PMPCA

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PMPCA* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 18, 2023. This gene encodes mitochondrial peptidase processing subunit alpha, the alpha subunit of a proteolytic heterodimer that, together with PMPCB, is responsible for cleaving the transit peptide from nuclear-encoded mitochondrial proteins after import into the mitochondria. *PMPCA* was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID: 25808372), in several individuals with cerebellar atrophy and ataxia. While various names have been given to the constellation of features seen in those with *PMPCA*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *PMPCA* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 unique variants [seven missense including c.1129G>A (p.Ala377Thr) that is a Lebanese founder variant, one frameshift, two splicing] identified in 26 affected individuals from 11 kindreds from seven publications (PMIDs: 25808372, 26657514, 27148589, 30617178, 33272776, 35803560, 37332652). Additional cases were reported in the medical literature but excluded from this curation as phasing was not performed (PMIDs: F4 in 25808372, 36233161). Additionally, there is a report of autosomal dominant inheritance of *PMPCA* variants (PMID: 35885985) that was also excluded from this curation as additional studies are needed to confirm this disease mechanism. Some affected individuals had developmental delay from early in life while others met their milestones on time with subsequent regression in the first couple years of life. The outcomes were variable, but all cases appeared to be living at the time of report except for one individual who died at 17 years of age (PMID: 35803560). Features in affected individuals include developmental delay, ataxia (both stable and progressive courses reported), dysarthria and tremor. Some affected individuals had intellectual disability and some had mood disorders. Other features seen include faltering growth, ophthalmoplegia, and optic atrophy; and one individual had hypertrophic cardiomyopathy. Muscle biopsy was not consistently performed and results were variable when this was completed. Brain imaging showed cerebellar atrophy and generalized brain atrophy. Metabolic screening labs were generally normal but some individuals had elevated lactate. This gene-disease association is also supported by its known biochemical function (PMID: 33340416), functional alteration in patient (PMID: 25808372) and non-patient cells (PMID: 26657514), and rescue in patient cells (PMID: 27148589). In summary, there is definitive evidence to support the relationship between *PMPCA* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 18, 2023 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0008943

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008943

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008943

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0008943

Submitter: Ambry Genetics