ALDH18A1 – SPG9A-related Hereditary Spastic Paraplegia

ALDH18A1 encodes Δ¹-pyrroline-5-carboxylate synthetase (P5CS), a bifunctional mitochondrial enzyme essential for proline, ornithine and arginine biosynthesis. Heterozygous missense mutations in ALDH18A1 cause SPG9A, an autosomal dominant form of hereditary spastic paraplegia (SPG9A, ALDH18A1).

In a four-generation Japanese family, exome sequencing and Sanger validation identified a de novo heterozygous ALDH18A1 c.755G>A (p.Arg252Gln) variant segregating with disease in five affected individuals, all presenting with pure or complicated spastic paraplegia ([PMID:33573605]). Haplotype analysis confirmed a new occurrence of this allele, which has been previously reported in two other ADHSP families and one sporadic SPG9A patient, underscoring recurrent hotspot mutability ([PMID:33573605]).

Functional studies demonstrate that missense substitutions in P5CS markedly diminish enzyme activity: the R84Q (p.Arg84Gln) variant reduces both gamma-glutamyl kinase and glutamate-5-semialdehyde dehydrogenase activities and destabilizes the long isoform in mammalian cells ([PMID:11092761]). More recently, characterization of p.Thr331Pro revealed impaired oligomerization and reduced biosynthesis of proline, glutamate-derived metabolites and polyamines, confirming loss of function in cellular models ([PMID:36067040]).

The weight of genetic segregation, de novo recurrence, and concordant enzymatic deficiency supports a dominant-negative mechanism for SPG9A. No reports contradict this association.

Collectively, these data meet Strong clinical validity for ALDH18A1 in SPG9A. ALDH18A1 testing should be included in diagnostic panels for autosomal dominant spastic paraplegia.

Key Take-home: De novo heterozygous ALDH18A1 missense variants causing P5CS deficiency are a confirmed cause of SPG9A and warrant targeted genetic evaluation in dominant HSP pedigrees.

References

• BMC Neurology • 2021 • SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report. PMID:33573605
• Human Molecular Genetics • 2000 • Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. PMID:11092761
• Human Molecular Genetics • 2023 • Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. PMID:36067040

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