The incidence of inherited metabolic disorders in the West Midlands, UK.

BACKGROUND: Inherited metabolic disorders (IMDs) are a heterogeneous group of genetic conditions mostly occurring in childhood. They are individually rare but collectively numerous, causing substantial morbidity and mortality. AIMS: To obtain up-to-date estimates of the birth prevalence of IMDs in an ethnically diverse British population and to compare these estimates with those of other published population-based studies. METHODS: Retrospective data from the West Midlands Regional Diagnostic Laboratory for Inherited Metabolic Disorders (Birmingham, UK) for the 5 years (1999-2003) were examined. The West Midlands population of 5.2 million is approximately 10% of the UK population. Approximately 11% of the population of the region is from black and ethnic minority groups compared with approximately 8% for the the UK. RESULTS: The overall birth prevalence was 1 in 784 live births (95% confidence interval (CI) 619 to 970), based on a total of 396 new cases. The most frequent diagnoses were mitochondrial disorders (1 in 4929; 95% CI 2776 to 8953), lysosomal storage disorders (1 in 5175; 95% CI 2874 to 9551), amino acid disorders excluding phenylketonuria (1 in 5354; 95% CI 2943 to 9990) and organic acid disorders (1 in 7962; 95% CI 3837 to 17 301). Most of the diagnoses (72%) were made by the age of 15 years and one-third by the age of 1 year. CONCLUSIONS: These results are similar to those of the comparison studies, although the overall birth prevalence is higher in this study. This is probably due to the effects of ethnicity and consanguinity and increasing ascertainment. This study provides useful epidemiological information for those planning and providing services for patients with IMDs, including newborn screening, in the UK and similar populations.     

Optic neuropathies in inherited metabolic disorders

Optic neuropathy is a common cause of childhood visual defects and early diagnosis is important for counseling, management and treatment of the underlying conditions. In most cases, careful examination, family history and neuroimaging are sufficient to identify the underlying cause. However, in unexplained cases, in cases where more than one individual in a family is affected and in cases where optic neuropathy is accompanied by other systemic signs and symptoms, a metabolic disorder should be considered. Metabolic disorders generally show a broad range of multisystem clinical symptoms, including eye defects. Here we review the substantial group of metabolic disorders that include optic neuropathies which may aid ophthalmologist, geneticist, neurologist, endocrinologist and other involved specialists in the diagnosis process.     

面对新生儿期遗传代谢病我们还应做些什么

在我国,儿科医生真正较普遍地关注遗传代谢病(inherited metabolic disorders,IMD)应该是从即将进入2l世纪时开始的[1].不到10年的时间,现在我国的一些医院,甚至一些商业公司的专业实验室中建立起了质谱(mass spectrometry,MS)技术诊断IMD的方法,透过多种途径广为推介,为新生儿科有症状或无症状新生儿的血、尿标本提供检测服务;通过各种类型的学习班和学术刊物的传播,IMD诊断处置及进展的知识已经在新生儿科中基本普及;一批IMD诊断和防治的研究结果已经在专业期刊上发表;形势确实喜人[2-6].     

积极开展遗传性代谢疾病诊断与治疗的研究

随着疾病谱的变化 ,既往较少见的遗传性疾病在儿科临床实践中的地位越来越重要。近年来生物化学和分子遗传学的迅猛发展 ,使既往许多不被认识的遗传性代谢疾病得以诊断或治疗。据统计 ,权威的《孟德尔人类遗传学》1965年初版时仅收录10 0 0多个病种 ,到 1998年底达 10 0 0 0种 ,截至 2 0 0 1年 6月已达 12 65 4种 (常染色体遗传病 1184 1种、Ｘ连锁遗传病 717种、Ｙ连锁遗传病 37种、线粒体遗传病 5 9种 )。其中已获得明确基因定位的就达90 0 0多种 (ＯＭＩＭＳｔａｔｉｓｔｉｃｓｆｏｒＪｕｎｅ 3,2 0 0 1.ｈｔｔｐ :/ /ｗｗｗ .ｎｃｂｉ .…     

小儿遗传代谢内分泌疾病诊断治疗进展

现将 2 0 0 2年我国儿科遗传代谢内分泌疾病诊断治疗进展简介如下。1　遗传代谢性疾病有关遗传病基因诊断、基因型与表型分析等方面的研究已逐步开展。有报道探讨了MeCP2基因热点突变分析在Rett综合征诊断中的应用 ,采用PCR、限制性内切酶分析和PCR产物测序等技术 ,在 2 3例Rett综合征患儿中发现 4例有T15 8M突变 ,2 1例患儿中 2例有R16 8X突变。在患儿双亲及正常女性对照均未发现以上两种突变[1] 。有报道采用多重引物PCR方法检测 30例杜氏肌营养不良相关基因缺失情况 ,发现有基因缺失者 17例 ,其中多重缺失9例 (5 2 9% ) ,以外显…     

Management and counseling of children with inherited metabolic disorders.

Although rare individually, as a group inborn errors of metabolism are relatively common in the pediatric population. Families need assistance with evaluation and referral, accurate counseling, and management issues. An overview of inherited metabolic disorders is presented, followed by discussion and examples of selected categories of disease.     

Clinical approach to inherited metabolic disorders in neonates: an overview

There are almost one hundred inborn errors of metabolism which can start in the neonatal period, but less than 20 are amenable to treatment. In general, an extremely evocative clinical setting is the course of a full-term baby born after normal pregnancy and delivery who, after an initial symptom-free period deteriorates relentlessly for no apparent reason and does not respond to symptomatic therapy. Investigations routinely performed in all sick neonates yield normal results. Emergency treatment must be undertaken in parallel with investigations. Five main presentations can be observed: a neurologic deterioration ‘intoxication’ type mostly suggests maple syrup urine disease, methylmalonic, propionic, isovaleric acidaemias and urea cycle disorders. Isolated seizures is the revealing symptom of pyridoxine-responsive and folinic acid responsive seizures. A jaundice or a liver failure suggest galactosaemia, fructosaemia, tyrosinaemia type I (after 3 weeks), phosphomannoisomerase deficiency or bile acid synthesis defects. Cardiac failure and heartbeat disorders should first suggest mitochondrial fatty acid oxidation (FAO) disorders. Persistent hypoglycaemia is the presenting sign of glyco/ gluconeogeneis defects, hyperinsulinism and FAO disorders. The first line investigation relies upon the collection at the same time of a few samples including blood gases electrolytes, prothrombin time, transaminases, ammonia and lactic acid, and the search for ketonuria. The storage of plasma, urine and blood (on filter paper) is an important element in the diagnosis. The utilization of these samples should be carefully planned after taking advice from specialists in inborn errors.     

Congenital hypothyroidism, seasonality and consanguinity in the West Midlands, England

Seasonal variation in the incidence of congenital hypothyroidism (CHT) is reported by some centres. Also, the incidence of CHT varies with ethnic origin. We report our experience in the West Midlands, England. The overall incidence of CHT among 1128 632 neonates screened over 16 years in the West Midlands was 1:2924 live births, but was increased (1:2323; p<0.05) between October and December. In the city of Birmingham between 1981 and 1991, the incidence of CHT was 1:781, 1:5540 and 1:2257 in Pakistani, Indian and North-West European children, respectively; no cases were seen in those from other ethnic groups. Consanguinity among those of Pakistani descent could account for the increased incidence within this population. Identification of the cause of seasonal variation may aid development of preventative strategies.     

Paediatric malignant tumours of the gastrointestinal tract in the West Midlands, UK, 1957-2000: a large population based survey

BACKGROUND: To investigate the incidence, clinical characteristics and survival of malignant tumours of the gastrointestinal tract in children in the West Midlands in Britain over a 44-year span time, to identify any change over this period and to compare the data with the world literature. PROCEDURE: Retrospective population based study. Fifty-seven patients were identified from the records of the West Midlands Regional Children's Tumour Registry. Age-standardised incidence rates were calculated using the world standardised population method. Statistical tests used were the Log rank test and survival curves were produced using the Kaplan-Meier method. RESULTS: The age-standardised incidence of overall gut tumours during the period 1957-2000 was 1.10/million/year. The age standardised incidence of non-Hodgkin lymphoma (NHL) was calculated as 0.9/million/year and for adenocarcinoma 0.14/million/year. CONCLUSION: Malignant tumours of the gastrointestinal tract remain rare in children. No changing trends in incidence were observed over the 44-year period. NHL was the commonest malignancy overall and of the small bowel while equal number of adenocarcinoma and NHL were identified in the large bowel. There was no significant difference in survival between sexes, site and age groups in both NHL and adenocarcinoma. Survival has improved over the last four decades for NHL patients but remains poor for the adenocarcinoma patients.     

Acute presentations of inherited metabolic disorders: investigation and initial management

Inborn errors of metabolism are individually rare, but so many have now been described that the general paediatrician will encounter one from time to time. For many, early treatment is important. Unfortunately, most that present acutely do so with non-specific symptoms and signs. It is therefore necessary to identify and investigate those at high risk. The most common problems are neurological (including coma, seizures and stroke-like episodes), hypoglycaemia, disorders of acid-base regulation, acute liver disease, rhabdomyolysis, cardiomyopathy and sudden collapse. Treatment should be started as soon as an inborn error is suspected. This review is a short, practical introduction and cannot cover all situations. If in doubt, consult your local specialist metabolic centre. Free, detailed instructions on the acute management of individual inborn errors of metabolism can be found on the British Inherited Metabolic Disease Group (BIMDG) Website: http://www.bimdg.org.uk/     

A fluorogenic allele-specific amplification method for DNA-based screening for inherited metabolic disorders

Rapidly growing mutation databases for various inherited metabolic diseases raise the possibility of neonatal screening by DNA-based diagnosis. It is therefore important to develop a simple DNA diagnostic method which is suitable for processing a large number of samples. We have devised an allele-specific amplification (ASA) method with a fluorogenic probe (TaqMan probe) to detect point mutations. A pairwise PCR amplification with two sets of allele-specific primers was performed in the presence of the TaqMan probe with real-time fluorescence monitoring on an ABI PRISM 7700 sequence detector. The difference in the amplification efficiency between two PCR reactions was determined by "threshold" cycles to differentiate mutant and normal alleles. The method, TaqMan-ASA, does not require post-PCR processing, thus obviating potential PCR contamination. Since the entire procedure can be carried out in a 96-well microtiter plate format, it is easy to automate. We successfully applied TaqMan-ASA to detect a common g727t mutation in Japanese patients with glycogen storage disease type Ia and a prevalent a985g mutation in Caucasian patients with medium-chain acyl-CoA dehydrogenase deficiency.     

疑似遗传代谢病的高危新生儿行质谱检测与高通量测序检测诊断准确性研究

目的 比较质谱检测与高通量测序（NGS）筛查疑似遗传代谢病（IMD）的高危新生儿的诊断效能。方法 纳入2016年8月至2018年6月复旦大学附属儿科医院（我院）临床表现疑似IMD的高危新生儿，患儿监护人知情同意患儿参加质谱检测和NGS筛查IMD，以NGS检测（包含2 742个已知致病基因）为金标准，以质谱检测（包含20种氨基酸代谢病、12种脂肪酸代谢病和19种有机酸代谢病）为待测标准，随访至6月龄结局。结果 纳入2 000例疑似IMD的高危新生儿，NGS诊断IMD 33例（1.7%），涉及21种IMD；质谱检测结果异常154例（7.7%），提示IMD可能26例、继发性改变可能128例。以NGS检测结果为金标准，质谱检测提示IMD可能+提示继发性改变可能为待测标准1，质谱检测的敏感度93.9%（95%CI：79.8%~99.3%），特异度93.8%（95%CI：92.6%~94.8%）。质谱检测提示IMD可能（待测标准2）与NGS相符13例；质谱检测提示某一类或某几种IMD可能11例，NGS均明确并细化了疾病类型；质谱检测提示IMD可能，但与NGS检测结果不一致2例；质谱检测提示继发性改变可能5例，NGS检测为致病/可疑致病变异，明确并细化了疾病类型。待测标准1中，质谱结果正常的1 846例中，NGS发现2例IMD。NGS诊断的IMD有5例不包含在本文质谱检测的病种中。NGS诊断IMD 33例，有机酸代谢异常8种15例、氨基酸代谢异常7种9例、脂肪酸氧化代谢异常3种6例、其他类型IMD共3例；可疑遗传代谢病家庭史12例；以6月龄为随访终点统计，13例IMD患儿家属放弃治疗死亡，2例抢救无效死亡；18例IMD患儿临床诊疗方案得以明确，7例因获得及时有效的治疗目前生长发育良好，11例有不同程度的发育落后，主要以精神运动发育迟缓为主，部分伴有听力损害。结论 质谱检测+NGS检测较单纯质谱检测可以更加快速且全面确诊临床表现疑似IMD的高危新生儿，尽早实施个体化治疗，改善患儿预后。     

A fluorogenic allele-specific amplification method for DNA-based screening for inherited metabolic disorders

Rapidly growing mutation databases for various inherited metabolic diseases raise the possibility of neonatal screening by DNA-based diagnosis. It is therefore important to develop a simple DNA diagnostic method which is suitable for processing a large number of samples. We have devised an allele-specific amplification (ASA) method with a fluorogenic probe (TaqMan probe) to detect point mutations. A pairwise PCR amplification with two sets of allele-specific primers was performed in the presence of the TaqMan probe with real-time fluorescence monitoring on an ABI PRISM 7700 sequence detector. The difference in the amplification efficiency between two PCR reactions was determined by "threshold" cycles to differentiate mutant and normal alleles. The method, TaqMan-ASA, does not require post-PCR processing, thus obviating potential PCR contamination. Since the entire procedure can be carried out in a 96-well microtiter plate format, it is easy to automate. We successfully applied TaqMan-ASA to detect a common g727t mutation in Japanese patients with glycogen storage disease type Ia and a prevalent a985g mutation in Caucasian patients with medium-chain acyl-CoA dehydrogenase deficiency.     

Liver transplantation for pediatric inherited metabolic disorders: Considerations for indications,complications, and perioperative management

LT is an effective therapeutic option for a variety of IEM. This approach can significantly improve the quality of life of patients who suffer from severe disease manifestations and/or life‐threatening metabolic decompensations despite medical/dietary management. Due to the significant risks for systemic complications from surgical stressors, careful perioperative management is vital. Even after LT, some disorders require long‐term dietary restriction, medical management, and monitoring of metabolites. Successful liver transplant for these complex disorders can be achieved with disease‐ and patient‐specific strategies using a multidisciplinary approach. In this article, we review indications, complications, perioperative management, and long‐term follow‐up recommendations for IEM that are treatable with LT.