Pyrroline-5-carboxylate reductase 2 (PYCR2) deficiency causes hereditary spastic paraplaegia in late childhood
Introduction
Pyrroline-5-carboxylate reductase 2 (PYCR2) is an enzyme in the endogenous synthesis of proline from glutamate [1]. PYCR2 is a mitochondrial enzyme and its deficiency has been associated with genetic hypomyelinating leukodystrophy type 10 with microcephaly (HLD10) (Online Mendelian Inheritance in Man, OMIM # 616420) phenotype. The HLD10 phenotype follows an autosomal recessive inheritance pattern and is characterized by severe developmental delay, epileptic encephalopathy, spasticity, movement disorder, acquired microcephaly, and hypomyelinating leukoencephalopathy [2].
The PYCR2 gene contains 7 exons and is located on chromosome 1q42.12; it encodes a protein that is composed of 320 amino acids [2]. Currently, 20 variants have been identified for the PYCR2 gene in the Human Gene Mutation Database® (HGMD®) Professional (https://portal.biobase-international.com/hgmd/pro/all.php), of which 16 are missense/nonsense, 2 are splice-site, 1 are small deletion, and 1 are small insertion variants.
Hereditary spastic paraplegia (HSP) is a general term for a group of inherited progressive genetic diseases that cause progressive lower limb spasticity [3]. HSPs are classified according to clinical manifestations, inheritance pattern, and time of symptom onset [4].
Childhood-onset HSPs could have been associated with underlying metabolic etiologies [5]. These HSPs typically involve the proximal muscles of the lower limbs and cause spastic gait. In recent years, the widespread use of genetic analysis has resulted in discovery of several other genes associated with the HSP phenotype.
The purpose of the present study was to present clinical findings of five patients from two related families, in whom we detected pathogenic variants of the PYCR2 gene via whole exome sequencing (WES) analysis. Considering that the current report presents clinical manifestations in patients with HSP clinical symptoms without hypomyelinating leukodystrophy, This is the first study that report the PYCR2 gene variants as a cause of HSP in the late childhood period. We believe it can contribute to expanding the spectrum of the phenotypes associated with PYCR2 gene.
Section snippets
Material and methods
This retrospective clinical study was approved by the institutional ethical committee (Istanbul Kartal Dr Lutfi Kirdar City Hospital, approval number, 2022/514/230/2). Informed consent for genetic testing and the use of data for scientific publication was obtained from the patients’ parents.
Clinical features
In summary, our patients had previously followed normal developmental stages, were cognitively normal, and had no dysmorphic features; however, they developed mild intention tremors and difficulty in writing at the age of approximately 6 years, and presented with impaired gait from the age of ∼10 years. The WES analysis performed in 5 patients with the same clinical features revealed a novel homozygous missense variant in the PYCR2 gene. A summary of clinical findings from these two related
Discussion
Pyrroline-5-carboxylate reductase (Pycr2) is a mitochondrial enzyme that catalyzes the final step of proline biosynthesis and reduces pyrroline-5-carboxylate (P5C) to l-proline using NADH as cofactor [12]. In 2015, Nakayama et al. reported that variants in the form of loss of function in this gene cause clinical manifestations of HLD10 [2]. In summary, these patients showed some common features including acquired microcephaly, hypomyelinating leukoencephalopathy, epilepsy, and severe
Conclusion
Some variants of PYCR2 are responsible for causing clinical features of HSP without hypomyelinating leukodystrophy.
Funding sources
No funding.
Declarations of competing interest
The authors declare no competing interests.
Acknowledgments
We are gratuating all our patients participating in this study.
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