Compound heterozygous mutations in two different domains of ALDH18A1 do not affect the amino acid levels in a patient with hereditary spastic paraplegia.

Neurogenetics
Maria SteenhofJens Michael Hertz

Abstract

Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary spastic paraplegia and autosomal recessive and dominant cutis laxa. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), which consists of two domains, the glutamate 5-kinase (G5K) and the gamma-glutamyl phosphate reductase (GR5P) domain. The location of the mutations in the gene has influence on whether the amino acid levels are affected. Mutations affecting the G5K domain have previously been found to cause reduced plasma levels of proline, citrulline and arginine, whereas such effect is not seen with mutations affecting the GR5P domain. We present a 19-year old male patient with autosomal recessive spastic paraplegia and compound heterozygosity for two ALDH18A1 mutations, one in each of the P5CS domains. This young man has spastic paraplegia with onset in childhood and temporal lobe epilepsy, but normal levels of proline, ornithine and arginine. To our knowledge, this is the first case with compound heterozygous mutations affecting both P5CS domains, where levels of plasma amino acids have been reported.

References

Jun 26, 2003·Nucleic Acids Research·Pauline C Ng, Steven Henikoff
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Aug 3, 2010·Nature Methods·Jana Marie SchwarzDominik Seelow
May 31, 2015·Brain : a Journal of Neurology·Marie CoutelierGiovanni Stevanin
Apr 30, 2017·Revue neurologique·L ParodiA Durr

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Citations

Feb 6, 2020·Journal of Inherited Metabolic Disease·Clara Marco-MarínVicente Rubio
Aug 14, 2019·Annals of Clinical and Translational Neurology·Pamela MaginiEmanuele Panza
Jun 30, 2021·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova·G E RudenskayaO P Ryzhkova

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Methods Mentioned

BETA
exome sequencing

Software Mentioned

MutationTaster
SIFT
PolyPhen

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