Outcome of the First 3-Years of a DNA-Based Neonatal Screening Program for Glutaric Acidemia Type 1 in Manitoba and Northwestern Ontario, Canada

Greenberg, Cheryl R.; Prasad, Asuri N.; Dilling, Louise A.; Thompson, James R.; Haworth, J. C.; Martin, Bruce D.; Wood-Steiman, Pauline; Seargeant, L.E.; Seifert, B; Booth, Frances A.; Prasad, Chitra

doi:10.1006/mgme.2001.3270

Cited by 72 publications

(65 citation statements)

References 29 publications

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“…(1). The estimated prevalence is 1:100,000 newborns (2), but it is considerably higher in some genetic isolates (3,4). More than 150 disease-causing GCDH gene mutations have been identified (5)(6)(7).…”

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confidence: 99%

“…As a result of variations in the natural history, and differences in the diagnostic criteria and therapeutic protocols, the outcome worldwide has been varied. This has hampered our understanding to such a degree that it is not certain whether the disorder is really treatable (4,6).…”

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confidence: 99%

“…In this light, inclusion of GCDH deficiency into MS/MS-based neonatal screening programs is crucial to improve the outcome. Alternative strategies, such as DNA-based screening, should be considered for the screening for known low excretor cohorts with private mutations (4).…”

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confidence: 99%

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Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

et al. 2006

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Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n ϭ 218) or presymptomatically by neonatal screening (n ϭ 23), high-risk screening (n ϭ 24), or macrocephaly (n ϭ 14). Most symptomatic patients (n ϭ 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

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Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

et al. 2006

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“…[2,3] Certain populations, such as the Old Order Amish of Pennsylvania, USA, [4] and the Oji-Cree Island Lake First Nation communities of Canada, [5] are known to have a higher disease burden. A higher carrier rate of the A293T mutation has been previously described in patients of black indigenous ancestry in the SA population.…”

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confidence: 99%

A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

2017

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“…Classical OAD, such as methylmalonic aciduria (MMA), propionic aciduria (PA), and isovaleric aciduria (IVA), characteristically present with metabolic acidosis, hypoglycemia, hyperketosis, elevated lactate, and hyperammonia during catabolic state, whereas cerebral OAD, such as glutaric aciduria type I (GA-I), predominantly exhibit neurologic symptoms (dystonia, ataxia, encephalopathy, seizures) (2,10,11,13-16,18 -21). At present, genotype phenotype correlation in the majority of these diseases is poorly understood and remarkable variations in the disease course have been described, ranging from asymptomatic patients to fatal course after neonatal onset (10,15,(22)(23)(24)(25)(26)(27).…”

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confidence: 99%

Quantitative Acylcarnitine Profiling in Peripheral Blood Mononuclear Cells Using In Vitro Loading With Palmitic and 2-Oxoadipic Acids: Biochemical Confirmation of Fatty Acid Oxidation and Organic Acid Disorders

et al. 2005

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Organic acid (OAD) and fatty acid oxidation disorders (FAOD) are inborn errors of metabolism often presenting with life-threatening metabolic decompensation followed by (irreversible) organ failure, and even death during catabolic state. Most of these diseases are considered as treatable, and metabolic decompensations can be avoided by early diagnosis and start of therapy. Confirmation of suspected diagnosis currently relies on enzymatic and mutation analyses and in vitro loading of palmitic acid in human skin fibroblast cultures. Furthermore, in some cases potentially life-threatening in vivo loading or fasting tests are still performed. In this study, we established a standardized in vitro loading test in peripheral blood mononuclear cells (PBMC) that allows reliable biochemical confirmation of a suspected diagnosis within 1 week. Patients with confirmed diagnosis of short-, medium-, very-long-chain, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies, methylmalonic, propionic, isovaleric acidurias, and glutaric aciduria type I were included in the study. PBMC, isolated from heparinized venous blood samples of these individuals were incubated for 5 days with palmitic acid or 2-oxoadipic acid (glutaric aciduria type I), respectively, and quantitative acylcarnitine profiling was subsequently performed in supernatants using electrospray ionization tandem mass spectrometry. All patients were clearly identified, including those with mild biochemical phenotypes who, in particular, are at risk to be missed under balanced metabolic conditions. In glutaric aciduria type I, the same results were also obtained using lymphoblasts. In conclusion, our assay allows biochemical confirmation of a number of FAOD and OAD and could easily be implemented into the confirmatory diagnostic work-up. Organic acids and fatty acids comprise a group of physiologically occurring intermediates in a variety of intracellular metabolic pathways, such as catabolism of amino acids, mitochondrial ␤-oxidation of fatty acids, tricarboxylic acid cycle, and cholesterol biosynthesis. Organic acid (OAD) and fatty acid oxidation disorders (FAOD) are caused by autosomal recessive inherited deficiencies of single enzymes (or in the metabolism of required coenzymes) in the outlined metabolic

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Outcome of the First 3-Years of a DNA-Based Neonatal Screening Program for Glutaric Acidemia Type 1 in Manitoba and Northwestern Ontario, Canada

Cited by 72 publications

References 29 publications

Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

Quantitative Acylcarnitine Profiling in Peripheral Blood Mononuclear Cells Using In Vitro Loading With Palmitic and 2-Oxoadipic Acids: Biochemical Confirmation of Fatty Acid Oxidation and Organic Acid Disorders

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