Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

Julian Theuriet,Sandra Vukusic,Antoine Pegat,Cécile Cazeneuve,Pascal Leblanc,Stéphanie Millecamps,Emilien Bernard,Marine Guillaud-Bataille,Guillaume Banneau

doi:10.3390/genes12121876

Abstract

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.

Highlights

Academic Editor: Abstract: Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5)
We report for the first time the occurrence of fatal amyotrophic lateral sclerosis/frontotemporal dementia (ALS/fronto-temporal dementia (FTD)) in a 67-year-old patient suffering from
The patient developed a progressive lower limb spasticity during childhood associated with pyramidal signs on the lower limbs; this led to the diagnosis of Hereditary spastic paraplegia (HSP) in early adulthood

Summary

Proband

The patient developed a progressive lower limb spasticity during childhood associated with pyramidal signs on the lower limbs; this led to the diagnosis of HSP in early adulthood He reported a progressive deterioration of spasticity, leading to the implantation of intrathecal baclofen pump at the age of 56 years and to the need for a walking aid at the age of 66 years. Diagnosis of ALS was made according to Gold Coast criteria [10]; riluzole 50 mg twice a day was introduced He became wheelchair-bound at the age of 69 years. The same year, cognitive disorders including executive functions impairment and behavior disorders such as socially inappropriate behavior, apathy, and binge eating were noted, associated with diffuse cortical atrophy on MRI, suggesting a probable associated fronto-temporal dementia (FTD). He died from a pulmonary infection the same year

Molecular Genetic Analyses

Conclusions