TY - JOUR
T1 - Phenotypic definition and genotype-phenotype correlates in pmpca-related disease
AU - Serpieri, Valentina
AU - Biagini, Tommaso
AU - Mazzotta, Concetta
AU - Pasquariello, Rosa
AU - Rubegni, Anna
AU - Santorelli, Filippo
AU - Ongari, Gerardo
AU - Cerri, Silvia
AU - Mazza, Tommaso
AU - Battini, Roberta
AU - Valente, Enza Maria
N1 - Funding Information:
Funding: This research was funded by Italian Ministry of Health (Ricerca Corrente 2020 and Ricerca Final-izzata grant number NET-2013-02356160) and Pierfranco and Luisa Mariani Foundation (PADAPORT).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/2
Y1 - 2021/1/2
N2 - 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.
AB - 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.
KW - Frataxin
KW - Mitochondrial encephalopathy
KW - Non progressive cerebellar atrophy
KW - PMPCA
KW - SCAR2
KW - Striatal hyperintensity
KW - α-MPP
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U2 - 10.3390/app11020748
DO - 10.3390/app11020748
M3 - Article
AN - SCOPUS:85099424433
VL - 11
SP - 1
EP - 9
JO - Applied Sciences (Switzerland)
JF - Applied Sciences (Switzerland)
SN - 2076-3417
IS - 2
M1 - 748
ER -