OGDH

Inheritance Pattern: AR

Disease ID:MONDO:0008759

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *OGDH* and *OGDH*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 19, 2026. The *OGDH* gene encodes oxoglutarate dehydrogenase, the E1 component of the α-ketoglutarate dehydrogenase (α-KGDH) complex. α-KGDH catalyzes the conversion of α-ketoglutarate to succinyl-coenzyme A (succinyl-CoA) in the tricarboxylic acid (TCA) cycle. The *OGDH* gene was first reported in relation to autosomal recessive *OGDH*-related primary mitochondrial disease in 2021 (PMID: 32383294), however the biochemical etiology was reported in several papers between 1982-2000 (PMIDs: 1640293, 10774994, 8295396, 7075624). *OGDH* has been associated with a single disease entity to date; oxoglutarate dehydrogenase deficiency [OMIM# 203740]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *OGDH*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four missense variants identified in five unrelated cases from two publications (PMIDs: 32383294, 36520152). The age of onset ranges from the neonatal period to early childhood and the reported outcomes range from death at 12 months old to living at 6 years old. Clinical features in affected individuals include global developmental delay, hypotonia, dystonia, dysmetria, ataxia, seizures, microcephaly, decompensation with illness, and dysmorphic features (bitemporal narrowing, full cheeks, nasal bridge abnormalities (broad, depressed), and micrognathia). Of note, there are reports of sudden deteriorations after events such as head trauma (PMID: 32383294) or anesthesia (reported in a case where only the biochemical phenotype was known, PMID: 8295396). Brain imaging shows ventriculomegaly, brain atrophy, agenesis of the corpus callosum, hypoplasia of the pons, delayed myelination, deep gray matter signal abnormalities (dentate nuclei, globi pallidi, subthalamic nuclei) and MRS showing lactate peak. Elevated lactate, elevated ammonia, and elevated urine α-ketoglutarate are also noted. 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) and *Drosophila melanogaster* model (PMID: 32383294). In summary, there is definitive evidence to support the relationship between *OGDH* and autosomal recessive *OGDH*-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 February 19, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0008759

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0008759

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008759

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008759

Submitter: Ambry Genetics