苯丙酮尿症患儿治疗前后脑白质病变的观察

目的：该研究应用MRI观察晚治苯丙酮尿症(PKU)患者治疗前后脑白质病变。方法：确诊为经典型PKU患者19例,进行低苯丙氨酸(PHE)饮食治疗随诊8～16月,治疗前后分别进行了头颅MRI及智商检查。头颅MRI采用常规矢状面、轴面T1W和轴面T2W扫描,对脑白质T2高信号病变按Thompson6级分级法进行分级并评分。观察比较治疗前后脑白质病变的改变。结果：9例晚治PKU患者头颅MRI均存在脑白质病变,其病变主要表现为侧脑室周围及三角区白质等区域存在孤立性斑片状异常T2高信号,治疗前后的平均MRI脑白质T2高信号分级分别为2.59和1.76,治疗前后MRI分级按分数计算,差异有显著性(P<0.01),治疗后T2高信号等级改善。19例均存在不同程度的智力发育落后,在智商改善与T2高信号等级改善可见部分一致关系。血PHE浓度与脑白质病变间有关。结论：晚治PKU患者脑白质病变及智力发育落后具高发生率,低苯丙氨酸饮食治疗降低血苯丙氨酸浓度后脑白质病变及智商均有部分改善,提示PKU患者脑白质病变及智力损害是部分可逆的,PKU患者脑白质改变可能是导致晚治PKU患者智能发育障碍的原因之一。     

苯丙酮尿症儿童脑部磁共振成像与临床生化的相关性

目的探讨苯丙酮尿症（PKU）患儿临床及生化与MRI异常改变的关系,评价常规MRI在PKU脑部病变中的价值。方法经临床生化证实为PKU患儿12例。其中4例为新生儿筛查证实,其后接受正规低苯丙氨酸（Phe）饮食治疗;8例未经任何治疗。12例均接受1.5TMRI扫描仪头部检查,应用T2WI、T1WI序列,且对T2WI上异常高信号进行分级,与智商（IQ）、血Phe质量浓度进行相关分析。结果未经治疗的PKU患儿均表现为脑白质T2WI异常高信号,呈斑片状、对称性分布,见于顶枕部脑室周白质。代表白质病变严重程度的MRI分级与血Phe质量浓度（r=-0.537 P〉0.05）及IQ（r=-0.279 P〉0.05）无相关性;血Phe质量浓度与IQ值亦无相关性（r=0.412 P〉0.05）。结论PKU患儿IQ低或血Phe高与常规T2WI上的异常范围并不成正比;常规MRI可很好显示PKU脑部病变,能为临床诊断及监控治疗提供帮助。     

苯丙酮尿症并癫(癎)患儿脑髓鞘病变的意义

目的 观察苯丙酮尿症(PKU)并癫(癎)患儿腩髓鞘延迟的情况,探讨PKU对神经系统的损伤.方法 PKU患儿42例,年龄3～72个月.经高压液相色谱法定量测定其血苯丙氨酸(PHE)水平>1.2 mmol/L,确诊为经典型PKU.其中21例根据脑电图及临床表现诊断为癫(癎)(癫(癎)组),余21例PKU患儿未并癫(癎)(对照组).42例患儿治疗前均行MRI检查,确诊后开始行低PHE饮食治疗.脑髓鞘发育评估采用Staudt评估标准.观察2组患儿10个区域(小脑、桥脑、中脑、内囊后肢、内囊前肢、枕叶、额叶、顶叶、颞叶、胼胝体)脑髓鞘延迟情况.结果 癫(癎)组患儿头颅MRI显示10个脑区脑髓鞘均有不同程度的延迟存在,其胼胝体延迟发生率为80.9%,10个脑区平均髓鞘延迟发生率为44.8%;对照组胼胝体髓鞘延迟发牛率为52.4%,10个脑区平均延迟发生率为30.9%,2组脑髓鞘延迟发生率比较有明显差异(P<0.01).脑电图轻度异常与中重度异常患儿治疗前后髓鞘延迟发生率比较有显著差异(P<0.01).结论 并癫(癎)的晚治PKU患者脑髓鞘延迟病变发牛率明显高于未并癫(癎)患者,低PHE饮食治疗在一定程度上可影响癫(癎)症状的改善,脑髓鞘发育延迟可能是导致PKU患者癫(癎)发作的主要原因之一.     

苯丙酮尿症患儿苯丙氨酸羟化酶基因突变的研究

目的了解宁夏地区苯丙酮尿症(PKU)儿童苯丙氨酸羟化酶(PAH)基因突变的特征。方法以经新生儿疾病筛查及气相色谱-质谱联用技术确诊的30例宁夏PKU儿童为病例组,30例正常儿童为对照组,应用PCR技术扩增PAH基因的3、5、6、7、11和12,六个外显子,再经单链构象多态性分析和DNA测序分析PCR扩增产物。结果在60个等位基因中检出51个突变基因,检出率85%;六个外显子共检出16种致病突变,包括8种错义突变(R241C、R243Q、R252Q、G 257 V、R359K*、R408Q、R 413 P、Q419R),3种剪接突变(IVS 4-1 GA、Y 204 C、IVS 7+2 TA),3种无义突变(R 111 X、Q160X、Y356X),1种同义突变(V399V)和1种缺失突变(N183del);R243Q突变频率最高,检出率为18.3%,其次是Y 204 C(11.7%)、IVS 4-1 GA(10.0%)、R 111 X(6.7%)和IVS 7+2 TA(6.7%)。病例组中发现Exon 6的N183del(C.547-549del GAA)缺失突变和Exon 11的R359K(C.1078GA)错义突变,为国内首次发现;病例组和对照组中均检出V245V(C.735GA)和Q232Q(C.696AG)两种静止突变,且差异无统计学意义(P0.05)。结论宁夏PKU儿童PAH基因六个外显子最常见的突变类型是错义突变,特别是R243Q;发现中国人群PAH基因的2种新的突变。     

甘肃省93例苯丙酮尿症患儿筛查分析

目的探讨甘肃省苯丙酮尿症(PKU)的发病情况。方法对1999年10月-2006年12月59 900例新生儿和在本院儿科门诊就诊的118例疑似PKU患儿,均采集足跟静脉血3滴,滴到新生儿筛查专用滤纸片上,形成3个直径0.8～1.0 cm的血斑。应用化学荧光分析法检测其血斑中的苯丙氨酸(phe)水平,根据血phe水平标准确诊PKU患儿。确诊患者予低phe饮食治疗,定期检测患儿血phe水平及体格和智能发育水平。测量患儿身高、体质量、头围等,1次/月,每0.5年测定患儿智商1次(采用Gesell发育量表测定)。采用SPSS11.0软件进行t检验。结果确诊治疗PKU患儿93例。通过筛查59 900例活产新生儿确诊36例PKU患儿,确诊年龄0.5～3.0个月。在儿科门诊的118例疑似PKU患儿共确诊57例,年龄0.5～6.0岁。晚发现的57例PKU患儿均有不同程度PKU的表现。经低phe饮食治疗后,早治患者的智能和体格发育正常,患儿身高、体质量和头围均在正常范围,智商结果为(92±12)分。晚治者的异常行为明显改善,智能也有不同程度提高,治疗前Gesell发育量表测定为(57±20)分,治疗12～18个月智商为(70±20)分,治疗前后智商比较有显著性差异(t=1.705 P<0.05)。结论早发现、早治疗对预防PKU智力低下的发生是十分必要的。     

苯丙酮尿症生化学异常与脑神经损伤关系的研究进展

苯丙酮尿症是以神经系统损伤为主要临床表现的遗传性氨基酸代谢性疾病，神经系统损害的发生机制尚未完全明了。近年来多认为与高苯丙氨酸血症引起的酪氨酸及其他大分子中性氨基酸在脑内摄入减少所造成的一系列相关重要神经递质及酶蛋白代谢障碍及合成减少有关，这些生化学改变影响着脑神经细胞的正常代谢与发育，从而引起一系列神经系统的损伤。     

苯丙酮尿症脑损害的研究进展

苯丙酮尿症可致智能障碍,故研究其脑损害具有重要意义。目前临床应用最直接而方便的研究方法是通过磁共振成像（ＭＲＩ）检查,发现大脑白质不同程度的改变,其神经脱髓鞘病变可能与胶细胞的可塑性机制有关。大脑氨基酸及糖代谢异常、酷氨酸水平降低使神经递质多巴胺合成减少,ＭＲＩ异常区域的白质糖代谢率降低。此外,Ｍ型乙酰胆碱受体及多巴胺受体减少,Ｎ型Ｃａ＾２＋通道减少而致神经细胞Ｃａ＾２＋转运障碍。这些研究对改进治     

苯丙酮尿症39例

目的探讨苯丙酮尿症(PKU)的诊断、治疗、预后及误诊原因。方法对1993年1月-2008年10月在本院住院确诊为PKU39例患儿[男21例,女18例;起病年龄(8.79±11.28)个月;确诊年龄(2.48±2.72)岁]临床表现、如何确诊、误诊分析、治疗前景等几方面进行回顾性分析。结果患儿均有不同程度智力及适应能力低下,有癫发作26例,鼠尿样体嗅21例,语言障碍11例,运动障碍2例。脑电图异常29例,头颅MRI异常5例。病例均存在误诊或延误诊治,确诊前病程(1.75±2.55)a,其中15例误诊为脑性瘫痪、脑发育不全。3例患儿表现为运动障碍或癫发作,缺乏毛发、皮肤改变及鼠尿样异味,经四氢生物蝶呤(BH4)负荷试验、尿液蝶呤分析,确诊为BH4缺乏症。结论PKU的临床表现以癫、智力障碍、精神行为异常等神经系统损害最为常见,临床易漏诊、误诊,早期诊断、早期干预是改善预后的关键。非经典PKU临床表现缺乏特征性,BH4负荷试验及尿液蝶呤分析有助于确诊。     

苯丙酮尿症防治现状及进展

苯丙酮尿症 (ｐｈｅｎｙｌｋｅｔｏｎｕｒｉａ ,ＰＫＵ)是一种常染色体隐性遗传性疾病 ,因苯丙氨酸羟化酶缺陷导致苯丙氨酸代谢障碍。患儿出生后如不能得到及时治疗 ,将因高苯丙氨酸血症以及中间代谢产物对中枢神经系统的毒性作用 ,导致严重的智能发育障碍。我国自 80年代初以来对ＰＫＵ开展了系统研究 ,在ＰＫＵ防治方面做了大量工作一、历史　苯丙酮尿症因Ｆｏｌｌｉｎｇ在 1934年发现病人尿中含有大量的苯丙酮酸而得名。 1947年Ｊｅｒｖｉｓ对病人进行苯丙氨酸负荷实验 ,发现正常人肝脏组织的上清液能将苯丙氨酸转变为酪氨酸 ,但是ＰＫＵ…     

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目的应用MRI观察苯丙酮尿症(PKU)患儿脑髓鞘发育延迟与血苯丙氨酸(PHE)浓度的关系。方法对2002—2004年北京中日友好医院PKU门诊确诊的经典型PKU患儿29例,治疗前进行头颅MRI及血苯丙氨酸浓度检查,脑髓鞘发育按Staudt标准对不同年龄阶段患儿脑10个区域进行量化评估。HPLC法定量测定血PHE浓度。根据开始接受治疗年龄不同分为甲(28~48周,11例)、乙(49~390周,18例)两组,另随机选取其中19例治疗1年后复查MRI进行治疗前后对照,根据该19例治疗中血苯丙氨酸浓度控制情况分为A组(血PHE控制在0.12~0.48mmol/L)和B组(血PHE控制在0.12~0.48mmol/L以外)。结果29例患儿治疗前均存在髓鞘发育延迟,在10个脑区域髓鞘发育延迟平均发生率为45.6%,主要部位在脑叶和胼胝体,其中甲组髓鞘发育延迟平均发生率为40.8%,乙组发生率为51.2%,甲乙组间差异有显著性意义(P<0.05);经低苯丙氨酸饮食治疗1年后,19例10个脑区域髓鞘发育延迟平均发生率为32.2%;治疗前后髓鞘延迟有显著性改善(P<0.01),且治疗中血PHE浓度控制较好的A组髓鞘延迟改善率为1.75±0.66,B组病例为0.78±0.44,差异有显著性(P<0.01),髓鞘延迟改善与血PHE浓度间有密切相关性。结论治疗延迟的PKU患儿的脑髓鞘发育延迟的高发病率,与高血PHE浓度影响时间有关;经低苯丙氨酸饮食治疗延迟的改善率,与治疗中血PHE浓度控制情况直接影响延迟改善,因此提示PKU患儿血PHE浓度是影响脑髓鞘发育延迟发生及改善的重要原因。     

Disturbed myelination in patients with treated hyperphenylalaninaemia: evaluation with magnetic resonance imaging

Cranial magnetic resonance imaging (MRI) was performed in nine treated adolescents with hyperphenylalaninaemia (HPA) in order to analyse possible changes in myelination. Three patients suffered from type I HPA, four from type II and two from type III (persistent HPA). Images were obtained with a 1.5T unit using spin-echo-sequences. In all patients with type I or type II HPA, abnormal findings in the cerebral white matter were demonstrated including band-like and/or confluent patchy areas of high signal intensity predominantly in the peritrigonal region, with anterior and posterior periventricular extension and/or involvement of the subcortical white matter. The extent of MRI changes did not correlate with the initiation, duration or quality of dietary treatment. There was also no consistent relationship between electrophysiological changes and white matter abnormalities on MRI. Our findings suggest a disturbance of myelination in patients with treated HPA. These results correspond well with earlier neuropathological and biochemical studies in untreated patients.     

Iatrogenic and transient hyperglycinemia in patients with phenylketonuria

Two patients with phenylketonuria detected by newborn screening for inborn errors of metabolism were treated with low phenylanine formulae.Serum phenylalanine levels were well controlled, but serum glycine levels were elevated until 4 or 5 months of age. This was probable due to the high content of glycine in the formulae. Glycine level returned to be normal in these patients, even though they were kept on the same formula, suggesting, immature metabolism of glycine during this period.No clinical problems were encountered in either patient.This investigation was supported by a Research grant by the Ministry of Health and Welfare of Japan 1978     

Scleroderma-like skin lesions in two patients with phenylketonuria

Two patients with phenylketonuria and scleroderma-like skin lesions are presented. Since scleroderma is a rare collagen disease of childhood, the occurrence of these two disorders in the same patient does not seem to be coincidental but raises the possibility of a causal relationship. Improvement in the skin lesions of the patients after the commencement of a low-phenylalanine diet supports this hypothesis.     

Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early

In 34 children with phenylketonuria (PKU) treated early the prognostic value of the age on institution of the diet (within the first 3 months of life) and of the quality of dietary treatment was determined in two different ways: 1) following intelligence closely (IQ) and (2) evaluating the EEG development up to their 12th (n=34) and 15th (n=18) years of life as appropriate. In general, IQ scores were found to be normal from the 4th–15th years of life. In our group of patients there was no effect on the IQ of the timing of diet onset. Children with strict dietary control showed a significantly higher IQ than those with loose control. One hundred and fifty-four EEGs (10/20 system, awake with eyes closed) were recorded at intervals of 2 years and conventionally evaluated. The development of alpha-activity was found to be normal. Beta-activity was enhanced. Abnormal EEG findings like general slowing and generalized paroxysmal activity (GPA) with or without spikes were more frequent in children with PKU than in controls, with the exception of focal abnormalities. EEG abnormalities increased with advancing age independently of IQ development and showed no relation to either the age at the onset nor the quality of dietary treatment.Abbreviations PKU phenylketonuria - PHE phenylalanine - GPA generalized paroxysmal activity - IDC index of dietary control     

Information processing in patients with early and continuously-treated phenylketonuria

A total of 33 patients with early and continuously-treated phenylketonuria (PKU) between 7 and 16 years of age and 33 matched controls participated in a study examining perceptual, central, and response-related mechanisms of information processing. The specific mechanisms studied were: perceptual filtering, memory search, response selection, response execution, and motor presetting. In addition, groups were compared on mean intelligence level and task oriented behaviour. The performance of the PKU patients practically matched that of the controls on all three tasks, suggesting that PKU patients who are continuously maintained on a well-controlled phenylalanine-restricted diet are not impaired in the elementary mechanisms of information processing. Furthermore, groups did not differ in mean IQ or task-oriented behaviour.     

Neurological outcome in adult patients with early-treated phenylketonuria

Due to the observation of severe neurological symptoms in single patients as well as brain imaging, neuropsychological and neurophysiological abnormalities, the long-term prognosis of treated phenylketonuria is still under discussion. We investigated the neurological outcome of 57 (24 male, 33 female) patients with phenylketonuria (diet onset <3 months) at a mean age of 23.6 (17–33) years in comparison to control subjects. Methods used were a clinical-neurological examination, tests for fine motor abilities, IQ test (WAIS-R), a neuropsychological attention task and MRI (30 patients only). Tremor was increased in the patients (28%) compared to controls (15%). Fine motor abilities were significantly reduced in three areas: hand-wrist steadiness, finger-hand dexterity and hand-wrist speed. Tremor as well as reduced fine motor skills were not associated with treatment-related variables, e.g. diet onset, strictness of biochemical control or amount of MRI white matter change. IQ was lower in patients (mean 97.6) compared to matched control subjects (mean 105.5). IQ at 12 years was correlated with biochemical control from birth up to the age of 12 and remained stable up to adult age, independent of biochemical control after 12 years of age. In contrast to the other outcome parameters, the performance in a neuropsychological attention task was influenced by the concurrent plasma phenylalanine concentration. Specific late-onset neurological impairment was not identified in this sample of early-treated adults with phenylketonuria. Conclusion Careful neurological investigation revealed subtle symptoms of brain damage even after early-initiated treatment in adult patients with phenylketonuria. At present it cannot be excluded that further neurological deterioration could emerge later in life. Thus, patients with phenylketonuria – either on or off diet – should be monitored throughout life. Received: 5 February 1998 / Accepted in revised form: 22 June 1998     

苯丙酮尿症患者生活质量研究进展

苯丙酮尿症是常见的先天性氨基酸代谢缺陷疾病,其遗传方式为常染色体隐性遗传,已经列入我国新生儿遗传代谢病筛查项目.早期筛查的普及和及时的治疗使得患者躯体症状得以改善,但仍会对远期社会功能以及心理发展产生不同程度的影响.随着医疗模式的改变,以心理和社会功能为主要内容的生活质量研究受到关注.目前国内外学者主要采用普适性量表和特异性量表等评估方法研究苯丙酮尿症对生活质量的影响,大部分研究结果表明早期、及时和长程的治疗有利于提高患者的生活质量水平.该文从苯丙酮尿症患者生活质量的评价方法、影响因素以及研究现状进行综述,对了解苯丙酮尿症患者生活质量现状、指导临床治疗以及判断预后具有重要意义.     

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目的应用磁共振成像(MRI)对原发性婴儿痉挛与苯丙酮尿症(PKU)合并婴儿痉挛患儿脑髓鞘病变进行观察并比较。方法 2002年8月至2009年7月中日友好医院确诊的婴儿痉挛患儿19例,其中原发性婴儿痉挛(原发组)8例、PKU合并婴儿痉挛(PKU组)11例。分别进行头颅MRI检查,脑髓鞘发育按Staudt标准对不同年龄段患儿脑10个区域:小脑(CL)、桥脑(PO)、中脑(MES)、内囊后肢(ICPL)、内囊前肢(ICAL)、枕叶(OL)、额叶(FL)、顶叶(PL)、颞叶(TL)、胼胝体(CC)进行量化评估。结果 19例中髓鞘化延迟发生率为89.5%(17/19),其中原发组髓鞘化延迟发生率为75.0%(6/8),PKU组延迟发生率为100.0%(11/11),原发组发生髓鞘化延迟范围较普遍,10个区域均有发生,PKU组髓鞘化延迟的主要部位在FL、DL和CC,髓鞘化延迟发生区域数≥5个的PKU组与原发组比较,差异有统计学意义(P<0.05)。结论婴儿痉挛有较高的髓鞘化延迟发生率,其中PKU合并婴儿痉挛髓鞘化延迟发生率更高,且发生区域更集中,可能与血中苯丙氨酸增高影响脑髓鞘形成有关。