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Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients
Ist Teil von
Journal of inherited metabolic disease, 2016-03, Vol.39 (2), p.243-252
Ort / Verlag
Dordrecht: Springer Netherlands
Erscheinungsjahr
2016
Quelle
Wiley-Blackwell Full Collection
Beschreibungen/Notizen
Background
The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in
SUCLA2
or
SUCLG1
. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.
Patients and results
Of the 71 patients, 50 had
SUCLA2
mutations and 21 had
SUCLG1
mutations. In the newly-reported 20
SUCLA2
patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported
SUCLG1
patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with
SUCLA2
mutations and at birth for
SUCLG1
patients. Median survival was 20 years for
SUCLA2
and 20 months for
SUCLG1
. Notable clinical differences between the two groups were hepatopathy, found in 38 % of
SUCLG1
cases but not in
SUCLA2
cases, and hypertrophic cardiomyopathy which was not reported in
SUCLA2
patients, but documented in 14 % of cases with
SUCLG1
mutations. Long survival, to age 20 years or older, was reported in 12 % of
SUCLA2
and in 10 % of
SUCLG1
patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of
SUCLA2
and 80 % of
SUCLG1
patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found.
Conclusions
To our knowledge, this is the largest study of patients with
SUCLA2
and
SUCLG1
deficiency. The most important findings were a significantly longer survival in patients with
SUCLA2
mutations compared to
SUCLG1
mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with
SUCLG1
mutations, whereas epilepsy was much more frequent in patients with
SUCLA2
mutations compared to patients with
SUCLG1
mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire
SUCLA2
gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known
SUCLA2
founder mutation in the Faroe Islands.