Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease

Valentina Serpieri,Tommaso Biagini,Silvia Cerri,Roberta Battini,Rosa Pasquariello,Enza Maria Valente,Anna Rubegni,Filippo Santorelli,Gerardo Ongari,Concetta Mazzotta,Tommaso Mazza

doi:10.3390/app11020748

Abstract

Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition.

Highlights

The advent of generation sequencing techniques has greatly eased the identification of novel genes causative of Mendelian disorders while disclosing a previously unsuspected degree of pleiotropy
Biallelic pathogenic missense variants in the peptidase mitochondrial processing alpha (PMPCA) gene have been associated with two distinct conditions
The first is an early onset, non-progressive cerebellar ataxia (NPCA) with or without developmental delay and intellectual disability, termed “recessive spinocerebellar ataxia type 2” (SCAR2), which should be kept distinct from SCA2, an autosomal dominant, adult-onset spinocerebellar ataxia due to a pathological trinucleotide expansion in the ataxin 2 gene

Summary

Introduction

The advent of generation sequencing techniques has greatly eased the identification of novel genes causative of Mendelian disorders while disclosing a previously unsuspected degree of pleiotropy. Variants in the same gene are often found to cause a broad spectrum of phenotypes, with variable severity and clinical presentation, possibly encompassing distinct disorders. The reasons underlying such pleiotropy are still mostly unknown, and genotype-phenotype correlates remain scarce. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition

Methods

Discussion

Conclusion