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Updated: May 3, 2026
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology
Vibhuti Rambani1, Miriam Kolnikova1, Michal Cagalinec1
1From the Institute of Experimental Endocrinology (V.R., M.C., M.S., D.G.), Biomedical Reserach Center, Slovak Academy of Sciences; Medical Faculty of Comenius University and National Institute of Childern's Diseases (M.K.); Centre of Excellence for Advanced Material Application (M.C.), Slovak Academy of Sciences, Bratislava, Slovakia.
Objectives:
The PMPCA gene encodes the α-subunit of mitochondrial processing peptidase (α-MPP), an enzyme responsible for cleavage of nuclear-encoded mitochondrial precursor proteins after their import into mitochondria. Mutations in this gene have been described in patients with nonprogressive or slow progressive cerebellar ataxia, with variable age at onset and severity. Cerebellar atrophy and striatum changes were found in severe cases.
Methods:
The patient was diagnosed using whole exome sequencing. Skin fibroblasts were used for confirmation of α-MPP levels using western blot and mitochondrial morphology assessment of immunofluorescent confocal microscopy images.
Results:
Two novel compound heterozygous variants in the PMPCA gene (p.Tyr241Ser and p.Met251Val) were identified in an 8-year-old proband with progressive spastic quadriparesis, delayed psychomotor development, and intellectual disability, with onset at 13 months. The brain imaging showed cortical and cerebellar atrophy, reduced volume of basal ganglia with striatum hyperintensity, and periventricular white matter changes. The patient's fibroblasts showed a decreased α-MPP level and reduced and fragmented mitochondria.
Discussion:
The described case contributes to the number of patients with progressive PMPCA-related disease with a severe intermediate phenotype. Moreover, we extend the phenotype to Leigh-like white matter changes that have not been described in previously reported cases.
Insights
Mutations in the PMPCA gene cause progressive spastic quadriparesis and intellectual disability. This study identifies novel variants and extends the PMPCA-related disease phenotype to include Leigh-like white matter changes.
Area of Science:
- Genetics
- Neuroscience
- Mitochondrial Biology
Background:
- The PMPCA gene encodes the alpha-subunit of mitochondrial processing peptidase (α-MPP), crucial for mitochondrial protein maturation.
- Mutations in PMPCA are linked to cerebellar ataxia, with varying severity and onset.
- Severe cases may exhibit cerebellar and striatal changes.
Purpose of the Study:
- To report a case of PMPCA-related disease with novel compound heterozygous variants.
- To characterize the clinical and molecular phenotype associated with these variants.
- To expand the known phenotypic spectrum of PMPCA-associated disorders.
Main Methods:
- Whole exome sequencing for genetic diagnosis.
- Western blot analysis to assess α-MPP protein levels in patient fibroblasts.
- Immunofluorescent confocal microscopy to evaluate mitochondrial morphology.
Main Results:
- Identified two novel compound heterozygous variants (p.Tyr241Ser and p.Met251Val) in the PMPCA gene.
- The 8-year-old proband presented with progressive spastic quadriparesis, developmental delay, and intellectual disability.
- Brain imaging revealed atrophy, basal ganglia abnormalities, and periventricular white matter changes; fibroblasts showed reduced α-MPP and abnormal mitochondria.
Conclusions:
- This case highlights a severe, intermediate PMPCA-related phenotype.
- The study expands the phenotype to include Leigh-like white matter changes, previously undescribed.
- Further research into PMPCA variants is warranted to understand genotype-phenotype correlations.
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