Common mechanism discovered
The ALDH18A1 gene, associated with both dominant (SPG9A) and recessive (SPG9B) forms of HSP, is also associated with three other metabolic disorders – ARG1 deficiency, P5CS deficiency and HHH syndrome. This study has found an impairment of ornithine/arginine metabolism as the common mechanism behind the neurodegeneration in each.
Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions.
As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated.
Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia.
These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype.
SOURCE: Front Neurol. 2019 Feb 22;10:131. doi: 10.3389/fneur.2019.00131. eCollection 2019. PMID: 30853934
Hereditary Spastic Paraplegia Is a Common Phenotypic Finding in ARG1 Deficiency, P5CS Deficiency and HHH Syndrome: Three Inborn Errors of Metabolism Caused by Alteration of an Interconnected Pathway of Glutamate and Urea Cycle Metabolism.
1 Medical Genetics Unit, S. Orsola-Malpighi Hospital, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
2 Division of Metabolism, Bambino Gesù Children’s Research Hospital, Rome, Italy.
3 Medical Genetics Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy.