# Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease
## 4 Discussion  
An increasing number of genes are progressively associated with a broad spectrum of phenotypes, even encompassing different disorders. In these cases, an accurate mapping of gene-associated phenotypes is mandatory, as it would help the diagnostic lab to select the appropriate gene panels (or virtual gene panels in case of exome sequencing), and therefore increase the diagnostic yield. Here we contribute to delineate the phenotypic spectrum associated with recessive mutations in the _PMPCA_ gene. So far, two well-distinct conditions have been delineated: (1) a severe progressive mitochondrial encephalopathy with multiorgan involvement, characterized by profound psychomotor delay, ptosis, ophthalmoplegia, hypotonia and severe generalized weakness, optic atrophy, cardiomyopathy, liver failure, global brain atrophy, and evidence of mitochondrial involvement (lactic acidemia, lactate peak at MRI spectroscopy, abnormal mitochondria at muscle biopsy); (2) a much milder neurological disorder characterized by non-progressive cerebellar atrophy and NPCA with or without intellectual disability, lacking any obvious mitochondrial sign. We now confirm the existence of a third PMPCA-associated phenotype of intermediate severity, presenting as a progressive encephalopathy with psychomotor regression, intellectual disability, spastic ataxia, and a variable hyperkinetic movement disorder, but without extra-neurological signs of mitochondropathy. In addition to cerebellar atrophy, patients present a peculiar neuroradiological hallmark, represented by bilateral symmetric T2-weighted hyperintensities of the basal ganglia, resembling those seen in [PERSON] syndrome. However, it is important to note that our patient lacked obvious signs of mitochondrial involvement (blood lactate, muscle biopsy, and MRI spectroscopy were normal), which instead were present in the first patient. Just before submission of this manuscript, a 15-year-old Japanese girl was reported with a similar phenotype of severe and progressive developmental delay, cerebellar ataxia, and extrapyramidal symptoms. Brain imaging showed cerebellar atrophy and abnormal signal in the basal ganglia, which was interpreted as iron accumulation; however, it is likely that this girl also fell in the \"_PMPCA_ intermediate phenotype\" category highlighted here, characterized by peculiar Leigh-like basal ganglia hyperintensities in association to cerebellar atrophy [7]. All pathogenic variants in the _PMPCA_ gene are missense variants variably distributed throughout the protein (Figure 3) that are highly conserved among vertebrates and consistently predicted as damaging by prediction software. Previous studies have attempted to define the functional impact of specific amino acid substitutions on the stability and function of \(\alpha\)-MPP protein and correlate these effects with the observed phenotype. In particular, mutant \(\alpha\)-MPP was found to impair processing of the mitochondrial protein frataxin, causing an accumulation of the intermediate forms and reduced levels of the processed protein [15]. Interestingly, abnormal frataxin processing was demonstrated in lymphoblasts and/or fibroblasts from patients presenting either with the severe (compound heterozygous for p.Ala377 Thr and p.Gly356 Ser variants) or the mild phenotype (homozygous for p.Ala377 Ser or for p.Val256 Met variants) [3; 4; 5]. Moreover, \(\alpha\)-MPP levels were measured in lymphoblasts from patients presenting the mild phenotype homozygous for two distinct mutations: while cells with the p.Ala377 Thr variant showed significantly reduced levels of \(\alpha\)-MPP, these were comparable to controls in cells carrying the p.Val256 Met variant [4; 5]. Taken together, these findings suggest a loss of function mechanisms underlying _PMPCA_ missense variants (as also pointed out by the frameshift mutation recently reported in the Japanese patient) but fail to disclose any specific genotype-phenotype correlates at the functional level.