DLAT and Pyruvate Dehydrogenase Deficiency

DLAT, encoding dihydrolipoamide acetyltransferase, is a critical component of the pyruvate dehydrogenase complex, which plays an essential role in cellular energy metabolism. Multiple independent studies have identified pathogenic variants in DLAT as causative for pyruvate dehydrogenase deficiency, a metabolic disorder characterized by lactic acidosis and a broad neurological spectrum. Patients typically present with features including paroxysmal dystonia, hypotonia, ataxia, ventriculomegaly, abnormal cerebral white matter morphology, persistent lactic acidosis, and lactic acidosis (PMID:20022530, PMID:39007626).

Genetic evidence is compelling with several unrelated probands harboring DLAT mutations. In one pivotal study, at least 9 probands were identified with DLAT mutations, and segregation analysis in familial cases further supports its role in disease (PMID:39007626). A representative pathogenic variant is c.1728C>A (p.Phe576Leu), which has been documented in multiple cases (PMID:16049940).

Functional studies, including cellular models and structural analyses, demonstrate that DLAT mutations lead to impaired enzymatic activity of the pyruvate dehydrogenase complex. These assays confirm that the resultant deficiency in complex activity is consistent with the observed clinical phenotypes, establishing a mechanistic link between the mutation and the metabolic derangements seen in patients (PMID:25356417).

Family studies have provided additional support with segregation of DLAT mutations in affected individuals, reinforcing its autosomal recessive mode of inheritance. Although the exact count of additional affected relatives is not consistently documented across all reports, the observed familial clustering further bolsters confidence in the association.

In summary, the convergence of robust genetic, functional, and segregation evidence supports a Strong association between DLAT mutations and pyruvate dehydrogenase deficiency. This integrated evidence framework is critical for guiding diagnostic decision‑making and therapeutic interventions, such as the early initiation of ketogenic diets in affected individuals.

Key Take‑home: Identification of DLAT alterations is pivotal for accurate diagnosis and tailored treatment strategies in pyruvate dehydrogenase deficiency.

References

• Annals of Neurology • 2005 • Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency PMID:16049940
• European Journal of Paediatric Neurology • 2010 • Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia PMID:20022530
• Journal of Neurogenetics • 2024 • Carbamazepine responsive episodic dystonia and hallucination due to pyruvate dehydrogenase E2 (DLAT) gene mutation PMID:39007626

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