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Abstract
Objective: We aimed to decipher the molecular genetic basis of disease in a cohort of children with a uniform clinical presentation of neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate.
Methods: We performed whole-exome sequencing of blood DNA from the index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions and a bacterial activity assay were performed to evaluate the functional consequences of the mutations. Mass spectrometry, Western blotting, and protein oxidation detection were used to analyze the effects of selenoprotein deficiency.
Results: Neuropathology indicated laminar necrosis and severe loss of myelin, with neuron loss and astrogliosis. In 3 families, we identified a missense (p.Thr325Ser) and a nonsense (p.Tyr429*) mutation in SEPSECS, encoding the O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, which was previously associated with progressive cerebellocerebral atrophy. We show that the mutations do not completely abolish the activity of SEPSECS, but lead to decreased selenoprotein levels, with demonstrated increase in oxidative protein damage in the patient brain.
Conclusions: These results extend the phenotypes caused by defective selenocysteine biosynthesis, and suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation.
GLOSSARY
- PCH2D=
- pontocerebellar hypoplasia type 2D;
- PEHO=
- progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy;
- RC=
- respiratory chain;
- SRM-MS=
- selected reaction monitoring–mass spectrometry;
- T4=
- thyroxine;
- tRNA=
- transfer RNA;
- TSH=
- thyroid-stimulating hormone;
- T3=
- triiodothyronine
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Supplemental data at Neurology.org
- Received November 17, 2014.
- Accepted in final form March 26, 2015.
- © 2015 American Academy of Neurology
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