# Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease
###### Abstract  
Background: Peptides 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.Trp278 Leu; p.Arg362 Gly). 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-atxic 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. 11 January 202  
One such example is the peptidase mitochondrial processing alpha (_PMPCA_) gene, encoding the alpha subunit of mitochondrial processing peptidase (\(\alpha\)-MPP), a heterodimer enzyme responsible for the cleavage of nuclear-encoded mitochondrial precursor proteins after import in mitochondria. \(\alpha\)-MPP is characterized by the glycine-rich loop (GRL, residues 345-358), a key structural element of MPP that recognizes and binds the precursor protein substrate toward the active site [1; 2; 3]. Biallelic pathogenic missense variants in the _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 \"receisive spinocerebellar ataxia type 2\" (SCAR2), which should be kept distinct from SCA2 (spinocerebellar ataxia type 2), an autosomal dominant, adult-onset spinocerebellar ataxia due to a pathological trinucleotide expansion in the ataxin 2 gene. Nineteen patients from five families have been reported, all presenting a typical pattern of non-progressive cerebellar atrophy at brain imaging. Muscle biopsy was normal, although mitochondrial complexes activity was mildly decreased in some cases [4; 5]. Patients from three families were homozygous for the p.Ala377 Thr variant, the probund in the fourth family was compound heterozygous for the p.Ser96 Leu and p.Gly515 Arg variants, while the two affected siblings in the fifth family were homozygous for the p.Val256 Met variant. The second condition is a much more severe progressive mitochondrial encephalopathy, presenting with profound developmental delay, ptosis, ophthalmoplegia, weakness, respiratory insufficiency, blindness, cardiomyopathy, liver failure, and lactic acidemia, reported in two siblings who were compound heterozygous for the recurrent p.Ala377 Thr and the novel p.Gly356 Ser variant. Brain MRI showed diffuse cerebellar and cerebral atrophy, with a lactate peak at MRI spectroscopy, while muscle biopsy demonstrated enlarged, structurally abnormal mitochondria [3]. Recently, we reported a 7-year-old Italian boy (here termed \"Ita-2\") homozygous for a novel _PMPCA_ missense variant (p.Arg185 Trp), presenting a phenotype of intermediate severity characterized by a progressive encephalopathy without extra-neurological involvement.