TPK1 – Leigh Syndrome

Biallelic variants in TPK1 cause an autosomal recessive thiamine metabolism dysfunction syndrome presenting with Leigh syndrome–like features (Leigh syndrome). The TPK1 enzyme catalyzes the conversion of thiamine to thiamine pyrophosphate, a critical cofactor for mitochondrial dehydrogenases. Deficiency of TPK1 leads to early-onset neurodegeneration with bilateral basal ganglia lesions, dystonia, ataxia, seizures, and lactic acidosis.

Genetic evidence supporting this association is robust. To date, pathogenic or likely pathogenic TPK1 variants have been described in at least 27 unrelated families, all showing biallelic inheritance and consistent phenotypes ([PMID:39140381]). Multiple case reports and series include two patients with novel homozygous missense mutations p.Ser160Leu and p.Asp222His expanding the phenotype to non-episodic Leigh syndrome–like global developmental delay ([PMID:25458521]). Recurrent founder variants such as c.620A>T (p.Asp207Val) have been observed in distinct populations, underscoring allelic heterogeneity.

The variant spectrum encompasses missense, frameshift, splice-site, and deep intronic changes. Missense variants affecting thiamine binding and catalytic residues (e.g., c.426G>C (p.Leu142Phe)) impair enzymatic activity ([PMID:31404531]). Loss-of-function alleles including early stop codons and frameshifts (e.g., p.Glu61fs) have also been reported. Deep intronic variants leading to aberrant splicing further broaden the mutational landscape.

Functional studies demonstrate that pathogenic TPK1 variants reduce kinase activity and thiamine binding. In vitro assays of patient-derived mutations show markedly decreased thiamine pyrophosphate formation and protein instability, while in silico structural analyses predict disrupted dimerization. Importantly, thiamine supplementation restores residual enzymatic activity and ameliorates clinical episodes in treated patients, representing a clear genotype–treatment correlation.

The mechanism of pathogenicity is loss of function leading to impaired mitochondrial energy metabolism. Biochemical rescue in patient cells and response to thiamine supplementation confirm causality and therapeutic tractability. No conflicting reports have emerged to date, and all functional and clinical data are concordant.

Integration of genetic and experimental findings establishes a strong gene–disease relationship. Early recognition of TPK1 deficiency enables prompt thiamine therapy, which can prevent or reduce neurologic decline. Key take-home: Biallelic TPK1 variants cause autosomal recessive Leigh syndrome–like disease that is potentially treatable with high-dose thiamine.

References

• Clinica chimica acta; international journal of clinical chemistry • 2019 • Thiamine phosphokinase deficiency and mutation in TPK1 presenting as biotin responsive basal ganglia disease. PMID:31404531
• Molecular genetics and metabolism • 2014 • Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations. PMID:25458521
• Clinical dysmorphology • 2024 • Report of a novel recurrent homozygous variant c.620A>T in three unrelated families with thiamine metabolism dysfunction syndrome 5 and review of literature. PMID:39140381

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