PDHA1

Inheritance Pattern: XL

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between PDHA1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 25, 2019. 31 articles were reviewed. PDHA1 was first reported in relation to X-linked Leigh syndrome spectrum in 1993 (Matthews et al., PMID 8498846). Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in numerous probands in numerous publications (PMIDs 7887409, 8962591, 8664900, 9187674, 9671272, 10679936, 12621116, 15384102, 20002461, 21914562). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the known biochemical function, protein interaction, functional studies in patient cell lines, and animal models. PDHA1 encodes the E1 alpha subunit of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. In summary, there is definitive evidence to support the relationship between PDHA1 and X-linked Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).

Inheritance Pattern: AR

Disease ID:MONDO:0010717

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: Natera

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: Genomics England PanelApp

Inheritance Pattern: XL

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PDHA1* and X-linked *PDHA1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 29, 2024. The *PDHA1* gene encodes the E1 alpha subunit of the pyruvate dehydrogenase complex which provides the primary link between glycolysis and the tricarboxylic acid cycle by catalyzing the conversion of pyruvate into acetyl-CoA. The *PDHA1* gene was first reported in relation to X-linked *PDHA1*-related primary mitochondrial disease in 1989 (PMID: 2537010). *PDHA1* has been associated with a single disease entity to date; pyruvate dehydrogenase E1-alpha deficiency [OMIM# 312170]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *PDHA1*-related primary mitochondrial disease. Of note, *PDHA1* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on March 25, 2019 (SOP v6), with a final classification of Definitive. This current curation for the association with *PDHA1*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine unique variants (eight missense, one frameshift) identified in nine unrelated cases from eight publications (PMIDs: 29756269, 34247546, 33592356, 38497591, 9187674, 8664900, 20002461, 21914562) although there have been many additional cases reported in the literature. Disease onset varies from the prenatal period to adulthood. Clinical features in affected individuals are variable and include neonatal lactic acidosis, LSS, developmental delay and regression, episodic or paroxysmal ataxia, hemiplegia, dystonia, microcephaly, exercise intolerance, and myopathy. Brain imaging is also variable and can show findings consistent with LSS as well as cerebral atrophy, dysgenesis or agenesis of corpus callosum, and periventricular cysts. Common biochemical findings include lactic acidosis and elevated pyruvate with a low or normal lactate/pyruvate ratio. Both affected males and females have been reported in the literature. While often de novo, familial inheritance with variable expressivity has also been reported, as has mosaicism (PMIDs: 21914562, 38497591). The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), a mouse model (PMID: 23840713), and functional alteration studies in patient cells (PMID: 28918066). In summary, there is definitive evidence to support the relationship between *PDHA1* and X-linked *PDHA1*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 29, 2024 (SOP Version 10).

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: G2P