Abstract
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.
Highlights
Hereditary Spastic Paraplegias (HSPs) represent a heterogeneous group of neurodegenerative conditions characterized by a progressive inability to walk due to length-dependent axonal degeneration of the pyramidal tract [1]
Mutations in ALDH18A1 can cause dominant (SPG9A, MIM#601162) and recessive (SPG9B, MIM#616586) forms of HSP. These forms are mainly characterized by spasticity of the lower limbs, and the clinical picture can be complicated by low plasma levels of proline, arginine, citrulline, and ornithine associated with hyperammonemia, developmental delay, persistent vomiting, hypotonia, early cataracts and connective tissues abnormalities [5, 6, 11]
The development of a neurological phenotype in HHH syndrome, ARG1 and P5CS deficiency, can be induced by the formation of toxic compounds, resulting from the accumulation of substrates, or alteration in mitochondria, where ornithine is low or absent in these conditions. These observations point toward an impairment of the ornithine/arginine metabolism as a common mechanism for the development of the neurodegenerative phenotype observed in all three metabolic HSPs
Summary
Hereditary Spastic Paraplegias (HSPs) represent a heterogeneous group of neurodegenerative conditions characterized by a progressive inability to walk due to length-dependent axonal degeneration of the pyramidal tract [1]. These forms are mainly characterized by spasticity of the lower limbs, and the clinical picture can be complicated by low plasma levels of proline, arginine, citrulline, and ornithine associated with hyperammonemia, developmental delay, persistent vomiting, hypotonia, early cataracts and connective tissues abnormalities [5, 6, 11].
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