DLAT – Leigh syndrome

DLAT encodes the E2 subunit of the pyruvate dehydrogenase complex (PDHC) and biallelic mutations cause autosomal recessive PDHC deficiency presenting as Leigh syndrome (MONDO:0009723) and episodic dystonia. A 15-year-old female with mild intellectual disability and paroxysmal dystonia was found to harbor a homozygous c.470T>G (p.Val157Gly) variant in DLAT, confirmed by exome sequencing and segregating with disease in her family (PMID:39007626). Brain MRI revealed basal ganglia signal abnormalities and an “Eye-of-the-tiger” sign, and carbamazepine therapy ameliorated dystonia and hallucinations, indicating clinical utility of genetic diagnosis and targeted treatment.

In vitro functional studies demonstrate that phenylbutyrate incubation increases PDHC enzymatic activity in patient fibroblasts harboring DLAT defects, consistent with stabilization of E2 subunit function and rescue of complex activity (PMID:25356417). These data support a loss-of-function mechanism via impaired E2 assembly and identify phenylbutyrate as a potential therapeutic adjuvant in DLAT-related PDHC deficiency. Additional cases and segregation studies are needed to reach higher evidence tiers.

References

• Journal of neurogenetics • 2024 • Carbamazepine responsive episodic dystonia and hallucination due to pyruvate dehydrogenase E2 (DLAT) gene mutation. PMID:39007626
• Annals of clinical and translational neurology • 2014 • Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. PMID:25356417

Evidence Based Scoring (AI generated)