic panel revealed lactic acidosis,indicative of mitochondrial disorder.Auditory brainstem response(ABR) showed the prolongation of the central auditory conduction time of brainstem pathways.Abnormal electromyography occurred on multiple peripheral neurogenic lesions,predominantly sensation and axon.Brain magnetic resonance imaging showed multiple T2 hyperintensity in the right frontal lobe and bilateral basal ganglia without restricted diffusion or enhancement with ventriculomegaly.Video electroencephalography revealed left occipital spike-and-wave discharges and EPC.The second generation sequencing of mitochondrial disease nuclear gene and mitochondrial gene revealed the complex heterozygous variation of POLG gene,of which pArg964 Cys came from his father and c2584 G>A came from his mother.The patient was diagnosed as Alpers syndrome.Conclusion Alpers syndrome is caused by POLG gene mutation and characterized by a progressive course and refractory seizures.It is important to recognize and diagnose Alpers syndrome.
Objective To investigate clinical characteristics of Alpers syndrome induced by POLG gene mutations.Methods Tata of a case with Alpers syndrome induced by POLG gene mutations were reviewed retrospectively and clinical features were analyzed.Results The patient was a 4 years and 3 months old boy,who was with developmental delay,short stature and myopathy and administrated because of recurrent seizures and epilepsia partialis continua(EPC).Physical examination revealed lessen muscle bulk,strength and tone in bilateral upper and lower extremities.Bilateral knee reflex was not drawn out.Lumbar puncture revealed an elevated protein level of above 1.0 g/L.A comprehensive metabolic panel revealed lactic acidosis,indicative of mitochondrial disorder.Auditory brainstem response(ABR) showed the prolongation of the central auditory conduction time of brainstem pathways.Abnormal electromyography occurred on multiple peripheral neurogenic lesions,predominantly sensation and axon.Brain magnetic resonance imaging showed multiple T2 hyperintensity in the right frontal lobe and bilateral basal ganglia without restricted diffusion or enhancement with ventriculomegaly.Video electroencephalography revealed left occipital spike-and-wave discharges and EPC.The second generation sequencing of mitochondrial disease nuclear gene and mitochondrial gene revealed the complex heterozygous variation of POLG gene,of which pArg964 Cys came from his father and c2584 G>A came from his mother.The patient was diagnosed as Alpers syndrome.Conclusion Alpers syndrome is caused by POLG gene mutation and characterized by a progressive course and refractory seizures.It is important to recognize and diagnose Alpers syndrome.
引文
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[11] Anagnostou ME,Ng YS,Taylor RW,et al.Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene:A clinical and molecular genetic review[J].Epilepsia,2016,57(10):1531-1545.
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[13] Hikmat O,Naess K,Engvall M,et al.Elevated cerebrospinal fluid protein in POLG-related epilepsy:Diagnostic and prognostic implications[J].Epilepsia,2018,59(8):1592-1602.
[14] Desguerre I,Hully M,Rio M,et al.Mitochondrial disorders and epilepsy[J].Rev Neurol,2014,170(5):375-380.
[15] Hasselmann O,Blau N,Ramaekers VT,et al.Cerebral folate deficiency and CNS inflammatory markers in Alpers disease[J].Mol Genet Metab,2010,99(1):58-61.
[16] Stricker S,Prüss H,Horvath R,et al.A variable neurodegenerative phenotype with polymerase gamma mutation[J].J Neurol Neurosurg Psychiatry,2009,80(10):1181-1182.
[17] Paleologou E,Ismayilova N,Kinali M.Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders[J].J Clin Med,2017,6(6):56.
[2] Wong LJ,Naviaux RK,Brunetti-Pierri N,et al.Molecular and clinical genetics of mitochondrial diseases due to POLG mutations[J].Hum Mutat,2008,29(9):E150-E172.
[3] Sha Tang,Jing Wang,Ni-Chung Lee,et al.Mitochondrial DNA polymerase γ mutations:an ever expanding molecular and clinical spectrum[J].J Med Genet,2011,48(10):669-681.
[4] Hikmat O,Tzoulis C,Chong WK,et al.The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations[J].Genet Med,2017,19(11):1217-1225.
[5] Hikmat O,Eichele T,Tzoulis C,et al.Understanding the Epilepsy in POLG Related Disease[J].Int J Mol Sci,2017,18(9):1845.
[6] Finsterer J,Zarrouk-Mahjoub S.Death in Pediatric Mitochondrial Disorders[J].Pediatr Neurol,2017,73:e1.
[7] Finsterer J,Scorza FA.Phenotypic spectrum of POLG1 mutations[J].Neurol Sci,2018,39(3):571-573.
[8] Park S,Kang HC,Lee JS.Alpers-Huttenlocher Syndrome First Presented with Hepatic Failure:Can Liver Transplantation Be Considered as Treatment Option[J]?Pediatr Gastroenterol Hepatol Nutr,2017,20(4):259-262.
[9] Saneto RP,Cohen BH,Copeland WC,et al.Alpers-Huttenlocher syndrome[J].Pediatr Neurol,2013,48(3):167-178.
[10] Qian Y,Ziehr JL,Johnson KA.Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms[J].Front Genet,2015,6:135.
[11] Anagnostou ME,Ng YS,Taylor RW,et al.Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene:A clinical and molecular genetic review[J].Epilepsia,2016,57(10):1531-1545.
[12] Li S,Guo J,Ying Z,et al.Valproic acid-induced hepatotoxicity in Alpers syndrome is associated with mitochondrial permeability transition pore opening-dependent apoptotic sensitivity in an induced pluripotent stem cell model[J].Hepatology,2015,61(5):1730-1739.
[13] Hikmat O,Naess K,Engvall M,et al.Elevated cerebrospinal fluid protein in POLG-related epilepsy:Diagnostic and prognostic implications[J].Epilepsia,2018,59(8):1592-1602.
[14] Desguerre I,Hully M,Rio M,et al.Mitochondrial disorders and epilepsy[J].Rev Neurol,2014,170(5):375-380.
[15] Hasselmann O,Blau N,Ramaekers VT,et al.Cerebral folate deficiency and CNS inflammatory markers in Alpers disease[J].Mol Genet Metab,2010,99(1):58-61.
[16] Stricker S,Prüss H,Horvath R,et al.A variable neurodegenerative phenotype with polymerase gamma mutation[J].J Neurol Neurosurg Psychiatry,2009,80(10):1181-1182.
[17] Paleologou E,Ismayilova N,Kinali M.Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders[J].J Clin Med,2017,6(6):56.