Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis

Davit–Spraul, Anne; Beinat, Marine; Debray, Dominique; Rötig, Agnès; Slama, Abdelhamid; Jacquemin, Emmanuel

doi:10.1007/8904_2013_278

Cited by 8 publications

(6 citation statements)

References 12 publications

(30 reference statements)

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“…The latter includes mutations in genes causing neuromuscular disorders ( ACTA1 and SEPN1 ), as well as genetic syndromes, such as Kabuki ( KDM6A ), Schinzel Gideon ( SETBP1 ) and Coffin-Siris ( ARID1B, SMARCA4 ). Several examples of non-MD diagnoses established in this way in patients initially suspected to have a MD have been published before (Davit-Spraul et al 2013 ; Lieber et al 2012 ; McCormick et al 2013 ; Monies et al 2014 ; Nishri et al 2014 ). In addition, we identified mutations in genes encoding proteins that are either known to be localized in mitochondria, or have a function associated with mitochondrial energy metabolism in five patients.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing of suspected mitochondrial patients in clinical practice

Wortmann

Koolen

Smeitink

et al. 2015

J of Inher Metab Disea

194

198

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Mitochondrial disorders are characterized by a broad clinical spectrum. Identical clinical signs and symptoms can be caused by mutations in different mitochondrial or nuclear genes. Vice versa, the same mutation can lead to different phenotypes. Genetic syndromes and neuromuscular disorders mimicking mitochondrial disorders further complicate the diagnostic process. Whole exome sequencing (WES) is the state of the art next generation sequencing technique to identify genetic defects in mitochondrial disorders. Until recently it has mainly been used as a research tool. In this study, the use of WES in routine diagnostics is described. The WES data of 109 patients, referred under the suspicion of a mitochondrial disorder, were examined in two steps. First, the data were filtered using a virtual gene panel of genes known to be associated with mitochondrial disease. If negative, the entire exome was examined. A molecular diagnosis was achieved in 39 % of the heterogeneous cohort, and in 57 % of the subgroup of 42 patients with the highest suspicion for a mitochondrial disease. In addition to mutations in genes known to be associated with mitochondrial disorders (e.g. TUFM, MTFMT, FBXL4), in the subgroup of patients with the lowest suspicion for a mitochondrial disorder we found mutations in several genes associated with neuromuscular disorders (e.g. SEPN1, ACTA1) and genetic syndrome (e.g. SETBP1, ARID1B). Our results show that WES technology has been successfully implemented as a state-of-the-art, molecular diagnostic test for mitochondrial disorders as well as for the mimicking disorders in daily clinical practice. It also illustrates that clinical and biochemical phenotyping is essential for successful application of WES to diagnose individual patients.

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Section: Discussionmentioning

confidence: 99%

Whole exome sequencing of suspected mitochondrial patients in clinical practice

Wortmann

Koolen

Smeitink

et al. 2015

J of Inher Metab Disea

194

198

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“…Until now, PC deficiency has not been described as a possible cause of secondary MRC deficiency except in one case of holocarboxylase synthetase deficiency [12] . However other diseases with secondary MRC defect have been described including pyruvate dehydrogenase (PDHc) deficiency (OMIM 312170 ), which is the most frequently reported one [12] , fatty acid oxidation defects [13] , [14] , [15] , [16] , neonatal hemochromatosis (OMIM 231100 ) [12] , [17] , pantothenate kinase deficiency (OMIM 606157 ) [12] , holocarboxylase synthetase deficiency (OMIM 253270 ) [12] , molybdenum cofactor deficiency [9] , spino-cerebellar ataxia type 7 (OMIM 164500 ) [18] , [19] , Menkes disease (OMIM 309400 ) [20] , [21] , Wilson disease (OMIM 277900 ) [17] , OTC deficiency (OMIM 311250 ) [17] , progressive familial intrahepatic cholestasis type 2 (OMIM 601847 ) [22] , hereditary spastic paraparesis type 7 (OMIM 607259 ) [23] , Fanconi–Bickel syndrome (OMIM 227810 ) [24] , autism spectrum disorder (ASD) [25] , [26] and more recently organic acidurias [27] , [28] .…”

Section: Discussionmentioning

confidence: 99%

Pyruvate carboxylase deficiency: An underestimated cause of lactic acidosis

Habarou

Brassier

Rio

et al. 2015

Molecular Genetics and Metabolism Reports

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Pyruvate carboxylase (PC) is a biotin-containing mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in gluconeogenesis and in energy production through replenishment of the tricarboxylic acid (TCA) cycle with oxaloacetate. PC deficiency is a very rare metabolic disorder. We report on a new patient affected by the moderate form (the American type A). Diagnosis was nearly fortuitous, resulting from the revision of an initial diagnosis of mitochondrial complex IV (C IV) defect. The patient presented with severe lactic acidosis and pronounced ketonuria, associated with lethargy at age 23 months. Intellectual disability was noted at this time. Amino acids in plasma and organic acids in urine did not show patterns of interest for the diagnostic work-up. In skin fibroblasts PC showed no detectable activity whereas biotinidase activity was normal. We had previously reported another patient with the severe form of PC deficiency and we show that she also had secondary C IV deficiency in fibroblasts. Different anaplerotic treatments in vivo and in vitro were tested using fibroblasts of both patients with 2 different types of PC deficiency, type A (patient 1) and type B (patient 2). Neither clinical nor biological effects in vivo and in vitro were observed using citrate, aspartate, oxoglutarate and bezafibrate. In conclusion, this case report suggests that the moderate form of PC deficiency may be underdiagnosed and illustrates the challenges raised by energetic disorders in terms of diagnostic work-up and therapeutical strategy even in a moderate form.

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“…Patient A carries two heterozygous pathogenic variants, c.1408C>T(p.R470*) and c.3945delC(p.T1316Lfs*64), in the ABCB11 gene. The c.1408C>T variant is a previously reported nonsense mutation that abolishes ABCB11 protein expression (29, 30). The c.3945delC variant is predicted to cause frameshift that eliminates the stop codon and extends the open reading frame of the mutant allele for 57 extra amino acids.…”

Section: Resultsmentioning

confidence: 99%

“…The c.1408C>T variant is a previously reported nonsense mutation that abolishes ABCB11 protein expression. (29,30) The c.3945delC variant is predicted to cause frameshift that eliminates the stop codon and extends the open reading frame of the mutant allele for 57 extra amino acids. The resulting mutant protein is predicted to preserve all of the transmembrane and nucleotide binding domains.…”

Section: Abcb11b Mutant Zebrafish Exhibited Hepatocellular Injury Simmentioning

confidence: 99%

Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency

et al. 2018

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Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis

Abstract: Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and often result in hepatic failure.

Cited by 8 publications

References 12 publications

Whole exome sequencing of suspected mitochondrial patients in clinical practice

Whole exome sequencing of suspected mitochondrial patients in clinical practice

Pyruvate carboxylase deficiency: An underestimated cause of lactic acidosis

Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency

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