SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature)

Maas, Roeltje R.; Marina, Adela Della; Brouwer, Arjan P.M. de; Wevers, Ron A.; Rodenburg, Richard J.; Wortmann, Saskia B.

doi:10.1007/8904_2015_464

Cited by 8 publications

(7 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, 51 patients have been reported with SUCLA2 deficiency [6,7,20,24,29,41,44,46,49,50,52,54], and 21 patients with SUCLG1 deficiency, due to different mutations [7]. Patients with SUCLG1 mutations may have an extremely severe phenotype with antenatal manifestations of the disorder, severe acidosis with lactic aciduria in the first day of life and death within 2–4 days [53] or a phenotype similar to those of patients with SUCLA2 mutations.…”

Section: Introductionmentioning

confidence: 99%

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Kacso

Ravasz

Dóczi

et al. 2016

Biochemical Journal

View full text Add to dashboard Cite

Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.

show abstract

Section: Introductionmentioning

confidence: 99%

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Kacso

Ravasz

Dóczi

et al. 2016

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Such finding seems to suggest that SCS A-β is critical for neuronal physiology. This has been supported by further clinical observations that mutations in SUCLA2 cause loss of SCS A-β function resulting in lethal neurological disorders including infantile Leigh or Leigh-like syndrome 5 – 7 . Furthermore, SUCLA2 +/− mice demonstrated pronounced brain mitochondrial dysfunction 8 .…”

Section: Introductionmentioning

confidence: 64%

Loss of succinyl-CoA synthase ADP-forming β subunit disrupts mtDNA stability and mitochondrial dynamics in neurons

Zhao

Tian

Sui

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Succinyl Coenzyme A synthetase (SCS) is a key mitochondrial enzyme. Defected SCS ADP-forming β subunit (SCS A-β) is linked to lethal infantile Leigh or leigh-like syndrome. However, the impacts of SCS A-β deficiency on mitochondria specifically in neurons have not yet been comprehensively investigated. Here, by down-regulating the expression levels of SCS A-β in cultured mouse neurons, we have found that SCS A-β deficiency induces severe mitochondrial dysfunction including lowered oxidative phosphorylation (OXPHOS) efficiency, increased mitochondrial superoxide production, and mtDNA depletion as well as aberrations of mitochondrial fusion and fission proteins, which eventually leads to neuronal stress. Our data also suggest that the deregulation of mitochondrial nucleoside diphosphate kinase (NDPK) together with defects in mitochondrial transcription factors including mitochondrial DNA pol γ and Twinkle contribute to SCS A-β deficiency-mediated mtDNA instability. Furthermore, we have found that SCS A-β deficiency has detrimental influence on neuronal mitochondrial dynamics. Put together, the results have furnished our knowledge on the pathogenesis of SCS A-β deficiency-related mitochondrial diseases and revealed the vital role of SCS A-β in maintaining neuronal mitochondrial quality control and neuronal physiology.

show abstract

“…Visual analysis of the structures (Fig. 3 ) showed that both loci fell near the protein’s “phosphate shuttle” loop [ 18 ], indicating that the replacement of the wild-type residue might interfere with the functional role of this loop. This was particularly noticeable for Gly326, which lies in close contact with residue His299 of the loop, and occurs at a packed location in the structure.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, the mitochondrial dysfunction in deficient fibroblasts from P24 was rescued via the stable expression of the SUCLA2 protein through lentiviral transduction. This suggests that SUCLA2 is the gene likely affected in this patient, although his/her symptoms were atypical [ 18 , 38 ]. With respect to ASCF3 , individuals P24, P25, P26 and P27 were diagnosed as having isolated MMA since the urinary malonic acid that identifies CMAMMA can be easily missed [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…The accumulated succinyl-CoA inhibits the metabolism of MMACoA to succinyl-CoA, leading to the accumulation of MMA in body fluids. Mutations in SUCLA2 give rise to typical (though rare) early onset dystonia combined with deafness [ 18 , 19 ]. An increase in MMA is also seen in patients with mutations in ACSF3 (MIM# 614265), in whom malonic acid levels may also be elevated (combined malonic and methylmalonic aciduria, CMAMMA) [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants

Brasil

Leal

Vega

et al. 2018

Orphanet J Rare Dis

View full text Add to dashboard Cite

BackgroundCellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.ResultsThis paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants.ConclusionsThe present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0862-y) contains supplementary material, which is available to authorized users.

show abstract

SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature)

Cited by 8 publications

References 19 publications

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Loss of succinyl-CoA synthase ADP-forming β subunit disrupts mtDNA stability and mitochondrial dynamics in neurons

Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants

Contact Info

Product

Resources

About