SGCE基因变异致儿童肌阵挛肌张力障碍综合征临床特点及基因分析

目的探讨SGCE基因变异导致儿童期起病的肌阵挛肌张力障碍综合征患儿的临床特点及基因分型.方法收集2018年5月至2019年10月首都医科大学附属北京儿童医院神经内科和北京大学第一医院儿科共同收集的9例经全外显子组测序方法以及多重链接依赖的探针扩增技术确诊的SGCE基因变异导致的肌阵挛肌张力障碍综合征患儿的临床资料,并对患儿进行随访,对临床特点及基因变异结果进行回顾性总结分析.结果9例患儿中男4例、女5例,起病年龄1岁~3岁2月龄.首发症状为肌阵挛者4例,肌张力障碍者5例.病程中,9例均有肌阵挛症状,8例有肌张力障碍症状.8例肌阵挛表现为双上肢不自主抖动.6例病程中曾有下肢突然抖动一下,导致步态不稳甚至跌倒.肌张力障碍症状表现为行走姿势异常,其中5例右下肢受累,3例左下肢受累.3例有阳性家族史.9例患儿智力发育均正常.发作期及发作间期视频脑电图未见明显异常,肌电图及头颅磁共振成像正常.基因结果示9例携带SGCE基因变异,其中3例为移码变异,2例为无义变异,2例为错义变异,1例为大片段缺失变异,1例为剪切位点变异;7例为遗传性变异,均为父源,2例为新生变异.治疗上,8例加用美多芭口服,6例肌阵挛较前有所减少,走路姿势不同程度改善.4例加用硝西泮,2例有效.结论SGCE基因变异可导致肌阵挛肌张力障碍综合征,多在幼儿期或学龄前期起病,肌阵挛和肌张力障碍均可为首发症状.非癫痫性肌阵挛是其突出症状,且有上肢优势特点.绝大多数病程中伴肌张力障碍,部分肌张力障碍可自行缓解.SGCE基因为母源印记基因,遗传性变异多为父源.     

苍白球黑质变性2个家系的临床和基因诊断

目的 对苍白球黑质变性(HSD)2个家系进行泛酸激酸2(PANK2)基因突变位点的筛查.方法 分别抽取2个家系 4名成员外周静脉血各2 mL,盐析法提取2个家系成员基因组DNA,用PCR方法扩增PANK2基因的全部编码外显子,纯化后直接测序.结果 在1号先证者的PANK2 基因上发现2个杂合的错义突变:外显子2上核苷酸序列第970位G>T突变(c.970G>T),导致编码的第324位氨基酸由天门冬氨酸(D)变成酪氨酸(Y)(D324Y);患儿母亲是这一突变的杂合携带者,具有正常表型.外显子3上核苷酸序列第1133位A>G突变(c.1133A>G),导致编码的第378位氨基酸从天门冬氨酸(D)变成甘氨酸(G) (D378G);患儿父亲是这一突变的杂合携带者,具有正常表型.在2号先证者的PANK2 基因上发现2个杂合的错义突变:外显子2上核苷酸序列第808位C>G突变(c.808C>G),导致编码的第270位氨基酸由亮氨酸(L)变成缬氨酸(V)(L270V);外显子3上核苷酸序列第1103位A>G突变(c.1103A>G),导致编码的第368位氨基酸从天门冬氨酸(D)变成甘氨酸(G) (D368G);该患儿为抱养儿,无法检测其父母的基因型.这4个错义突变均能引起PANK2 基因编码氨基酸的改变,从而引起蛋白质结构和功能的异常.结论 在这2个家系中,c.970G>T、c.1133A>G、c.808C>G和c.1103A>G错义突变导致2个先证者出现HSD的表型.实用儿科临床杂志,2011,26(16 ):1276-1278     

Two novel mutations of SRD5A2 gene in Indonesian siblings with clinical 5-alpha-reductase deficiency

Steroid 5-alpha-reductase 2 deficiency is an autosomal recessive disorder with clinical spectrum ranges from a male phenotype with hypospadia to a female phenotype with normal wolffian structures. Over 50 different mutations of SRD5A2 gene has been described in affected patients and several mutations were detected in specific populations. DNAs of two 46,XY DSD Indonesian siblings, aged 13 and 18 years old, with clinically suspected of 5-alpha-reductase deficiency and their mother were analysed for molecular defects of SRD5A2 gene. Different from other reports, in our series three mutations were found in each patient. Two novel mutations were detected in these patients and their mother, which are p.Gly34fs and c.699-1G>T. The other mutation detected was c.680G>A or p.Arg227Gln, which commonly described in Far East Asian population. Whether the p.Arg227Gln mutation is considered a polymorphism or a mutation in Indonesian population warrants further study.     

多巴反应性肌张力障碍临床分析及GCH Ⅰ基因突变的研究

目的探讨多巴反应性肌张力障碍(DRD)临床及GTP环化水解酶Ⅰ(GCH Ⅰ)基因突变特点.方法对14例DRD患儿的临床资料进行总结分析,并对其中6例进行了GCH Ⅰ基因全长外显子的突变检测.结果14例患儿平均发病年龄为(10±3)岁,女性起病较男性早,发病年龄(9±4)岁,男性发病年龄(12±1)岁.常见的首发症状为步态异常、下肢僵硬和震颤.伴晨轻暮重者9例(64%).小剂量多巴制剂治疗3个月后痊愈13例(93%),显效1例(7%),长期随访未发现多巴制剂的不良反应.对6例患儿进行GCH Ⅰ基因突变检测,在3例患儿中发现了2种GCH Ⅰ基因突变.其中一家系2例患儿存在第6号外显子的Lys224Arg杂合错义突变,临床表型较轻,与国外研究报道一致.在1例散发病例中发现了国际上未曾报道过的位于第3号外显子的Gln161Pro突变,临床表型较重.结论DRD临床表现复杂多样,晨轻暮重是其特点之一.多巴制剂对其有快速、显著和持续的疗效.GCH Ⅰ基因突变类型与临床表型之间有一定关联,对GCH Ⅰ基因突变的检测有助于不典型病例的早期诊断.     

Differential diagnosis between Pendred and pseudo-Pendred syndromes: clinical, radiologic, and molecular studies

The disease gene for Pendred syndrome has been recently characterized and named PDS. It codes for a transmembrane protein called pendrin, which is highly expressed at the apical surface of the thyroid cell and functions as a transporter of chloride and iodide. Pendrin is also expressed at the inner ear level, where it appears to be involved in the maintenance of the endolymph homeostasis in the membranous labyrinth, and in the kidney, where it mediates chloride-formate exchange and bicarbonate secretion. Mutations in the PDS gene and the consequent impaired function of pendrin leads to the classic phenotype of Pendred syndrome, i.e. dyshormonogenic goiter and congenital sensorineural hearing loss. In the present study, we performed a detailed clinical, radiologic, and molecular analysis of six families presenting with clinical diagnosis of Pendred syndrome. In two families a homozygous pattern for PDS mutations was found, whereas the affected members of the other four families were compound heterozygotes. One family did not harbor PDS mutations. Among the four novel mutations described, one is a transversion in exon 2 (84C>A), leading to the substitution S28R. Two other novel mutations lie in exon 4 (398T>A) and in exon 16 (1790T>C), leading to the substitutions S133T and L597S, respectively. The fourth novel mutation (1614+1G>A) is located in the first base pair of intron 14, probably affecting the splicing of the PDS gene. Clinically, all patients had goiter with positive perchlorate test, hypothyroidism, and severe or profound sensorineural hearing loss. In all the individuals harboring PDS mutations, but not in the family without PDS mutations, inner ear malformations, such as enlargement of the vestibular aqueduct and of the endolymphatic duct and sac, were documented. The pseudo-Pendred phenotype exhibited by the family without PDS mutations is likely caused by an autoimmune thyroid disease associated with a sensorineural hearing loss of different origin.     

Japanese familial case of myoclonus–dystonia syndrome with a splicing mutation in SGCE

Myoclonus–dystonia syndrome (MDS) is a rare autosomal‐dominant movement disorder characterized by brief, frequently alcohol‐responsive myoclonic jerks that begin in childhood or early adolescence, caused by mutations in the ε‐sarcoglycan gene (SGCE). The patient was a 6‐year‐old boy. At 2 years 8 months, he had abnormal movement when he ran due to dystonia of his left leg. At 3 years 5 months, he exhibited dystonia and myoclonic movement of his arms when eating. Myoclonus was likely to develop when he felt anxiety or exhaustion. Genomic DNA showed a heterozygous mutation in SGCE (c.109 + 1 G > T). His father and uncle with the same mutation also experienced milder dystonia or myoclonic movements. SGCE mutation can cause a broad range of clinical symptoms between and within families. We should consider MDS as a differential diagnosis for patients with paroxysmal walking abnormalities and/or myoclonic movements.     

3例低血磷性抗维生素D佝偻病的基因诊断及文献复习

对3例临床疑似X连锁低血磷抗维生素D佝偻病（XLH）患儿进行磷酸盐调节基因（PHEX）分析并确诊的临床资料进行回顾性分析及相关文献复习,探讨中国人存在的突变热点和突变类型。3例患儿均检测到PHEX基因突变,1例为无义突变（c.58C>T）,2例为剪接突变（c.1645+1G>A,c.436+1G>A）,其中c.436+1G>A为新突变。至2014年1月,世界上已报道的PHEX基因突变共有329个,错义突变占数量最多（24%）,突变热点区域有3个。不同地区的病例总数和突变类型存在差异。中国人群中,89例XLH病人进行了PHEX基因检测,发现28种突变,其中在22外显子上发现的突变数量最多（18%）,突变类型最多的为错义突变（61%）。总之,在中国人群中,XLH病人PHEX基因最常见的突变位置为第22外显子,最常见的突变类型为错义突变;c.436+1G>A 为PHEX基因的新突变。     

A new DAX-1 mutation in a family with a case of neonatal adrenal insufficiency and a sibling with adrenal hypoplasia and sudden death at 3 years of age

Adrenal hypoplasia congenita (AHC) is a hereditary disorder that leads to adrenal insufficiency and hypogonadotropic hypogonadism (HHG) in childhood. The gene responsible for the X-linked form of AHC, DAX1 (dosage-sensitive sex-reversal, AHC, on the X-chromosome, gene 1)/NR0B1, encodes for a nuclear factor which lacks the characteristic zinc finger DNA-binding domain that is highly conserved in nuclear receptors. Deletions and point mutations in the DAX1 gene have been described in more than 70 AHC families. We present the clinical and genetic data of two brothers affected by AHC. We report a new DAX1 gene mutation in a family with two affected members: one with neonatal adrenal insufficiency, and a sibling with adrenal hypoplasia and sudden death at 3 years old. The NR0B1/DAX1 gene was amplified in three PCR fragments from the patient's and mother's gDNA extracted from peripheral lymphocytes. Sequencing revealed a novel single nucleotide deletion in codon 419 from exon 2 that resulted in a frameshift and a stop codon 17 nucleotides downstream (c.1256 delA). The mother was heterozygous for this mutation. In conclusion, a novel DAX-1 mutation was detected in two family members with different phenotype: one live infant with adrenal hypoplasia, his mother, and probably his dead brother.     

海南省妇女儿童医学中心5246名女性新生儿葡萄糖-6-磷酸脱氢酶基因型与酶活性分析

目的 分析海南省妇女儿童医学中心女性新生儿葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症的基因突变特点,探讨基因型与酶活性的关系。方法 以2017—2019年在海南省妇女儿童医学中心新生儿疾病筛查中心完成G6PD初筛的女性新生儿血样本为研究对象,收集G6PD酶缺乏的干血斑样本2153份,同时为提高女性杂合子的检出率,随机抽取酶活性正常的干血斑样本3093份,共计5246份样本纳入研究。提取脱氧核糖核酸（DNA）,采用多色探针荧光聚合酶链反应（PCR）熔解曲线法（MMCA法）检测G6PD基因突变。结果 在5246份女性新生儿样本中共检出基因突变2801份,总检出率为53.39%(2801/5246),其中酶活性正常者占26.24%(735/2801)。发现13个突变位点的变异,有32种突变基因型,包括杂合突变型12种,纯合突变型6种和复合突变型14种。前7位最常见的突变位点依次是c.1376G>T、c.1388G>A、c.871G>A、c.95A>G、c.1024C>T、c.392G>T、c.519C>T,其中c.871G>A的检出率高于c.95...     

XPC gene mutations in families with xeroderma pigmentosum from Pakistan; prevalent founder effect

Xeroderma pigmentosum (XP) is a rare autosomal recessive skin disorder characterized by hyperpigmentation, premature skin aging, ocular and cutaneous photosensitivity, and increased risk of skin carcinoma. We investigated seven consanguineous XP families with nine patients from Pakistan. All the Patients exhibited typical clinical symptoms of XP since first year of life. Whole genome SNP genotyping identified a 14 Mb autozygous region segregating with the disease phenotype on chromosome 3p25.1. DNA sequencing of XPC gene revealed a founder homozygous splice site mutation (c.2251‐1G>C) in patients from six families (A–F) and a homozygous nonsense mutation (c.1399C>T; p.Gln467*) in patients of family G. This is the first report of XPC mutations, underlying XP phenotype, in Pakistani population.     

Three novel and six common mutations in 11 patients with methylmalonic acidemia

BACKGROUND: Patients with a defect in methylmalonyl-coenzyme A mutase (MCM) are classified as having methylmalonic acidemia, which is divided into two subclasses: mut(0) and mut(-). Fifty-five disease-causing mutations have been identified. Although most are private mutations, only three (E117X, G717V, and N219Y) are reportedly common in Japanese, Black, and Caucasian populations, respectively. Here we identified mutations in 11 Japanese patients with MCM deficiency. METHODS: Mutational analysis was performed in 11 unrelated Japanese patients with MCM deficiency using polymerase chain reaction and direct sequencing. RESULTS: Three novel (L494X, R727X, and 449_461del) and six previously reported (R93H, E117X, N219Y, R369H, G648D and IVS2 + 5G>A) mutations were identified. The L494X mutation was found in three unrelated patients, and the R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations occurred more than once. Two of the patients were classified as mut(-) phenotype because of residual [(14)C]-propionate incorporation in the presence of a high concentration of hydroxocobalamin. The two mut(-) patients were heterozygous for the G648D mutation and presented with lethargy and metabolic acidosis after 2 years of life. Their psychomotor development has been documented as normal. The patients with the R727X or c.374_385del [corrected] mutations clinically exhibited mut(0) phenotype. Two patients with mut(0) phenotype died in infancy. One presented early in the neonatal period; the other was symptomatic in the late infantile period. CONCLUSIONS: The L494X, R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations are found in more than two unrelated families in the Japanese population. The short-term outcome was generally poor in patients with mut(0), and therefore alternative treatments should be considered.     

Menkes病临床及ATP7A基因突变和拷贝数改变分析

目的通过ATP7A基因突变及拷贝数改变（CNV）分析,了解13例临床诊断为经典型Menkes病患儿的临床表型以及ATP7A基因型特征,探讨其基因型、表型的相关性。方法收集并分析13例Menkes病患者的临床资料,采用DNA直接测序进行ATP7A基因突变检测,发现突变后用DNA限制性内切酶酶切进行验证;应用多重连接依赖的探针扩增技术（MLPA）对未发现突变的患儿行CNV分析,阳性患者用长片段PCR进行验证,并进行基因型、表型相关性分析。结果临床特点:（1）13例均为男性,有典型的毛发改变、癫发作、肌张力减低、智力运动发育迟缓和结缔组织异常,3例有阳性家族史;（2）起病年龄早,均在出生7个月内（3 d～7个月）,除1例患儿以智力运动发育落后起病外均以癫起病,伴严重发育停滞和倒退;（3）均呈进行性加重,随访5例患儿,均于14个月内死亡;（4）12/12例患儿（100%）铜蓝蛋白降低;6/8例患儿（75%）血清铜降低;4/4例患儿（100%）脑血管成像见血管走行紊乱,呈"螺丝锥样"改变,1例为47XXY/46XY嵌合体。基因突变确诊9例:（1）DNA直接测序检测到6种突变,包括2种缺失突变,2种错义突变及2种剪切位点突变,其中3种为国际上未报道过的新突变,均位于高度保守区,100例健康男性对照中相应位点均未发现上述突变;（2）MLPA检测发现1例患儿为第10外显子缺失突变,长片段PCR验证其断点为c.2173-346₂407-346del,共1 783 bp,导致p.F725_K802del,其母亲为表型正常的携带者。基因型-表型关系:同为c.2179G>A（p.G727R）突变患儿,47XXY/46XY嵌合体起病年龄早于核型正常者,且临床症状较重。结论 Menkes病ATP7A基因大片段缺失或重复突变检测中ML-PA方便、快捷,Menkes病的致病机制可能与ATP7A基因剂量关系密切。     

青岛市苯丙氨酸羟化酶缺乏症患儿基因突变分析

目的探讨青岛市苯丙氨酸羟化酶(phenylalanine hydroxylase,PAH)缺乏症患儿的基因突变特点,为青岛市PAH缺乏症的产前诊断、治疗提供科学参考依据。方法对经青岛市新生儿疾病筛查确诊的44例PAH缺乏症患儿,应用第二代高通量测序及多重连接酶探针依赖扩增(multi-ligase probe dependent amplification,MLPA)技术进行基因分析,检测患儿基因突变位点,应用Sanger测序对其父母的PAH基因相应突变位点进行检测并验证。根据患儿血苯丙氨酸浓度,分为经典型苯丙酮尿症、轻度苯丙酮尿症和轻度高苯丙氨酸血症。结果①44例PAH缺乏症患儿PAH基因中均检测到2个突变位点,其中2例为纯合突变,纯合突变的频率为4.6%,所有突变在患儿父母相应突变位点处均能检测到。②44例PAH缺乏症患儿共检测到突变36种,其中c.728G>A突变频率最高(15.9%,14/88),其次是c.1068C>A(10.2%,9/88),再次为c.158G>A(9.1%,8/88)。③21例经典型苯丙酮尿症患儿PAH基因突变19种,其中c.1068C>A突变频率最高(21.4%,9/42),其次是c.728G>A(19.0%,8/42)。10例轻度苯丙酮尿症患儿PAH基因突变14种,其中c.721C>T/722delG突变频率最高(15.0%,3/20),其次为c.1197A>T、c.1301C>A、c.721C>T、c.728G>A(均为10.0%,2/20)。13例轻度高苯丙氨酸血症患儿PAH基因突变17种,其中c.158G>A突变频率最高(26.9%,7/26),其次为c.728G>A(15.4%,4/26)。结论青岛市PAH缺乏症患儿PAH基因突变以复合杂合突变为主,具有明显热点突变(c.728G>A、c.1068C>A、c.158G>A),经典型苯丙酮尿症患儿以c.1068C>A、c.728G>A为主,轻度苯丙酮尿症患儿以c.721C>T/722delG为主,轻度高苯丙氨酸血症患儿以c.158G>A为主。本研究明确了青岛市PAH缺乏症患儿基因的突变类型与特点,为深入开展PAH缺乏症的诊断以及进一步的基因治疗奠定了基础。     

Myoclonus in fraternal twin toddlers: A French family with a novel mutation in the SGCE gene

Myoclonus dystonia is a rare movement disorder caused by mutations in the SGCE gene on chromosome 7q21 (DYT11) encoding the epsilon-sarcoglycan. Myoclonus is present in almost all patients and affects most often neck, trunk and upper limbs. Dystonia is present in about half of the patients. The mode of inheritance is autosomal dominant with variable clinical expression and maternal imprinting. Onset is usually in childhood or adolescence. Alcohol might relieve symptoms.We present a 33 month old girl and her twin brother with disabling involuntary jerky movements during intentional tasks. Family history of this French family was positive for the paternal uncle, his two daughters and the paternal great grandfather. Sequencing of the SGCE gene revealed a novel nonsense mutation c.942C > A (p.Tyr314X) in exon 7, confirming the diagnosis of myoclonus dystonia. Treatment with valproic acid significantly reduced myoclonic episodes and ameliorated life quality.     

Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry

Background: Maturity‐onset diabetes of the young, type 2 (MODY2) is caused by mutations in the glucokinase gene (GCK). The aim of our study was to determine the prevalence of GCK mutations in the Norwegian MODY Registry and to delineate the clinical phenotype of identified GCK mutation carriers. Methods: We screened 122 probands referred to the MODY Registry for mutations in GCK and studied extended families with MODY2. Results: We found 2 novel (S76Y and N231S) and 13 previously reported (V62A, G72R, L146R, R191W, A208T, M210K, Y215X, M235T, R275C, E339G, R377C, S453L, and IVS5+1G>C) GCK mutations in 23 probands and in their 33 family members. The prevalence of MODY2 was 12% in the Norwegian MODY Registry. The subjects with GCK mutations had features of mild diabetes. Yet, 15 of 56 MODY2 subjects were treated with oral drugs or insulin. Three subjects had retinopathy and one had macrovascular disease. Also, a limited number of cases had elevated fasting serum triglyceride values. Moreover, two GCK mutation carriers were diagnosed with type 1 diabetes. Conclusions: According to our diagnostic screening of GCK in the MODY Registry, MODY2 is less prevalent than MODY3 in Norway but is likely to be underreported. Recognizing MODY2 in diabetic patients is important in order to prevent overtreatment. Finally, our study demonstrates the co‐occurrence of MODY2 in families with type 1 or type 2 diabetes.     

NRAS基因突变致系统性红斑狼疮1例并文献复习

摘要 目的：报告1例NRAS基因突变致系统性红斑狼疮（SLE）的临床特征,提高对NRAS基因突变表型谱的认识。方法：收集患儿的临床资料,包括病史特点、相关实验室检查和家族史等。采用外显子捕获的方法对患儿及其父母进行全外显子高通量测序,并进行生物信息学分析,通过Sanger测序对高通量测序结果进行验证。进行相关文献复习。结果：先证者,男,2.6岁,1岁后反复出现发热、外周血PLT和RBC计数下降;2.6岁时出现皮疹、左膝关节肿痛,有轻度蛋白尿,抗核抗体和抗ds-DNA抗体等多种自身抗体阳性。患儿无明显面容异常,其他脏器无畸形。测序发现NRAS基因c.38G>A （p.G13D）杂合突变,其父母均未携带,为新发突变。Sanger法验证了上述高通量测序结果。c.38G>A突变为已报道的致病性突变。结论：本研究显示生殖细胞NRAS基因突变患儿可仅有SLE表型,进一步丰富了NRAS基因突变表型谱。     

Expanding the mutation and clinical spectrum of Roberts syndrome

Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.     

隐睾及隐睾合并其他泌尿生殖系统畸形的外显子测序分析

目的对隐睾及隐睾合并其他泌尿生殖系统畸形的不同表型患儿进行外显子测序,以探索不同临床表型的分子病因。方法提取19例隐睾及隐睾合并其他泌尿生殖系统畸形患儿外周血基因组DNA进行外显子测序,并对测序结果进行生物信息学分析,其中3例行全基因外显子测序,16例行常见基因外显子测序,再采用Sanger测序对获得候选致病突变的患儿及其父母的外周血样本进行突变位点验证。结果本研究纳入的19例患儿中,6例外显子测序结果经生物信息学分析后发现存在异常结果,并提示有3个基因可能与相关表型发病有关:①AR基因发生3处错义突变(c.1600C>A;p.Pro534Thr)、(c.2599G>A;p.Val867Met)和(c.528C>A;p.Ser176Arg);②NR5A1基因发生移码突变(c.442delG;p.Glu148Serfs*148)和错义突变(c.43G>A;p.Val15Met);③ATRX基因发生剪切位点突变(c.4317+13T>C)。其中c.2599G>A和c.43G>A为已知突变,其余4处未见相关研究报道,为新发突变。Sanger测序结果表明6处突变均得以验证,5例患儿母亲存在对应位点突变、患儿父亲未见异常,1例患儿父母均未见异常。结论AR基因错义突变、NR5A1移码和错义突变及ATRX的剪切位点突变可能是隐睾及隐睾合并其他泌尿生殖系统畸形发病的危险因素。     

多巴反应性肌张力障碍患儿临床特征及基因突变分析（附6例报告）

目的　分析多巴反应性肌张力障碍（DRD）患儿临床及基因突变特点。方法　收集2016年8月至2019年3月于上海交通大学医学院附属上海儿童医学中心神经内科就诊的6例DRD患儿临床表现、实验室检查及治疗效果进行回顾性分析。结果　6例患儿中男2例,女4例,就诊年龄1岁1月龄至11岁5月龄。首发症状多为下肢活动障碍,病情呈进行性进展,就诊时主要症状存在足内翻（3例）、姿势异常（4例）、不自主运动（3例）、痉挛性斜颈（1例）、癫痫样发作（1例）、智力及生长发育落后（1例）;5例具有晨轻暮重特点。6例均行基因检测,5例检测到GCH1基因突变［4例为新发突变,分别为c.131C＞G（p.Ala44Gly）、c.325T＞C（p.Tyr109His）、c.225C＞G（p.Tyr75*）与c.5dupA（p.Lys3Glufs*62）］,1例为TH基因c.698G＞A（p.Arg233His）和c.971_982dup的复合杂合突变,其中c.971_982dup为新发突变。6例均给予美多芭治疗,除1例效果不明显外,其余5例症状均明显好转。3例患儿治疗中出现兴奋、双下肢抖动表现,2例调整药物剂量后症状消失。结论　绝大多数DRD表现为晨轻暮重的肢体活动障碍和（或）步态异常,其临床表型与基因型之间尚无确切对应关系。新发现的4个GCH1突变和1个TH突变丰富了DRD基因突变谱。