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.

Keywords:

• ERLIN2
• MFN2
• spastic paraplegia 18 (SPG18)
• charcot–marie–tooth disease type 2A (CMT2A)
• whole exome sequencing (WES)

Acknowledgement

We thank the patients and their family members for participating in the study.

Ethical approval

All participants, after being informed of the nature of the research, consented to participate. This research was performed in accordance with the Declaration of Helsinki and with approval of the ethics board of the University of Social Welfare and Rehabilitation Sciences (IR.USWR.REC.1400.053).

Disclosure statement

All authors claim absence of financial interests and absence of non-financial interests that are directly or indirectly related to the manuscript submitted for publication.

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Additional information

Funding

We acknowledge the University of Social Welfare and Rehabilitation Sciences for funding the research (Grant number: 2592).