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

Serpieri, Valentina and Biagini, Tommaso and Mazzotta, Concetta and Pasquariello, Rosa and Rubegni, Anna and Santorelli, Filippo and Ongari, Gerardo and Cerri, Silvia and Mazza, Tommaso and Battini, Roberta and Valente, Enza Maria (2021) Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease. Applied Sciences, 11 (2). p. 748. ISSN 2076-3417

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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.

Item Type: Article
Subjects: AP Academic Press > Engineering
Depositing User: Unnamed user with email support@apacademicpress.com
Date Deposited: 05 Jan 2023 10:09
Last Modified: 17 Jul 2024 09:26
URI: http://info.openarchivespress.com/id/eprint/50

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