ALDH18A1 – Autosomal Recessive Complex Spastic Paraplegia Type 9B

ALDH18A1 encodes Δ¹-pyrroline-5-carboxylate synthase (P5CS), a mitochondrial bifunctional enzyme critical for proline, ornithine and arginine biosynthesis. Biallelic variants in ALDH18A1 underlie spastic paraplegia type 9B (SPG9B), characterised by lower limb spasticity, cerebellar ataxia and variable cognitive impairment ([HP:0001251], [HP:0100543]).

Initial genetic evidence arose from two Japanese families each harboring compound heterozygous (c.1321T>C/c.1994G>A) and homozygous (c.383G>A) ALDH18A1 variants in SPG9B probands, establishing autosomal recessive inheritance and expanding SPG9B beyond Caucasian cohorts (PMID:29915212). A targeted sequencing screen in 24 Chinese AR/sporadic HSP patients identified a p.Ser242Asn substitution in ALDH18A1, corroborating recurrence in diverse populations (PMID:31289639).

Further SPG9B cases include two novel missense alleles—c.1582G>A (p.Gly528Arg) and c.1112G>A (p.Arg371Gln)—demonstrated as pathogenic in a baculovirus–insect cell P5CS expression system (PMID:31402623), and a family carrying a splice variant c.-28-13A>G with missense c.880T>C (p.Ser294Pro) validated by ELISA-based reduction in plasma P5CS concentration (PMID:34093392).

Segregation analyses across five unrelated families confirmed that all affected individuals are compound heterozygous or homozygous for ALDH18A1 loss-of-function variants, with obligate carriers unaffected, totaling six probands and at least five segregating relatives (PMID:29915212; PMID:34093392).

Functional assays reveal that SPG9B-associated variants impair P5CS enzymatic activity and oligomerization: mutant proteins exhibit >50% activity reduction in cell‐based assays, fail to form stable oligomers in insect cells, and alter downstream proline/glutathione metabolism in patient fibroblasts (PMID:31402623; PMID:36067040). These concordant findings support a recessive loss-of-function mechanism.

Collectively, biallelic ALDH18A1 mutations in SPG9B show robust genetic segregation and consistent functional deficits in P5CS activity. Additional variants and patient series continue to be reported, but the existing data meet ClinGen criteria for a Strong gene–disease association. Key Take-home: ALDH18A1 testing should be considered in AR HSP patients with cerebellar ataxia and cognitive impairment for accurate diagnosis and counseling.

References

• Journal of human genetics | 2018 | Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment. PMID:29915212
• Translational neurodegeneration | 2019 | Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia. PMID:31289639
• Annals of clinical and translational neurology | 2019 | P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9. PMID:31402623
• Frontiers in neurology | 2021 | Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia. PMID:34093392
• Human molecular genetics | 2023 | Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. PMID:36067040

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