A 2.5-month-old girl admitted for failure to thrive and severe pancytopenia was diagnosed with methylmalonic acidemia (MMA) secondary to transcobalamin II deficiency, an inborn error of vitamin B12 metabolism. Opportunistic Cytomegalovirus and Pneumocystis jirovecii pneumonia led to severe acute respiratory distress syndrome (ARDS) and immune reconstitution inflammatory syndrome (IRIS) after treatment initiation with vitamin B12 supplementation. In children with interstitial pneumonia-related ARDS, normal lymphocyte count should not delay invasive procedures required to document opportunistic infections. MMA can be associated with underlying lymphocyte dysfunction and vitamin B12 supplementation can fully reverse the associated immunodeficiency. IRIS may appear in highly treatment-responsive forms of pancytopenia in children and prompt treatment of dysregulated inflammation with high-dose corticosteroids should be initiated.

BACKGROUND AND PURPOSE:Defects in the mitochondrial respiratory chain (MRC) can lead to combined MRC dysfunctions (COXPDs) with heterogenous genotypes and clinical features. We report a patient carrying heterozygous variants in the TUFM gene who presented with clinical features compatible with COXPD4 and radiological findings mimicking multiple sclerosis (MS).METHODS:A 37-year-old French Canadian woman was investigated for recent onset of gait and balance problems. Her previous medical history included recurrent episodes of hyperventilation associated with lactic acidosis during infections, asymptomatic Wolff-Parkinson-White syndrome, and nonprogressive sensorineural deafness.RESULTS:Neurological examinations revealed fine bilateral nystagmus, facial weakness, hypertonia, hyperreflexia, dysdiadochokinesia, dysmetria, and ataxic gait. Brain magnetic resonance imaging (MRI) showed multifocal white matter abnormalities in cerebral white matter as well as cerebellar hemispheres, brainstem, and middle cerebellar peduncles, some of which mimicked MS. Analysis of native-state oxidative phosphorylation showed a combined decrease in CI/CII, CIV/CII, and CVI/CII. Exome sequencing detected two heterozygous TUFM gene variants. Little clinical progression was noted over a 5-year follow-up. Brain MRI remained unchanged.CONCLUSIONS:Our report broadens the phenotypic and radiological spectrum of TUFM-related disorders by adding milder, later onset forms to the previously known early onset, severe presentations. The presence of multifocal white matter abnormalities can be misinterpreted as due to acquired demyelinating diseases, and thus TUFM-related disorders should be added to the list of mitochondrial MS mimickers.

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The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive intermediates that non-enzymatically modify proteins. Based on this mechanism, we predicted, validated, and characterized a protein modification: 3-hydroxy-3-methylglutaryl(HMG)-lysine. In a model of altered HMG-CoA metabolism, we found evidence of two additional protein modifications: 3-methylglutaconyl(MGc)-lysine and 3-methylglutaryl(MG)-lysine. Using quantitative proteomics, we compared the "acylomes" of two reactive acyl-CoA species, namely HMG-CoA and glutaryl-CoA, which are generated in different pathways. We found proteins that are uniquely modified by each reactive metabolite, as well as common proteins and pathways. We identified the tricarboxylic acid cycle as a pathway commonly regulated by acylation and validated malate dehydrogenase as a key target. These data uncover a fundamental relationship between reactive acyl-CoA species and proteins and define a new regulatory paradigm in metabolism.

Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.

HT1 is a severe autosomal recessive disorder due to the deficiency of fumarylacetoacetate hydrolase (FAH), the final enzyme in the degradation of tyrosine. Before the era of treatment with 2-(2-N-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), even with newborn screening and optimal diet therapy, HT1 patients often developed liver failure. Death was common in patients who did not undergo liver transplantation. For the last two decades, NTBC has revolutionized the management of HT1 patients. In screened newborns treated within the first month of life, we have not observed hepatocarcinoma. If patients are not detected at birth by neonatal screening, the diagnosis and treatment must be performed on an emergency basis, and patients are at risk for complications. Long term adhesion to treatment and reliable early detection of hepatocellular carcinoma (HCC) are two important challenges. In this chapter, we describe the clinical, biological, histo-pathological and imaging findings of HT1 in Québec before the era of NTBC. We also describe the hepatic status of nontransplanted tyrosinemic patients in Quebec and current management practices in the Quebec NTBC Study.

Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with “mild” SCOT mutations may have nonketotic periods. T2-deficient patients with “mild” mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.

BACKGROUND The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. METHODS Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. RESULTS Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. CONCLUSIONS The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies.The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.

Abstract Background: The completion of the Human Genome Project has increased the pace of discovery of genetic markers for disease. Despite tremendous efforts in fundamental research, clinical applications still lag behind expectations, partly due to the lack of effective tools to systematically search for and summarize published data relative to the clinical assessment of new diagnostic molecular tests. Methods: Through a collaborative process using published tools and an expert panel, we developed a detailed checklist of the evidence that needs to be collected or produced to evaluate the potential usefulness of a new molecular diagnostic test. This tool is called GETT, for Genetic testing Evidence Tracking Tool. Results: GETT allows 1) researchers to summarize the current evidence and to identify knowledge gaps for further research and; 2) stakeholders to collect data related to a given molecular test and improve their decision-making process. GETT comprises 72 clearly defined items/questions, grouped into 10 categories and 26 sub-themes, including an overview of disease epidemiology and genetics, the available diagnostic tools, and their analytical and clinical performances, availability of quality control programs, laboratory and clinical best practice guidelines, clinical utility, and impact on health care and psycho-social, ethical and legal implications. It also includes a summary of the evidence available and attempts to prioritise knowledge gaps related to the testing. We also compare GETT to other existing frameworks. Conclusions: This systematic evidence-based tracking tool, which is more detailed than existing frameworks and provides clear definition for each item, will help streamline collection of the available evidence to appraise the potential for clinical application of new molecular diagnostic tests and prioritize research to produce the evidence-base relative to the clinical implementation of molecular diagnostic tests. Clin Chem Lab Med 2010;48:1397–407.