3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis.

3-Methylglutaconyl-CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate. It is an ultra-rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention.

Cognitive and Behavioural Outcomes of Paediatric Liver Transplantation for Ornithine Transcarbamylase Deficiency.

Ornithine Trans-Carbamylase (OTC) deficiency is the most common disorder of the urea cycle. Cognitive impairments in skills such as attention and executive function have been reported in individuals with OTC deficiency who are managed with medication. In some cases, children undergo liver transplantation (LTx) to correct the metabolic defect.

Smith-Lemli-Opitz syndrome: clinical and biochemical correlates.

Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis.

Methods: We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features.

The Validity of Bioelectrical Impedance Analysis to Measure Body Composition in Phenylketonuria.

Aim: To compare the measurement of total body water (TBW) and fat-free mass (FFM) using the criterion method of deuterium dilution space (HO) with bioelectrical impedance analysis (BIA) using a portable QuadScan 4000, Bodystat in children and adolescents with phenylketonuria (PKU).

Methods: Sixteen patients with PKU, median age is 12.5 (range 5-20.

The relationship between dietary intake, growth and body composition in Phenylketonuria.

Aim: Phenylketonuria (PKU) is an inborn error of protein metabolism that results from perturbation in phenylalanine hydroxylase activity leading to elevated blood levels of phenylalanine (phe). We aimed to explore the relationships between dietary patterns (total-protein, natural-protein, amino-acid formula), and the ratio of protein to energy intake with growth and body composition.

Method: Longitudinal prospective data (1-6 measurements) of growth, dietary intake and body composition in patients treated with phe-restricted diet only (D-PKU; n=32), and tetrahydrobiopterin (BH)±phe-restricted diet (BH-PKU; n=5) were collected over a two-year period.

The Relationship between Dietary Intake, Growth, and Body Composition in Inborn Errors of Intermediary Protein Metabolism.

Objectives: To examine relationships between dietary intake, growth and body composition patterns in patients with inborn errors of intermediary protein metabolism and to determine a safe protein:energy ratio (P:E ratio) associated with optimal growth outcomes.

Study Design: Retrospective longitudinal data of growth and dietary intake in patients (n = 75) with isovaleric acidemia (IVA; n = 7), methylmalonic acidemia/propionic acidemia (MMA/PA; n = 14), urea cycle defects (UCD; n = 44), classical maple syrup urine disease (MSUD; n = 10) were collected. Prospective longitudinal data of growth, dietary intake, and body composition from 21 patients: IVA (n = 5), MMA/PA (n = 6), UCD (n = 7), and MSUD (n = 3) were collected at clinic visits.

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries.

VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype-phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited.

Parent Coping and the Behavioural and Social Outcomes of Children Diagnosed with Inherited Metabolic Disorders.

Objective: To explore the level of coping and management of parents of children with inherited metabolic disorders (IMD) and the relationship with children's cognitive, behavioural and social functioning.

Methods: Parents of children (n = 22) with confirmed IMD (glutaric aciduria type I, methylmalonic aciduria, propionic aciduria, isovaleric aciduria, glycogen storage disease, maple syrup urine disease, ornithine transcarbamylase or very long-chain acyl-CoA dehydrogenase deficiency) completed standardised questionnaires regarding psychological distress, coping and family management. Children completed cognitive assessments and parents rated their behavioural and social functioning on standardised questionnaires.

Metabolite studies in HIBCH and ECHS1 defects: Implications for screening.

3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is a rare inborn error of the valine catabolic pathway associated with Leigh-like disease. We report a female patient who presented at the age of 5months with hypotonia, developmental delay and cerebral atrophy on MRI. Pyruvate dehydrogenase deficiency was initially suspected and decreased activity was shown in fibroblasts.

Signal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanism.

Signal transduction is the process by which external or internal signals exert their intracellular biological effects and by which intracellular communication is regulated. An important component of the signalling pathway is the second messenger, which is produced upon stimulation of the cell and mediates its effects downstream through phosphorylation and dephosphorylation of target proteins. Intracellular accumulation or deficiency of metabolites that serve as second messengers, due to inborn errors of their metabolism, may lead to perturbation of signalling pathways and disruption of the balance between them, serving as a missing link between the genotype, biochemical phenotype and clinical phenotype.

An audit of newborn screening procedure: impact on infants presenting clinically before results are available.

Background And Objective: Tandem mass spectrometry-based newborn screening (NBS) is a powerful screening tool. The NBS process includes sample collection, shipment, testing, analysis, reporting and communication with the infant's family. We explored the NBS programme-related factors that may delay diagnosis and may influence timely initiation of treatment in neonates who present before the screening results are available and therefore urgently need diagnosis and treatment.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations.

Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (HMCS2) deficiency results in episodes of hypoglycemia and increases in fatty acid metabolites. Metabolite abnormalities described to date in HMCS2 deficiency are nonspecific and overlap with other inborn errors of metabolism, making the biochemical diagnosis of HMCS2 deficiency difficult. Urinary organic acid profiles from periods of metabolic decompensation were studied in detail in HMCS2-deficient patients from four families.

Neurodevelopmental profiles of children with glutaric aciduria type I diagnosed by newborn screening: a follow-up case series.

Glutaric aciduria type I (GA-I) is an inherited metabolic disorder that may lead to severe motor disorder and cognitive impairment. GA-I is now included in the newborn screening programme in many countries as early detection allows for prompt treatment and effectively reduces the risk of poor developmental outcome. Information regarding the long-term neurodevelopmental outcome of children with GA-I treated early is sparse.

Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening.

Background: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation with an estimated incidence of between 1:31,500 and 1:125,000. There is limited information regarding neurodevelopmental outcomes, probably because the disorder is perceived as affecting the skeletal and heart muscles, and many children are deemed asymptomatic. The aim of this study was to utilise a comprehensive neuropsychological assessment battery that assessed IQ, language, attention, memory, executive functioning, motor skills, behaviour, and social skills in children 4 to 10 years old diagnosed with VLCAD deficiency through newborn screening.

New ways of defining protein and energy relationships in inborn errors of metabolism.

Dietary restrictions required to manage individuals with inborn errors of metabolism (IEM) are essential for metabolic control, however may result in an increased risk to both short and long-term nutritional status. Dietary factors most likely to influence nutritional status include energy intake, protein quality and quantity, micronutrient intake and the frequency and extent to which the diet must be altered during periods of increased physical or metabolic stress. Patients on the most restrictive diets, including those with intakes consisting of low levels of natural protein or those with recurrent illness or frequent metabolic decompensation carry the most nutritional risk.

Dietary protein in urea cycle defects: How much? Which? How?

Dietary recommendations for patients with urea cycle disorders (UCDs) are designed to prevent metabolic decompensation (primarily hyperammonaemia), and to enable normal growth. They are based on the 'recommended daily intake' guidelines, on theoretical considerations and on local experience. A retrospective dietary review of 28 patients with UCDs in good metabolic control, at different ages, indicates that most patients can tolerate a natural protein intake that is compatible with metabolic stability and good growth.

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment.

Unlabelled: Pyruvate dehydrogenase complex (PDHC) deficiency is a disorder of energy metabolism that leads to a range of clinical manifestations. We sought to characterise clinical manifestations and biochemical, neuroimaging and molecular findings in thiamine-responsive and nonresponsive PDHC-deficient patients and to identify potential pitfalls in the diagnosis of PDHC deficiency. We retrospectively reviewed all medical records of all PDHC-deficient patients (n = 19; all had PDHA1 gene mutations) and one patient with severe PDHC deficiency secondary to 3-hydroxyisobutyryl-CoA hydrolase deficiency managed at our centre between 1982 and 2012.

Clinical presentation and outcome in a series of 88 patients with the cblC defect.

Unlabelled: The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients.

Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene.

Liver phosphorylase b kinase (PhK) deficiency (glycogen storage disease type IX), one of the most common causes of glycogen storage disease, is caused by mutations in the PHKA2, PHKB, and PHKG2 genes. Presenting symptoms include hepatomegaly, ketotic hypoglycemia, and growth delay. Clinical severity varies widely.

Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling.

Mitochondrial respiratory chain (RC) disorders are the most prevalent inborn metabolic diseases and remain without effective treatment to date. Up-regulation of residual enzyme activity has been proposed as a possible therapeutic approach in this group of disorders. As resveratrol (RSV), a natural compound, was proposed to stimulate mitochondrial metabolism in rodents, we tested the effect of this compound on mitochondrial functions in control or in Complex I (CI)- or Complex IV (CIV)-deficient patients' fibroblasts.

Linear growth of children on a ketogenic diet: does the protein-to-energy ratio matter?

Ketogenic diet is a structured effective treatment for children with intractable epilepsy. Several reports have indicated poor linear growth in children on the diet but the mechanism of poor growth has not been elucidated. We aimed to explore whether the protein to energy ratio plays a role in linear growth of children on ketogenic diet.

Development of MLPA for human ACAT1 gene and identification of a heterozygous Alu-mediated deletion of exons 3 and 4 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

Mitochondrial acetoacetyl-CoA thiolase deficiency is an autosomal recessive disorder, characterized by intermittent ketoacidosis. We developed a multiplex ligation-dependent probe amplification method for mutation detection in the ACAT1 gene, which encodes this enzyme, and validated it using DNAs from two previously reported patients having partial deletion and duplication in this gene. Using this method, we identified a heterozygous deletion including exons 3-4 in a third patient, likely due to Alu-mediated non-equal homologous recombination between Alu sequences.

Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes.

Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-S proteins) are present in mitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair.

Histopathological findings in livers of patients with urea cycle disorders.

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.