Combined D2-/L2-hydroxyglutaric aciduria: An intermediate phenotype with myasthenia gravis crises and response to citrate treatment

Abstract

Background: Combined D2-/L2-hydroxyglutaric aciduria (DL-2HGA) (OMIM #615182) is caused by pathogenic mutations in the SLC25A1 gene which encodes the mitochondrial citrate carrier (CIC). It is usually lethal in the first years of life, although a sibling pair, who manifested with milder congenital myasthenia gravis has been reported. Aims: To describe the clinical, molecular, and biochemical features of a child with an intermediate phenotype and his response to citrate replacement. History, Methods, Results: The patient was diagnosed biochemically at 3 months of age during an acute life-threatening apnoea. At 7 years of age he has significant global developmental delay, with diurnal fatigability in upper and lower limb function and bilateral ptosis, which were more prominent during an intercurrent illness. Supplementation with citrate (800 mg/kg/day) commenced at age 5.5 years of age. Prior to this he had 6 acute life-threatening events of central apnoea with respiratory arrests needing aggressive resuscitation, during intercurrent infective illnesses. LC-MSMS demonstrated elevated D-2-HG 81 μmol/mmol creatinine (RR < 9.3) and L-2-HG 53 μmol/mmol creatinine (RR <10.8). SLC25A1 sequencing identified c.844C>T; p.Arg282Cy and c.605T>C; p.Met202Thr. Discussion/ Conclusion: Depletion of cytosolic citrate and accumulation of mitochondrial citrate inside mitochondria play key roles in the pathophysiology of DL-2HGA, CIC mediates efflux of the mitochondrial citrate and isocitrate for cytosolic malate. SLC25A1 knockdown zebrafish demonstrate neuromuscular junction impairment, indicating a key role for CIC in normal neuromuscular presynaptic function. Our patient represents an intermediate phenotype characterized by episodes of myasthenic crisis during intercurrent illness, which have been averted by citrate supplementation.L6298898692019-11-22 <br />