The relationship between LIPT2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 29, 2024. LIPT2 encodes lipoyl(octanoyl) transferase 2, an enzyme important for lipoic acid biosynthesis.
The first and only report of variants in LIPT2 being associated with autosomal recessive primary mitochondrial disease was in 2017 (PMID: 28757203). While various names have been given to the constellation of features seen in those with LIPT2-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the LIPT2 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 three missense variants in two probands from one publication (PMID: 28757203). Clinical features in affected individuals include severely delayed to absent psychomotor development, microcephaly, epilepsy, dystonia, spastic tetraparesis, and respiratory distress. Brain imaging showed cortical atrophy, leukodystrophy, delayed myelination, progressive thalamus and putamen abnormalities, and decreased gyrification of the cerebral hemispheres. Pyruvate dehydrogenase complex activity was reduced in skin fibroblasts.
The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of LIPT2 in lipoic acid biosynthesis and functional studies in patient cells (PMID: 28803783).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 29, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.