High prevalence of carriers of variant c.1528G&gt;C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland

Nedoszytko, Bogusław; Siemińska, Alicja; Strapagiel, Dominik; Dąbrowski, Sławomir; Słomka, Marcin; Sobalska‐Kwapis, Marta; Marciniak, Błażej; Wierzba, Jolanta; Skokowski, Jarosław; Fijałkowski, Marcin; Nowicki, Roman

doi:10.1371/journal.pone.0187365

Cited by 16 publications

(15 citation statements)

References 39 publications

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“…The prevalence of LCHAD deficiency is reported to be high in Baltic Sea countries compared to other populations in the world. Recently, the LCHAD variant 1528G>C was identified to be highly prevalent in the Kashubian population of northern Poland (one carrier in 57 individuals), southern Poland (one in 107), northern Pomerania (one in 207) and isolated regions of Poland (one in 187) [ 43 ]. The 1528G>C mutation in the HADHA gene corresponds to the amino acid change of Glu to Gln at position 474 of the mature LCHAD domain, which resides in the active site of the enzyme.…”

Section: Maternal Liver Disease Associated With Fatty Acid Oxidatimentioning

confidence: 99%

“…This mutation affects and reduces LCHAD catalytic enzyme activity and decreases the protein stability [ 44 ]. The LCHAD mutation is also highly prevalent in the populations of Finland (one in 240), Netherlands (one in 680), Sweden (one in 540) and Estonia (one in 173) [ 9 , 25 , 43 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Due to the high incidence and prevalence of LCHAD mutation, the Swedish government mandated neonatal screening for LCHAD mutation in 2012 as a routine practice to minimize the incidence of AFLP [ 44 ].…”

Section: Maternal Liver Disease Associated With Fatty Acid Oxidatimentioning

confidence: 99%

“…LCHAD-deficient patients were also shown to have defective brain docosahexaenoic acid (DHA) biosynthesis due to the defect in mitochondrial β-oxidation, since β-oxidation in the brain is critical for the final step in DHA biosynthesis [ 11 , 102 ]. Studies have shown that patients with LCHAD deficiency were also more likely to develop seizures, mental retardation, retinopathy and neuropathy, possibly due to the defect in DHA biosynthesis [ 43 , 48 , 51 , 53 , 54 , 103 ]. LCHAD deficient children also show exercise intolerance, early development disability, mental retardation, microcephaly, skeletal myopathy, cardiomyopathy, encephalopathy in addition to hepatomegaly with microvesicular steatosis.…”

Section: 3-hfa and Pediatric Complications Unique To Lchad Deficiementioning

confidence: 99%

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Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

Natarajan

Ibdah

2018

IJMS

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Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency.

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Section: Maternal Liver Disease Associated With Fatty Acid Oxidatimentioning

confidence: 99%

Section: Maternal Liver Disease Associated With Fatty Acid Oxidatimentioning

confidence: 99%

Section: 3-hfa and Pediatric Complications Unique To Lchad Deficiementioning

confidence: 99%

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Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

Natarajan

Ibdah

2018

IJMS

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“…LCHADD, a disorder of fatty-acid beta-oxidation, is caused by pathogenic variants in the HADHA gene, which encodes the alpha subunit of the mitochondrial trifunctional protein (MTP; EC 1.1.1.211) ( IJlst et al , 1994 ). Variant c.1528G>C (p.Glu510Gln) in exon 15 was observed in 87–91% of European patients with clinically overt disease ( Nedoszytko et al , 2017 ). Certain variants in the MUT gene, which codes for the enzyme methylmalonyl-CoA mutase (MUT; EC 5.4.99.2), are responsible for mut 0 MMA, a disorder of propionate catabolism ( Ledley et al , 1988 ).…”

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confidence: 99%

Prevalence of the most common pathogenic variants in three genes for inborn errors of metabolism associated with sudden unexpected death in infancy: a population-based study in south Brazil

et al. 2020

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Citrullinemia type 1 (CTLNI), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), and mut 0 methylmalonic acidemia (mut 0 MMA) are inborn errors of metabolism (IEMs) associated with sudden unexpected death in infancy (SUDI). Its most common pathogenic variants are: c.1168G>A (CTLNI, ASS1 gene), c.1528G>C (LCHADD, HADHA gene), c.655A>T and c.1106G>A (mut 0 MMA, MUT gene). Considering the absence of estimates regarding the incidence of these diseases in Brazil, this study sought to investigate the prevalence of its main pathogenic variants in a healthy population in the southern region of the country. A total of 1,000 healthy subjects from Rio Grande do Sul were included. Genotyping was performed by real-time PCR. Individuals found to be heterozygous for c.1528G>C underwent further acylcarnitine profile analysis by tandem mass spectrophotometry. Allele and genotype frequencies were calculated considering Hardy-Weinberg equilibrium. The c.1528G>C variant was detected in heterozygosity in two subjects (carrier frequency = 1:500; allele frequency = 0.001; minimum prevalence of LCHADD = 1: 1,000,000), whose acylcarnitine profiles were normal. Variants c.1168G>A, c.655A>T, and c.1106G>A were not identified. These results denote the rarity of these IEMs in Southern Brazil, highlighting the need to expand the investigation of IEMs in relation to infant morbidity and mortality within the country.

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“…; DNA; the collection was created for the project TESTOPLEK; retrospective; anonymized; POPULOUS_ BLUL[3][4][15][16][17][18][19][20][21][22][23].…”

mentioning

confidence: 99%

Biobank Lodz – population based biobank at the University of Lodz, Lodz, Poland

Dobrowolska¹,

Michalska-Madej²,

Słomka³

et al. 2019

Eur J Trans Clin Med

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Background: Biobank Laboratory of the University of Łódź is a unit in the organizational structure of the Department of Molecular Biophysics at the Faculty of Biology and Environmental Protection. It was established in 2014 as one of the results of the TESTOPLEK project. One of the main goals of the unit is to collect and share biological material of human origin and related clinical and survey data. Moreover, Biobank Laboratory conducts work in the field of genetics and molecular biology on human biological material. Biobank Laboratory gathers over 40.000 samples such as DNA, FFPE, saliva, together with their data. Data about its material is available for researchers in directories e.g. BBMRI-ERIC Directory 4.0. Since 2014, the unit belongs to the national Consortium BBMRI.pl, and since 2017 it executes a project entitled Research Infrastructure for Biobanks and Biomolecular Resources BBMRI-ERIC, co-creating the Polish Network of Biobanks. Biobank Laboratory is focused on cooperation with domestic and foreign scientific institutions and medical units, as well as entities from the local, business and public sector.

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High prevalence of carriers of variant c.1528G>C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland

Cited by 16 publications

References 39 publications

Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

Prevalence of the most common pathogenic variants in three genes for inborn errors of metabolism associated with sudden unexpected death in infancy: a population-based study in south Brazil

Biobank Lodz – population based biobank at the University of Lodz, Lodz, Poland

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