一个中国家族性低钾型周期性麻痹家系中的CACNA1S基因R1239H突变

目的筛查家族性低钾型周期性麻痹（hypokalaemic periodic paralysis，HOKPP）相关基因突变位点，总结该病基因型和临床表型的相关性。方法应用PCR和DNA测序技术，对1个HOKPP家系（包括2例患者共11名成员）进行候选基因CACNA1S和SCN4A的筛查，并总结该家系患者的临床特点。结果此家系的2例患者符合HOKPP的诊断标准，突出特点为：儿童期发病，青春期加重，成年后病情减轻；女性在月经前期好发，而妊娠期无发作；钾剂和乙酰唑胺治疗有效。DNA测序结果发现2例患者的CACNA1S基因第30外显子上均存在3716（G→A）杂合突变，导致氨基酸序列改变R1239H，家族其他成员未见此突变。结论中国家族性HOKPP存在CACNA1S基因R1239H突变。     

低血钾型周期性麻痹一家系12例

先证者（Ⅲ11）男，17岁。因发作性四肢无力10年，加重1d就诊。患者7岁起出现发作性四肢无力等症状，未发生呼吸困难，补钾后24h内症状逐渐好转。此次发病因1d前剧烈活动，感恶心、呕吐后出现四肢无力并迅速发展至颈部，无心慌胸闷，呼吸困难等症状。血钾1．78mmol／L，钠137．2mmol／L，氯105．3mmol／L，钙2．4mmol／L。心电图示T波低平，U波增高等低钾改变，甲状腺功能检查正常，结合家族史，诊断为家族性低钾型周期性麻痹。     

正常血钾型周期性麻痹一家系28例分析

目的：报道一正常血钾型周期性麻痹（normoKPP）家系,以提高对该病的认识。方法：调查一normoKPP家系,分析其家系中28例normo KPP患者的临床表现、辅助检查以及治疗结果,并复习相关文献。结果：患者均于儿童期起病,周期性发作四肢迟缓性瘫痪,发作期血钾正常,葡萄糖酸钙治疗有效。结论：normoKPP 是少见的常染色体显性遗传的骨骼肌病,依据其家族史、临床表现及相关辅助检查可诊断,基因分析可确诊。     

一个遗传性低钾周期性麻痹家系的CACNA1S基因突变研究

目的在中国人低钾周期性麻痹（hypokalemic periodic paralysis，HOKPP）家系中寻找HOKPP新的突变。方法分析了一个具有4代共46名家族成员的中国HOKPP家系。应用聚合酶链反应、连锁分析、DNA测序和限制性片段长度多态性分析技术研究了第1和第2代成员，以发现该家系可能的致病基因突变；然后用上述研究的结果检测第3和第4代成员，进一步验证结果并对正常成员作出患病的预测。结果对第1和第2代的连锁分析显示该家系的致病基因为CACNAIS基因，其LOD值为3．71；DNA测序显示1582位的核苷酸C被G所替代，为一种新的突变R528G；所有患病个体均带有此突变，而200名对照中没有此突变。检测第3和第4代成员R528G突变，发现所有患者和两名正常年轻女性携带此突变基因。结论发现了CACNAIS基因的一个R528G新突变，能导致中国人低钾周期性麻痹，其外显率可能存在性别差异，此突变将有助于低钾周期性麻痹的诊断和预测。     

表现较特殊的低钾型周期性麻痹4例报告

低钾型周期性麻痹的特点是起病急 ,血清钾可在短时间内降至很低 ,影响神经肌肉及心血管系统 ,表现为四肢软瘫 ,腱反射减低或消失 ,但有时症状不典型 ,治疗不及时或方法不当 ,致使病情加重 ,甚至死亡 ,现将 4例报告如下。1　典型病例例 1,男性 ,35岁。 1999年 1月 19日晨起后感四肢麻木无力 ,不能下床 ,无大小便障碍。半月前有受凉史。入院时查 :T37 5℃ ,P 86次 min ,R 2 3次 min ,Bp 14/ 9kPa。神志清楚 ,心肺正常 ,双下肢肌力 0级 ,双上肢肌力Ⅰ级 ,四肢肌张力减低 ,无感觉障碍 ,双膝反射 (+) ,病理反射征阴性。血常规正常。血清钾 :4 1…     

低血钾型周期性麻痹一家系五例

患者　男 ,46岁。因“全身不能活动 ,瘫软伴呼吸困难 1天”入院。患者入院前一天晚上因劳累后出现下肢乏力 ,不能行走 ,后发展至全身无力 ,完全不能动弹 ,处于软瘫状态。能眨眼 ,说话、咳嗽困难 ,声音含糊 ,并大口喘气。发病前无明显饮食量增加及性情改变 ,未服用任何药物。既往史 :患者于 10年前和数月前各发病 1次 ,发病时仅表现为四肢无力 ,诊断为“家族性周期性麻痹”,给予补钾治疗后症状好转。查体 :意识清楚 ,体温 :37℃ ,心率 :70次 /分 ,呼吸 :2 1次 /分 ,血压 :15 2 /70 mm Hg(1mm Hg=0 .133k Pa) ,无突眼征 ,未触及甲状腺肿大 ,…     

低钾周期性麻痹的分子遗传学研究进展

目前已知原发性低钾型周期性麻痹（HoKPP）与遗传有关,根据其突变的基因的不同分为HoKPP1型与HoK-PP2型,两种HoKPP有着各自不同的突变基因、突变热点与外显率,这对HoKPP病人的致病基因的筛选与鉴定带来了困难。本文回顾了以往的HoKPP病例报道,优化了候选基因的筛查步骤并阐述了不同位点突变所带来的特殊表型,希望对以后的HoKPP的诊断以及发现新的突变位点带来帮助。     

同胞三兄弟同患低钾性周期性麻痹

同胞三兄弟同患低钾性周期性麻痹徐平，欧阳瑶例１男，１９岁。因四肢无力３天于１９８９年１０月６日初诊。既往无特殊病史。足月顺产第１胎。查体：神清，内科检查无异常。颅神经正常，四肢肌力３级，肌张力减低，感觉正常，腱反射减弱，病理征阴性。血清钾２．７ｍｍｏ...     

同胞兄弟同患低钾性周期性麻痹

先证者　男 ,2 1岁。因连续备考数日后晨起突发四肢瘫 ,于第 3天就诊 ,自述就诊时症状已减轻。半年前类似发作一次 ,症状较本次轻 ,持续 5天后自行缓解。两次发作均伴轻微肌肉酸胀感 ,无呼吸、吞咽困难 ,无呛咳 ,无头晕、头痛、意识障碍、肢体疼痛或麻木 ,无发热、腹泻等症状。查体 :意识清 ,发育及营养良好 ,计算及定向力正常 ,脑神经体征阴性 ,双上肢肌力基本正常 ,双下肢肌力 级 ,四肢腱反射对称性减弱 ,双侧跖反射明显减弱 ,深浅感觉无异常 ,脑膜刺激征阴性。血压 114 / 80 mm Hg。血钾 2 .9mmol/ L,血钠 14 1mmol/ L,血尿素氮、肌酐…     

正常血钾型周期性麻痹存在SCN4A基因V781I突变

目的研究两例散发正常血钾型周期性麻痹(normokalemicperiodicparalysis,normoKPP)患者的临床特点及其电压门控钠通道型α亚单位(α-subunittypeofvoltage-gatedsodiumchannel,SCN4A)基因的突变。方法应用变性高效液相色谱(denaturinghighperformanceliquidchromatography,DHPLC)技术及测序分析检测患者SCN4A基因第13、19、23、24(部分)外显子是否发生已知导致高钾型周期性麻痹(hyperKPP)的突变(T704M、A1156T、M1360V、I1495F、M1592V);随后应用DHPLC技术筛查SCN4A基因其余外显子,对出现异常洗脱峰者进行测序分析。结果两例患者的SCN4A基因发生点突变2418(G→A)并引起氨基酸序列改变V781I,且为SCN4A基因唯一错义突变。病例1的父亲也发生该突变,但未发病。结论中国人normoKPP患者存在V781I突变,该突变可能是导致normoKPP的突变之一。     

Mutation screening in Chinese hypokalemic periodic paralysis patients

Thyrotoxic periodic paralysis (TPP), familial periodic paralysis (FPP), and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (hypoKPP). The patients present with similar clinical features characterized by episodic attacks of muscle weakness and a decrease in blood potassium. Mutations in the gene encoding the voltage-sensor coding regions of the skeletal muscle sodium channel gene (SCN4A) and the alpha-1 subunit of the skeletal muscle calcium channel gene were analyzed in 23 Chinese hypoKPP patients, including 1 FPP pedigree, 14 TPP patients, and 8 SPP patients. In addition, R83H mutation of the potassium channel subunit gene which was originally published as periodic paralysis mutation was also analyzed. A heterozygous CGT-TGT mutation at codon 672 in SCN4A gene was identified to segregate with the disease in the FPP family. Mutations in these regions were excluded in those patients with SPP and TPP. The results suggest that a likely genetic basis for FPP does not contribute to TPP and SPP, despite close similarities among FPP, TPP, and SPP.     

Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family

Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. The skeletal muscle calcium channel -subunit gene CACNA1S is a major disease-causing gene for HypoPP, however, only three specific HypoPP-causing mutations, Arg528His, Arg1,239His and Arg1,239Gly, have been identified in CACNA1S to date. In this study, we studied a four-generation Chinese family with HypoPP with 43 living members and 19 affected individuals. Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6.7. DNA sequence analysis revealed a heterozygous C to G transition at nucleotide 1,582, resulting in a novel 1,582CG (Arg528Gly) mutation. The Arg528Gly mutation co-segregated with all affected individuals in the family, and was not present in 200 matched normal controls. The penetrance of the Arg528Gly mutation was complete in male mutation carriers, however, a reduced penetrance of 83% (10/12) was observed in female carriers. No differences were detected for age-at-onset and severity of the disease (frequency of symptomatic attacks per year) between male and female patients. Oral intake of KCl is effective in blocking the symptomatic attacks. This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease.Qiufen Wang and Mugen Liu contributed equally to this work     

CACNA1S基因突变致低钾周期性麻痹的产前基因诊断

目的对CACNA1S基因R1239H突变导致的低钾周期性麻痹（HoKPP1型）家系中的1例中期妊娠者进行产前基因诊断,从而预防HoKPP患儿出生。方法患者于16孕周在B超下进行羊膜囊穿刺,抽取羊水10 mL,提取羊水细胞基因组DNA。选择3个多态性STR位点,D13S317、D8S1179和D16S539,排除母体细胞的污染。在此基础上对CAC-NA1S基因外显子30进行扩增,PCR产物进行正、反向测序。结果 STR多态性位点分析,证明无母体细胞污染,胎儿CACNA1S基因30外显子测序结果显示,胎儿带有和母亲同样的CACNA1S基因突变R1239H。结论对于有HoKPP风险的胎儿进行产前基因诊断非常重要,可以明确胎儿基因型,预防患儿出生。     

Modifications in the sarcoplasmic reticulum and subcellular calcium distribution in skeletal muscle in a case of Westphal's disease (hypokalemic periodic paralysis)

Summary In a case of hypokalemic periodic paralysis with characteristic alterations of the sarcoplasmic reticulum (SR) in the skeletal muscle, subcellular calcium re-partition, as revealed with the pyroantimonate technique, appears disturbed during paralysis. Pyroantimonate precipitates, normally concentrated in the terminal cisternae of the SR, were localized in the T tubules, whereas the terminal cisternae appeared empty. The increase (about 14%) in muscular calcium during paralysis may result from the accumulation of calcium in the extracellular compartment (T tubules). Defects in calcium uptake and storage by the SR may be. involved in the pathogenesis of the periodic paralysis syndrome.     

运动诱发试验在低钾型周期性麻痹诊治中的应用

目的：探讨运动诱发试验（exercisetest,ET）在低钾型周期性麻痹中的诊断价值及相关影响因素。方法：对我院门诊确诊低钾型周期性麻痹的30例患者,在发作期检查肌力、血清钾（K^＋）、肌酸激酶（CK）、甲状腺功能,发作间期复查肌力、K^＋、CK值,并进行ET测定。同时选择30例健康人作为对照组。结果：发作期K^＋值的高低与肌力改变呈正相关,与CK值的高低呈负相关。发作间期行ET,30例患者波幅逐渐下降（45．56％±19．91％）,其波幅减低百分比显著大于对照组（P=0．001）。ET波幅变化百分比与肌力、K^＋、CK水平无明显相关性。结论：ET可作为低钾型周期性麻痹发作间期的重要辅诊方法。ET阳性与发病机制有关,与起病形式、严重程度无相关性。     

Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree

Hyperkalemic periodic paralysis (HPP) is caused by mutations of the adult skeletal muscle sodium channel (SCN4A) gene on chromosome 17. Malignant hyperthermia (MH) is a genetically heterogeneous autosomal-dominant disorder occurring in association with various neuromuscular diseases or without other apparent abnormalities. In some families, MH is associated with mutations of a calcium release channel (RYR1) gene on chromosome 19. In other families, linkage of this disorder to the SCN4A gene on chromosome 17 has been suggested. We report on linkage analysis in a family in which both HPP and MH are inherited as autosomal-dominant traits. Two polymorphisms within the SCN4A locus, an RFLP and a (C-A)_n repeat, were typed on multiple family members. The findings were consistent with linkage of the polymorphic markers within the SCN4A gene to both HPP (Z_max = 6.79 at θ = 0.0) and MH (Z_max = 1.76 at θ = 0) in this family. Our data provide further evidence that MH is linked to the SCN4A locus in some families. Am. J. Med. Genet. 76:21–27, 1998. © 1998 Wiley-Liss, Inc.     

The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis

Familial hypokalemic periodic paralysis (HOPP) is a rare autosomal-dominant disease characterized by reversible attacks of muscle weakness occurring with episodic hypokalemia. Mutations in the skeletal muscle calcium (CACNA1S) and sodium channel (SCN4A) genes have been reported to be responsible for familial HOPP. Fifty-one HOPP patients from 20 Korean families were studied to determine the relative frequency of the known mutations and to specify the clinical features associated with the identified mutations. DNA analysis identified known mutations in 12 families: 9 (75%) were linked to the CACNA1S gene and 3 (25%) to the SCN4A gene. The Arg528His mutation in the CACNA1S gene was found to be predominant in these 12 families. Additionally, we have detected one novel silent exonic mutation (1950C>T) in the SCN4A gene. As for a SCN4A Arg669His mutation, incomplete penetrance in a woman was observed. Characteristic clinical features were observed both in patients with and without mutations. This study presents comprehensive data on the genotype and phenotype of Korean families with HOPP.     

Identification of mutations in the CACNL1A3 gene in 13 families of Scandinavian origin having hypokalemic periodic paralysis and evidence of a founder effect in Danish families

Familial hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder characterised by episodic attacks of paralysis of varying severity. Recently, linkage was found to markers in 1q31–32 and to the gene encoding the muscle DHP-sensitive calcium channel α 1-subunit (CACNL1A3). Subsequently, three mutations in this gene were identified in patients with hypoPP: Arg528His, Arg1239His and Arg1239Gly. In this study, two different mutations were found in the CACNL1A3 gene in 13 Scandinavian families, 10 of whom have the Arg528His mutation while 3 families have the Arg1239His. Furthermore, there is evidence of a founder effect in 8 of the 9 Danish hypoPP families investigated, consisting of haplotypes of microsatellite markers close to and within the CACNL1A3 gene and of the geographic origin of the families. For the first time, reduced penetrance in males with the Arg528His mutation was found in several cases. Am. J. Med. Genet. 69:102–106, 1997. © 1997 Wiley-Liss, Inc.