Characterization of a patient-derived variant of GPX4 for precision therapy.

Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.

To Be or No B2: A Rare Cause of Stridor and Weakness in a Toddler.

We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.