Reye and Reye-like Syndromes: Result of a Pilot Stud in Peninsular Malaya, 1986

A pilot epidemiologic study of all cases of Reye and Reye-like syndromes was undertaken at 8 representative major hospitals in Peninsular Malaya from January 1st to December 31st 1986. The cases were classified as definitive Reye's syndrome, clinical Reye's syndrome and encephalo-hepatopathies. Less than 50% of cases reviewed fulfined the National Center for Disease Control criteria for clinical Reye's syndrome. Causes of Reye-like syndromes/encephalo-hepatopathies included fulminant hepatitis, Japanese B encephalitis, dengue, septicaemia, and complex febrile fits. It was not possible to differentiate clinical Reye's syndrome from the other encephalo-hepatopathies by either the clinical features (except for jaundice) or biochemical parameters. Liver biopsy is necessary for a definitive diagnosis of Reye's syndrome in Malaysia, because of the high prevalence of Reye-like diseases. The mortality rate in the 2 groups of patients is similar. Ingestion of salicylates was not found to be significantly associated with Reye and Reye-like syndromes in this study.     

Pearson bone marrow-pancreas syndrome with insulin-dependent diabetes,progressive renal tubulopathy,organic aciduria and elevated fetal haemoglobin caused by deletion and duplication of mitochondrial DNA

We report a patient with a clinical picture consisting of small birth weight, connatal hypoplastic anaemia, vacuolised bone marrow precursors, failure to thrive, and, subsequently, by insulin-dependent diabetes, renal Fanconi syndrome, lactic acidosis, complex organic aciduria, and elevation of haemoglobin F and of adenosine deaminase activity. The clinical course was progressive and death occurred at age 19 months. A high proportion of mitochondrial (mt) DNA molecules with a deletion of nucleotides 9238 to 15575 were identified in several tissues; about half of the shortened mtDNA molecules were concatenated to form circular dimers. The clinical and laboratory findings support recent conclusions that Pearson syndrome is not confined to bone marrow and pancreas, as originally described, but is a multi-organ disorder associated with delctions in part of the mtDNA molecules. The tissue distribution and the relative proportions of the abnormal mtDNA molecules apparently determine the phenotype and clinical course.     

A familial progressive neurodegenerative disease with 2-oxoglutaric aciduria

A boy and a girl born to a consanguineous Tunisian couple are suffering from a slowly progressive nervous disorder. Initially they both had normal psychomotor development with acquisition of gait and speech. First symptoms in the boy were athetoid movements during the second year of life. He later lost all motor and language skills and developed muscular rigidity and intention tremor. At the age of five years, he was completely bedridden while he appeared mentally much less affected. His younger sister followed a similar course. The major specific abnormality detected was a strikingly elevated excretion of 2-oxoglutaric acid, which was identified by gas liquid chromatography, mass spectrometry, and enzymatic analysis. 2-oxoglutarate dehydrogenase activity in homogenates of cultured skin fibroblasts was reduced to about 25% of control values in both children. Although the pathogenetic mechanisms leading to brain damage remain obscure, the finding strongly suggest an autosomal recessive neurometabolic disease with predominant involvement of the extrapyramidal system.Supported by Deutsche Forschungsgemeinschaft, SFB33Part of the results was obtained during work for a medical thesis by G. H.     

Metabolic function and liver histopathology in Reye-like illnesses

Forty children with Reye syndrome (RS) or Reye-like illnesses were investigated to elucidate the underlying aetiologies. Extensive biochemical studies including patterns of organic acids and amino acids, liver histopathology, and, if available, a DNA approach were performed. In addition to classical RS ( n = 10), the causes of Reye-like conditions included hereditary organic acidaemias ( n = 13), urea cycle defects ( n = 4), mitochondrial disorders ( n = 3), fulminant hepatitis ( n = 2), tyrosinaemia ( n = 1), valproate-associated hepatotoxicity ( n = 1), and other non-specific generalized organic acid disorders ( n = 6). It is important to collect specimens when encephalopathy with liver dysfunction of unknown causes is noted. When the underlying inherited metabolic disorders are confirmed, the prevention of the recurrence by adequate diet control and medications, and genetic counselling become possible.     

Pitfalls in aminoacid and organic acid analysis: 3-Hydroxypropionic aciduria

Pitfalls in organic acid analysis can originate from inadequate methodology, analytical interferences, in vivo interactions and from pre-analytical conditions which often are unknown to the specialized analytical laboratory. Among the latter, ingested food and additives, metabolites of food processing or medications have to be considered. Bacterial metabolites from the gastrointestinal or urogenital system or formed after sample collection can lead to pitfalls as well. An example of such a patient whose urinary metabolites mimick at first glance inherited propionic aciduria is described.     

A new amino acid mixture permits new approaches to the treatment of phenylketonuria

A new amino acid mixture for incorporation into medical foods for the treatment of hyperphenylalaninemia has been tested in a regular clinic. The mix is designed to be as unobtrusive as possible, consistent with good nutrition. After more than 1 year of trial as a beverage, we have shown that it is safe and well tolerated but that plasma phenylalanine is no better controlled than with some other products. The mix can be incorporated into a large number of different foods without affecting the taste. Occult monitoring of the quantity of medical foods purchased compared with the amounts reported to be consumed in diet histories provides an excellent way to monitor dietary compliance.     

用尿脱氧吡啶啉及羟脯氨酸排泄率评价肾病综合征患儿骨吸收功能状况

目的　观察糖皮质激素（激素）对肾病综合征(肾病)患儿骨吸收功能的影响。方法　采用酶联免疫竞争法和分光光度比色法,对68例泼尼松治疗不同阶段的肾病患儿及同龄健康儿童16例尿脱氧吡啶啉（DPD）及羟脯氨酸（HOP）进行检测。结果　（1）激素足量治疗组DPD/肌酐(Cr)为（30±17）nmol/mmol,较正常对照组［（21±5）nmol/mmol］、初发激素治疗前组［(20±8)nmol/mmol］及激素减量治疗组［(20±11)nmol/mmol］均有升高（P均<0.05);（2）与DPD/Cr值变化趋势一致,激素足量治疗组HOP/Cr为［(5.3±2.7)mg/mmol］,与正常对照组［(3.2±1.2)mg/mmol］、初发激素治疗前组［(3.5±0.9)mg/mmol］及激素减量治疗组［(3.7±1.7)mg/mmol］比较差异均有显著意义(P＜0.05,<0.01,<0.05);（3）DPD/Cr与HOP/Cr两指标在正常对照组及肾病各组均呈明显正相关(r=0.64、0.65、0.76、0.78,P均<0.01)。结论　超生理剂量的泼尼松治疗能使肾病患儿骨吸收功能增强,易导致骨质疏松。     

Medium-chain acyl-CoA dehydrogenase deficiency in two siblings with a Reye-like syndrome

An increasing number of reports indicate that patients with some inherited metabolic diseases may have symptoms resembling those of Reye syndrome. We describe two siblings who developed a Reye-like syndrome at ages 16 and 18 months, respectively, after a viral illness and salicylate therapy. Both had fasting hypoglycemia and hypoketonemia. At the time of the acute episode and after ingestion of a medium-chain triglyceride load, one of them excreted large amounts of abnormal metabolites derived from the omega- and (omega-1)-oxidation of medium-chain fatty acids. Medium-chain acyl-CoA dehydrogenase activity was lower than 20% of control values in fibroblasts from both patients. This enzyme defect should be considered in children with a Reye-like syndrome with these distinctive manifestations.     

Argininosuccinic aciduria: Metabolic studies and effects of treatment with keto-analogues of essential amino acids

A 22 years old female with the late-onset type of argininosuccinic aciduria was successfully treated for 5 months with a mixture of essential amino acids and their keto-analogues. There was a marked change in plasma ammonia, plasma amino acids and argininosuccinic acid excretion. A long term anabolic response was reflected by an increase of total serum proteins and serum albumin by about 1 g/dl during the first 5 months of treatment. There was a striking improvement in the patient's seizure disorder following institution of the keto-analogue therapy.     

Transesophageal electropharmacologic test in a newborn with familial Wolff-Parkinson-White syndrome

Summary A newborn infant with familial Wolff-Parksinson-White (WPW) syndrome presented with a supraventricular tachycardia of 300 beats/min, refractory to digoxin and flecainide administration. Serial electropharmacologic tests were performed via the esophagus before and during oral therapy with verapamil at 40, 80, and 60 mg daily. Before treatment, tachycardia could be induced with programmed stimulation. A regimen of verapamil at 60 mg daily, which resulted in the initiation of nonsustained (<10 s) reciprocating tachycardia only, without clinical recurrences, was identified as suitable long-term oral therapy. The efficacy of this drug regimen in preventing episodes of tachycardia was confirmed during a 1-month follow-up period. It is concluded that transesophageal atrial pacing is a useful, noninvasive means of selecting treatment in neonates with supraventricular tachycardia, when nonconventional drugs are considered for prophylaxis.     

Allgrove syndrome with features of familial dysautonomia: a novel mutation in the AAAS gene

Allgrove syndrome (or triple-A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency (glucocorticoid in the majority of cases) and autonomic/neurological abnormalities. This disease is now known to be caused by mutation in the AAAS gene located on chromosome 12q13. Diagnosis should be readily available when the full-blown features are there, but it becomes less apparent when presentation is atypical or in the evolving process. We present a brother and sister (12 and 19 y old, respectively) born to consanguineous parents of Palestinian origin with Allgrove syndrome. The index patient was erroneously diagnosed to be a case of familial dysautonomia before the diagnosis of adrenal insufficiency was made at the age of 7.5 y, while his elder sister had only alacrima from birth and developed achalasia at the age of 15 y. She started to develop early evidence of adrenal disease at the age of 19 y. Both of them had neuroautonomic dysfunction. The diagnosis of Allgrove syndrome was confirmed in these two patients by studying the gene mutation in the family. The sequencing of the AAAS gene in the two patients identified a novel homozygous mutation within intron 5 (IVS5+1G-->A). Both parents as well as all three other children were heterozygous for the same mutation. CONCLUSION: These two cases illustrate the heterogenous nature and the intrafamilial phenotypic variability of Allgrove syndrome.     

伴染色体核型异常的毛发-鼻-指(趾)综合征1例并文献复习

摘要目的探讨毛发-鼻-指（趾）综合征(TRPSs)主要临床特征和基因突变特点,提高对该病的认识。方法对1例TRPSs女性患儿临床特征、实验室检查、影像学检查及家系染色体核型进行分析,提取其家系外周血白细胞基因组DNA,PCR扩增TRPS1基因全部编码区序列后测序分析,并复习相关文献。结果患儿头皮毛发稀疏、细软,眉毛外侧稀疏,耳大竖立,梨状鼻,人中长而扁平,上唇薄;指间关节弯曲粗大,双手X线片发现锥形骨骺;染色体核型分析示：46,XX,t(2q-;8q+),其弟及其父母染色体核型均正常;家系外周血基因突变分析结果为阴性。结论TRPSs的诊断以临床特征和影像学表现为主要依据。外周血TRPS1基因突变分析结果为阴性,结合患儿染色体核型分析结果,推测可能存在TRPS1基因突变以外的其他致病因素。     

Complex bone abnormalities with fatal outcome: a new familial syndrome]

A new lethal disorder affecting two brothers is described. The features were curvature of the long bones, multiple fractures, dysmorphic facies, syndactyly and absence of ossification in the cranial vault. The condition could be inherited as an autosomal recessive or sex linked condition.     

Novel mutations, no detectable mRNA and familial genetic analysis of the Wiskott-Aldrich syndrome protein gene in six Japanese patients with Wiskott-Aldrich syndrome

The Wiskott-Aldrich syndrome (WAS) is a primary X-linked immunodeficiency disease caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene. The present molecular studies of six Japanese WAS patients identified five different mutations of WASP, including two novel mutations (45delG, 395insGGAGAT), the latter appearing to have occurred de novo. Familial carriers were detected by polymerase chain reaction-single strand conformational polymorphism analysis, restriction enzyme digestion and direct sequencing of PCR products. Neither mRNA nor the protein product were detectable in any of the patients, while various amounts of WASP protein were expressed in carriers, normal controls, haematopoietic cell lines of all lineages and in one patient after receiving allogeneic bone marrow transplantation. Conclusion Genetic and protein analysis is useful in the definite diagnosis and follow up of Wiskott-Aldrich syndrome patients and in carrier detection, especially of atypical or sporadic patients. Received: 14 January 1999 / Accepted: 8 April 1999     

Urine amino and organic acids analysis in developmental delay or intellectual disability

OBJECTIVES: To determine the proportion of urine amino and organic acids screening tests (UMS) undertaken for patients referred with developmental delay or intellectual disability (DD/ID), and within the group with DD/ID, to determine the diagnostic yield, the proportion of diagnoses with a therapy and the associated recurrence risks. METHODS: A retrospective review of request forms and results of UMS, in individuals older than 28 days, referred to the Women's and Children's Hospital, North Adelaide, between 1 January 1992 and 31 December 1998 was carried out. Urine was analysed by ion exchange chromatography (amino acids), gas chromatography/mass spectrometry (organic acids), colorimetric assay (orotic acid) and stable isotope-dilution mass spectrometry (trimethylamine). RESULTS: A total of 3316 samples were received, 1447 being from patients with DD/ID. A diagnosis was determined for 1.8% of all referrals. For patients with DD/ID, the diagnostic yield was 1.1%, with a similar yield for isolated DD/ID and DD/ID with other features (9/828 vs 7/619; chi2 = 0.006; P = 0.93). Specific therapies were available for 69% of diagnoses associated with DD/ID and 87.5% had known Mendelian or mitochondrial inheritance. CONCLUSION: Urine metabolic screening is an important part of the evaluation of children with DD/ID as it can enable families to make reproductive decisions and children to receive appropriate therapy early.     

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??Objective??To study the clinical features and SCN1A gene mutation in a familial inherited Dravet syndrome family with dizygotic twins. Methods??The clinical manifestations of dizygotic twins with Dravet syndrome and GEFS + mother were summarized and SCN1A gene was sequenced. The relationship between genotype-phenotype of SCN1A gene and Dravet syndrome was analyzed by literature. Results??The dizygotic twins and their mother have de novo SCN1A gene mutant c.3624A??T??p.R1208S?? at the second loop of Na+ channel α subunit. This is very rare compared to the usual mutation domain at S4 or S5-S6. It is the first report in China that Dravet syndrome dizygotic twins inherited SCN1A gene mutation from their mother who was diagnosed as GEFS+. Point mutations of SCN1A were more common??accounting for 93.8%. The relationships between phenotype-genotype were very complex??since other pathogenic factors may be involved in. Conclusion??It is the first report in China that SCN1A gene mutation in a familial inherited Dravet syndrome with dizygotic twins and found a de novo SCN1A gene mutation of c.3624A??T??p.R1208S????which is located at the very rare region of the protein.     

Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism

Background  

Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period.