A Novel Cause of CIDP: Homozygous Hotspot Mutation, c.793 C > T in CASP8 Gene.

Abstract

Background: Caspase-8 enzyme deficiency (CED) is a rare autosomal recessive inborn error of immunity with autoimmune lymphoproliferative syndromes (ALPS), deficient extrinsic apoptosis and hyperactivation of the mammalian target of rapamycin (mTOR) pathway.

Methods: Features of our patient with early onset chronic inflammatory demyelinating polyneuropathy (CIDP) are presented in detail. We report features of ALPS due to CED (ALPS-CED) in 6 patients in previous literature and our patient with the homozygous hotspot mutation, c.793 C > T in the CASP8 gene, and demonstrate that such mutation is a novel cause of CIDP.

Results: Our patient fits the spectrum of genetic disorders causing ALPS with dysregulation of the mTOR pathway. Autoimmune lymphoproliferative syndrome with FAS mutations (ALPS-FAS) is also associated with hyperactivation of the mTOR pathway but hematologic symptoms are more severe than ALPS-CED. Both ALPS-FAS and ALPS-CED lead to autoimmunity and improve with use of mTOR inhibitors. ALPS-FAS is characterized by the elevation of alpha beta-double negative T-cells (DNT) and hypergammaglobulinemia, while such features are not prominent in ALPS-CED. Patients with ALPS-CED not only suffer from ALPS but also present with an immune deficiency and a chronic inflammatory state both related to non-apoptotic functions of caspase-8.

Conclusions: Both ALPS-FAS and ALPS-CED are characterized by deficient extrinsic apoptosis and dysregulation of the mTOR pathway. Compared to ALPS-FAS, the phenotype of ALPS-CED is more complex due to a more diffuse dysfunction of the non-apoptotic pathways. To our knowledge, early onset CIDP in a patient with homozygous hotspot mutation, c.793 C > T in CASP8, has not been reported previously.