A case report of concurrent occurrence of two inherited axonopathies within a family: the benefit of whole-exome sequencing.

Abstract

Mutations in ERLIN2 and MFN2 lead to the development of spastic paraplegia-18 (SPG18) and Charcot-Marie-Tooth type-2A (CMT2A), respectively. These disorders are unified by the fact that both can be termed inherited axonopathies. With whole-exome sequencing (WES), more patients of neurological disorders with clinical overlaps receive a genetic result than ever before. This study describes an Iranian family who harbor mutations in ERLIN2 and MFN2, simultaneously. The proband was a 73-year old man who has experienced weakness and spasticity of lower limbs since late childhood. He was diagnosed with hereditary spastic paraplegia (HSP). His WES identified a novel homozygous variant in ERLIN2 as well as a known heterozygous variant in MFN2. These variants were cosegregated with the phenotypes among the family members. His sister with a similar phenotype just carried the homozygous ERLIN2 variant, whereas, his asymptomatic brother and daughter carried the heterozygous variant of MFN2. Re-evaluation of the MFN2 variant carriers by nerve conduction study revealed that only the proband's daughter has peripheral neuropathy. Herein, using WES two distinct disease-causing variants with different modes of inheritance in ERLIN2 and MFN2 were detected in the proband. As expected, individuals with a defined MFN2 variant, p.Arg468His, were asymptomatic or had a mild phenotype. The co-occurrence of such diseases, SPG18 and CMT2A, may result in the milder phenotype to be overlooked or its features considered as a part of the symptoms of other disease. Certainly, providing genetic counseling in such cases can be challenging. These cases reveal the importance of WES.