Concurrent Cobalamin C and Plasminogen Deficiencies in a Patient with Chronic Thrombotic Microangiopathy

Abstract

<b><i>Background:</i></b> Although most patients with atypical hemolytic uremic syndrome (aHUS) have variants in genes participating in alternative complement pathways, rare variants in non-complement pathway-related genes, including <i>DGKE, INF2, MMACHC, PLG,</i> and <i>THBD</i>, have also been described. <b><i>Case Presentation:</i></b> We report an 18-year-old male patient with renal biopsy-proven chronic thrombotic microangiopathy that raised suspicion of aHUS. Whole-exome sequencing revealed a novel pathogenic homozygous <i>MMACHC</i> c.484G&gt;T (p.Gly162Trp) variant. Subsequently, clinical and laboratory findings confirmed cobalamin C (Cbl C) deficiency. Also, homozygous missense c.1112C&gt;T <i>PLG</i> (p.Thr371Ile) variant was detected (it had been reported as a variant of unknown significance). However, the low serum plasminogen (PLG) activity proved the pathogenicity of c.1112C&gt;T. Hence, the patient was diagnosed with concurrent Cbl C and PLG deficiencies. Segregation analysis revealed that the mother and father had the same heterozygous <i>PLG</i> and <i>MMACHC</i> variants. <i>PLG</i> variants have generally been described in aHUS patients concomitant with complement gene variants in the literature; therefore, the association between aHUS and <i>PLG</i> variants is controversial. The possible contribution of PLG deficiency to thrombotic microangiopathy was also discussed in this case. <b><i>Conclusion:</i></b> Non-complement-mediated aHUS is an exceptional disorder. A limited number of genes are involved in this entity. To our knowledge, this is the first aHUS patient diagnosed with both Cbl C and PLG deficiencies in the literature.