Tremor as an early sign of hereditary spastic paraplegia due to mutations in ALDH18A1

Abstract

Background: The ALDH18A1 gene is located at 10q24.1 and encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), a mitochondrial bifunctional enzyme that catalyzes the first two steps in de novo biosynthesis of proline, ornithine, citrulline, and arginine. ALDH18A1-related disorders have been classified into four groups, such as autosomal dominant and recessive hereditary spastic paraplegia (SPG9A and SPG9B, respectively), as well as autosomal dominant and recessive cutis laxa (ADCL3 and ARCL3A, respectively). Neurodegeneration is a characteristic feature of all groups.Case report: Here, we report a girl with compound heterozygous disease-causing variants (c.-28-2A>G and c.383G>A, p. Arg128His) in the ALDH18A1 gene, revealed by whole exome sequencing. The c.-28-2A>G variant in intron 1, inherited from the mother, is a novel mutation, while the c.383G>A variant in exon 4, inherited from the father, has already been reported. The patient presented with vigorous infantile tremor preceding progressive spastic paraplegia. Dysmorphic features included elongated face, deep-set ears, upturned nose, long philtrum and pointed chin. Intrauterine and postnatal growth retardation, microcephaly, global developmental delay and profound intellectual disability were also noticed. Blood fasting ammonia level, plasma proline, ornithine and arginine levels were normal, while citrulline level was slightly decreased. Brain MRI revealed moderate hypoplasia of the corpus callosum and reduction of white matter volume.Conclusions: The patient represents SPG9B, a rare form of autosomal recessive hereditary spastic paraplegias. The early onset tremor, preceding lower limb spasticity appears to be a unique early manifestation of neurodegeneration in this case.

The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia

“…At age 36, the patient manifested, in addition to severe spasticity of the legs, distal amyotrophy, and pes cavus, sensory neuropathy, spasticity of the bulbar region, as well as mild cerebellar signs with nystagmus and past-pointing in the arms. This is the first report of SPG9B in sub-Saharan Africa, with previous reports in European and Japanese populations ( 53 , 54 ). The majority of these missense variants occur in the L-glutamyl-5-phosphate reductase (G5PR) domain, where the p.Val451Met variant is also located.…”

Carnosol ameliorated cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways

“…P5CS has an important function for the regulation of glutamine metabolism and the Krebs cycle. The most important roles it plays are catalyzing the reduction conversion and coupled phosphorylation and synthesizing proline from glutamate (Guo et al, 2020;Kalmar et al, 2021;Pickwick et al, 2022). Furthermore, a recent study conducting a functional assessment of homozygous P5CS variants revealed alterations in amino acid and antioxidant metabolism (Colonna et al, 2023), which further supported the important role of P5CS in regulating the antioxidant system.…”

Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia

“…A spectrum of 13 mutations in the ALDH18A1 gene have been identified in 17 patients with autosomal recessive HSP, including 10 missenses, 2 splicing mutations, and a non-sense mutation (Table 1). Most notably, the previously reported p.R128H mutation was found in seven patients (2,3,25), making it the most frequently occurring ALDH18A1 mutation thus far identified in SPG9B patients. The patients reported to carry the p.R128H mutation invariably exhibited an earlier age of onset.…”