Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance.

Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material.

Long-term effect on body composition and metabolic parameters after treatment with recombinant human growth hormone (r-hGH) in HIV-1 infected patients with lipodystrophy.

Several studies have shown reduction of visceral adipose tissue (VAT) using recombinant human growth hormone (r-hGH) in HIV-1+ patients, but whether these effects are maintained after the end of treatment is unknown. In a prospective, randomized study we previously studied the effects of r-hGH 4 mg daily vs 3 times/week over 12 weeks, followed by a 2 mg daily maintenance dose for an additional 12 weeks. T1 weighted MRI flash sequences were performed of the face, abdomen and at mid-thigh level (MTF) at baseline, week 12, week 24 and at follow-up. Of 20 subjects who completed the 24-week study, follow-up is available for 16 patients (15 male, mean age 44.8 y, mean duration of HIV infection 13.5 y). After a median time of follow-up of 9 months, VAT remained overall 18% below baseline level (p =0.005). MTF was significantly reduced by 12% compared to its baseline level (p =0.03). Fasting glucose levels significantly improved by 21% compared to baseline (p =0.006). These results suggest that the achieved reduction of VAT using r-hGH in lipodystrophic HIV+ patients is in part maintained after a median follow-up of 9 months.