Saturday, March 9, 2024

Spastic paraplegia-35

Inspired by a patient

Jordans S, Hardt R, Becker I, Winter D, Wang-Eckhardt L, Eckhardt M. Age-Dependent Increase in Schmidt-Lanterman Incisures and a Cadm4-Associated Membrane Skeletal Complex in Fatty Acid 2-hydroxylase Deficient Mice: a Mouse Model of Spastic Paraplegia SPG35. Mol Neurobiol. 2022 Jul;59(7):3969-3979. doi: 10.1007/s12035-022-02832-4. Epub 2022 Apr 20. PMID: 35445918; PMCID: PMC9167166.


PNS and CNS myelin contain large amounts of galactocerebroside and sulfatide with 2-hydroxylated fatty acids. The underlying hydroxylation reaction is catalyzed by fatty acid 2-hydroxylase (FA2H). Deficiency in this enzyme causes a complicated hereditary spastic paraplegia, SPG35, which is associated with leukodystrophy. Mass spectrometry-based proteomics of purified myelin isolated from sciatic nerves of Fa2h-deficient (Fa2h-/-) mice revealed an increase in the concentration of the three proteins Cadm4, Mpp6 (Pals2), and protein band 4.1G (Epb41l2) in 17-month-old, but not in young (4 to 6-month-old), Fa2h-/- mice. These proteins are known to form a complex, together with the protein Lin7, in Schmidt-Lanterman incisures (SLIs). Accordingly, the number of SLIs was significantly increased in 17-month-old but not 4-month-old Fa2h-/- mice compared to age-matched wild-type mice. On the other hand, the relative increase in the SLI frequency was less pronounced than expected from Cadm4, Lin7, Mpp6 (Pals2), and band 4.1G (Epb41l2) protein levels. This suggests that the latter not only reflect the higher SLI frequency but that the concentration of the Cadm4 containing complex itself is increased in the SLIs or compact myelin of Fa2h-/- mice and may potentially play a role in the pathogenesis of the disease. The proteome data are available via ProteomeXchange with identifier PXD030244.

Cao L, Huang XJ, Chen CJ, Chen SD. A rare family with Hereditary Spastic Paraplegia Type 35 due to novel FA2H mutations: a case report with literature review. J Neurol Sci. 2013 Jun 15;329(1-2):1-5. doi: 10.1016/j.jns.2013.02.026. Epub 2013 Apr 6. PMID: 23566484.


Background: Hereditary Spastic Paraplegia Type 35 is a complicated form of HSP characterized by progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Mutations in the fatty acid 2-hydroxylase (FA2H) gene have been associated SPG35.

Methods: Sequencing of FA2H gene was conducted in a Chinese non-consanguineous family with two affected siblings manifesting with typical clinical features of SPG 35. 100 healthy individuals were set for control.

Result: Triple heterozygous mutations in FA2H gene (c.968C>A; c.976G>A; c.688G>A) were identified in the two affected siblings. All the mutations were not documented previously and were not detected among 100 healthy controls.

Conclusion: In this study we identified the first SPG 35 family in Han population. Triple FA2H mutations seem to result in a severe phenotype while more patients are needed to establish the genotype-phenotype correlations.

Mo L, Tie X, Che F, Zhang L, Li B, Wang G, Yang Y. A Novel Homozygous Deletion Including Exon 1 of FA2H Gene Causes Spastic Paraplegia-35: Genetic and Lipidomics Analysis of the Patients. Pediatr Neurol. 2024 Mar;152:200-208. doi: 10.1016/j.pediatrneurol.2023.12.031. Epub 2024 Jan 5. PMID: 38306901.


Background: 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 nonconsanguineous 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 cosegregation verification. The use of lipidomics of patient pedigree peripheral blood mononuclear cells further substantiated alterations in lipid metabolism attributable to the FA2H exon 1 deletion.

Results: The proband exhibited gait disturbance from age 5 years; 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 with healthy controls, with 62 metabolites increased and 40 metabolites decreased. We specifically zeroed in on 19 different sphingolipid metabolites, which comprised ceramides, ganglioside, etc., with only three of these sphingolipids previously reported.

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

Hardt R, Jordans S, Winter D, Gieselmann V, Wang-Eckhardt L, Eckhardt M. Decreased turnover of the CNS myelin protein Opalin in a mouse model of hereditary spastic paraplegia 35. Hum Mol Genet. 2021 Jan 21;29(22):3616-3630. doi: 10.1093/hmg/ddaa246. PMID: 33215680.


Spastic paraplegia 35 (SPG35) (OMIM: 612319) or fatty acid hydroxylase-associated neurodegeneration (FAHN) is caused by deficiency of fatty acid 2-hydroxylase (FA2H). This enzyme synthesizes sphingolipids containing 2-hydroxylated fatty acids, which are particularly abundant in myelin. Fa2h-deficient (Fa2h-/-) mice develop symptoms reminiscent of the human disease and therefore serve as animal model of SPG35. In order to understand further the pathogenesis of SPG35, we compared the proteome of purified CNS myelin isolated from wild type and Fa2h-/- mice at different time points of disease progression using tandem mass tag labeling. Data analysis with a focus on myelin membrane proteins revealed a significant increase of the oligodendrocytic myelin paranodal and inner loop protein (Opalin) in Fa2h-/- mice, whereas the concentration of other major myelin proteins was not significantly changed. Western blot analysis revealed an almost 6-fold increase of Opalin in myelin of Fa2h-/- mice aged 21-23 months. A concurrent unaltered Opalin gene expression suggested a decreased turnover of the Opalin protein in Fa2h-/- mice. Supporting this hypothesis, Opalin protein half-life was reduced significantly when expressed in CHO cells synthesizing 2-hydroxylated sulfatide, compared to cells synthesizing only non-hydroxylated sulfatide. Degradation of Opalin was inhibited by inhibitors of lysosomal degradation but unaffected by proteasome inhibitors. Taken together, these results reveal a new function of 2-hydroxylated sphingolipids namely affecting the turnover of a myelin membrane protein. This may play a role in the pathogenesis of SPG35.

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