Pyrroline-5-carboxylate reductase 2 (PYCR2) deficiency causes hereditary spastic paraplaegia in late childhood

https://doi.org/10.1016/j.ejpn.2023.04.002Get rights and content

Highlights

  • PYCR2 gene variants can cause Hereditary Spastic Paraplegia (SPG) in the late childhood period.

  • Normal Brain MRI can de seen in PYCR2 gene variants although they are associated with hypomyelinating leukodystrophy type 10.

  • MR spectroscopy findings are helpful for diagnosis.

Abstract

Objectives

PYCR2 gene variants are extremely rare condition which is associated with hypomyelinating leukodystrophy type 10 with microcephaly (HLD10). The aim of the present study is to report the clinical findings of patients having novel PYCR2 gene variant that manifest Hereditary Spastic Paraplegia (HSP) is the only symptom without hypomyelinating leukodystrophy. This is the first study that report the PYCR2 gene variants as a cause of HSP in late childhood. We believe it can contribute to expanding the spectrum of the phenotypes associated with PYCR2.

Methods

It is a retrospective study. Of the patients with similar clinical features from two related families, “patient 1” was designated as the index case, and was analyzed using Whole Exome Squence analysis (WES). The detected variation was investigated in the index case's parents, relatives, and sibling with a similar phenotype. Clinical, brain magnetic resonance (MR) images and MR spectroscopic findings of the patients were reported.

Results

A novel homozygous missense (NM_013328: c.383T > C, p.V128A) variant in the PYCR2 gene is detected in 5 patient from 2 related families. All the patients were male, their ages ranges from 6 to 26 years (15.58 ± 8,33 yrs). Developmantal milestones were normal without dysmorphic features. 4 (%80) patients exhibit mild intention tremor started at the age of approximately 6 years of age. 4 (%80) patients had gait difficulty and progressive lower limb spasticity started at the age of 8–12 years. White matter myelination was normal in all patients. Glycine peakes were detected on the MR spectroscopy in all patients.

Conclusion

Some variants of PYCR2 gene are responsible for causing clinical features of HSP without hypomyelinating leukodystrophy in the pediatric patients.

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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