Δ¹‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder

Abstract

The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this neurocutaneous syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the neurocutaneous syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two neurocutaneous syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss‐of‐function by dominant‐negative mechanisms.

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

“…Monoallelic and biallelic mutations in ALDH18A1 (OMIM 138250), located at 10q24.1, can cause neurodegeneration in association with various nonneurological features [1][2][3]. Based on genotypic and phenotypic features the ALDH18A1-related disorders have been classified into four groups, such as autosomal dominant and recessive hereditary spastic paraplegia (SPG9A, OMIM 601162 and SPG9B, OMIM 616586, respectively), as well as autosomal dominant and recessive cutis laxa (ADCL3, OMIM 616603 and ARCL3A, OMIM 219150, respectively) [1][2][3]. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS, EC 1.2.1.41 and 2.7.2.11), a mitochondrial bifunctional enzyme that catalyzes the first two steps in the biosynthesis of proline, ornithine, citrulline, and arginine from glutamate.…”

“…ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS, EC 1.2.1.41 and 2.7.2.11), a mitochondrial bifunctional enzyme that catalyzes the first two steps in the biosynthesis of proline, ornithine, citrulline, and arginine from glutamate. It comprises two domains, with different enzymatic activities: an N-terminal glutamate 5-kinase (G5K) domain, responsible for the glutamate phosphorylation to gamma-glutamyl phosphate, and a Cterminal glutamate 5-phosphate reductase (G5PR) domain, which catalyzes the reduction and conversion to gamma-glutamyl semialdehyde, which is further metabolized to proline and ornithine [1][2][3]. Two isoforms of P5CS are generated, differing only by 2 amino acid insert in the G5K domain.…”

SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report

“…These diseases are classified as delta-1-pyrroline-5-carboxylate-synthedase (P5CS) deficiency [1], which is a urea cycle-related disorder. P5CS deficiency includes SPG9A [OMIM #601162], SPG9B [OMIM #616586], ADCL3 [OMIM #616603], and ARCL3A [OMIM #219150] [2]. The disease severity in P5CS deficiency might increase in the order of SPG9A < SPG9B < ADCL3 ≤ ARCL3A [2].…”

“…P5CS deficiency includes SPG9A [OMIM #601162], SPG9B [OMIM #616586], ADCL3 [OMIM #616603], and ARCL3A [OMIM #219150] [2]. The disease severity in P5CS deficiency might increase in the order of SPG9A < SPG9B < ADCL3 ≤ ARCL3A [2]. These diseases can be understood with the concept of a disease continuum caused by various levels of loss of P5CS function [2].…”

“…The disease severity in P5CS deficiency might increase in the order of SPG9A < SPG9B < ADCL3 ≤ ARCL3A [2]. These diseases can be understood with the concept of a disease continuum caused by various levels of loss of P5CS function [2]. P5CS deficiency exhibits a broad clinical spectrum including cutis laxa, connective tissue weakness, global developmental delay, microcephaly, cataracts, vomiting, hypotonia, spasticity, pyramidal signs, motor disability, and corpus callosum hypotrophy with variable disease severity.…”