Selenium, a trace element that is essential for human health, is in corporated as selenocysteine (Sec) into 25 different human proteins, including the deiodinase enzymes. A complex molecular mechanism mediates Sec incorporation into proteins during their biosynthesis (Figure1); consequently, genetic defects in this pathway result in a multisystem disorder due to deficiency of di verse selenoproteins, with lack of deiodinase activities mediating abnormal thyroid function.
Fig1. Mechanism of selenoprotein biosynthesis. The 3’- untranslated region of selenoprotein mRNAs contains a stem- loop RNA structure (SECIS element) which interacts with a protein complex that includes SECIS binding protein 2 (SECISBP2) and Sec- specific elongation factor (eEFSec), to enable ribosomal recruitment of selenocysteyl- transfer RNA (tRNASec) to the UGA codon and incorporation of selenocysteine (Sec) into the nascent polypeptide. Failure of this mechanism results in miscoding of the UGA as a stop codon, terminating protein synthesis.
Clinical Features
Many cases have presented in childhood due to growth retardation with raised circulating fT4, normal to low fT3, and raised reverse T3 levels, reflecting deficiency of all three deiodinase enzymes.
Muscle weakness due to progressive rigid spine muscular dystrophy, affecting axial and proximal limb muscles with raised creatine kinase (CK) levels and fatty infiltration on MRI scan, is attributable to deficiency of selenoprotein N which is enriched in skeletal muscle. Male azoospermic infertility reflects loss of specific selenoproteins (e.g. mitochondrial GPx4, thioredoxin- glutathione reductase, selenoprotein V) required for spermatogenesis.
Lack of antioxidant selenoenzymes results in cellular accumulation of hydrogen peroxide and reactive oxygen species (ROS), mediating with oxidative DNA damage and peroxidation of membrane lipids. Clinical consequences of raised cellular ROS include skin photosensitivity, sensorineural hearing loss which worsens with age and increased total body adipose tissue mass, but associated paradoxically with preserved or enhanced systemic insulin sensitivity. We have documented significant, progressive dilatation of the ascending aorta due to cystic medial degeneration requiring cardiac surgery in older patients.
Additional age- dependent phenotypes such as neurodegeneration, premature ageing or neoplasia may emerge, but have not been described hitherto.
Molecular Genetics
To date, 13 individuals from 11 families, with compound heterozygous or homozygous SECISBP2 defects have been described; residual production of functional SBP2 protein likely preserves some selenoprotein synthesis and precludes the disorder being embryonic lethal, as occurs in secisbp2 knockout mice. As SBP2 is differentially rate- limiting for Sec incorporation into different proteins, a hierarchy of selenoprotein synthesis preserves production of essential, cellular housekeeping selenoproteins (e.g. thioredoxin reductases) at the expense of other factors (e.g. deiodinases) that are dispensable for survival.
In one patient, a homozygous mutation in TRU- TCA1- 1, affecting synthesis and posttranscriptional modification of selenocysteine transfer ribonucleic acid (RNA), has been described.
Mutations in SEPSECS, an enzyme mediating synthesis of tRNAsec, are associated with cerebrocerebellar atrophy and a pro found neurological phenotype due to disruption of selenoprotein synthesis in the CNS, but are not associated with a thyroid bio chemical phenotype.
Management Oral selenium supplementation raises circulating selenium levels but with no effect on circulating selenoprotein or TH levels. T3 treatment can improve growth in childhood; antioxidant (vitamin E) administration reduces cellular lipid peroxidation but other clinical effects have not been determined.
