Glutaric aciduria type 1 in South Africa—high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans

Watt, George van der; Owen, Elizabeth; Berman, Peter; Meldau, Surita; Watermeyer, Nicholas D.; Olpin, S. E.; Manning, N. J.; Baumgarten, Ingrid; Leisegang, Felicity; Henderson, Howard

doi:10.1016/j.ymgme.2010.07.018

Cited by 44 publications

(21 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The biochemical characterization of MADD includes organic acid and acylcarnitine profiling, which indicates, increased levels of aliphatic mono-and dicarboxylic acids, acylglycine conjugates as well as an increase of C4-C18 acylcarnitines in blood [1]. Although mutations are most frequently encountered in the ETFDH gene in the late-onset form of MADD, for the most severe (type I) neonatal form of the disease mutations in ETFDH, ETFA, and ETFB are found more or less in equal frequency [2,3,[4][5][6][7][8] As mutation screening is not currently offered routinely in our (South African) population, and since biochemical data through routine metabolic screening suggests that MADD may be in the same order of prevalence as other organic acidemias in South African populations [9,10] we've begun to retrospectively investigate the molecular genetics of MADD with metabolic data as the denominator. From the initial explorative investigations in three Caucasian patients, we've identified a novel pathogenic variant present in all three cases, with the homozygous form in the index case presenting as a (type I) severe neonatal onset form of the disease.…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency

Westhuizen

Smuts

Honey

et al. 2018

Journal of the Neurological Sciences

View full text Add to dashboard Cite

Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD type I) is an autosomal recessive disorder of the electron transfer flavoprotein function characterized by a severe clinical and biochemical phenotype, including congenital abnormalities with unresponsiveness to riboflavin treatment as distinguishing features. From a retrospective study, relying mainly on metabolic data, we have identified a novel mutation, c.1067G>A (p.Gly356Glu) in exon 8 of ETFDH, in three South African Caucasian MADD patients with the index patient presenting the hallmark features of type I MADD and two patients with compound heterozygous (c.1067G>A+c.1448C>T) mutations presenting with MADD type III. SDS-PAGE western blot confirmed the significant effect of this mutation on ETFDH structural instability. The identification of this novel mutation in three families originating from the South African Afrikaner population is significant to direct screening and strategies for this disease, which amongst the organic acidemias routinely screened for, is relatively frequently observed in this population group.

show abstract

Section: Introductionmentioning

confidence: 99%

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency

Westhuizen

Smuts

Honey

et al. 2018

Journal of the Neurological Sciences

View full text Add to dashboard Cite

show abstract

“…High-risk populations with a prevalence of up to 1 in 300 newborns have been identified. This includes the Amish Community in Lancaster County, Pennsylvania, USA [4], the Oji-Cree First Nations in Western Ontario and Manitoba, Canada [5], the Lumbee in North Carolina, USA [6], the Irish Travellers in Ireland and the United Kingdom [7], and indigenous South Africans [8].…”

Section: Introductionmentioning

confidence: 99%

Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

Heringer

Boy

Burgard

et al. 2015

IJNS

View full text Add to dashboard Cite

More than 15 years ago glutaric aciduria type I has been included in newborn screening programmes and pilot studies evaluating the potential benefit of early diagnosis and start of metabolic treatment for patients with this disease have been initiated. At that time many important questions on epidemiology, diagnostic quality, natural history, treatment, and cost effectiveness were not sufficiently answered. In particular, it was rather unknown whether early treatment improves the outcome. After implementation of glutaric aciduria type I in an increasing number of countries, and with careful evaluation of disease course and impact of early treatment, there is now solid evidence that affected individuals do have substantial benefit and that newborn screening for this disease is a cost-effective diagnostic intervention. Despite this success, there are still limitations concerning diagnostic sensitivity for patients with a low excreting phenotype and knowledge on longterm disease outcome. In conclusion, it has become evident that tandem mass spectrometrybased newborn screening for glutaric aciduria type I is a powerful and cost-effective tool to prevent the manifestation of prognostically-relevant movement disorders in the majority of early diagnosed patients.

show abstract

“…The overall prevalence is approximately 1 in 100,000 newborns, but this varies among different countries [1], [2]. Because GCDH activity is central to the catabolism of lysine and tryptophan, glutaric acid (GA) and related metabolites accumulate in the tissues and fluids of affected patients.…”

Section: Introductionmentioning

confidence: 99%

Effects of Targeted Suppression of Glutaryl-CoA Dehydrogenase by Lentivirus-Mediated shRNA and Excessive Intake of Lysine on Apoptosis in Rat Striatal Neurons

Gao

Zhang

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

In glutaric aciduria type 1 (GA1), glutaryl-CoA dehydrogenase (GCDH) deficiency has been shown to be responsible for the accumulation of glutaric acid and striatal degeneration. However, the mechanisms by which GA1 induces striatal degeneration remain unclear. In this study, we aimed to establish a novel neuronal model of GA1 and to investigate the effects of GCDH deficiency and lysine-related metabolites on the viability of rat striatal neurons. Thus we constructed a lentiviral vector containing short hairpin RNA targeted against the GCDH gene expression (lentivirus-shRNA) in neurons. A virus containing a scrambled short hairpin RNA construct served as a control. Addition of lysine (5 mmol/L) was used to mimic hypermetabolism. Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Apoptosis was assessed using Hoechst33342 staining and Annexin V-PE/7-AAD staining. The mitochondrial membrane potential (MPP) was monitored using tetramethylrhodamine methyl ester. The expression levels of caspases 3, 8, and 9 were determined by Western blotting. We found that lentivirus-shRNA induced apoptosis and decreased MMP levels in neurons, and addition of 5 mmol/L lysine enhanced this effect markedly. Lentivirus-shRNA upregulated the protein levels of caspases 3 and 9 regardless of the presence of 5 mmol/L lysine. The expression level of caspase 8 was higher in neurons co-treated with lentivirus-shRNA and 5 mmol/L lysine than in control. Benzyloxy-carbonyl-Val-Ala-Asp(OMe)-fluoromethylketone, a pan-caspase inhibitor, blocked the apoptosis induced by lentivirus-shRNA and 5 mmol/L lysine to a great extent. These results indicate that the targeted suppression of GCDH by lentivirus-mediated shRNA and excessive intake of lysine may be a useful cell model of GA1. These also suggest that GA1-induced striatal degeneration is partially caspase-dependent.

show abstract

Glutaric aciduria type 1 in South Africa—high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans

Cited by 44 publications

References 31 publications

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency

Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

Effects of Targeted Suppression of Glutaryl-CoA Dehydrogenase by Lentivirus-Mediated shRNA and Excessive Intake of Lysine on Apoptosis in Rat Striatal Neurons

Contact Info

Product

Resources

About