Inborn errors of metabolism

Maple syrup urine disease (MSUD) is a metabolic disorder caused by mutations in three of the branched-chain α-keto acid dehydrogenase complex (BCKDC) genes. Classical MSUD symptom can be observed immediately after birth and include ketoacidosis, irritability, lethargy, and coma, which can lead to death or irreversible neurodevelopmental delay in survivors. The molecular diagnosis of MSUD can be time-consuming and difficult to establish using conventional Sanger sequencing because it could be due to pathogenic variants of any of the BCKDC genes...

Supplemental Digital Content is available in the textABSTRACT OBJECTIVES:: Wilson disease (WD) is a rare inborn error of copper metabolism with diverse manifestations. There has been no study of zinc (Zn), the copper's antagonist, in WD diagnosis and severity so far. Our aims were to evaluate serum Zn in WD and its correlation with the disease severity score (revised WD index). Although the ATP7B mutation analysis is highly accurate for WD diagnosis, it may not be readily available in a resource-limiting setting...

INTRODUCTION: Neonatal hyperammonemia secondary due to inborn errors of metabolism is a rare condition with a high rate of neurological sequelae and mortality. Initial medical management is often insufficient to stop the progressive increase of ammonia, with the consequent deterioration of the patient. For this reason, depurative techniques have been implemented, including peritoneal dialysis, intermittent hemodialysis and continuous renal replacement therapy (CRRT). OBJECTIVE: To describe our experience with continuous extracorporeal dialysis in severely ill neonates with hyperammonemia...

Likely pathogenic variants in CD320 cause transcobalamin receptor defect, a recently discovered inborn errors of cobalamin metabolism. Only 12 cases have been reported to date. There are no long-term clinical and biochemical outcome reports since its first description. In this report, we present two new cases and report their long-term treatment outcome. Two asymptomatic cases were identified through a positive newborn screening for propionic/methylmalonic aciduria. Biochemical abnormalities were normalized on a short course of oral cyanocobalamin (1 mg/day)...

Metabolomics holds considerable promise to advance our understanding of human disease, including our understanding of inborn errors of metabolism (IEM). The application of metabolomics in IEM research has already led to the discovery of several novel IEMs and the identification of novel IEM biomarkers. However, with hundreds of known IEMs and more than 700 associated IEM metabolites, it is becoming increasingly challenging for clinical researchers to keep track of IEMs, their associated metabolites, and their corresponding metabolic mechanisms...

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is an inborn error of bile acid metabolism caused by mutations of SLC10A1 gene. This paper reports the clinical and genetic features of a patient with this disease. A 3.3-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 3 months. Physical examination revealed moderate jaundice of the skin and sclera. The liver was palpable 3.5 cm below the right subcostal margin with a medium texture. Serum biochemistry analysis revealed markedly elevated bilirubin (predominantly direct bilirubin) and total bile acids (TBA), as well as decreased 25-OH-VitD level...

Clinico-pathological studies that focus on sudden unexpected death (SUD) in the neonatal period are rare. The objective of this study was to elucidate the frequency and pathological spectrum of anatomical causes of death (CODs), found in the setting of sudden unexpected death in neonates (SUD-N), and to correlate the COD with premortem circumstantial information. We conducted a detailed review of all autopsy reports on SUD-N cases at our institution from 1997 to 2015. Analyzed clinical data included obstetrical history, postpartum/neonatal medical course, and circumstances surrounding death...

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7-Oxocholesterol (7-OC), 5,6-epoxycholesterol (5,6-EC) and its hydrolysis product cholestane-3β,5α,6β-triol (3β,5α,6β-triol) are normally minor oxysterols in human samples, however, in disease their levels may be greatly elevated. This is the case in plasma from patients suffering from some lysosomal storage disorders e.g. Niemann Pick disease type C, or the inborn errors of sterol metabolism e.g. Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis. A complication in the analysis of 7-OC and 5,6-EC is that they can also be formed ex vivo from cholesterol during sample handling in air causing confusion with molecules formed in vivo...

Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1). If untreated, the disease leads to an important intellectual disability (IQ <50). Although many facts are common between phenylalanine (Phe) and tryptophan (Trp) metabolism, little is known about Trp metabolism modification in PKU. Our aim was to evaluate the modifications of Trp metabolism in a phenylketonuric population. A monocentric study was conducted between October 2016 and March 2017...

Significant improvements in automated image analysis have been achieved in recent years and tools are now increasingly being used in computer-assisted syndromology. However, the ability to recognize a syndromic facial gestalt might depend on the syndrome and may also be confounded by severity of phenotype, size of available training sets, ethnicity, age, and sex. Therefore, benchmarking and comparing the performance of deep-learned classification processes is inherently difficult. For a systematic analysis of these influencing factors we chose the lysosomal storage diseases mucolipidosis as well as mucopolysaccharidosis type I and II that are known for their wide and overlapping phenotypic spectra...

An inborn error of metabolism should be considered in any neonate who presents to the emergency department in extremis and in any young child who presents with altered mental status and vomiting. In children with unknown diagnoses, it is crucial to draw the appropriate laboratory studies before the institution of therapy, although treatment needs rapid institution to mitigate neurologic damage and avoid worsening metabolic crisis. Although there are hundreds of individual genetic disorders, they are roughly placed into groups that present similarly...

Mucolipidosis type II, also known as I-cell disease, is an autosomal recessive inborn error of metabolism, resulting from loss-of-function mutations in GNPTAB. Affected infants exhibit multiple physical anomalies and developmental delay, and death from disease follows in early childhood. Here we present an instructive case of mucolipidosis type II affecting 1 fetus and placental disk in a dichorionic-diamnionic twin pregnancy delivered at 36-wk gestation. The second twin and placental disk showed no abnormality...

INTRODUCTION: Fungal endocarditis is reported less frequently than bacterial endocarditis, with an incidence of 0-12% of the total pediatric infective endocarditis. OBJECTIVE: In this study, the incidence of infective endocarditis in Candida bloodstream infections in a tertiary hospital during the periods of 2007 and 2016 was reviewed. METHODS: Patients with positive blood or catheter cultures in terms of Candida spp. during the study period of January 2007 and January 2016 were analyzed in terms of Candida infective endocarditis...

Pyridox(am)ine-5-phosphate oxidase deficiency is an inborn error of vitamin B6 metabolism that is characterized by neonatal seizures, requiring lifelong therapy with pyridoxal-5-phosphate. We present the first case of a patient with pyridox(am)ine-5-phosphate oxidase deficiency and mild hemophilia A, whose bleeding symptoms were exacerbated by the vitamin B6 therapy essential for his epileptic disorder. This report expands the spectrum of known vitamin B6 toxicity and demonstrates a need for vigilance in monitoring for bleeding symptoms in patients requiring pyridoxine or pyridoxal-5-phosphate supplementation...

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c...

Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in the phenylalanine hydroxylase ( PAH ) gene or by defects in the tetrahydrobiopterin (BH4) synthesis pathway. Here, by positional cloning, we report that the 6-pyruvoyl-tetrahydropterin synthase ( PTPS ) gene, encoding a key enzyme of BH4 biosynthesis, is responsible for the alc (albino C) mutation that displays pale body color, head shaking, and eventually lethality after the first molting in silkworm. Compared to wild type, the alc mutant produced more substrates (phenylalanine (Phe) and tyrosine (Tyr)) and generated less DOPA and dopamine...

INTRODUCTION: Inborn errors of tetrahydrobiopterin (BH4 ) biosynthesis or recycling are a group of very rare neurometabolic diseases. Following growing awareness and improved availability of drug treatment the number of patients with BH4 disorders reaching adulthood is constantly increasing. Pregnancy care of patients with these disorders is therefore a new challenge for clinicians. METHODS: This retrospective study summarises for the first time clinical and biochemical monitoring data of 16 pregnancies in seven women with different disorders of BH4 metabolism and evaluates treatment regimens before and during pregnancy in relation to the obstetrical outcome and paediatric follow-up...

A myeloablative regimen that includes total-body irradiation (TBI) before hematopoietic stem cell transplantation results in higher patient survival rates than achieved with regimens without TBI. The TBI protocol, however, varies between institutions. In October 2015, the Japanese Radiation Oncology Study Group initiated a national survey of myeloablative TBI (covering 2010-2014). Among the 186 Japanese institutions performing TBI, 90 (48%) responded. The 82 institutions that had performed myeloablative TBI during this period treated 2698 patients with malignant disease [leukemia (2082 patients, 77...

AIM: Gamma-aminobutyric acid (GABA) is a major modulator in brain maturation and its role in many different neurodevelopmental disorders has been widely reported. Although the involvement of GABA in different disorders has been related to its regulatory function as an inhibitory neurotransmitter in the mature brain, co-transmitter, and signalling molecule, little is known about its role as a clinical biomarker in neuropaediatric disorders. The aim of this study is to report the cerebrospinal fluid (CSF) free-GABA concentrations in a large cohort of patients (n=85) with different neurological disorders...