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Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m 2 fludarabine and 180 mg/m 2 Mel or 42 g/m 2 treosulfan were used as conditioning., (© 2024. Japanese Society of Hematology.)

Background: Unmanipulated haploid HSCT for SAA has resulted in improved outcomes over recent years. However, studies related to unmanipulated haploid HSCs combined with tp-UCB transplantation for other types of NMD are rare. Accordingly, we present the outcomes of 109 pediatric patients with life-threatening NMD undergoing unmanipulated haploid HSCs combined with tp-UCB transplantation., Procedure: We retrospectively investigated 109 pediatric patients with life-threatening NMD treated with unmanipulated haploid HSCs combined with tp-UCB transplantation in a single center., Results: The median days of neutrophil and platelet engraftment were +13 and +22 days, respectively. None of the cases experienced PGF. The incidence rates for grade I-II, III-IV aGVHD and cGVHD were 44.9%, 24.8%, and 9.3%, respectively. The incidence rates of CMV and EBV viremia were 46.7% and 39.4%, respectively. The median follow-up duration was 997 days. In total, 106 patients survived, including 104 cases with FFS and 2 cases with SGF. Three patients died. The 5-year TRM, OS, and FFS were 2.8%, 97.2%, and 96.2%, respectively., Conclusion: The results of unmanipulated haploid HSCs combined with tp-UCB in pediatric patients with life-threatening NMD were promising. However, further research is now needed to determine specific factors that might influence the engraftment of HSCs., (© 2021 Wiley Periodicals LLC.)

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations., (© 2020 The Author(s).)

Fumarate hydratase deficiency (FHD) is a rare metabolic disease caused by two defective copies of the FH gene, which encodes the Krebs cycle enzyme fumarase. FHD is associated with brain and developmental abnormalities, seizures, and high childhood mortality. We describe the symptoms and treatment of a patient with FHD. While infantile spasms are common in FHD, the patient presented with epileptic spasms later in childhood. Also unexpectedly, the patient responded excellently to lacosamide for her non-convulsive status epilepticus and epileptic spasms after three first-line medication trials failed. We biochemically analyzed the patient's two fumarase variants (E432Kfs*17 and D65G). While E432Kfs*17 was extremely enzymatically defective, D65G exhibited only a mild defect, possibly playing a role in the patient's longer survival., (© 2019 Wiley Periodicals, Inc.)

Several recent studies have reported that toxic metabolites accumulated in the body as a product of inborn errors of metabolism (IEM) are eliminated more rapidly with continuous venovenous hemodiafiltration (CVVHDF) than with peritoneal dialysis (PD). However, there is still uncertainty about the impacts of dialysis modalities on the short-term outcome. Here, it was aimed to investigate the effects of dialysis modalities on the short-term outcome. This retrospective study included 40 newborn infants who underwent PD (29 patients) or CVVHDF (11 patients) due to inborn errors of metabolism at a tertiary centre, between June 2013 and March 2018. The outcomes and the potential effects of the dialysis modality were evaluated. Of 40 patients, 21 were urea cycle defect, 14 were organic academia, and 5 were maple syrup urine disease. The median 50% reduction time of toxic metabolites were shorter in patients treated with CVVHDF (p < 0.05). Catheter blockage was the most common complication observed in PD group (24.1%), whereas in CVVHDF group hypotension and filter blockage were more common. There was no significant difference in mortality between dialysis groups (38% vs. 45.4%, p > 0.05). In patients with hyperammonaemia, duration of plasma ammonia > 200 μg/dL was the most important factor influencing mortality (OR 1.05, CI 1.01-1.09, p = 0.007).Conclusion: This study showed that CVVHDF is more efficient than PD to rapidly eliminate toxic metabolites caused by IEM in newborn infants, but not in improving survival. What is Known: •Toxic metabolites are eliminated more rapidly with CVVHDF than with PD. •Higher complication rates were reported with rigid peritoneal catheters in PD and catheter blockage in CVVHDF. What is New: •Prolonged duration of plasma ammonia levels above a safe limit (200 μg/dL) was associated with increased mortality. •Lower catheter-related complication rates may have been associated with the use of Tenckhoff catheters in PD and the use of right internal jugular vein in CVVHDF.

Fatty acid β-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient.Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well. What is Known: • Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders. • Neonatal screening intends to reduce the incidence of severe metabolic crisis and death. What is New: • Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening. • Sudden deaths were not avoided by starting treatment precociously.

Background: The literature suggests that 0.9 to 6% of infants who die unexpectedly may have had a metabolic disorder. At least 43 different inborn errors of metabolism (IEMs) have been associated with sudden death (SUDI). To date, the frequency of IEM-associated SUDI has not been studied in Brazil. The present study sought to characterize infant mortality related to IEMs known to cause SUDI disaggregated by each of the regions of Brazil., Methods: This was a descriptive, cross-sectional, population-based study of data obtained from the Brazilian Ministry of Health Mortality Information System (SIM). Death records were obtained for all infants (age < 1 year) who died in Brazil in 2002-2014 in whom the underlying cause of death was listed as ICD-10 codes E70 (Disorders of aromatic amino-acid metabolism), E71 (Disorders of branched-chain amino-acid metabolism and fatty-acid metabolism), E72 (Other disorders of amino-acid metabolism), or E74 (Other disorders of carbohydrate metabolism), which are known to be associated with SUDI., Results: From 2002 to 2014, 199 deaths of infants aged < 1 year were recorded in the SIM with an underlying cause corresponding to one of the IEMs of interest. The prevalence of IEM-related deaths was 0.67 per 10,000 live births (0.58-0.77). Of these 199 deaths, 18 (9.0%) occurred in the North of Brazil, 43 (21.6%) in the Northeast, 80 (40.2%) in the Southeast, 46 (23.1%) in the South, and 12 (6.0%) in the Center-West region. Across all regions of the country, ICD10-E74 was predominant., Conclusions: This 13-year time-series study provides the first analysis of the number of infant deaths in Brazil attributable to IEMs known to be associated with sudden death.

Background: Although inborn errors of metabolism (IEM) are rare individually, collectively IEM cause substantial morbidity and mortality and the diagnosis is challenging., Aims: To analyse epidemiological and clinical data, final diagnosis and clinical outcomes of patients with a suspected diagnosis of IEM (small molecule disorders type) admitted to a paediatric intensive care unit (PICU)., Methods: We collected and analysed medical records data of all patients admitted to the PICU at Alexandria University Children's Hospital, from January 2010 to December 2014, with a suspected or confirmed diagnosis of small molecule disorders, including clinical presentations, laboratory results and clinical outcomes., Results: A total of 34 patients had a suspected or confirmed diagnosis of small molecule disorders at PICU admission. Diagnosis was confirmed in 22.7% of suspected cases at admission and in 25% of suspected cases during PICU stay. Consanguineous marriage was found in 50% of cases with confirmed small molecule disorders., Conclusions: A high index of suspicion is important for diagnosing and categorizing small molecule disorders in screening of high-risk individuals in low- and middle-income countries., (Copyright © World Health Organization (WHO) 2018. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo).)

Auxiliary partial orthotopic liver transplantation (APOLT) in selected noncirrhotic metabolic liver diseases (NCMLDs) is a viable alternative to orthotopic liver transplantation (OLT) as it supplements the function of the native liver with the missing functional protein. APOLT for NCMLD is not universally accepted due to concerns of increased technical complications and longterm graft atrophy. Review of a prospectively collected database of all pediatric patients (age ≤16 years) who underwent liver transplantation for NCMLD from August 2009 up to June 2017 was performed. Patients were divided into 2 groups: group 1 underwent APOLT and group 2 underwent OLT. In total, 18 OLTs and 12 APOLTs were performed for NCMLDs during the study period. There was no significant difference in the age and weight of the recipients in both groups. All APOLT patients needed intraoperative portal flow modulation. Intraoperative peak and end of surgery lactate were significantly higher in the OLT group, and cold ischemia time was longer in the APOLT group. There were no differences in postoperative liver function tests apart from higher peak international normalized ratio in the OLT group. The incidence of postoperative complications, duration of hospital stay, and 1- and 5-year survivals were similar in both groups. In conclusion, we present the largest series of APOLT for NCMLD. APOLT is a safe and effective alternative to OLT and may even be better than OLT due to lesser physiological stress and the smoother postoperative period for selected patients with NCMLD., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Background: Renal replacement therapy (RRT) is becoming increasingly necessary for supporting critically ill neonates. Few studies have reported the use of RRT in the neonatal intensive care unit (NICU). Therefore, we performed a retrospective study to describe the use of RRT in our NICU and its associated efficacy, complications, and outcomes., Methods: We identified patients requiring RRT between January 2009 and January 2017. Demographic data, mode of RRT, and associated factors were recorded. Efficacy was calculated as the percentage reduction in the blood urea nitrogen (BUN) or toxic metabolite level after 24 h of RRT. Complications including hypotension, electrolyte disturbance, and technical and catheter-related complications were documented. Measures of clinical outcome included in-hospital survival, presence of neurological sequelae, and chronic kidney disease. The chi-square test and Mann-Whitney U test were used for categorical and continuous variables, respectively., Results: We included 17 neonates in our study. The median gestational age at birth was 37 weeks (32-39 weeks), and the median birth weight was 2.7 kg (1.5-3.6 kg). Twelve neonates, including three with inborn errors of metabolism (IEM), received continuous RRT (CRRT), and five neonates underwent peritoneal dialysis (PD). The percentage reduction in ammonia in neonates with IEM who received CRRT was 87.2% at 24 h. The percentage reductions in BUN in the non-IEM neonates in the CRRT and PD groups were 33.7% and 23.7% at 24 h, respectively. The main complication was electrolyte disturbance including hypokalemia, hypocalcemia, and hypophosphatemia. All neonates with IEM survived, whereas the mortality rates for the non-IEM neonates in the CRRT and PD groups were 78% and 80%, respectively., Conclusion: Our study findings reveal RRT to be feasible, even in preterm neonates with low birth weight. CRRT had a higher efficacy level, particularly in neonates with IEM, and the complications encountered were transient and correctable., (Copyright © 2018. Published by Elsevier B.V.)

Hematopoietic stem cell transplantation (HSCT) has been accessible to the population residing in Lebanon and surrounding countries since 1997. HSCT programs were developed in two major hospitals in Beirut: American University of Beirut Medical Center (AUBMC) and Makassed General Hospital. Mount Lebanon Hospital initiated an autologous HSCT activity later. Between 2012 and 2016, the HSCT activity in Lebanon reached a total of 897 transplants, among which 303 (33.8%) were allogeneic HSCT and 594 (66.2%) were autologous HSCT. Overall, autologous HSCT activity has remained stable over the past 5years, whereas allogeneic HSCT activity has seen a steep increase between 2012 and 2013 followed by a modest increase later. Haploidentical transplantation has mushroomed and represented almost half of allogeneic HSCT activity in 2016. AUBMC and Makassed General Hospital are members of the European Blood and Marrow Transplantation (EBMT) and East Mediterranean Blood and Marrow Transplantation groups, and AUBMC has been accredited by JACIE (Joint Accreditation Committee - ISCT & EBMT) since 2016. The past 5years have seen an increase in HSCT-related research and publications, mainly from AUBMC. These research activities were predominantly focused on personalized conditioning for allogeneic HSCT and post-transplant maintenance therapy., (Copyright © 2017. Published by Elsevier B.V.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for a variety of congenital disorders. We report the experience of children affected by congenital diseases other than bone marrow failure syndromes who received allo-HSCT over a period of 25 years at G. Gaslini Paediatric Research Institute. HSCTs were performed in 57 children with congenital diseases (25 with congenital immunodeficiencies, 10 with severe combined immunodeficiencies, and 22 with metabolic diseases). Overall survival rate at 3 years in the whole group of patients was 76.9%, with a trend in favor of better outcome in children with metabolic diseases and in those who received cord blood cells (85.9%) vs bone marrow cells (72.4%)., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Allogeneic hematopoietic stem cell transplantation has demonstrated efficacy for numerous inherited metabolic disorders (IMDs). Umbilical cord blood transplant (UCBT) is increasingly used as a graft source in IMDs, but little is known of the impact of cord blood unit (CBU)/recipient HLA allelic disparity on key outcomes following UCBT for IMD. We reviewed outcomes of 106 consecutive first, single UCBTs for IMD at the University of Minnesota with regard to CBU/recipient HLA allelic matching (HLA-A, -B, -C, and -DRB1). The median age at UCBT was 1 year, and 87 patients (82%) received myeloablative conditioning. Primary diagnoses were Hurler syndrome (41%), cerebral adrenoleukodystrophy (35%), metachromatic leukodystrophy/globoid cell leukodystrophy (9%), and other (16%). The 5-year overall survival (OS) for the entire cohort was 70% (95% confidence interval, 59% to 79%). Rates of severe acute and chronic graft-versus-host disease were low (6% for each). CBU/recipient HLA conventional matching was based on antigen-level matching at HLA-A and -B, and on allele-level matching at HLA-DRB1. Of 46 conventional matched UCBTs, 20 (43%) were mismatched at 1 or more alleles. Of 49 conventional 5/6 UCBTs, 30 (61%) were mismatched at ≥2 alleles and 19 (39%) were mismatched at ≥3 alleles. Within the 6/6 conventional match stratum, comparisons of key outcomes between allele-matched and allele-mismatched UCBT were as follows: 5-year OS, 88% versus 42% (P < .01); 1-year engrafted survival (ES) with ≥90% donor chimerism, 73% versus 60% (P = .33); graft failure, 8% versus 30% (P = .05); and transplantation-related mortality (TRM), 8% versus 30% (P = .04). For patients undergoing conventional 5/6 HLA-matched UCBT, better allelic matching was associated with similar outcomes: 5-year OS, 77% versus 74% (P = .72); 1-year ES, 73% versus 47% (P = .06); graft failure, 17% versus 42% (P = .05); and TRM, 10% versus 16% (P = .54). On multivariable analyses, fewer allele-level mismatches within each conventional match stratum continued to predict more favorable outcomes following UCBT. These data provide evidence that allele-level HLA matching considerations within a conventional HLA match stratum may better predict outcomes of interest after UCBT for IMD. Larger studies are warranted to confirm these findings and explore other allele-level HLA match dynamics., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This review summarizes the main results of haematopoietic stem cell transplantation (HSCT) in selected inborn errors of metabolism (IEMs)., Recent Findings: Early diagnosis and immediate referral to an IEM specialist is of paramount importance to improve clinical outcome: patients who are transplanted early or in their presymptomatic phase generally achieve better correction of their somatic symptoms and neurocognitive development. Long-term outcome in children with Hurler syndrome is influenced by age at HSCT, baseline clinical status and post-HSCT enzyme levels. Myeloablative Busulfan-based conditioning regimens with therapeutic drug monitoring are recommended to achieve full donor engraftment and more robust enzyme delivery after HSCT. Gene therapy can lead to production of supranormal enzyme levels, and preliminary clinical results are also promising in IEMs historically not responsive to allogeneic HSCT., Summary: Allogeneic HSCT has largely contributed to the improved survival and quality of life of many children affected by IEMs. Neonatal screening could enable earlier HSCT, and this might significantly reduce residual disease burden and improve clinical outcome. Novel strategies, such as gene therapy, have shown encouraging clinical results in selected IEMs and might become more widely available in the future, with potentially better enzyme delivery and reduced transplant-related toxicity.

Background: Continuous renal replacement therapy (CRRT) has emerged as the modality of choice for the management of high-risk neonates with acute kidney injury (AKI), inborn errors of metabolism and multi-organ dysfunction. The aim of this study was to evaluate fluid overload (FO) and investigate the factors associated with outcomes in neonates undergoing CRRT., Methods: We retrospectively reviewed the medical records of 34 neonates with AKI who were admitted to the neonatal intensive care unit (NICU) of Samsung Medical Center, Seoul, Republic of Korea between January 2007 and December 2014 where they underwent at least 24 h of CRRT., Results: The survival rates of patients with an FO of ≥30 % at the time of CRRT initiation were lower than those of patients with an FO of <30 % at the same time-point. Univariate Cox regression analysis revealed that a higher percentage FO at CRRT initiation and decreased urine output at the end of CRRT were associated with mortality, and multivariate Cox regression analysis indicated that mortality was associated with decreased urine output at the end of CRRT. Univariate linear regression analysis revealed that the length of hospital stay was associated with higher levels of serum creatinine at CRRT initiation, longer stay in the NICU prior to initiation of CRRT, longer duration of CRRT and lower body weight at the time of NICU admission., Conclusions: Neonates with a higher percentage FO and higher levels of serum creatinine at CRRT initiation showed poor outcomes. Early initiation of CRRT before the development of severe FO or azotemia might improve the outcomes of neonates requiring CRRT.

Background: Treatment of children with hypertrophic cardiomyopathy might be improved if the risk of death or heart transplantation could be predicted by risk factors present at the time of diagnosis., Methods: We analysed data from the Pediatric Cardiomyopathy Registry, which collected longitudinal data for 1085 children with hypertrophic cardiomyopathy from 1990 to 2009. Our goal was to understand how patient factors measured at diagnosis predicted the subsequent risk of the primary outcome of death or heart transplantation. The Kaplan-Meier method was used to calculate time-to-event rates from time of diagnosis to the earlier of heart transplantation or death for children in each subgroup. Cox proportional-hazards regression was used to identify univariable and multivariable predictors of death or heart transplantation within each causal subgroup., Findings: The poorest outcomes were recorded for the 69 children with pure hypertrophic cardiomyopathy with inborn errors of metabolism, for whom the estimated rate of death or heart transplantation was 57% (95% CI 44-69) at 2 years. Children with mixed functional phenotypes also did poorly, with rates of death or heart transplantation of 45% (95% CI 32-58) at 2 years for the 69 children with mixed hypertrophic and dilated cardiomyopathy and 38% (95% CI 25-51) at 2 years for the 58 children with mixed hypertrophic and restrictive cardiomyopathy. For children diagnosed with hypertrophic cardiomyopathy at younger than 1 year, the rate of death or transplantation was 21% (95% CI 16-27) at 2 years. For children diagnosed with hypertrophic cardiomyopathy and a malformation syndrome, the rate of death or transplantation was 23% (95% CI 12-34) at 2 years. Excellent outcomes were reported for the 407 children who were diagnosed with idiopathic hypertrophic cardiomyopathy at age 1 year or older, with a rate of death or heart transplantation of 3% (95% CI 1-5) at 2 years. The risk factors for poor outcomes varied according to hypertrophic cardiomyopathy subgroup, but they generally included young age, low weight, presence of congestive heart failure, lower left ventricular fractional shortening, or higher left ventricular end-diastolic posterior wall thickness or end-diastolic ventricular septal thickness at the time of cardiomyopathy diagnosis. For all hypertrophic cardiomyopathy subgroups, the risk of death or heart transplantation was significantly increased when two or more risk factors were present and also as the number of risk factors increased., Interpretation: In children with hypertrophic cardiomyopathy, the risk of death or heart transplantation was greatest for those who presented as infants or with inborn errors of metabolism or with mixed hypertrophic and dilated or restrictive cardiomyopathy. Risk stratification by subgroup of cardiomyopathy, by characteristics such as low weight, congestive heart failure, or abnormal echocardiographic findings, and by the presence of multiple risk factors allows for more informed clinical decision making and prognosis at the time of diagnosis., Funding: US National Institutes of Health and Children's Cardiomyopathy Foundation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Growing evidence indicates that inherited metabolic diseases are increasingly being recognised. Life expectancy for many patients is progressively improving because new therapeutic strategies are available. Because most inherited metabolic diseases are systemic disorders, virtually all organs may be involved. Respiratory disease complicates the management of several inherited metabolic diseases, either at presentation or as late-onset features. This review will describe the most exemplary respiratory manifestations of inherited metabolic diseases in childhood and adulthood. Since airways disease worsens the morbidity of many inherited metabolic disorders, leading to increased hospitalisations, mortality and overall healthcare costs, respiratory manifestations of inherited metabolic diseases need to be carefully recognised and treated. All patients with inherited metabolic disease and suspected airway disease should undergo a detailed diagnostic work-up. Current treatments for several inherited metabolic diseases (including enzyme replacement therapy, substrate reduction, bone marrow transplantation, or even more innovative strategies such as pharmacological chaperone or gene therapies) may provide significant benefits for associated respiratory disease. The integration of several specialists dedicated to airway disease management in a multidisciplinary team is essential to provide the most appropriate care to children and adults with inherited metabolic disease.

Introduction: The early establishment of an etiology for acute liver failure (ALF) in infants is essential for the start of adequate treatment in the shortest timeframe possible., Aim: To identify markers of inherited metabolic disease on admission in children under two years of age with ALF., Material and Methods: A retrospective review of the medical records of all children (< 2 years old) with ALF admitted to the pediatric hepatology or intensive care units of a tertiary center over a twenty-three year period (January 1989 to December 2011) was done. Patients were divided into two groups: with (group A) or without (group B) a metabolic etiology. Clinical and laboratory parameters on admission were compared., Results: Twenty-three children met inclusion criteria. Twelve had ALF of metabolic origin (group A). The median age in this group was 2.25 (Q1-Q3: 0.63-4.65) months and in group B 8.0 (Q1-Q3: 1.5-15) months. History of failure to thrive and/or vomiting was more frequent in group A (p = 0.022). Age, gender, encephalopathy and left ventricular hypertrophy were similar in both groups (p = 0.147, p = 1.000, p = 0.637, p = 1.000, respectively). Laboratory tests on admission (plasma lactate, ammonia, cholesterol, phosphate, INR, glucose, bilirubin, ALT, base excess and the presence of reducing substances in urine) showed no statistically significant differences between groups., Conclusion: This study showed that although infants with inborn errors of metabolism showed a trend towards lower age at presentation, the only marker of inherited metabolic disease found on admission was history of vomiting and/or failure to thrive.

We report the long-term follow-up of children transplanted with Treosulfan (TREO)-based conditioning in Germany and Austria. Nine centres reported a total of 109 transplantations. Patients were stratified according to the paediatric TRM risk score derived from the paediatric BMT registry (PRST) and compared with the historical transplant population of this registry. Underlying diseases were malignancies, immunodeficiencies, and haematologic and metabolic disorders. TREO total dose ranged from 21-42 g/m(2). Additional conditioning drugs included fludarabine, thiotepa, melphalan, CY and/or TBI. EFS at 3 years for non-malignant and malignant diseases was 88% and 49%, respectively. Leukaemia patients in remission had a survival of 51% at 3 years; nonremission patients relapsed and died within 18 months. TRM and OS in the low-risk groups 0 and 1 were similar to PRST controls. TRM in the high-risk groups 2 and 3 was markedly lower (9% vs 28% and 13% vs 53%, respectively) than in the PRST group, but OS was similar. In conclusion, TREO-based conditioning regimens in children resulted in excellent engraftment and long-term survival in nonmalignant disease. In high-risk malignancy, low acute toxicity was followed by low TRM but it did not translate into increased survival.

Inborn errors of metabolism (IEM) have greater repercussions in neonatology units. The aim of our study was to evaluate the impact of IEM in a neonatal intensive care unit (NICU) and the resources required to care for these neonates. All patients with IEM admitted in our unit during a 4-year period were evaluated for specific diagnosis, demographic data, clinical features, biochemical characteristics at admission, need for mechanical ventilation, use of extracorporeal removal therapy, and outcome at NICU discharge. The study group comprised 2742 infants, 39 of which required admission to the NICU (1.42% of admissions) because of severe symptoms and/or newborn screening. Five of the 39 had an earlier diagnosis and treatment because of expanded newborn screening. The average age at admission was 5 days [interquartile range (IQR, 3-9 days)] and the median length of stay in the NICU for the study population was 5 days (IQR, 3-12 days). Aggressive support was often necessary (extracorporeal removal therapy, mechanical ventilation). Ten patients died; thus the death rate was 25.6%. Overall mortality in the NICU was 10.4% during the study period. These observations shown that IEM may be very common in our population. Most patients with IEM admitted to a NICU require aggressive support (including mechanical ventilation and extracorporeal removal therapies), and consume significant resources for relatively shorter stays.

Objective: To investigate etiology, outcome and complications related to neonatal peritoneal dialysis (PD)., Methods: Neonates treated with PD in our neonatal intensive care unit during 2007-2010 were analyzed retrospectively., Results: Among 4036 hospitalized neonates; 20 neonates (0.5%) who underwent 21 cycles of PD [7 preterm, 13 term; 13 female, 7 male] were included. The mean birth weight was 2930.2 ± 720.6 g (1120-4570), mean gestational age was 37.5 ± 3.5 weeks (27-41). The etiologic disorders included inborn errors of metabolism (propionic acidemia, methylmalonic acidemia, citrullinemia, glutaric aciduria type 2, maple syrup urine disease, 10), or acute renal failure secondary to perinatal asphyxia (4), sepsis (2), prematurity (2), hypoplastic left heart syndrome (1), kernicterus (1). The complications included peritonitis (2), early leakage (4), hemorrhage (1), catheter removal (3) and occlusion (2). The mortality rate was 50%. The gestational ages and birth weights of surviving neonates were higher (p < 0.05). Among surviving neonates, chronic renal failure (1), severe (4) and moderate neuromotor impairment (2) developed within 4-43 months., Conclusion: PD, although invasive, is an effective therapy in neonates. The complexity and invasiveness of the procedure is probably responsible for high rate of complications and mortality. If appropriate catheter selection and technique in the placement should be done, PD might improve outcome.

It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD), and inborn errors of metabolism (IEM) return to rates observed in the general population, matched for age, sex, and nationality. We studied patients with SCID (n = 201), non-SCID PIDD (n = 405), and IEM (n = 348) who survived for at least 2 years after transplantation with normal T cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rate was significantly higher in these patients compared with the general population for several years after transplantation. The rate decreased toward the normal rate in patients with SCID and non-SCID PIDD beyond 6 years after transplantation, but not in patients with IEM. Active chronic graft-versus-host disease at 2 years was associated with increased risk of late mortality for all diseases (hazard ratio [HR], 1.87; P = .05). In addition, late mortality was higher in patients with non-SCID PIDD who received T cell-depleted grafts (HR 4.16; P = .007) and in patients with IEM who received unrelated donor grafts (HR, 2.72; P = .03) or mismatched related donor grafts (HR, 3.76; P = .01). The finding of higher mortality rates in these long-term survivors for many years after transplantation confirms the need for long-term surveillance., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Tandem mass spectrometry (MS/MS) has been available in China for 8 years. This technique makes it possible to screen for a wide range of previously unscreened inborn errors of metabolism (IEM) using a single test. This 3-year pilot study investigated the screening, diagnosis, treatment and outcomes of IEM in symptomatic infants and children., Methods: All children encountered in the Newborn Screening Center of Zhejiang Province during a 3-year period with symptoms suspicious for IEM were screened for metabolic diseases. Dried blood spots were collected and analyzed by tandem mass spectrometry. The diagnoses were further confirmed by clinical symptoms and biochemical analysis. Neonatal intrahepatic cholestasis caused by citrin deficiency, ornithine transcarbamylase deficiency and primary carnitine deficiency were confirmed by DNA analysis., Results: A total of 11,060 symptomatic patients (6,720 boys, 4,340 girls) with a median age of 28.8 months (range: 0.04-168.2 months) were screened. Among these, 62 were diagnosed with IEM, with a detection rate of 0.56%. Thirty-five were males and 27 females and the median age was 3.55 months (range 0.07-143.9 months). Of the 62 patients, 27 (43.5%) had aminoacidemias, 26 (41.9%) had organic acidemias and nine (14.5%) had fatty acid oxidation disorders., Conclusions: Because most symptomatic patients are diagnosed at an older age, mental retardation and motor delay are difficult to reverse. Additionally, poor medication compliance reduces the efficacy of treatment. More extensive newborn screening is thus imperative for ensuring early diagnosis and enhancing the treatment efficacy of IEM.

Newborn screening (NBS) by tandem mass spectrometry started in Galicia (Spain) in 2000. We analyse the results of screening and clinical follow-up of inborn errors of metabolism (IEM) detected during 10 years. Our programme basically includes the disorders recommended by the American College of Medical Genetics. Since 2002, blood and urine samples have been collected from every newborn on the 3rd day of life; before then, samples were collected between the 5th and 8th days. Newborns who show abnormal results are referred to the clinical unit for diagnosis and treatment. In these 10 years, NBS has led directly to the identification of 137 IEM cases (one per 2060 newborns, if 35 cases of benign hyperphenylalaninemia are excluded). In addition, 33 false positive results and 10 cases of transitory elevation of biomarkers were identified (making the positive predictive rate 76.11%), and 4 false negative results. The use of urine samples contributed significantly to IEM detection in 44% of cases. Clinical symptoms appeared before positive screening results in nine patients (6.6%), four of them screened between days 5 and 8. The death rate was 2.92%; of the survivors, 95.5% were asymptomatic after a mean observation period of 54 months, and only two had an intellectual/psychomotor development score less than 85. Compared to other studies, a high incidence of type I glutaric aciduria was detected, one in 35,027 newborns. This report highlights the benefits of urine sample collection during screening, and it is the first study on expanded newborn screening results in Spain., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Objective: Cardiomyopathy in childhood is a rare entity. Inborn errors of metabolism can cause myocardial involvement by several mechanisms., Patients and Methods: Patients under 16 years diagnosed with cardiomyopathy and EIM in a period of 11 years (1998-2009) were included., Results: A total of 12 patients were studied (8% of all cardiomyopathies), 9 boys and three girls, with a median age at diagnosis of 6 months (range: birth-8.8 years). Fifty percent had an onset with cardiac symptoms and heart failure was associated with an earlier diagnosis of the disease (P<.05). On ultrasound 10 patients had ventricular hypertrophy, which was associated with mitochondrial and lysosomal disease; only 2 patients had ventricular dilatation, which was associated with altered fatty acid metabolism (P<.05). The median survival was 5 months (range: 2-11 months). No variable was significantly associated with the likelihood of death., Conclusions: Patients with heart failure at onset are diagnosed earlier (before 3 months of life). Echocardiography helps in the diagnosis and monitoring of metabolic disease., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Unlabelled: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder with especially high mortality and uncertain long-term outcome. The aim of the study was to analyze the influence of diagnostic approach on survival in 59 affected children. Referral to a metabolic center was replaced over time by urine/blood testing in centralized metabolic laboratory (selective screening) and by pilot tandem mass spectrometry newborn screening (NBS). Molecular analysis revealed the prevalent mutation in the HADHA gene in all 58 examined cases. Twenty patients died. The number of detections and number of deaths were respectively 9 and 4 (44%) in the patients recognized by differential diagnosis, 28 and 9 (32%) - by selective screening, and 11 and 1 (9%) - by NBS. In 80% of cases the death occurred before or within 3 weeks from the identification. Urgent and active metabolic service remarkably influenced the surviving. The current age of 39 survivors is 0.5 to 23 yrs (mean 7.2 yrs). The disease frequency estimated on the patients number was 1: 115 450, whereas in the pilot NBS - 1: 109 750 (658 492 neonates tested). Interestingly, the phenylalanine level in asymptomatic neonates frequently exceeded the cut-off values., Conclusions: 1) Urgent metabolic intervention decreases mortality of LCHAD-deficient patients, but the prognosis is still uncertain. 2) Emergent metabolic reporting and service are crucial also for the survival of neonates detected by NBS. 3) The nationwide selective screening appeared efficient in LCHADD detection in the country. 4) Transient mild hyperphenylalaninaemia may occur in LCHAD-deficient newborns.

This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S-adenosylhomocysteine, S-adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain.

In a 10-year review of the utilization of continuous veno-venous hemofiltration (CVVH) for the treatment of neonatal hyperammonemia, 14 patients were identified with hyperammonemia due to either a urea cycle defect or an organic acidemia. Intensive care survival was 64%. The pretreatment level of serum ammonia and the rapidity of ammonia clearance did not differ between survivors and non-survivors (p = 0.16 and p = 0.93, respectively). Likewise, the duration of CVVH therapy did not differ between survivors and non-survivors (p = 0.1). Indicators of pretreatment physiological stress showed either a correlation with non-survival [Pediatric Risk of Mortality (PRISM) score, p = 0.006, cardioactive drug requirement, p = 0.003], or demonstrated a trend to such a correlation (serum lactate, p = 0.06). Complications associated with the CVVH technique were infrequent. Hypotension was seen in seven patients, but in only one patient did it arise de novo following the initiation of CVVH. In conclusion, neither the severity of the hyperammonemic state nor the efficacy of ammonia removal correlated with patient outcome. The pre-CVVH PRISM score and requirement for cardio-active medication were significantly greater in those patients who did not survive their acute illness. The pre-CVVH physiological condition of the neonates in this cohort was the main determinant of outcome.

Aim: To assess the efficacy of the perimortem protocol in neonates with suspected inborn errors of metabolism (IEM)., Methods: Retrospective analysis of medical records from January 2000 through December 2007 was performed. Only neonates (

Objective: Tandem mass spectrometry is widely applied to routine newborn screening but there are no long-term studies of outcome. We studied the clinical outcome at six years of age in Australia., Methods: In a cohort study, we analyzed the outcome at 6 years for patients detected by screening or by clinical diagnosis among >2 million infants born from 1994 to 1998 (1,017,800, all unscreened) and 1998 to 2002 (461,500 screened, 533,400 unscreened) recording intellectual and physical condition, school placement, other medical problems, growth, treatment, diet, and hospital admissions. Results were analyzed separately for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and other disorders, and grouped patients as those who presented clinically or died in the first 5 days of life; patients presented later or diagnosed by screening, and those with substantially benign disorders., Results: Inborn errors, excluding phenylketonuria, were diagnosed in 116 of 1,551,200 unscreened infants (7.5/100,000 births) and 70 of 461,500 screened infants (15.2/100,000 births). Excluding MCADD, 21 unscreened patients with metabolic disorders diagnosed after 5 days of life died or had a significant intellectual or physical handicap (1.35/100,000 population) compared with 2 of the screened cohort (0.43/100,000; odds ratio: 3.1 [95% CI: 0.73-13.32]). Considering the likely morbidity or mortality among the expected number of never-diagnosed unscreened patients, there would be a significant difference. Growth distribution was normal in all cohorts., Conclusion: Screening by tandem mass spectrometry provides a better outcome for patients at 6 years of age, with fewer deaths and fewer clinically significant disabilities.

There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies.

Outcomes of 159 young patients with inherited metabolic disorders (IMDs) undergoing transplantation with partially HLA-mismatched unrelated donor umbilical cord blood were studied to investigate the impact of graft and patient characteristics on engraftment, overall survival (OS), and graft-versus-host disease (GVHD). Patients received myeloablative chemotherapy (busulfan, cyclophosphamide, ATG) and cyclosporine-based GVHD prophylaxis. Infused cell doses were high (7.57 x 10(7)/kg) because of the patients' young age (median, 1.5 years) and small size (median, 12 kg). Median follow-up was 4.2 years (range, 1-11 years). The cumulative incidences of neutrophil and platelet engraftment were 87.1% (95% confidence interval [CI], 81.8%-92.4%) and 71.0% (95% CI, 63.7%-78.3%). A total of 97% achieved high (> 90%) donor chimerism. Serum enzyme normalized in 97% of patients with diseases for which testings exist. Grade III/IV acute GVHD occurred in 10.3% (95% CI, 5.4%-15.2%) of patients. Extensive chronic GVHD occurred in 10.8% (95% CI, 5.7%-15.9%) of patients by 1 year. OS at 1 and 5 years was 71.8% (95% CI, 64.7%-78.9%) and 58.2% (95% CI, 49.7%-66.6%) in all patients and 84.5% (95% CI, 77.0%-92.0%) and 75.7% (95% CI, 66.1%-85.3%) in patients with high (80-100) performance score. In multivariate analysis, favorable factors for OS were high pretransplantation performance status, matched donor/recipient ethnicity, and higher infused colony forming units.

Succinate-CoA ligase catalyses the reversible conversion of succinyl-CoA and ADP or GDP to succinate and ATP or GTP. It is a mitochondrial matrix enzyme and at least the ADP-forming enzyme is part of the Krebs cycle. The substrate specificity is determined by the beta subunit of succinate-CoA ligase, which is encoded by either SUCLA2 or SUCLG2. In patients with severe hypotonia, deafness and Leigh-like syndrome, mutations have been found in SUCLA2. Mutations have also been reported in SUCLG1, which encodes the alpha subunit found in both enzymes, in patients with severe infantile acidosis and lactic aciduria. Elevated methylmalonate and methylcitrate and severe mtDNA depletion were found in both disorders. The mtDNA depletion may be explained by the interaction of succinate-CoA ligase with nucleoside diphosphate kinase, which is involved in mitochondrial nucleotide metabolism.

We present two siblings with a previously undescribed congenital disorder of glycosylation (CDG). The first child died in utero with severe hydrops fetalis and the second presented following preterm delivery with respiratory insufficiency, generalised edema and a protein-losing enteropathy. Both had a similar pattern of facial dysmorphism and joint contractures. The diagnosis of CDG-I was made following the birth of the second child based on the serum transferrin isoform pattern. CDG-Ia and -Ib were excluded by specific enzyme analysis. Joint contractures are a relatively uncommon finding in CDG, although fetal hydrops (CDG-Ia) and protein-losing enteropathy (CDG-Ib) are well recognized. CDG must be considered in the differential diagnosis of hydrops fetalis, congenital hypoproteinemia and death in early infancy, particularly when associated with dysmorphic features., (Copyright 2007 Wiley-Liss, Inc.)

The authors conducted a retrospective analysis of the patients admitted to a pediatric intensive care unit (PICU) during a five-year period, with specific focus on those with a suspected or confirmed diagnosis of inborn errors of metabolism (IEM), in order to ascertain the resources required to care for these patients. Medical records were reviewed for all admissions between January 1998 and December 2002 in a single metabolic referral center, and a subset of patients were identified with suspected IEM at admission or diagnosed IEM at hospital discharge. These patient charts were then further reviewed and the following information was extracted: IEM diagnosis, demographic data, biochemical characteristics at admission, need for mechanical ventilation, use of extracorporeal removal therapy, and outcome at PICU discharge. The study population comprised 70 patients (2.2% of all admissions during the study period) and included 33 neonates and 37 children aged >28 days. IEM diagnosis was known at the time of admission to the PICU in 9/33 of the neonates and 23/37 of the older children. Forty-three of the patients required invasive mechanical ventilation, while continuous extracorporeal removal therapy was used in 27 children. The median length of PICU stay was 3 days (range, 1 to 13 days) and 20 patients (28.6%) died. In conclusion, these observations show that inherited metabolic disease may be as frequent a primary diagnosis as septic shock in some PICUs. In neonates, these diseases are not usually diagnosed prior to PICU admission. Patients with IEM admitted to a PICU require aggressive support (including mechanical ventilation and extracorporeal removal therapies), and consume significant resources for relatively short PICU stays. These patients constitute a significant diagnostic and therapeutic challenge for pediatric intensivists.

Objectives: In 2005, in Ontario, Canada, newborns were only screened for phenylketonuria (PKU) and hypothyroidism. Tandem mass spectrometry (MS/MS) has since been implemented as a new screening technology because it can screen for PKU and many other diseases simultaneously. We estimated the cost-effectiveness of using this technology to expand the Ontario newborn screening program to screen for each disease independently and for hypothetical bundles of up to 21 metabolic diseases., Methods: We constructed a decision-analytic model to estimate the incremental costs and life-years of survival that can be gained by screening or changing screening technologies. Costs and health benefits were estimated for a cohort of babies born in Ontario in 1 year. Secondary sources and expert opinion were used to estimate the test characteristics, disease prevalence, treatment effectiveness, disease progression rates, and mortality. The London Health Sciences Centre Case Costing Initiative, the Ontario Health Insurance Plan Schedule, and the Ontario Drug Benefits plan formulary were used to estimate costs., Results: Changing screening technologies, from the Guthrie test to MS/MS, for PKU detection had an incremental cost of $5,500,000 per life-year (LY) gained. We identified no diseases for which the incremental cost of screening for just that disease was less than $100,000 per LY gained. The incremental costs of screening ranged from $222,000 (HMG-CoA lyase deficiency) to $142,500,000 (glutaric acidemia type II) per LY gained. Screening for a bundle of diseases including PKU and the 14 most cost-effective diseases to screen for cost less than $70,000 per LY gained, and the incremental cost-effectiveness of adding each of the 14 diseases to the bundle was less than $100,000 per LY gained. The incremental cost of adding the 15th most cost-effective disease was $309,400 per LY gained., Conclusions: Early diagnosis and treatment of metabolic disease is important to reduce disease severity and delay or prevent the onset of the disease. Screening at birth reduces the morbidity, mortality, and social burden associated with the irreversible effects of disease on the population. Our analysis suggests that the cost-efficiencies gained by using MS/MS to screen for bundles of diseases rather than just one disease are sufficient to warrant consideration of an expanded screening program. It is, however, not cost-effective to screen for all diseases that can be screened for using this technology.

Background: Data regarding the mortality rates of patients with growth hormone deficiency (GHD), whether or not treated with growth hormone (GH), are limited, but an increased mortality rate among hypopituitary patients compared with the general population has been documented. Cardiovascular disease has been suggested as a primary cause of death, whereas cancer statistics might be influenced by the number of malignancies causing the pituitary disease. Furthermore, differences in mortality rates in females and males have been reported., Methods: Epidemiological studies of mortality in hypopituitary and GHD patients were identified and reviewed., Results: Most studies showed an increased mortality rate in hypopituitary and GHD patients and an increased mortality among female compared with male patients. There is a possibility that differences between patients with adult-onset and childhood-onset GHD might also exist. Two studies showed a normal mortality rate in GHD patients treated with GH compared with the general population., Conclusions: Although an increased mortality rate in hypopituitary patients is well documented, further research is needed to provide more reliable estimates of the actual causes. Caution should be taken in the interpretation of results regarding mortality and GH treatment due to the limited amount of data and the limitations of the study designs., (Copyright (c) 2007 S. Karger AG, Basel.)

Objective: Analysis of mortality and risk factors for mortality in the use of renal replacement therapy to correct metabolic disturbances associated with confirmed or suspected inborn errors of metabolism., Study Design: A retrospective review of an institutional review board-approved pediatric acute renal failure data base at the University of Michigan. Eighteen patients underwent 21 renal replacement therapy treatments for metabolic disturbances caused by urea cycle defects (n = 14), organic acidemias (n = 5), idiopathic hyperammonemia (n = 1), and Reye syndrome (n = 1)., Results: There were 14 boys (74%) and 4 girls (26%), with a mean age and weight of 56.2 +/- 71.0 months and 18.5 +/- 19.2 kg, respectively, at the initiation of renal replacement therapy. Overall treatment mortality rate was 57.2% (12 of 21 treatments), with 11 of the 18 patients (61.1%) dying before hospital discharge. Two-year follow-up on those patients demonstrated that 5 patients (71.4%) remained alive. Initial therapy with hemodialysis was associated with improved survival. Ten treatments (47.6%) required transition to another form of renal replacement therapy to maintain ongoing metabolic control, with a mean duration of 6.1 +/- 9.8 days. Time to renal replacement therapy >24 hours was associated with an increased risk of mortality, whereas a blood pressure >5th percentile for age at the initiation of therapy and the use of anticoagulation were associated with a decreased risk of mortality., Conclusions: Renal replacement therapy can correct the metabolic disturbances that accompany suspected or confirmed inborn errors of metabolism. Our experience demonstrates an approximately 60% mortality rate associated with renal replacement treatment, with more than 70% of survivors living longer than 2 years.

Background: Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders., Methods: We report 20 years of experience in 71 patients. The disorders include 7 immunodeficiencies, 21 hematological disorders, 13 histiocytic disorders, 9 mucopolysaccharoidoses, 7 metachromatic leukodystrophies (MLD), 3 adrenoleukodystrophies (ALD), 2 adrenomyeloneuropathy (AMN), 6 patients with Gaucher's disease, 1 Sandhoff's disease, and 2 patients with aspartylglucosaminuria. Their median age was 4 (0-39) years. The donors were 29 HLA-identical related, 27 matched unrelated (MUD) and 15 HLA mismatches., Results: In recipients of HLA-identical sibling grafts, none developed acute GVHD grades II-IV as against 22% in all others. The overall cumulative incidence of chronic GVHD was 17%. The 5-year survival rates were 93%, 84%, and 46% in recipients of grafts from HLA-identical siblings, MUD and HLA-mismatches, respectively. The overall 10-year survival rate was 69%. All of the surviving patients with immunodeficiencies and hemoglobinopathies are well. Four patients with Hurler's disease are also well, apart from skeletal problems. Five patients with Gaucher's disease are between 14 and 22 years after the transplant. Two infants with MLD deteriorated, a girl with the juvenile form has stable disease and one woman with the adult form has improved. Among four survivors with ALD/AMN, three are well and one has dementia. Two patients with aspartylglucosaminuria have stable disease., Conclusion: In patients with inborn errors of metabolism, ASCT gives a high survival rate using HLA-matched donors. Beneficial effects are seen in those who are transplanted early.

Improvements in screening programs, diagnostic tests and therapeutic interventions in inborn errors of metabolism (IEM) have led to increasing and prolonged patient survival and improved prognosis of affected subjects. Today, in Germany about 200 patients with IEM survive per year into adulthood. They need specialized adult care. However, adult-oriented care is poor or absent in IEM, because traditionally, no specific adult service exists for this subspecialty and adult patients with IEM are a relatively new phenomenon. Part 1 of this overview deals with the diagnostic procedures of IEM in infancy, the principles of therapy in childhood, and the problems of transition/transfer of patients from pediatric to adult-oriented care. In part 2 the necessities of treatment in adults with the currently most important IEM are reported, which are mainly phenylketonuria and lysosomal storage diseases and less frequently glycogen storage disease type I, galactosemia, urea cycle disorders, and homocystinuria.

Background: Potassium deficiency may cause cardiac arrhythmias culminating in syncope or sudden death., Methods: An inquiry performed among physicians caring for a total of 249 patients with inborn salt-losing tubulopathies revealed that acute cardiac complications occurred in seven children., Results: Four patients died suddenly and three had severe syncope. These episodes occurred in the context of severe chronic hypokalaemia (< or =2.5 mmol/l) or were precipitated by acute diseases, which exacerbated hypokalaemia (< or =2.0 mmol/l)., Conclusions: In conclusion, severe chronic or acute hypokalaemia is hazardous in inborn salt-losing tubulopathies.

Autopsy is invaluable in identifying the causes of severe depression and very low Apgar score after birth and in assessing contributory conditions. Brain scans are increasingly used in the care of neonates who fail to respond to resuscitation at birth but their interpretation depends on the information gained from sound neuropathological studies. Asphyxia, both acute intrapartum asphyxia and chronic asphyxia, is an important cause of low Apgar scores. The gestational age and the nature of the asphyxial insult both have a profound influence on the ultimate pattern of injury. Asphyxia in the preterm brain tends to damage preferentially the white matter but some white matter damage is also seen in many infants who have an hypoxia-ischaemic insult at term though the predominant site of injury is to the central grey matter. The nature of the cellular damage and reactive change seen at autopsy is described. There is an association between low Apgar scores and intrauterine exposure to infection and maternal pyrexia. Detailed autopsy examination should include the search for infection. The placenta, cord and membranes should be examined in view of the mounting evidence of the association between intrauterine infection of the placenta and fetal membranes and prenatal brain damage. Additionally, the presence of placental thrombosis and infarction should be sought in relation to focal and global injury in the full term infant. Acquired prepartum lesions rarely cause the infant to present with a low Apgar score. The exception to this is severe damage to the brainstem and basal ganglia. Traumatic injury to the brain is now much less common than in previous decades. Subdural haemorrhage occurs more frequently than intraventricular or subarachnoid haemorrhage. Instrumental and assisted deliveries are associated with an increased incidence of subdural haemorrhage though these rarely cause significant long term damage. Careful autopsy, particularly of the neck and paravertebral tissues, spinal cord, brainstem and nerve roots is important where trauma is suspected. Tearing of nerve roots or fibre bundles in the spinal cord is readily demonstrated under the microscope using immunocytochemistry to beta-amyloid precursor protein. Disorders of the spinal cord, peripheral nerve and muscle as well as some metabolic diseases may cause a baby to be both floppy and weak. Metabolic disease, including peroxisomal disorders, non-ketotic hyperglycinaemia, lipid and glycogen storage disorders and mitochondrial diseases may cause profound hypotonia and respiratory failure at birth or shortly afterwards., (Copyright 2004 Elsevier Ltd.)

Neonatal deaths in infants born at term are relatively rare in the USA, occurring in 0.9/1000 live births. Congenital malformations, perinatal asphyxia, infections and inborn errors of metabolism are the leading causes. Chromosomal malformation syndromes, congenital heart disease, pulmonary hypoplasia and severe neural tube defects comprise the majority of lethal malformations. Several skeletal dysplasias are lethal in the newborn infant. Group B Streptococcus still plays a major role in neonatal mortality while deaths due to other infectious agents have decreased. Hypoxic ischaemic encephalopathy is a significant cause of neonatal death. Inborn errors of metabolism have variable presentations but some, such as the fatty acid oxidation disorders, may present in neonates and cause sudden death., (Copyright 2004 Elsevier Ltd.)

Background: Transplantation of allogeneic haemopoietic stem cells can cure several non-malignant disorders in children. Transplantation with reduced intensity preparation might achieve the same goals but with less toxicity. We undertook a pilot study to determine engraftment rates, kinetics of engraftment, toxicity, and acute graft-versus-host disease (GVHD) associated with a uniform reduced intensity haemopoietic stem-cell transplant (HSCT) regimen for children with non-malignant diseases., Methods: We studied 13 paediatric patients with non-malignant disorders who underwent reduced intensity HSCT at Children's Memorial Hospital from January, 2000, to February, 2004. Stem-cell sources included unrelated donor, matched-sibling peripheral blood stem cells, and unrelated cord blood. A uniform preparative regimen was used, consisting of fludarabine, busulfan, and anti-thymocyte globulin. Major endpoints were engraftment, transplant-related mortality at day 100, short-term toxicities, and incidence of acute GVHD., Results: 72% of evaluable patients achieved full donor engraftment. There was rapid reconstitution of platelets (median 13.5 days) and neutrophils (median 18 days). Short-term toxicities were minimal, as seen by a median length of hospital stay of 7 days (between days 0-100). Incidence of grade II-IV acute GVHD was 8%. Two patients died before day 100 from underlying disease and viral infection, respectively (day 100 transplant-related mortality of 15%). The 1-year overall survival was 84% (95% CI 64-100). Most patients with immunodeficiencies and metabolic disorders had excellent donor engraftment and disease resolution or stabilisation, but most of those with haemoglobinopathies rejected their graft., Interpretation: This reduced intensity regimen followed by HSCT provides a good alternative to myeloablative HSCT for children with non-malignant disorders, except for haemoglobinopathies, in which engraftment is poor. Even patients with unrelated donor haemopoietic stem-cell transplants had adequate engraftment with acceptable toxicities.

Unlabelled: Infants with an apparent life-threatening event (ALTE) should not be treated nor monitored without a detailed medical evaluation, as different medical causes may be responsible for the initial clinical presentation. Standard and specific evaluation procedures are listed to help identify a cause for the ALTE. The most frequent problems associated with an ALTE are digestive (about 50%), neurological (30%), respiratory (20%), cardiovascular (5%), metabolic and endocrine (under 5%), or diverse other problems, including child abuse. Up to 50% of ALTEs remain unexplained. The finding of medical or surgical anomalies leads to specific treatments. Surveillance programmes with the use of home monitoring devices may be undertaken, preferably with cardiorespiratory monitors, and when possible, with event monitors, although no currently available home monitoring device is free of false alarms or offers complete protection. Long-term follow-up programmes of infants with an apparent life-threatening event contribute to adapt medical attitudes to the child's needs and to confirm the medical diagnosis., Conclusion: a systematic diagnostic evaluation, together with a comprehensive treatment programme, increases survival and quality of life for most affected infants.

Unlabelled: With regard to the principles established for neonatal population screening, the question arises whether for patients with urea cycle disorders there is an accepted treatment which really affects the disease course and prognosis as compared to the natural history of these diseases. A retrospective study of 88 patients was performed. Based on questionnaires, the survival rate and neurodevelopmental outcome of patients treated with protein restriction alone was compared to the new therapy introduced in the 1980s with added citrulline/arginine, essential amino acids for improving the amino acid composition of the restricted natural protein and benzoate. Survival of patients with neonatal presentation was improved by the extensive therapy but this mostly at the cost of an increasing number of retarded patients. Long-term outcome did not differ significantly between the two treatments. Of all patients, 56% were symptomatic within 4 days of age and 67% within the 1st week. Thus a prevention of irreversible damage by neonatal screening on blood obtained at 3-4 days of life is questionable. Whether the benefit of obtaining a rapid diagnosis, e.g. for allowing proper counselling and prospective treatment, is acceptable for the parents of prospective patients remains open. The organisation of a dense network of specialised metabolic centres with sufficient staff and resources is a prior condition for any screening programme in order to ensure the rapid diagnosis, follow-up of treatment and counselling of a cumulative number of affected chronic patients needing this support. A commitment on a long-term basis by the institutions is needed in view of the health budget restrictions., Conclusion: in the short term, the goal is to detect hyperammonaemic patients as early as possible with special emphasis on sick neonates. In practice, quantitative plasma ammonia determination without delay is recommended in any newborn for whom a sepsis work-up is considered and in children who refuse feeding or vomit and show alterations of consciousness and/or neurological symptoms.