Necesidades sanitarias y socioeducativas de niños con enfermedades raras de tipo metabólico y sus familias: estudio cualitativo en un hospital de tercer nivel

Introduction

Rare diseases are a challenge for public health due to the lack of information on their magnitude. These include inborn errors of metabolism. The objective of this study was to assess the quality of life and social, health, economic, and educational needs of a group of paediatric patients with inborn errors of metabolism attended to in a hospital.

Leukodystrophies and other genetic metabolic leukoencephalopathies in children and adults

Abnormalities of CNS white matter are frequently detected in patients with neurological disorders when MRI studies are performed. Among the many causes of such abnormalities, a large group of rare genetic diseases poses considerable diagnostic problems. Here we present a compilation of genetic leukoencephalopathies to consider when one is confronted with white matter disease of possibly genetic origin. The table contains essentials such as age at onset of symptoms, clinical and MRI characteristics, basic defect, and useful diagnostic studies. The table serves as a diagnostic check list.     

Genetic basis of galactosemia.

Classic galactosemia is an inborn error of galactose metabolism and results from deficiency of the ubiquitously expressed enzyme galactose-1-phosphate uridyltransferase (GALT). Nine missense mutations, three splicing mutations, three GALT protein polymorphisms, and one silent nucleotide substitution have been identified to date. Most of the disease-causing mutations are rare among patients. The most common mutation, Q188R, has a frequency of only one-fourth in the patient population examined. Three classes of disease-causing mutations have been reported: CRM+ missense mutations (the most common class), CRM- missense mutations, and splicing mutations. Thus, galactosemia is heterogeneous at the molecular level, which is noteworthy in light of the well-documented clinical variability observed in this disorder. It has also been shown that eight of nine galactosemia missense mutations occur in evolutionarily well-conserved domains, suggesting that they affect functionally and/or structurally important residues. In contrast, all protein polymorphisms alter variable amino acids which presumably are not important for the enzyme's function.     

Gorlin综合征的临床表现

目的 探讨Gorlin综合征患者的临床及影像学表现形式.方法 回顾性总结2000～2011年期间诊治的9例Gorlin综合征患者,就其临床及影像学表现进行分析归纳.结果 患者最初症状均表现为颌骨膨隆,其他症状有皮肤多发痣4例(44.4％),掌足陷凹2例(22.2％),脊柱肋骨畸形9倒(100％),特殊面征4例(44.4％),智力低下1例(11.1％),先天性唇裂1例(11.1％),鸡胸1倒(11.1％),粉刺2例(22.2％),眶距增宽5例(55.5％),手掌或脚掌增大1例(11.1％).全景片或CT检查示9例患者均有颌骨囊性影,大多表现为多发性;胸片检查示分叉肋5例,脊柱弯曲6例,心脏改变1例;脑部CT示大脑镰和小脑幕钙化6倒.结论 Gorlin综合征患者临床及影像学表现形式多样,多发性牙源性角化囊性瘤是其重要也是最先出现的临床表现之一.     

A Japanese case of β-ureidopropionase deficiency with dysmorphic features

β-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation, and it is caused by a mutation in the UPB1 gene. Approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. Non-neurological symptoms have been rarely reported. We describe a case of this disease with developmental delay and dysmorphic features. Gas chromatography–mass spectrometry-based urine metabolomics demonstrated significant (?+4.5 standard deviation after logarithmic transformation) elevations of β-ureidopropionic acid and β-ureidoisobutyric acid, strongly suggesting a diagnosis of β-ureidopropionase deficiency. Subsequent quantitative analysis of pyrimidines by liquid chromatography–tandem mass spectrometry supported this finding. Genetic testing of the UPB1 gene confirmed compound heterozygosity of a novel mutation (c.976C>T) and a previously-reported mutation (c.977G>A) that is common in East Asians. β-Ureidopropionase deficiency is probably underdiagnosed, considering a wide phenotypical variability, non-specific neurological presentations, and an estimated prevalence of 1/5000–6000. Urine metabolomics should be considered for patients with unexplained neurological symptoms.     

Glutaric acidemia type II patient with thalassemia minor and novel electron transfer flavoprotein-A gene mutations: A case report and review of literature

Glutaric acidemia type II (GAII), also known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAII with novel electron transfer flavoprotein (ETF)-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, riboflavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor development was normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.     

Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of “red flags” which should prompt additional evaluation.     

代谢性疾病相关脑病的诊治

脑病是脑功能障碍的总称,由各类代谢紊乱引起的脑功能障碍称之为代谢性脑病,如维生素代谢异常性疾病、叶酸代谢障碍、尿素循环障碍及线粒体疾病等均可引起脑功能障碍。一些先天代谢性疾病相关脑病,可以通过特殊饮食、补充相关辅酶等得到良好控制,因此,在不可逆的脑功能损害发生前,早期诊断和治疗非常重要。癫痫是代谢性脑病的最常见表现。代谢性脑病的病因多源,起病隐匿,诊断代谢性脑病对临床医生是个很大的挑战。对于临床表现为癫痫伴生长发育迟缓、智力障碍和多系统受累的患儿,均应及时进行代谢性疾病的相关检查,如尿有机酸分析、血氨基酸分析、血酰基肉碱分析、脑脊液的相关代谢产物检测以及基因诊断。     

遗传代谢病高危新生儿病因谱及发病特征分析

目的:分析新生儿重症监护室(neonatal intensive care unit,NICU)中遗传代谢病(或称先天性代谢缺陷,inborn errors of metabolism,IEM)高危新生儿的病因谱及发病特征.方法:联合应用液相色谱-串联质谱(liquid chromatography-tandem mass spectrometry,LC-MS/MS)和气相色谱-质谱(gas chromatography-mass spectrometry,GC-MS)技术,对2007年9月-2012年8月复旦大学附属儿科医院收治的859例IEM高危新生儿进行血尿代谢标志物的检测和分析,并对确诊为IEM患儿的病因和临床表现进行分析.结果:859例IEM高危新生儿中共诊断IEM22例(2.7％),其中氨基酸代谢病11例(50％),以枫糖尿病(7例)多见;有机酸代谢病11例(50％),以甲基丙二酸血症(8例)多见.22例IEM患儿的临床表现各不相同,多在出生后一个短暂的“正常”期后起病,以拒食、呕吐、惊厥发作等消化系统或神经系统症状为主.结论:高危新生儿IEM病因谱复杂多样,以甲基丙二酸血症和枫糖尿病最多见,临床应重视早期联合运用LC-MS/MS和GC-MS技术对NICU中IEM高危新生儿进行IEM检测,以便早期诊断和干预.