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Abstract: Background: Urea cycle disorders (UCD) are caused by genetic defects in enzymes that constitute the hepatic ammonia detoxification pathway. Patients may present with variable clinical manifestations and with hyperammonaemia. Liver abnormalities have been associated with UCD, but only a few reports on the histopathological findings in the liver of UCD patients have been published. Methods: We conducted a retrospective review of liver biopsies, ex-planted livers and livers at post-mortem of patients with UCD. A single pathologist reviewed all specimens. Results: There were 18 liver samples from 13 patients with confirmed UCD: four ex-planted livers from patients with Ornithine Transcarbamylase (OTC) (n=3) and Carbamoyl Phosphate Synthetase 1 (CPS 1) (n=1) deficiencies, eight post-mortem samples from patients with CPS 1 (n=2), OTC (n=4), Argininosuccinate Synthetase (ASS) (n=1) and Argininosuccinate Lyase (ASL) (n=1) deficiencies, and six liver biopsies, three of which came from one patient with ASL deficiency. The other three liver biopsies were from patients who subsequently received liver transplantation. Histopathological findings in samples from neonates were non-specific. Samples from three late onset OTC deficient and one ASL deficient patients showed thin fibrous septa with portal to portal bridging fibrosis and focal marked enlargement and pallor of the hepatocytes due to accumulation of glycogen particles, resembling glycogenosis and resulting in a prominent nodular pattern. Serial liver biopsies in four UCD patients with interval between samples ranging from 1year 2months to 17years showed progression in fibrosis in one OTC and one ASL deficient patients. Moderate fatty changes to no progression in liver disease were noted in the two patients (OTC=1 and CPS=1). A variety of non-specific features such as fatty change, mild inflammation, cholestasis and focal necrosis were seen in the other UCD patients. Conclusions: Histopathological changes in livers from neonates with UCD are non-specific. Older patients with UCD seem to show variable hepatic fibrosis compared to those who died early. Some of these patients also show focal and superficial resemblance to a glycogen storage disorder and cirrhosis. However, progression of these changes seems to be slow. To clarify the long term consequence of these changes, more extensive periods of follow up in a larger population series is needed. [Copyright &y& Elsevier]

Beta-ureidopropionase deficiency, caused by variants in UPB1 , has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism. We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype. Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases. Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1. Pending the availability of further evidence, UPB1 should be considered a 'gene of uncertain clinical significance'. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening. The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain. • The relationship between damaging UPB1 variants and human phenotypes is uncertain. • Described beta-ureidopropionase deficiency cases do not have a consistent phenotype. • Loss of function UPB1 variants are common in the general population. • Care must be used in ascribing diagnostic value to variants in UPB1. • UPB1 should not be included on carrier screening panels. [ABSTRACT FROM AUTHOR]

Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD. • Serum FGF21 and GDF15 were elevated in a range of pediatric mitochondrial diseases. • Serum GDF15 was elevated in non-mitochondrial pediatric disease cohorts. • Serum FGF21 was not elevated in non-mitochondrial pediatric disease cohorts. • Serum FGF21 was elevated in both mitochondrial myopathy and neuronal phenotypes. • Serum FGF21 was a good biomarker of pediatric mitochondrial disease. [ABSTRACT FROM AUTHOR]

Abstract: Congenital disorders of glycosylation (CDG) represent an expanding family of metabolic disorders with a wide range of biochemical, molecular and clinical phenotypes. ALG3-CDG (CDG-Id), due to a defect in endoplasmic reticulum (ER) mannosyltransferase VI, is one of the less common types of CDG-I. We describe two Vietnamese siblings with confirmed ALG3-CDG (CDG-Id) by molecular testing. As far as we are aware, they are the oldest reported patients in the literature at 15 and 21years. They share similar clinical features with previously reported patients including facial dysmorphism, severe psychomotor retardation, microcephaly, seizures, and gastrointestinal symptoms. Furthermore, our sibling pair highlights the intrafamilial variability, the natural clinical course of ALG3-CDG (CDG-Id) and the benefit of reassessing patients with undiagnosed and complex syndromes, particularly when they present with neurological deterioration. [Copyright &y& Elsevier]

Abstract: Between October 2001 and September 2007, a total number of 391,651 neonates were screened in Victoria using Tandem Mass Spectrometry and 6 newborns were diagnosed as having GA I, giving an incidence of 1:65,275 (CI: 1:29,988=1:177,861). Another patient was diagnosed through cascade screening of children born before the implementation of the expanded newborn screening program. Patients were treated by mild protein restriction (2–2.5g/kg/day) and carnitine supplementation when well, focussing on the aggressive management of intercurrent illnesses (temporary cessation of protein intake, increase in calorie intake, IV carnitine, aggressive anti febrile and anti infectious treatment), including prophylactic admissions to hospital. Overall, our patients had 35 admissions to hospital, of which 15 were in the first year of life. None had a post infectious dystonic syndrome. Neuropsychological examinations revealed normal to high cognitive and gross motor function in all patients but one, with some deficiencies in fine motor activities and different levels of speech abnormalities in all patients. Since therapeutic approaches for GA I, although not uniform, are well established and have been documented to be effective, newborn screening for this disorder should prove justified. A therapeutic approach of dietary modification, IV carnitine and aggressive treatment of intercurrent illness seems to prevent the severe neurological complications of GA I. More in-depth consideration of speech and language function is necessary to document specific deficits in children with GA I and plan proactive interventions. [Copyright &y& Elsevier]