LIPT1 – Leigh syndrome

LIPT1 encodes the mitochondrial lipoyltransferase responsible for attaching lipoic acid to E2 subunits of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes. Autosomal recessive variants in LIPT1 have been identified in four unrelated probands presenting with Leigh syndrome, supporting a Strong ClinGen gene–disease association. The overall evidence includes multiple compound heterozygous cases with concordant biochemical and functional data across independent studies.

Genetic evidence supports an autosomal recessive inheritance mode with trans biallelic inheritance in all reported cases. Four probands ([PMID:24341803], [PMID:24256811], [PMID:31042466], [PMID:39199267]) harbor six pathogenic alleles, including two protein-truncating variants (c.244C>T (p.Gln82Ter) and c.875C>G (p.Ser292Ter)) and four missense variants affecting conserved residues. One recurrent truncating allele, c.875C>G (p.Ser292Ter), was first reported in the initial Leigh syndrome case ([PMID:24341803]).

Segregation data demonstrate that each variant segregates in trans in the probands’ families, consistent with autosomal recessive transmission. Although extended pedigree studies are limited, no unaffected homozygotes have been described, and parental carrier status was confirmed where available.

Functional studies reveal a loss-of-function mechanism. Patient fibroblasts lack lipoylated E2-PDH and E2-KGDH, and display markedly reduced 14CO2 production from labeled substrates, reflecting combined PDH and α-KGDH deficiency ([PMID:24341803]). cDNA transfection rescues enzyme activities and normalizes metabolite levels, confirming pathogenicity in vitro.

Additional experimental models further corroborate these findings. A homozygous knockin mouse model exhibits embryonic lethality due to impaired 2-ketoacid dehydrogenase lipoylation and metabolic imbalance ([PMID:31042466]). Yeast lip3Δ strains demonstrate improved growth upon lipoic acid supplementation, and patient-derived induced neurons treated with an antioxidant/mitochondrial cocktail show restored LIPT1 expression and lipoylation ([PMID:39199267]).

Together, genetic and functional data establish that biallelic LIPT1 variants cause Leigh syndrome via a loss of lipoylation of mitochondrial dehydrogenase complexes. These findings justify genetic testing for LIPT1 in suspected Leigh syndrome and support potential therapeutic avenues such as lipoic acid or antioxidant supplementation. Key take-home: AR LIPT1 loss-of-function causes Leigh syndrome with specific dehydrogenase lipoylation defects, amenable to molecular and metabolic rescue.

References

• Orphanet Journal of Rare Diseases • 2013 • Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase complexes PMID:24341803
• Human Molecular Genetics • 2014 • Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes PMID:24256811
• Cell Reports • 2019 • Functional assessment of lipoyltransferase-1 deficiency in cells, mice, and humans PMID:31042466
• Antioxidants (Basel, Switzerland) • 2024 • A multi-target pharmacological correction of a lipoyltransferase LIPT1 gene mutation in patient-derived cellular models PMID:39199267

Evidence Based Scoring (AI generated)