A Novel Homozygous Deletion Including Exon 1 of FA2H Gene Causes Spastic Paraplegia-35: Genetic and Lipidomics Analysis of the Patients

Abstract

Objective

Fatty acid 2-hydroxylase (FA2H) is encoded by the FA2H gene, with mutations therein leading to the neurodegenerative condition, spastic paraplegia-35 (SPG35). We aim to elucidate the genetic underpinnings of a non-consanguineous Chinese family diagnosed with SPG35 by examining the clinical manifestations, scrutinizing genetic variants and establishing the role of FA2H mutation in lipid metabolism.

Methods

Using next-generation sequencing analysis to identify the pathogenic gene in this pedigree and family co-segregation verification. The use of lipidomics of patient pedigree PBMCs further substantiated alterations in lipid metabolism attributable to the FA2H exon 1 deletion.

Results

The proband exhibited gait disturbance from the age of 5, he developed further clinical manifestations such as scissor gait and dystonia. His younger sister also presented with a spastic gait from the same age. We identified a homozygous deletion in the region of FA2H exon 1, spanning from chr16:74807867 to chr16: 74810391 in the patients. Lipidomic analysis revealed significant differences in 102 metabolites compared to healthy controls, with 62 metabolites increased and 40 metabolites decreased. We specifically zeroed in on 19 different sphingolipids metabolites, which comprised ceramides, ganglioside, et cetera, with only three of these sphingolipids previously reported.

Interpretation

This is the first study of lipid metabolism in the blood of SPG35 patients. The results broaden our understanding of the SPG35 gene spectrum, offering insights for future molecular mechanism research and laying a groundwork for determining metabolic markers.