Leukoencephalopathy with accumulated succinate is indicative of SDHAF1 related complex II deficiency
Andreas Ohlenbusch1, Simon Edvardson, Johannes Skorpen
1Department of Pediatrics and Pediatric Neurology, Georg August University, Robert Koch Str, 40, Göttingen, 37075, Germany. aohlenb@gwdg.de
Background:
Deficiency of complex II (succinate dehydrogenase, SDH) represents a rare cause of mitochondrial disease and is associated with a wide range of clinical symptoms. Recently, mutations of SDHAF1, the gene encoding for the SDH assembly factor 1, were reported in SDH-defective infantile leukoencephalopathy. Our goal was to identify SDHAF1 mutations in further patients and to delineate the clinical phenotype.
Methods:
In a retrospective data collection study we identified nine children with biochemically proven complex II deficiency among our cohorts of patients with mitochondrial disorders. The cohort comprised five patients from three families affected by SDH-defective infantile leukoencephalopathy with accumulation of succinate in disordered cerebral white matter, as detected by in vivo proton MR spectroscopy. One of these patients had neuropathological features of Leigh syndrome. Four further unrelated patients of the cohort showed diverse clinical phenotypes without leukoencephalopathy. SDHAF1 was sequenced in all nine patients.
Results:
Homozygous mutations of SDHAF1 were detected in all five patients affected by leukoencephalopathy with accumulated succinate, but not in any of the four patients with other, diverse clinical phenotypes. Two sisters had a mutation reported previously, in three patients two novel mutations were found.
Conclusion:
Leukoencephalopathy with accumulated succinate is a key symptom of defective complex II assembly due to SDHAF1 mutations.
Insights
Mutations in the SDHAF1 gene cause complex II deficiency, leading to infantile leukoencephalopathy with succinate accumulation. This finding links SDHAF1 mutations to a specific mitochondrial disease presentation.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Complex II (succinate dehydrogenase, SDH) deficiency is a rare mitochondrial disorder with varied symptoms.
- SDHAF1 gene mutations have been linked to SDH-defective infantile leukoencephalopathy.
- The clinical spectrum and genetic basis of SDH deficiency require further elucidation.
Purpose of the Study:
- To identify SDHAF1 mutations in patients with complex II deficiency.
- To define the clinical phenotype associated with SDHAF1 mutations.
- To investigate the role of SDHAF1 in mitochondrial complex assembly.
Main Methods:
- Retrospective analysis of nine children with biochemically confirmed complex II deficiency.
- Genetic sequencing of the SDHAF1 gene in all patients.
- In vivo proton MR spectroscopy to detect succinate accumulation in cerebral white matter.
Main Results:
- Homozygous SDHAF1 mutations were found in five patients with leukoencephalopathy and succinate accumulation.
- No SDHAF1 mutations were detected in four patients with diverse clinical phenotypes.
- Two known and two novel SDHAF1 mutations were identified.
Conclusions:
- SDHAF1 mutations are a significant cause of complex II assembly defects.
- Leukoencephalopathy with succinate accumulation is a key clinical feature of SDHAF1-related mitochondrial disease.
- Genetic testing of SDHAF1 is crucial for diagnosing this specific form of mitochondrial disorder.
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