Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients

@article{Carrozzo2015SuccinateCoALD,
  title={Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients},
  author={Rosalba Carrozzo and Daniela Verrigni and M Rasmussen and Ren{\'e} de Coo and Hernan M. Amartino and Marzia Bianchi and Daniela Buhas and Samir Mesli and Karin Naess and Alfred Peter Born and Berit Woldseth and Paolo Prontera and Mustafa Batbayli and Kirstine Ravn and Frodi Joensen and Duccio Maria Cordelli and Filippo Maria Santorelli and M{\'a}r H. Tulinius and Niklas Dar{\'i}n and M. Duno and Philippe Jouvencel and Alberto Burlina and Gabriela Stangoni and Enrico Silvio Bertini and Isabelle Redonnet-vernhet and Flemming Wibrand and Carlo Dionisi-Vici and Johanna Uusimaa and P{\"a}ivi Vieira and Andr{\'e}s Nascimento Osorio and Robert Mcfarland and Robert W. Taylor and Elisabeth Holme and Elsebet Ostergaard},
  journal={Journal of Inherited Metabolic Disease},
  year={2015},
  volume={39},
  pages={243-252}
}
BackgroundThe encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. [...] Key MethodPatients and resultsOf the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations.Expand
Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder.
TLDR
The results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization ofSUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.
Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion.
TLDR
Although it is shown that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM, and a better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of mitochondrial enzymes of oxidative metabolism, and independently mitochondrial DNA depletion (common in other cases of A-SCS deficiency), is needed.
Co‐occurring Down syndrome and SUCLA2‐related mitochondrial depletion syndrome
TLDR
This report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21, a rare autosomal recessive disorder caused by homozygous p.Arg284Cys pathogenic variants in SUCLA2.
SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease
TLDR
It is shown that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl -CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation.
SUCLG1 mutations and mitochondrial encephalomyopathy: a case study and review of the literature.
TLDR
A novel, homozygote missense variant chr2: 84676796 A > T in the SUCLG1 gene is identified that the mutation might explain the observed phenotype in the family, and the mutated position in the genome is well conserved in mammalians.
Germline SUCLG2 Variants in Patients with Pheochromocytoma and Paraganglioma.
TLDR
This study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL, and large-scale sequencing may uncover additional cases harboring SU CLG2 variants and provide more detailed information about their prevalence and penetrance.
Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations
TLDR
It is concluded 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.
Phenotypic variability in deficiency of the α subunit of succinate‐CoA ligase
TLDR
An individual with a novel biallelic pathogenic mutation in SUCLG1 is described with a less severe phenotype dominated by behavioral problems, and liquid chromatography tandem mass spectrometry‐based enzyme activity assay revealed a markedly reduced activity of succinyl‐CoA synthetase enzyme when both ATP and GTP were substrates.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 43 REFERENCES
The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein
TLDR
The results suggest that SUCLG1 mutations that lead to complete absence of SU CLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLg1 protein.
The novel mutation p.Asp251Asn in the β-subunit of succinate-CoA ligase causes encephalomyopathy and elevated succinylcarnitine
SUCLA2 is one of several nuclear-encoded genes that can cause encephalomyopathy accompanied by mitochondrial DNA depletion. The disorder usually manifests in early childhood and leads to early death.
A SUCLG1 mutation in a patient with mitochondrial DNA depletion and congenital anomalies
TLDR
A patient with fatal infantile lactic acidosis and multiple congenital anomalies (MCAs) including renal and cardiac defects is described and it is unclear whether the MCAs observed in this patient are a result of the SUCLG1 mutation or alterations in a second gene.
Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion
TLDR
A homology model for human succinyl-CoA synthetase was made and predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations of SUCLA2, and the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme.
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness.
TLDR
In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands and the findings on this inborn error of metabolism in the TCA cycle are confirmed.
A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria
TLDR
A patient is reported with a novel homozygous missense mutation in SUCLG1, whose phenotype is similar to that of patients with SUCLA2 mutations.
Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations.
TLDR
12 patients with autosomal recessive mitochondrial encephalomyopathy with elevated methylmalonic acid were identified, and some of the patients fulfilled the criteria for Leigh syndrome, and a novel splice site mutation in SUCLA2 was identified leading to skipping of exon 4.
A Novel SUCLA2 Mutation in a Portuguese Child Associated With “Mild” Methylmalonic Aciduria
TLDR
Expanding the array of SUCLA2 mutations, it is suggested that reactive oxygen species scavengers are likely to impact on disease prognosis.
A novel homozygous mutation in SUCLA2 gene identified by exome sequencing
New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria.
TLDR
The report enlarges the phenotypic spectrum of SUCLG1 mutations and confirms that a characteristic metabolic profile and basal ganglia MRI lesions are the hallmarks of SCS defects, suggesting that diagnosis should not be based on it, but also that alternative physiopathological mechanisms may be considered to explain the combined respiratory chain deficiency observed in SCS patients.
...
1
2
3
4
5
...