Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation

Wortmann, Saskia B.; Rodenburg, Richard J.; Huizing, Marjan; Loupatty, Ference J.; Koning, Tom de; Kluijtmans, Leo A. J.; Engelke, Udo F. H.; Wevers, Ron A.; Smeitink, Jan A.M.; Morava, Éva

doi:10.1016/j.ymgme.2006.01.013

Cited by 60 publications

(43 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2006, we reported four patients with a distinct clinical phenotype called MEGDEL association (Wortmann et al 2006). These patients presented with neuroradiological evidence of Leigh disease, sensorineural hearing loss, recurrent lactic academia, severe neonatal infections, and hypoglycemia.…”

Section: -Mga-uria Type IV (Mim 250951)mentioning

confidence: 99%

The 3‐methylglutaconic acidurias: what's new?

Wortmann

Kluijtmans

Engelke

et al. 2010

J of Inher Metab Disea

View full text Add to dashboard Cite

The heterogeneous group of 3-methylglutaconic aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction.

show abstract

Section: -Mga-uria Type IV (Mim 250951)mentioning

confidence: 99%

The 3‐methylglutaconic acidurias: what's new?

Wortmann

Kluijtmans

Engelke

et al. 2010

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…Neurodegeneration in mitochondrial disease is correlated clinically with an increased incidence of upper respiratory tract infections and other common infections (Naviaux, 1999). Other reports have indicated that children and adults with mitochondrial disorders have a high risk of recurrent infection (Edmonds et al, 2002;Edmonds, 2004;Wortmann et al, 2006). Furthermore, recurrent infection has been reported in individuals with specific mitochondrial diseases such as Kearns-Sayre syndrome (Katsanos et al, 2002) and Pearson syndrome (Lacbawan et al, 2000).…”

Section: Dmmbiologistsorg 484mentioning

confidence: 99%

“…Depending on which tissues are affected most severely, the phenotypic outcomes are diverse and can include diabetes, blindness, deafness, stroke-like episodes, epilepsy, ataxia, muscle weakness, exercise intolerance and kidney disease (Wallace et al, 1988;Goto et al, 1992;Tatuch and Robinson, 1993;Mackey et al, 1996;Geromel et al, 2001;Rossignol et al, 2003;McKenzie et al, 2004). A number of reports suggest that mitochondrial disease patients are more susceptible to recurrent bacterial infections, particularly of the respiratory tract (Lacbawan et al, 2000;Edmonds et al, 2002;Katsanos et al, 2002;Ogawa et al, 2003;Edmonds, 2004;Wortmann et al, 2006). However, the mechanisms that underlie such increased susceptibility have not been studied and are not understood.…”

Section: Introductionmentioning

confidence: 99%

Legionella pneumophilamultiplication is enhanced by chronic AMPK signalling in mitochondrially diseased Dictyostelium cells

Francione

Smith

Accari

et al. 2009

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

SUMMARYHuman patients with mitochondrial diseases are more susceptible to bacterial infections, particularly of the respiratory tract. To investigate the susceptibility of mitochondrially diseased cells to an intracellular bacterial respiratory pathogen, we exploited the advantages of Dictyostelium discoideum as an established model for mitochondrial disease and for Legionella pneumophila pathogenesis. Legionella infection of macrophages involves recruitment of mitochondria to the Legionella-containing phagosome. We confirm here that this also occurs in Dictyostelium and investigate the effect of mitochondrial dysfunction on host cell susceptibility to Legionella. In mitochondrially diseased Dictyostelium strains, the pathogen was taken up at normal rates, but it grew faster and reached counts that were twofold higher than in the wild-type host. We reported previously that other mitochondrial disease phenotypes for Dictyostelium are the result of the activity of an energy-sensing cellular alarm protein, AMP-activated protein kinase (AMPK). Here, we show that the increased ability of mitochondrially diseased cells to support Legionella proliferation is suppressed by antisense-inhibiting expression of the catalytic AMPKα subunit. Conversely, mitochondrial dysfunction is phenocopied, and intracellular Legionella growth is enhanced, by overexpressing an active form of AMPKα in otherwise normal cells. These results indicate that AMPK signalling in response to mitochondrial dysfunction enhances Legionella proliferation in host cells.

show abstract

“…Besides these well-defined forms of MGTA, an unclassified group known as type IV has been reported in many patients presenting variable psychomotor retardation, spasticity, hypertonicity and cardiomyopathy (Gibson et al, 1991Gunay-Aygun, 2005). Some MGTA patients have elevated lactic acid or citric acid cycle intermediates, as well as abnormalities of the mitochondrial electron transport chain (Ibel et al, 1993;Besley et al, 1995;Ruesch et al, 1996), including deficiency of the activities of respiratory chain complexes I, II, III, IV and V Sweetman and Williams, 2001;Gunay-Aygun, 2005;Wortmann et al, 2006), strongly indicating mitochondrial dysfunction.…”

mentioning

confidence: 99%