多囊肾病的临床实践指南

多囊肾病(polycystic kidney disease,PKD)是由基因突变所导致的一类遗传性肾病,按其遗传方式又分为常染色体显性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)和常染色体隐性多囊肾病(autosom al recessive polycystic kidney disease,ARPKD)。该病的主要病理特点是肾脏囊肿进行性增大、增多,破坏正常的肾脏结构,最终导致终末期肾病(end stage renal disease,ESRD),患者只能依靠透析或肾移植维持生命。我们在参考国内外本领域的基础研究、临床研究和相关指南共识的基础上,结合中国人群的实际情况编写了该项指南,旨在总结多囊肾病的医学遗传学知识和临床处置要点,以提高临床医师的认识水平,为该病的诊治提供规范化建议。     

小儿常染色体隐性遗传多囊肾病临床分析

目的探讨小儿常染色体隐性遗传多囊肾病（autosomal recessive polycystic kidney disease，ARPKD）的临床特点。方法回顾我院1995年1月～2006年12月收治的16例小儿ARPKD的临床资料。结果16例ARPKD中，男11例，女5例，影像学诊断14例，病理学诊断2例，肾脏影像学显示囊肿广泛分布于皮质和髓质。起病时以泌尿系症状就诊仅7例（43．75％），以肾脏外症状就诊3例（18．75％），其他就诊原因包括早产1例，出生时重度窒息1例，血尿素氮-肌酐（Bun—Cr）升高2例，贫血1例，外伤后肾囊肿破裂性腹痛1例。确诊时有12例（75％）肾衰竭，8例（50％）生长迟缓，10例（62．5％）合并肾脏外病变。随诊8例，4例死亡（分别死于先天性肺发育不良、重度窒息后多器官功能衰竭、进行性肾衰竭以及终末期肾病合并胆管细胞癌肾脏转移），1例透析，1例肾移植，1例肾功能正常，1例肝硬化。结论ARPKD为先天遗传性、进行性的肾脏和肝脏损害，小儿期临床表现形式多样，产前诊断对减少ARPKD畸形儿的出生有重要意义。     

Clinical and genetic studies of muscular dystrophy in young girls

During the years 1971-81, we treated 7 girls with clinical features suggestive of Duchenne dystrophy. Muscle weakness developed at 1.5 or at 5–8 years and progressed rapidly. Two girls were in wheel-chairs in their teens. Muscle atrophy began in the proximal parts of the lower extremities and pseudohypertrophy of the calf occurred in all patients. Serum creatine phosphokinase (CPK) activity was moderately to highly elevated in all cases and EMG showed a moderate to marked myopathic pattern. Chromosomal studies showed normal finding in the five examined. Mental retardation (IQ 37–73) was present in four. Consanguinity was present in 3 out of the 7 cases. Two mothers showed elevated levels of CPK and myopathic patterns on EMG. In addition, one mother had slight muscle weakness at the age of 42 and another had prominent pseudohypertrophy of the calf. Sex-linked recessive inheritance might be considered here, because carriers of autosomal recessive type never showed elevated levels of CPK or mild myopathic symptoms. The other five of our seven might be cases of autosomal recessive inheritance, because the mothers had normal serum CPK levels and in 2 families there was a consanguinity.     

Pkhd1基因的缺失可促进ApcMin/+小鼠肠道肿瘤的发展演进

目的 确定人类常染色体隐性遗传性多囊肾病(ARPKD)致病基因Pkhd1在ApcMin/小鼠肠道肿瘤发生中的作用.方法 Pkhd1基因敲除小鼠模型(Pkhd1-/-)与肠道肿瘤模型ApcMin/+小鼠杂交后,比较不同月龄(1、3、6月)单一ApcMin/+小鼠与缺失Pkhd1的ApcMin/+小鼠(Pkhd1-/-;ApcMin)肠道肿瘤的数目及大小,并观察其肠道肿瘤组织病理的变化.结果 与单一的ApcMin/+小鼠相比,Pkhd1-/-;ApcMin/+小鼠在1月龄时,肠道肿瘤数目及大小均无显著差异.但该小鼠在3月龄和6月龄时肠道肿瘤数目及大小均显著增加(P=0.017、P=0.022).此外,在6月龄时,Pkhd1-/-;ApcMin/+小鼠病理表型有向恶性转化的明显趋势.结论 具有Pkhd1缺失的Apc Min/+小鼠与单一的ApcMin/小鼠相比能够显著促进肠道肿瘤的发生和发展,并具有促进其肿瘤恶性转化的趋势.     

Refinement of the gene locus for autosomal recessive juvenile parkinsonism (AR-JP) on chromosome 6q25.2-27 and identification of markers exhibiting linkage disequilibrium

Autosomal recessive juvenile parkinsonism (AR-JP) (MIM 600116) is a hereditary neurodegenerative disorder characterized by levodopa-responsive parkinsonism with a mean age at onset of 23.2 years. We recently mapped the AR-JP gene locus to a 17-cM interval on chromosome 6q25.2-27. To further narrow the candidate region of the AR-JP gene, we performed detailed linkage analysis using densely placed genetic markers in this region (D6S437, D6S1581, D6S1579, D6S305, D6S411, SOD2, D6S253, D6S1599, D6S1719 and D6S264). Pairwise linkage analysis revealed the highest cumulative maximal lod score of 9.13 at D6S1579 (θ = 0.05), and multipoint linkage analysis revealed the highest cumulative lod score of 12.4 at the locus 3 cM telomeric to D6S1599. Observation of obligate recombination events narrowed the candidate region to a 13-cM region between D6S1579 and D6S264. Furthermore, we identified two marker loci, D6S1579 and D6S1599, which exhibit strong linkage disequilibrium with the AR-JP locus: χ² (2 ×n table) = 84.22; P < 0.0001, χ² [likelihood-ratio test (LRT)] = 20.66; P < 0.0001, λ = 0.40 and χ² (2 ×n table) = 63.37; P < 0.0001, χ² (LRT) = 10.32; P <0.0001, λ = 0.30, respectively. These results suggest that the candidate region for the AR-JP gene is most likely located near the 4-cM region encompassing D6S1579 and D6S1599. Received: October 22, 1997 / Accepted: December 5, 1997     

Co-inheritance of pathogenic variants in PKD1 and PKD2 genes presenting as severe antenatal phenotype of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is caused by pathogenic variants in either PKD1 or PKD2 genes. Disease severity is dependent on various factors including the presence of modifier genes. We describe a family with recurrent foetal presentation of ADPKD due to co-inheritance of pathogenic variants in both PKD1 [c.3860T > C; p.(Leu1287Pro)] and PKD2 [(c.1000C > A; p.(Pro334Thr)] genes. Familial segregation studies revealed the mother and the father to be heterozygous for the same variants in the PKD1 and PKD2 genes, respectively, as found in the foetus. Renal ultrasonography detected evidence of cystic disease in the mother and two of her family members. No cysts were detected in the father, however the paternal grandfather died of renal cystic disease. The absence of disease in the father can be explained by the phenomenon of incomplete penetrance, or Knudson's two-hit hypothesis of cystogenesis in the grandfather. This case underscores the importance of sequencing PKD2 gene even in the presence of a familial PKD1 variant, as well as genetic testing of the cysts for evidence of the second hit.     

The “muscular variant” of Pompe disease: Clinical,biochemical and histologic characteristics

We report on a 2-yr-old boy with progressive muscular weakness and respiratory failure. There was no clinical evidence of heart muscle involvement. Autopsy showed marked intralysosomal glycogen deposition in skeletal muscle and liver with no histological evidence of glycogen deposition in cardiac muscle. The activity of the lysosomal enzyme α-1,4-glucosidase was deficient in skin fibroblasts, skeletal muscle, cardiac muscle, and liver; however, the enzymatic activity in peripheral blood leukocytes was in the low normal range. The child's mother had normal enzymatic activity in leukocytes but heterozygote levels in skin fibroblasts.     

Clinical and molecular findings of chronic granulomatous disease in Oman: family studies

Chronic granulomatous disease (CGD), a rare inherited disorder of the innate immune system, results from mutations in any one of the five genes encoding the subunits of the nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH) oxidase enzyme, and is characterized by recurrent life‐threatening bacterial and fungal infections. Molecular analysis of 14 Omani CGD patients from 10 families, diagnosed to have CGD on clinical (recurrent infections) and biochemical grounds (positive for both the nitroblue tetrazolium (NBT) test and the dihydrorhodamine (DHR‐1,2,3 assay), revealed that only one patient had X‐linked CGD, with a large deletion involving both the gp91‐phox gene (CYBB) and the McLeod gene (XK). The remaining 13 patients were all homozygotes from a previously described c.579G>A (p.Trp193X) mutation in the NCF1 gene on chromosome 7, responsible for autosomal recessive CGD (AR‐CGD). Although X‐linked CGD is the most common type of CGD disorder in most population groups, AR‐CGD is the most prevalent type in Oman.     

多参数量化~(131)I剂量法治疗Graves病的临床研究

目的　探讨利用计算机技术开发出多参数量化131I剂量法的软件 ,在用于Graves病治疗的可行性 .方法　2 0 6例经确诊为Graves病的患者 ,10 9例行多参数量化131I治疗 ,另 97例以传统的单位甲状腺重量吸收剂量法治疗 ,并进行对照 .结果　多参数量化131I治疗组与单位甲状腺重量吸收剂量法治疗组的有效率皆为 90 % ,治愈率分别是93.5 %和 85 .4%、复发率分别是 3.8%和 5 .1%、早发性甲低发生率分别为 3 .6 %和 5 .1% .结论　多参数下利用131I治疗Graves病是可行的 ,可规范和指导131I治疗Graves病 ,提高总活度投给量的准确性 ,减少复发率和早发性甲低 .     

Biochemical genetics of the Lapland dog model of glycogen storage disease type II (acid α-glucosidase deficiency)

A recently described canine model (Lapland dog) of glycogen storage disease type II (GSD II, Pompe disease, acid α-glucosidase deficiency) was identified with several biochemical genetic methods. Complementation studies in which fibroblasts from a GSD II dog were fused with fibroblasts derived from control dogs and from human patients with different clinical forms of the disease did not lead to restoration of acid α-glucosidase activity in the heterokaryon cell populations. These results indicate that acid α-glucosidase deficiency is the primary defect in canine GSD II and that there is a close genetic parallelism with human GSD II. Immunotitration analysis of the residual acid α-glucosidase activity in the canine GSD II fibroblasts and liver demonstrated that this residual activity was not due to acid α-glucosidase enzyme, in which respect canine GSD II was similar to the infantile form of the human disease. Double immunodiffusion studies showed the presence of catalytically inactive acid α-glucosidase enzyme protein in canine GSD II. This is consistent with a structural gene mutation. It is concluded that canine GSD II in the Lapland dog is a homologous model of the infantile form of human GSD II, a conclusion in concordance with clinical and pathological studies.     

PKU: high plasma phenylalanine concentrations are associated with increased prevalence of mood swings

In phenylketonuria, knowledge about the relation between behavior and plasma phenylalanine is scarce. The aim of this study was to determine whether high phenylalanine is associated with disturbed behavior noticed by the patient and or close environment (parents or partners). 48 early treated PKU patients (median age 8.5, range 0–35 years) participated (median phenylalanine concentration in total sample 277 (range 89–1171) μmol/l; and in patients < 12 years 238 (range 89–521) μmol/l). After sending blood samples, patients or close environment were interviewed with a standardized questionnaire whether they noticed hyperactivity, annoying behavior, mood swings and introvert or extravert behavior. The interviewer as well as the respondents were blinded with regard to the phenylalanine concentration. Results: Patients reported less deviant behavior compared to close environment. Mood swings were positively associated with phenylalanine concentrations in the total group (P = 0.039) and patients < 12 years (P = 0.042). The relationships between temporary high phenylalanine concentrations and hyperactivity, annoying behavior, introvert and extravert behavior were not statistically significant. Conclusion: there is a positive association between phenylalanine concentrations and mood swings.     

Compound heterozygosity for loss‐of‐function FARSB variants in a patient with classic features of recessive aminoacyl‐tRNA synthetase‐related disease

Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in phenotypically diverse dominant and recessive human diseases. The charging of tRNA^PHE with phenylalanine is performed by a tetrameric enzyme that contains two alpha (FARSA) and two beta (FARSB) subunits. To date, mutations in the genes encoding these subunits (FARSA and FARSB) have not been implicated in any human disease. Here, we describe a patient with a severe, lethal, multisystem, developmental phenotype who was compound heterozygous for FARSB variants: p.Thr256Met and p.His496Lysfs*14. Expression studies using fibroblasts isolated from the proband revealed a severe depletion of both FARSB and FARSA protein levels. These data indicate that the FARSB variants destabilize total phenylalanyl‐tRNA synthetase levels, thus causing a loss‐of‐function effect. Importantly, our patient shows strong phenotypic overlap with patients that have recessive diseases associated with other ARS loci; these observations strongly support the pathogenicity of the identified FARSB variants and are consistent with the essential function of phenylalanyl‐tRNA synthetase in human cells. In sum, our clinical, genetic, and functional analyses revealed the first FARSB variants associated with a human disease phenotype and expand the locus heterogeneity of ARS‐related human disease.     

神经电生理检查在运动神经元病中的诊断价值

目的:研究神经电生理检查在运动神经元病(MND))中的诊断价值。方法:分别对25例MND患者进行了磁刺激运动诱发电位(mMEP)、肌电图(EMG)、神经传导速度(NCV)、体感诱发电位(SEP)测定,并与健康对照组20例进行比较。结果:MND组mMEP皮层潜伏期和中枢运动传导时间(CMCT)均明显长于对照组;EMG神经原性损害占70％;NCV 30％患者异常;SEP未见明显异常。结论:mMEP结合EMG检查在MND的诊断和分型中具有重要价值。     

Quantification of the vestibulo-ocular reflex and visual-vestibular interaction for the purpose of clinical diagnosis

Pseudorandom vestibular rotatory stimuli covering the normal head movement range (0–6 Hz) and power spectrum analysis techniques are used to clinically evaluate the vestibulo-ocular reflex (v.o.r.). Measurements of compensatory eye movements are recorded during fixation of a stationary target, during fixation of a target moving with the subject and in darkness. The gain above 3 Hz quantifies vestibular function under all these conditions. A frequency-dependent v.o.r. asymmetry indicates the side of a peripheral lesion. The fixation suppression curve at medium frequencies quantifies visual-vestibular interaction. Thus the new test is a powerful diagnostic tool applicable to disease of the labyrinth and central vestibular pathways. This test is evaluated on monkeys before unilateral labyrinthectomy and for an extended period of time after.     

中药协同131I治疗Graves病的临床研究

探讨中药石麦清液协同131I治疗Graves病(GD)的疗效及给药方法.GD患者100例随机分为A组:131I治疗,B组:131I 石麦清液治疗,服131I后7d服石麦清液20mL每天3次共40d.以治疗前和治疗后30d、90d测定血清FT3、FT4和TSH并选择8种症状,采用Kupperman四级评分评估.结果表明B组临床症状提前改善,安全渡过131I治疗一月后出现的FT3、FT4反跳性升高,A组30d后临床症状重于治疗前,FT3、FT4高于治疗前.B组90d临床症状显著改善,FT3、FT4和TSH测值正常,A组临床症状改善,但FT3、FT4低于正常,TSH高于正常.30d后B组安全渡过高危期,90d治疗后,减轻甲状腺功能减退症发病率疗效优于A组.石麦清液无毒性、安全和可在临床推广应用.     

Brief report: illness intrusiveness and adjustment among Native American and Caucasian parents of children with juvenile rheumatic diseases

OBJECTIVE: To investigate cognitive appraisal-adjustment relationships in Native American (NA) and Caucasian parents of children diagnosed with juvenile rheumatic diseases. METHODS: NA (n = 16) and Caucasian (n = 24) parents completed measures of disease status, illness intrusiveness, and adjustment; the rheumatologist provided estimates of disease severity. RESULTS: Hierarchical regression analysis revealed a moderating effect for racial group membership on the illness intrusiveness-parent adjustment relationship. Specifically, parent-perceived illness intrusiveness was more closely related to poorer adjustment among NA parents relative to Caucasian parents. Post hoc tests indicated that illness intrusiveness was significantly associated with poorer adjustment in NA parents, but was unrelated to parent adjustment in the Caucasian sample. CONCLUSIONS: Results highlight the importance of examining racial group differences in cognitive appraisal-adjustment outcome relationships. Results are discussed with respect to the need for incorporating cultural issues into pediatric chronic illness research and treatment.     

AECOPD患者血浆BNP、cTnI、UA测定对疾病诊断和治疗的临床观察

目的:探讨生物标志物水平测定对急性加重期慢性阻塞性肺病(AECOPD)患者诊断和治疗的临床意义.方法:化学发光免疫分析143例AECOPD患者的血浆中脑钠肽(BNP)和肌钙蛋白I(cTnI)水平、生化法测定血尿酸(UA)水平,并与40例正常对照组进行了对比性观察.结果:143例AECOPD患者被分成Ⅰ级、Ⅱ级、Ⅲ级和Ⅳ...     

血清Tg变化在甲癌术后131I首次清甲中的价值

目的:评价在分化型甲状腺癌患者术后<'131>I首次清甲中血清Tg变化对于清甲效果的预测价值.方法:38例接受甲状腺全切或次全切手术后行放射性<'131>I首次清甲治疗的分化型甲状腺癌患者,应用放射免疫分析所有患者服用<'131>I前的血清Tg(TgD0),以及服用<'131>I后第5d的血清Tg(TgD5),观察清甲...     

A case of autosomal recessive hypercholesterolemia caused by a new variant in the LDL receptor adaptor protein 1 gene

We report a new variant in the LDLRAP1 gene associated with autosomal recessive hypercholesterolemia in a woman of central European ancestry.     

采用放射性内照射建立甲状腺功能减低及相关性眼病Wistar大鼠模型

目的：采用人类促甲状腺激素（hTSH）刺激及放射性碘-131（131I）注射Wistar大鼠的方法,建立甲状腺功能减低（甲减）及其甲状腺相关眼病（TAO）的动物模型。方法：将20只Wistar大鼠随机分为实验组和正常组,实验组大鼠腹腔内注射hTSH。第8周腹腔内注射131I,根据不同剂量将实验组分为低剂量组（A组）、中剂量组（B组）及高剂量组（C组）。第16周后处死所有大鼠,机械分离甲状腺,取眼眶组织做病理学观察,采用常规HE染色方法,观察和分析大鼠眼眶内的病理学变化。用电化学发光法测定血清FT3和FT4,酶联免疫吸附法测大鼠血清促甲状腺素（rTSH）和TRAb水平。结果：131I注射后8周,大鼠血清FT4水平A组（16.98±2.92）pmol/L、B组（1.84±0.44）pmol/L和C组（1.35±0.37）pmol/L均降低,三组与正常组（D组）比较差异均有显著性（P〈0.05）;且C组和B组明显低于A组,差异有显著性（P〈0.05）;血清rTSH水平C组（2.53±0.10）mIU/L、B组（2.37±0.32）mIU/L略高于D组（2.17±0.38）mIU/L,A组（1.78±0.36）mIU/L略低于D组,但差异均无显著性（P〉0.05）;A组血清TRAb（4.69±1.52）IU/ml和B组（4.49±2.60）IU/ml水平明显低于D组12.79±0.75）IU/ml,而C组血清TRAb（10.36±4.48）IU/ml与D组比较无明显差异（P〉0.05）。眼眶组织学观察,实验组出现眼眶组织黏液变性、水肿,眼肌水肿以及肥大细胞为主的浸润,细胞间隙明显增宽。随着131I剂量的增加,B和C组出现脂肪组织和纤维组织增生,肌纤维变性断裂,肌细胞核肥大变性,眼眶血管扩张,C组肌纤维甚至有空泡形成。结论：采用hTSH刺激和131I注射制作的动物模型具有甲减及TAO的普遍特征,并证实甲减伴有TAO的存在,方法简便易行,不仅可用于131I治疗后甲减基础研究的需要,也可作为对其他原因所致甲减或TAO机制探索的模型。